COMPOSITIONS FOR PREVENTING OR TREATING INFLUENZA INFECTIONS

Abstract

The present application provides chimeric proteins comprising an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof, and a positively charged mucoadhesive peptide fragment. Compositions comprising the chimeric proteins described herein are useful for preventing or treating an infection caused by an influenza virus or a variant thereof in an individual.

Description

REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

The content of the electronic sequence listing (256442000201SEQLIST.xml; Size: 503,697 bytes; and Date of Creation: Oct. 11, 2024) is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

The invention relates to compositions and methods for preventing or treating infections caused by an influenza virus or variants thereof.

BACKGROUND

Influenza, also commonly known as the flu, is a highly contagious respiratory illness caused by a number of RNA influenza viruses that infect humans. Influenza and its complications can cause significant morbidity and mortality. Worldwide, the WHO estimates about 1 billion infections, 3-5 million cases of severe illness and 300,000-500,000 deaths annually. In the United States, the Centers for Disease Control and Prevention (CDC) estimates that flu has resulted in 9 million-41 million illnesses, 140,000-710,000 hospitalizations and 12,000-52,000 deaths annually between 2010 and 2020. (Krammer et al., Nat Rev Dis Primers, 4(1):1-21 (2018); Tyrrell et al., Medicine (Abingdon), 49(12):797-804 (2021).

There are three types of influenza viruses that infect humans: types A, B, and C. Type A influenza virus is the most virulent and is most likely to give rise to epidemics and pandemics. Type A influenza virus, also called influenza A, can infect both humans and animals (e.g., bovine, equine, and avian). Influenza A is subclassified into two groups based on two virus surface proteins, hemagglutinin (HA) and neuraminidase (NA). There are 18 different HAs and 11 different NAs discovered among various influenza A viruses, resulting in many varying subtypes or strains (e.g., H1N1, H5N1). Type B influenza virus does not usually cause as severe disease as type A does, and is more commonly seen in children, long-term care facilities, college campuses, and military camps. Influenza C virus generally causes a mild respiratory illness.

People with viral influenza can spread it to others up to about 6 feet away, mainly through aerosolized droplets expelled when people with flu talk, cough or sneeze. These droplets enter through the mouths or noses of people nearby or can be inhaled into their lungs. A person can also contract the virus by touching a surface or object that has flu virus on it and then touching their own mouth, nose, or eyes. The period that an infected person may be contagious ranges from 1 day before they become symptomatic and 5 to 7 days afterwards. Infected asymptomatic people can still spread the virus.

Most influenza infections can be prevented with the annual influenza vaccine. Historically, influenza vaccines have been manufactured by inoculating eggs, generating virus-inactivated allantoic fluid from the eggs, and purifying relevant viral antigens. Currently, influenza vaccines are often produced in cell culture as either inactivated influenza vaccines (IIVs) or live attenuated influenza vaccines (LAIV). IIVs are produced to protect against three (trivalent) or four (quadrivalent) different strains of influenza viruses; LAIVs are produced exclusively as quadrivalent vaccines.

In addition, four antiviral medications have been approved by the Food and Drug Administration (FDA) for the treatment of influenza, they include three neuraminidase inhibitors, oseltamivir (Tamiflu), peramivir (Rapivab) and zanamivir (Relenza), along with an endonuclease inhibitor, baloxavir marboxil (Xofluza). Baloxavir inhibits the endonuclease activity of the polymerase acidic protein found in the influenza virus RNA polymerase complex, ultimately inhibiting viral replication.

Although influenza causes a mild, self-resolving upper respiratory illness in most people (e.g., cough, headache, chills, muscle aches and fever), complications can also occur, which include pneumonia, bronchitis and sinus infections. In rare cases, influenza infection can cause severe viral pneumonia and acute respiratory distress syndrome (ARDS) with multi-organ failure, caused by the exacerbation of underlying chronic conditions such as asthma, congestive heart failure and chronic obstructive pulmonary disease. People classified as high risk of developing complications from influenza include individuals who are 65 years or older or less than 5 years of age, immunocompromised, pregnant, within 2 weeks of giving birth, or living in group settings (e.g., dormitories, military barracks, nursing homes), and individuals who have preexisting chronic illnesses (e.g., asthma, congestive heart failure, and diabetes) or obesity.

Influenza viruses are constantly changing through a process called reassortment. The influenza A genome is composed of eight separate single-stranded RNA segments. When differing viruses co-infect a cell, they are able to exchange gene segments. The viral diversity generated through reassortment is immense and plays an important role in the global evolution of influenza viruses, making it challenging to predict which strains to include in the yearly upcoming influenza vaccine. To meet the global need for surveillance, the World Health Organization has established National Influenza Centers responsible for collecting and performing a preliminary analysis of influenza specimens in their regions, which are sent to WHO Collaborating Centers for advanced evaluation. These analyses are used to inform the composition of influenza vaccines each year. This is a daunting task every year, and the vaccine compositions each season are not always protective for the season. In the 2018-2019 season, the overall effectiveness of the 2018 vaccines was low (only 29%), and many of the 2020 predicted flu strains had to be changed in the influenza vaccine for the 2020-2021 flu season. (Xu et al., MMWR, 68(24):544-551 (2019)). These factors make prevention of influenza infection (currently mostly done with vaccination) costly (time-wise and resource-wise) and unpredictable (with regard to efficacy). In addition, some patients cannot or choose not to take the influenza vaccines due to various reasons, including patients having strong adverse reactions to vaccines. (Tyrrell et al., Dec; 49(12):797-804 (2021)). Currently circulating influenza strains (March 2023) are the Influenza A H1N1pdm09 strain (the 2009 pandemic strain) and H3N2 worldwide. The composition of the 2022-2023 vaccine was A/H1N1/pdm09 and A/Darwin/6/2021 (H3N2); for influenza B, the B/Yamagata and B/Austria/1359417/2021 strains, and closely mirror current infections.

As for medication, there are patients who cannot tolerate the adverse effects of the available flu medicines and patients for whom the medicines are not effective. Also, these medications are not readily accessible to many patients around the world.

Additional compositions and methods to prevent or treat influenza infection, especially using means that are inexpensive, safer, more efficacious, and more flexible, are still in great demand.

BRIEF SUMMARY

The present application provides compositions and methods for preventing or treating an infection caused by an influenza virus or a variant thereof. Thus, one aspect of the present application provides a chimeric protein comprising: (a) an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa.

In some embodiments, the chimeric protein comprises a single polypeptide chain.

In some embodiments, the chimeric protein comprises two or more polypeptide chains.

In some embodiments, the chimeric protein comprises two or more mucoadhesive peptide fragments. In some embodiments, each of the two or more mucoadhesive peptide fragments comprises at least about 5 positively charged amino acid residues.

In some embodiments according to any of the preceding embodiments of the chimeric protein, the mucoadhesive peptide fragment comprises at least about 6 positively charged amino acid residues.

In some embodiments according to any of the preceding embodiments of the chimeric protein, the positively charged amino acid residues are selected from the group consisting of lysine, arginine, histidine, ornithine, and combinations thereof. In some embodiments, the positively charged amino acid residues comprise lysines. In some embodiments, the mucoadhesive peptide fragment comprises about 5, about 6, about 12, or about 30 lysines. In some embodiments, the positively charged amino acid residues comprise arginines. In some embodiments, the mucoadhesive peptide fragment comprises about 6, about 12, or about 30 arginines. In some embodiments, the positively charged amino acid residues comprise histidines. In some embodiments, the mucoadhesive peptide fragment comprises about 6, about 12, or about 30 histidines. In some embodiments, the positively charged amino acid residues comprise ornithines. In some embodiments, the mucoadhesive peptide fragment comprises about 6, about 12, or about 30 ornithines.

In some embodiments according to any of the preceding embodiments of the chimeric protein, the mucoadhesive peptide fragment comprises at least 5 contiguous positively charged amino acids.

In some embodiments according to any of the preceding embodiments of the chimeric protein, the positively charged amino acid residues are interspersed with one or more non-positively charged amino acid residues. In some embodiments, the non-positively charged amino acid residues are non-polar amino acids or polar uncharged amino acids. In some embodiments, the non-positively charged amino acid residues are selected from the group consisting of isoleucine, valine, alanine, tryptophan, leucine, glycine, methionine, proline, phenylalanine, threonine, cysteine, tyrosine, glutamine, serine, and asparagine, and combinations thereof. In some embodiments, at least 50% of the amino acid residues in the mucoadhesive peptide fragment are positively charged amino acid residues.

In some embodiments according to any of the preceding embodiments of the chimeric protein, the mucoadhesive peptide fragment is no more than about 15 kD. In some embodiments, the mucoadhesive peptide fragment has an isoelectric point (pI) higher than the pH of the mucosa. In some embodiments according to any of the preceding embodiments of the chimeric protein, the half-life of the chimeric protein on the mucosa is at least 12 hours. In some embodiments, the mucoadhesive peptide fragment does not facilitate penetration of the chimeric protein into a cell of the mucosa. In some embodiments, the mucoadhesive peptide fragment does not disrupt folding of the chimeric protein within a host cell expressing the chimeric protein. In some embodiments, the mucoadhesive peptide fragment does not block secretion of the chimeric protein from a host cell expressing the chimeric protein. In some embodiments, the mucoadhesive peptide fragment does not interfere with the binding between the antibody moiety and the component of the influenza virus or variant thereof.

In some embodiments according to any of the preceding embodiments of the chimeric protein, the mucoadhesive peptide fragment comprises an amino acid sequence of any one of SEQ ID NOs: 291-325 and 407-413, or variants thereof comprising up to about 3 amino acid substitutions.

In some embodiments according to any of the preceding embodiments of the chimeric protein, the mucoadhesive peptide fragment is fused to the antibody moiety.

In some embodiments according to any of the preceding embodiments of the chimeric protein, the mucoadhesive peptide fragment is fused to the antibody moiety via a bond.

In some embodiments according to any of the preceding embodiments of the chimeric protein, the mucoadhesive peptide fragment is fused to the antibody moiety via a peptide linker. In some embodiments, the peptide linker comprises one or more oligomerization and/or multimerization domains. In some embodiments, the peptide linker comprises the constant region of a heavy chain of a full-length antibody or a fragment thereof. In some embodiments, the peptide linker comprises the constant region of a light chain of a full-length antibody or a fragment thereof. In some embodiments, the linker comprises a CH₁, CH₂, CH₃, CH₄, and/or C_L domain or fragments thereof. In some embodiments, the linker comprises an Fc region or a fragment thereof. In some embodiments, the linker comprises a detectable enzymatic tag. In some embodiments, the enzymatic tag is an alkaline phosphatase. In some embodiments, the enzymatic tag is a glutathione-s-transferase. In some embodiments, the peptide linker comprises a basic helix-loop-helix leucine zipper (bZIP) domain. In some embodiments, the peptide linker comprises a bZIP isoleucine zipper domain. In some embodiments, the peptide linker comprises a bZIP-leucine/isoleucine zipper domain. In some embodiments, the peptide linker comprises a collagen-like peptide. In some embodiments, the peptide linker comprises a p53 tetramerization domain. In some embodiments, the peptide linker comprises a streptavidin (SA) protein. In some embodiments, the peptide linker comprises a SA protein and a dextran scaffold. In some embodiments, the peptide linker comprises a SA protein and one or more maleimide polymers (DMGS). In some embodiments, the peptide linker comprises a bacteriophage T7 fibritin protein or a portion thereof. In some embodiments, the peptide linker comprises a cartilage oligomeric matrix protein (COMP) protein.

In some embodiments according to any of the preceding embodiments of the chimeric protein, the antibody moiety is a full-length antibody. In some embodiments, the antibody moiety is selected from the group consisting of an IgG, an IgA, an IgM, and an IgD.

In some embodiments according to any of the preceding embodiments of the chimeric protein, the antibody moiety is an antigen-binding fragment selected from the group consisting of a Fab, a Fab′, a (Fab′)₂, an Fv, a single chain Fv (scFv), an scFv-Fc, a disulfide stabilized Fv fragment (dsFv), a (dsFv)₂, an scFv dimer, a domain antibody, a camelized single domain antibody (sdAb), a bivalent domain antibody, a minibody, and a V_HH.

In some embodiments according to any of the preceding embodiments of the chimeric protein, the antibody moiety is animal, human, humanized, camelid, or chimeric.

In some embodiments according to any of the preceding embodiments of the chimeric protein, the mucoadhesive peptide fragment is fused to a C-terminus of the antibody moiety.

In some embodiments of the chimeric protein, the antibody moiety is a full-length antibody, and wherein the mucoadhesive peptide fragment is fused to the C-terminus of a heavy chain of the full-length antibody via a first optional peptide linker. In some embodiments, the antibody moiety is a full-length antibody, and wherein the mucoadhesive peptide fragment is fused to the C-terminus of a light chain of the full-length antibody via a second optional peptide linker. In some embodiments, the antibody moiety is a full-length antibody, and wherein: (1) the mucoadhesive peptide fragment is fused to the C-terminus of a heavy chain of the full-length antibody via a first optional peptide linker; and (2) the mucoadhesive peptide fragment is fused to the C-terminus of a light chain of the full-length antibody via a second optional peptide linker. In some embodiments, the chimeric protein comprises: i) a first and a second polypeptide chain each comprising from the N-terminus to the C-terminus: the heavy chain of the full-length antibody, the first optional peptide linker, and the mucoadhesive peptide fragment; and ii) a third and a fourth polypeptide chain each comprising the light chain of the full-length antibody.

In some embodiments according to any of the preceding embodiments of the chimeric protein, the influenza virus is a Type A influenza virus (IAV), a Type B influenza virus (IBV), a Type C influenza virus (ICV), a Type D influenza virus (IDV), or a variant, subtype, or reassortant thereof. In some embodiments, the influenza virus comprises a hemagglutinin (HA) antigen selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof. In some embodiments, the influenza virus comprises a neuraminidase (NA) antigen selected from the group consisting of N1, N2, N3, N7, N8, and N9, or a variant or reassortant thereof. In some embodiments, the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof.

In some embodiments according to any of the preceding embodiments of the chimeric protein, the component of the influenza virus or variant thereof is a viral surface protein or fragment thereof.

In some according to any of the preceding embodiments of the chimeric protein, the viral surface protein is HA. In some embodiments, the chimeric protein comprises a heavy chain complementarity determining region (HC-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region (LC-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 4, an LC-CDR2 comprising the amino acid sequence WAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the chimeric protein comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 235, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 238, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 415. In some embodiments, the chimeric protein comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 439, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 440, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 441, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 443, an LC-CDR2 comprising the amino acid sequence of SND, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 445. In some embodiments, the chimeric protein comprises (i) a heavy chain variable domain (V_H) Comprising the amino acid sequence of SEQ ID NO: 76, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 76, and a light chain variable domain (V_L) comprising the amino acid sequence of SEQ ID NO: 77, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 77. In some embodiments, the chimeric protein comprises a V_H comprising the amino acid sequence of SEQ ID NO: 78, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 78, and a V_L comprising the amino acid sequence of SEQ ID NO: 79, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 79. In some embodiments, the chimeric protein comprises a V_H comprising the amino acid sequence of SEQ ID NO: 438, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 438, and a V_L comprising the amino acid sequence of SEQ ID NO: 442, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 442. In some embodiments, the chimeric protein comprises a heavy chain (HC) polypeptide comprising the amino acid sequence of SEQ ID NO: 414, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 414, and a light chain (LC) polypeptide comprising the amino acid sequence of SEQ ID NO: 217, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 420, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 420, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 244, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 446, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 446, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 447, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 216, 218-234, 236, 237, 239-242, and 416-419, and a third and a fourth polypeptide chain each having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 243, 245-258, and 422-425, and a third and a fourth polypeptide chain each having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently comprising the amino acid sequence of any one of SEQ ID NOs: 448-468, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 448-468, and a third and a fourth polypeptide chain each independently comprising the amino acid sequence of SEQ ID NO: 447, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 447.

In some embodiments according to any of the preceding embodiments of the chimeric protein, the viral surface protein is NA. In some embodiments, the chimeric protein comprises a HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 104, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 106, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 107, an LC-CDR2 comprising the amino acid sequence of AAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 109. In some embodiments, the chimeric protein comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 110, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 111, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 112, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 113, an LC-CDR2 comprising the amino acid sequence of GAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 115. In some embodiments, the chimeric protein comprises a V_H comprising the amino acid sequence of SEQ ID NO: 188, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 188, and a V_L comprising the amino acid sequence of SEQ ID NO: 189, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 189. In some embodiments, the chimeric protein comprises a V_H comprising the amino acid sequence of SEQ ID NO: 190, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 190, and a V_L comprising the amino acid sequence of SEQ ID NO: 191, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 191. In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 426, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 426, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 260, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 432, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 432, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 276, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chains each independently having at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 259, 261-274, and 428-431, and a third and a fourth polypeptide chains each having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chains each independently having at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 275, 277-290, and 434-437, and a third and a fourth polypeptide chains each having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 276.

In some embodiments according to any of the preceding embodiments of the chimeric protein, the mucosa is selected from the group consisting of nasal mucosa, larynx mucosa, trachea mucosa, bronchi mucosa, lung mucosa, eye mucosa, and combinations thereof.

In some aspects, provided herein is a pharmaceutical composition comprising the chimeric protein of any one of the preceding embodiments, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a plurality of the chimeric proteins, and wherein at least two of the plurality of the chimeric proteins are different from each other. In some embodiments, the pharmaceutically acceptable carrier comprises about 0.05% to about 0.2% (w/w) methionine. In some embodiments, the pharmaceutically acceptable carrier has a pH of about 4.5 to about 7.5. In some embodiments, the pharmaceutically acceptable carrier comprises about 20 mM to about 50 mM citrate. In some embodiments, the pharmaceutically acceptable carrier comprises about 100 mM to about 150 mM NaCl. In some embodiments, the pharmaceutically acceptable carrier comprises about 0.01% to about 0.1% (w/w) polysorbate 80. In some embodiments, the pharmaceutically acceptable carrier comprises about 1% to about 10% (w/w) glycerin. In some embodiments, the pharmaceutically acceptable carrier comprises about 0.05% to about 0.2% (w/w) potassium sorbate. In some embodiments, the pharmaceutically acceptable carrier: (i) comprises about 0.05% to about 0.2% (w/w) methionine; (ii) has a pH of about 4.5 to about 7.5; (iii) comprises about 20 mM to about 50 mM citrate; (iv) comprises about 100 mM to about 150 mM NaCl; (v) comprises about 0.01% to about 0.1% (w/w) polysorbate 80; (vi) comprises about 1% to about 10% (w/w) glycerin; and (vii) comprises about 0.05% to about 0.2% (w/w) potassium sorbate. In some embodiments, the pharmaceutical composition is formulated for intranasal administration, intraocular administration, and/or intrabronchial administration.

In other aspects, provided herein is an isolated nucleic acid or a set of isolated nucleic acids encoding the chimeric protein of any one of the preceding embodiments.

In some aspects, provided herein is a vector or a set of vectors comprising the nucleic acid or the set of nucleic acids of the previous embodiment.

In additional aspects, provided herein is a host cell comprising the chimeric protein of any one of the preceding embodiments, the nucleic acid or set of nucleic acids of the preceding embodiment, the vector or set of vectors of the preceding embodiment.

In further aspects, provided herein is a method of preparing a chimeric protein, comprising: (a) culturing a host cell of the preceding embodiment under a condition effective to express the chimeric protein; and (b) obtaining the expressed chimeric protein from the host cell.

In further aspects, provided herein is a method of preventing or treating an infection caused by an influenza virus or a variant thereof in an individual, comprising administering to the individual an effective amount of any one of the chimeric proteins disclosed herein. In some embodiments, the chimeric protein or the pharmaceutical composition is administered to the individual before the individual is exposed to the influenza virus or variant thereof. In some embodiments, the chimeric protein or the pharmaceutical composition is administered to the individual within about 72 hours after the individual is exposed to the influenza virus or variant thereof. In some embodiments, the chimeric protein or the pharmaceutical composition is administered topically onto the mucosa. In some embodiments, the chimeric protein or the pharmaceutical composition is administered via a nasal spray, an inhaler, a nebulizer, or an eye drop. In some embodiments, the chimeric protein or the pharmaceutical composition is administered once daily.

In other aspects, provided herein is an in vitro method of killing or neutralizing a virus, comprising contacting a virus with the chimeric protein of any of the preceding embodiments, in the presence of at least one component of the complement system, optionally wherein the at least one component of the complement system is C1, C4, or membrane attack complex (MAC). In some aspects, provided herein is a method of killing or neutralizing a virus in an individual, comprising administering to the individual an effective amount of the chimeric protein of any one of the preceding embodiments, or the pharmaceutical composition of any one of any one of the preceding embodiments. In some aspects, provided herein is a method of activating the complement pathway in an individual, comprising administering to the individual an effective amount of the chimeric protein of any one of the preceding embodiments, or the pharmaceutical composition of any one of any one of the preceding embodiments. In some embodiments, at least one virus is killed or neutralized on the mucosa. In some aspects, provided herein is a method of preventing, treating, or reducing infection caused by a virus in an individual, comprising administering to the individual an effective amount of the chimeric protein of any one of the preceding embodiments, or the pharmaceutical composition of any one of the preceding embodiments, wherein at least one virus is killed or neutralized on the mucosa. In some embodiments, the chimeric protein activates the complement pathway in the individual. In some embodiments, the killing or neutralization is via activation of the complement pathway. In some embodiments, the virus is an influenza virus. In some embodiments, the influenza virus is selected from the group consisting of a Type A influenza virus (IAV), a Type B influenza virus (IBV), a Type C influenza virus (ICV), a Type D influenza virus (IDV), or a variant, subtype, or reassortant thereof. In some embodiments, the influenza virus comprises an HA antigen selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof. In some embodiments, the influenza virus comprises an NA antigen selected from the group consisting of N1, N2, N3, N7, N8, and N9, or a variant or reassortant thereof. In some embodiments, the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings illustrate certain embodiments of the features and advantages of this disclosure. These embodiments are not intended to limit the scope of the appended claims in any manner.

FIG. 1 shows that the exemplary mucoadhesive chimeric human antibody HA1-IgG-12K binds well to the hemagglutinin (His-tagged) from influenza A H1N1 (A/Wisconsin/588/2019)/(A/Victoria/2570/2019). Binding was unaffected by the presence of polycationic moieties. All steps were aligned by step sensor location).

FIG. 2 shows that the exemplary mucoadhesive chimeric human antibody HA2-IgG-12K binds well to hemagglutinin (ECD, His-tagged) from the influenza A H3N2 (A/Aichi/2/1968) strain. Binding was unaffected by the presence of polycationic moieties. All steps were aligned by step sensor location.

FIG. 3 shows that the exemplary mucoadhesive chimeric human antibody NA1-IgG-12K binds well to the neuraminidase protein (His-tagged) from the influenza B (B/PHUKET/3073/2013) strain. Binding was unaffected by the presence of polycationic moieties. All steps were aligned by step sensor location).

FIG. 4 shows that modified chimeric human antibodies HA1-IgG-12K and HA15-IgG-12K bind mucin in vitro significantly better than their unmodified counterparts. HRP-anti-human IgG fluorescence at 450 nM measures the binding of HA-IgG mucoadhesive antibodies compared to HA-IgG antibodies alone.

FIGS. 5A-5B show the association of the chimeric antibodies to HA examined by BLI using a ForteBio Octet KQ with a with an anti-hFC capture biosensor. Influenza A H1N1 (A/Wisconsin/588/2019)/(A/Victoria/2570/2019) His-tagged HA protein binding was unaffected by the presence of the cationic peptides of HA-1-IgG (FIG. 5A) and HA15-IgG (FIG. 5B) mucoadhesive antibodies.

FIGS. 6A-6B show the association of the chimeric antibodies to HA examined by BLI using a ForteBio Octet KQ with a with an anti-hFC capture biosensor. Influenza A H3N2 (A/Aichi/2/1968) His-tagged HA antigen binding was unaffected by the presence of the cationic peptides of HA-1-IgG (FIG. 6A) and HA15-IgG (FIG. 6B) mucoadhesive antibodies.

FIGS. 7A-7B show the in vitro neutralization of pseudoviral infection of HEK293F cells using luciferase bioluminescence. The relative infection value determined with the intensity of bioluminescence indicates that the virus infection level of the transduced cells is inhibited by HA1-IgG-12K (FIG. 7A) and HA15-IgG-12K (FIG. 7B) mucoadhesive antibody binding to H1N1 (left panels) or H3N2 (right panels) pseudovirus.

FIGS. 8A-8B show the neutralization of pseudoviral infection in a mouse model. H3N2 pseudovirus infection is attenuated by pretreatment with mucoadhesive HA1-IgG-12K antibody compared to pretreatment without antibody (Vehicle). Bioluminescent imaging of mice (FIG. 8A) and corresponding graph (FIG. 8B) shows protection by HA1-IgG-12K antibody from pseudoviral infection on Day 5 and Day 7 post pretreatment (Day-1).

FIGS. 9A-9B show the neutralization of pseudoviral infection in a mouse model. H3N2 pseudovirus infection is attenuated by pretreatment with mucoadhesive HA15-IgG-6K/HA15-IgG-12K antibody compared to unmodified HA15-IgG antibody or pretreatment without antibody (Vehicle). Bioluminescent imaging of mice (FIG. 9A) and corresponding graph (FIG. 9B) shows protection by HA15-IgG-6K/12K antibodies from pseudoviral infection on Day 5 and Day 7 post pretreatment (Day-1).

FIG. 10 demonstrates that the addition of various mucoadhesive peptides increases the attraction of a different viral antigen-binding chimeric protein ACE2-Fc1 to mucin proteins. An ELISA assay using mucin-coated plates was conducted to compare the mucin-binding ability of various ACE2-Fc1 mucoadhesive chimeric proteins to that of ACE2-Fc1 without mucoadhesive peptide. Binding was detected using horseradish peroxidase (HRP)-conjugated goat anti-human IgG and staining was detected at OD₄₅₀.

DETAILED DESCRIPTION

The present application provides compositions and methods for preventing or treating an infection caused by an influenza virus or variant thereof that infects through a mucosa in an individual by targeting the influenza virus or variant thereof using a chimeric protein that has a positively charged mucoadhesive peptide fragment. For example, the compositions described herein may comprise a chimeric protein or cocktails of different chimeric proteins, comprising an antibody moiety that targets a viral surface protein (e.g., a hemagglutinin (HA) or a neuraminidase (NA) protein) and is modified with a positively charged peptide, that prevents the influenza virus or variant thereof from reaching its primary target cell population in the respiratory tract (e.g., nasal) mucosa for human infection. The compositions can be administered via the nasal passages using a respiratory spray.

Inventors of the present application developed chimeric proteins comprising antibodies (e.g., human and animal) that recognize the HA viral surface protein or the NA viral surface protein (“anti-HA antibodies” and “anti-NA antibodies”) of an influenza virus or variant thereof and anti-HA and anti-NA antibodies fused to a positively charged mucoadhesive peptide fragments. The chimeric proteins have significantly enhanced affinity to mucin molecules compared to unmodified anti-HA or anti-NA antibodies, which leads to improved stability in respiratory mucosa. The chimeric proteins show improved potency as compared to unmodified anti-HA or anti-NA antibodies in blocking influenza infection in a cell-based assay. The protection against influenza virus is effective in both nasal and lung areas. Additionally, the chimeric proteins may activate innate immune functions, and may be able to kill influenza virus via activation of the complement pathway. The exemplary chimeric protein is highly stable and maintained its influenza virus neutralizing activity in a nasal spray formulation. Nasal spray of the chimeric proteins can be developed as an affordable and effective prophylactic product to protect people from infection by exposure to influenza virus in the air (e.g., via the nasal passages).

Compared to other methods that block microbial infection, which involve systemic administration of antibodies that do not have a positively charged mucoadhesive peptide fragment, the methods described herein require administration of much less protein, leading to a large cost reduction that is critical for any pandemic situation. The compositions may also be self-administered, which would greatly relieve the burden on an overwhelmed health care system. Importantly, the methods described herein can avoid the potential problem of antibody dependent enhancement (ADE) resulting from conventional antibody therapy or vaccination.

Accordingly, one aspect of the present application provides a chimeric protein comprising: (a) an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa. In some embodiments, the positively charged amino acid residues are interspersed with non-positively charged amino acid residues.

The chimeric proteins provided herein are useful for treating or preventing an infection by a virus (e.g., an influenza virus or a variant thereof) in an individual. The chimeric proteins provided herein may be useful for killing or neutralizing a virus (e.g., an influenza virus or a variant thereof) in an individual via activation of the complement pathway.

I. Definitions

As used herein, a “mucoadhesive peptide fragment” refers to a peptide that carries one or more positive charges and is capable of interacting with a mucosa, e.g., via electrostatic interactions.

As used herein, a “receptor” refers to a receptor on a host cell that facilitates or mediates microbial entry into the host cell. A receptor may be membrane-bound or a soluble receptor.

As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this application, beneficial or desired clinical results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease, preventing or delaying the occurrence or recurrence of the disease, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission (whether partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival. Also encompassed by “treatment” is a reduction of pathological consequence of the disease. The methods of the present application contemplate any one or more of these aspects of treatment.

“Preventing,” as used herein, includes providing prophylaxis with respect to the occurrence or recurrence of a disease in a subject that may be predisposed to the disease but has not yet been diagnosed with the disease.

An “effective amount” of an agent refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival. For purposes of this application, an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective amount” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved. The effective amount can be ascertained by measuring relevant physiological effects, and it can be adjusted in connection with the dosing regimen and diagnostic analysis of the subject's condition, and the like.

The terms “individual,” “subject,” and “patient” are used interchangeably herein to describe a mammal, including humans. In some embodiments, the individual is human. In some embodiments, an individual suffers from a respiratory infection. In some embodiments, the individual is in need of treatment.

The terms “polypeptide” and “protein” are used interchangeably to refer to a polymer of amino acid residues and are not limited to a minimum length. Such polymers of amino acid residues may contain natural or non-natural amino acid residues, and include, but are not limited to, peptides, oligopeptides, dimers, trimers, and multimers of amino acid residues. Both full-length proteins and fragments thereof are encompassed by the definition. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. Furthermore, for purposes of the present application, a “polypeptide” refers to a protein which includes modifications, such as deletions, additions, and substitutions (generally conservative in nature), to the native sequence, as long as the protein maintains the desired activity. These modifications may be deliberate, as through site-directed mutagenesis, or may be accidental, such as through mutations of hosts, which produce the proteins or errors due to PCR amplification.

As used herein, the term “antibody” or “antibody moiety” includes full-length antibodies (including full-length 4-chain antibodies or full-length heavy chain antibodies, which have an immunoglobulin Fc region), and antigen-binding fragments thereof.

As used herein, a “neutralizing antibody” refers to an antibody that defends a host cell from an infectious agent by neutralizing any effect (e.g., cytotoxicity) it has biologically. A “non-neutralizing antibody” refers to an antibody that specifically binds to an infectious agent but is incapable of ameliorating the biological effects of the infectious agent on the host cell. A “sub-neutralizing antibody” refers to an antibody that is capable of partially neutralizing the biological effects of the infectious agent on the host cell. A sub-neutralizing antibody may ameliorate one or more biological effects of an infectious agent on the host cell by no more than about n % compared to a neutralizing antibody, where n % is selected from 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, or less.

A full-length four-chain antibody comprises two heavy chains and two light chains. The variable regions of the light and heavy chains are responsible for antigen-binding. The variables region in both chains generally contain three highly variable loops called the complementarity determining regions (CDRs) (light chain (LC) CDRs including LC-CDR1, LC-CDR2, and LC-CDR3, heavy chain (HC) CDRs including HC-CDR1, HC-CDR2, and HC-CDR3). CDR boundaries for the antibodies and antigen-binding fragments disclosed herein may be defined or identified by the conventions of Kabat, Chothia, or Al-Lazikani (Al-Lazikani 1997; Chothia 1985; Chothia 1987; Chothia 1989; Kabat 1987; Kabat 1991). The three CDRs of the heavy or light chains are interposed between flanking stretches known as framework regions (FRs), which are more highly conserved than the CDRs and form a scaffold to support the hypervariable loops. The constant regions of the heavy and light chains are not involved in antigen-binding but exhibit various effector functions. Antibodies are assigned to classes based on the amino acid sequence of the constant region of their heavy chain. The five major classes or isotypes of antibodies are IgA, IgD, IgE, IgG, and IgM, which are characterized by the presence of α, δ, ε, γ, and μ heavy chains, respectively. Several of the major antibody classes are divided into subclasses such as IgG1 (γ1 heavy chain), IgG2 (γ2 heavy chain), IgG3 (γ3 heavy chain), IgG4 (γ4 heavy chain), IgA1 (α1 heavy chain), or IgA2 (α2 heavy chain).

The term “heavy chain-only antibody” or “HCAb” refers to a functional antibody, which comprises heavy chains, but lacks the light chains usually found in 4-chain antibodies. Camelid animals (such as camels, llamas, or alpacas) are known to produce HCAbs. The variable region of a heavy chain-only antibody is referred herein as “V_HH.” A V_HH is one type of single-domain antibody. A “single-domain antibody” or “sdAb” refers to a single antigen-binding polypeptide having three complementary determining regions (CDRs). The sdAb alone is capable of binding to the antigen without pairing with a corresponding CDR-containing polypeptide. Some V_HHs may also be known as Nanobodies. Camelid V_HH is one of the smallest known antigen-binding antibody fragments (see, e.g., Hamers-Casterman et al., Nature 363:446-8 (1993); Greenberg et al., Nature 374:168-73 (1995); Hassanzadeh-Ghassabeh et al., Nanomedicine (Lond), 8:1013-26 (2013)). A basic V_HH has the following structure from the N-terminus to the C-terminus: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, in which FR1 to FR4 refer to framework regions 1 to 4, respectively, and in which CDR1 to CDR3 refer to the complementarity determining regions 1 to 3.

The term “antigen-binding fragment” as used herein refers to an antibody fragment including, for example, a diabody, a Fab, a Fab′, a F(ab′)2, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv)₂, a bispecific dsFv (dsFv-dsFv′), a disulfide stabilized diabody (ds diabody), a single-chain antibody molecule (scFv), an scFv dimer (bivalent diabody), an scFv-Fc fusion protein, a minibody (i.e., scFv-CH3 fusion protein), a multispecific antibody formed from a portion of an antibody comprising one or more CDRs, a VHH, a camelized single domain antibody, a nanobody, a domain antibody, a bivalent domain antibody, or any other antibody fragment that binds to an antigen but does not comprise a complete antibody structure. An antigen-binding fragment is capable of binding to the same antigen to which the parent antibody or a parent antibody fragment (e.g., a parent scFv) binds. In some embodiments, an antigen-binding fragment may comprise one or more CDRs from a particular human antibody grafted to a framework region from one or more different human antibodies.

The term “epitope” as used herein refers to the specific group of atoms or amino acids on an antigen to which an antibody or antibody moiety binds. Two antibodies or antibody moieties may bind the same epitope within an antigen if they exhibit competitive binding for the antigen.

As used herein, a first antibody moiety “competes” for binding to a target (e.g., influenza virus surface protein) with a second antibody moiety when the first antibody moiety inhibits target binding of the second antibody moiety by at least about 50% (such as at least about n %, where n % is selected from 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% and 99%) in the presence of an equimolar concentration of the first antibody moiety, or vice versa. A high throughput process for “binning” antibodies based upon their cross-competition is described in PCT Publication No. WO 03/48731.

As use herein, the term “specifically binds,” “specifically recognizing,” or “is specific for” refers to measurable and reproducible interactions, such as binding between a target and an antibody or antibody moiety that is determinative of the presence of the target in the presence of a heterogeneous population of molecules, including biological molecules. For example, an antibody or antibody moiety that specifically recognizes a target (which can be an epitope) is an antibody or antibody moiety that binds this target with greater affinity, avidity, more readily, and/or with greater duration than its bindings to other targets. In some embodiments, an antibody or antibody moiety that specifically recognizes an antigen reacts with one or more antigenic determinants of the antigen (such as an influenza virus surface protein) with a binding affinity that is at least about 10 times its binding affinity for other targets (such as a non-respiratory-pathogen protein).

As used herein, the term “CDR” or “complementarity determining region” is intended to mean the non-contiguous antigen combining sites found within the variable region of both heavy and light chain polypeptides. These particular regions have been described by Kabat et al., J. Biol. Chem. 252:6609-6616 (1977); Kabat et al., U.S. Dept. of Health and Human Services, “Sequences of proteins of immunological interest” (1991); Chothia et al., J. Mol. Biol. 196:901-917 (1987); Al-Lazikani B. et al., J. Mol. Biol., 273: 927-948 (1997); MacCallum et al., J. Mol. Biol,. 262:732-745 (1996); Abhinandan and Martin, Mol. Immunol., 45: 3832-3839 (2008); Lefranc M. P. et al., Dev. Comp. Immunol., 27: 55-77 (2003); and Honegger and Plückthun, J. Mol. Biol., 309:657-670 (2001), where the definitions include overlapping or subsets of amino acid residues when compared against each other. Nevertheless, application of either definition to refer to a CDR of an antibody or grafted antibodies or variants thereof is intended to be within the scope of the term as defined and used herein. The amino acid residues which encompass the CDRs as defined by each of the above cited references are set forth below in Table A as a comparison. CDR prediction algorithms and interfaces are known in the art, including, for example, Abhinandan and Martin, Mol. Immunol., 45: 3832-3839 (2008); Ehrenmann F. et al., Nucleic Acids Res., 38: D301-D307 (2010); and Adolf-Bryfogle J. et al., Nucleic Acids Res., 43: D432-D438 (2015). The contents of the references cited in this paragraph are incorporated herein by reference in their entireties for use in the present invention and for possible inclusion in one or more claims herein.

TABLE A
CDR Definitions
	Kabat1	Chothia2	MacCallum3	IMGT4	AHo5
VH CDR1	31-35	26-32	30-35	27-38	25-40
VH CDR2	50-65	53-55	47-58	56-65	58-77
VH CDR3	95-102	96-101	93-101	105-117	109-137
VL CDR1	24-34	26-32	30-36	27-38	25-40
VL CDR2	50-56	50-52	46-55	56-65	58-77
VL CDR3	89-97	91-96	89-96	105-117	109-137
1Residue numbering follows the nomenclature of Kabat et al., supra
2Residue numbering follows the nomenclature of Chothia et al., supra
3Residue numbering follows the nomenclature of MacCallum et al., supra
4Residue numbering follows the nomenclature of Lefranc et al., supra
5Residue numbering follows the nomenclature of Honegger and Plückthun, supra

The term “chimeric antibodies” refer to antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit a biological activity of this invention (see U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)).

The term “semi-synthetic” in reference to an antibody or antibody moiety means that the antibody or antibody moiety has one or more naturally occurring sequences and one or more non-naturally occurring (i.e., synthetic) sequences.

“Fv” is the minimum antibody fragment, which contains a complete antigen-recognition and -binding site. This fragment consists of a dimer of one heavy- and one light-chain variable region domain in tight, non-covalent association. From the folding of these two domains emanate six hypervariable loops (3 loops each from the heavy and light chain) that contribute the amino acid residues for antigen binding and confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.

“Single-chain Fv,” also abbreviated as “sFv” or “scFv,” are antibody fragments that comprise the VH and VL antibody domains connected into a single polypeptide chain. In some embodiments, the scFv polypeptide further comprises a polypeptide linker between the VH and VL domains, which enables the scFv to form the desired structure for antigen binding. For a review of scFv, see Plückthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

The term “diabodies” refers to small antibody fragments prepared by constructing scFv fragments (see preceding paragraph) typically with short linkers (such as about 5 to about 10 residues) between the V_H and V_L domains such that inter-chain but not intra-chain pairing of the V domains is achieved, resulting in a bivalent fragment, i.e., fragment having two antigen-binding sites. Bispecific diabodies are heterodimers of two “crossover” scFv fragments in which the V_H and V_L domains of the two antibodies are present on different polypeptide chains. Diabodies are described more fully in, for example, EP 404,097; WO 93/011161; and Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).

“Humanized” forms of non-human (e.g., rodent) antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region (HVR) of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or non-human primate having the desired antibody specificity, affinity, and capability. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies can comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992).

The “CH₁ domain” of a human IgG Fc region (also referred to as “C₁” of “H1” domain) usually extends from about amino acid 118 to about amino acid 215 (EU numbering system).

“Hinge region” is generally defined as stretching from Glu216 to Pro230 of human IgG₁ (Burton, Molec. Immunol. 22:161-206 (1985)). Hinge regions of other IgG isotypes may be aligned with the IgG₁ sequence by placing the first and last cysteine residues forming inter-heavy chain S—S bonds in the same positions.

The “CH₂ domain” of a human IgG Fc region (also referred to as “C₂” of “H2” domain) usually extends from about amino acid 231 to about amino acid 340. The CH₂ domain is unique in that it is not closely paired with another domain. Rather, two N-linked branched carbohydrate chains are interposed between the two CH₂ domains of an intact native IgG molecule. It has been speculated that the carbohydrate may provide a substitute for the domain-domain pairing and help stabilize the CH₂ domain. Burton, Molec Immunol. 22:161-206 (1985).

The “CH₃ domain” (also referred to as “C₂” or “H3” domain) comprises the stretch of residues C-terminal to a CH₂ domain in an Fc region (i.e., from about amino acid residue 341 to the C-terminal end of an antibody sequence, typically at amino acid residue 446 or 447 of an IgG).

The “CH₄ domain” found in IgE and IgM molecules, is situated C-terminal to the CH₃ domain, comprising residues 466-572 of human IgM and residues 323-427 of hIgE. The term “substantially similar” or “substantially the same,” as used herein, denotes a sufficiently high degree of similarity between two or more numeric values such that one of skill in the art would consider the difference between the two or more values to be of little or no biological and/or statistical significance within the context of the biological characteristic measured by said value. In some embodiments the two or more substantially similar values differ by no more than about n %, where n % is selected from 5%, 10%, 15%, 20%, 25%, and 50%.

A polypeptide “variant” means a biologically active polypeptide having at least about 80% amino acid sequence identity and no more than 100% identity with the native sequence polypeptide after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Such variants include, for instance, polypeptides wherein one or more amino acid residues are added, or deleted, at the N- or C-terminus of the polypeptide. In some embodiments, a variant has at least about 80% amino acid sequence identity (such as at least about n % amino acid sequence identity, where n % is selected from 80%, 85%, 90%, 95%, and 99%). In some embodiments, a variant has at least about 90% amino acid sequence identity (such as at least about n % amino acid sequence identity, where n % is selected from 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%). In some embodiments, a variant has at least about 95% amino acid sequence identity (such as at least about n % amino acid sequence identity, where n % is selected from 95%, 96%, 97%, 98%, and 99%) with the native sequence polypeptide.

As used herein, “Percent (%) amino acid sequence identity” with respect to a peptide, polypeptide or antibody sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN™ (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

The term “label” when used herein refers to a detectable compound or composition, which can be conjugated directly or indirectly to an antibody moiety (e.g., anti-HA or anti-NA antibody). The label may be detectable by itself (e.g., radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition, which is detectable.

The term “isolated nucleic acid” as used herein is intended to mean a nucleic acid of genomic, cDNA, or synthetic origin or some combination thereof, which by virtue of its origin the “isolated nucleic acid” (1) is not associated with all or a portion of a polynucleotide in which the “isolated nucleic acid” is found in nature, (2) is operably linked to a polynucleotide which it is not linked to in nature, or (3) does not occur in nature as part of a larger sequence.

Unless otherwise specified, a “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. The phrase nucleotide sequence that encodes a protein or an RNA may also include introns to the extent that the nucleotide sequence encoding the protein may in some version contain an intron(s).

The term “operably linked” refers to functional linkage between a regulatory sequence and a heterologous nucleic acid sequence resulting in expression of the latter. For example, a first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Generally, operably linked DNA sequences are contiguous and, where necessary to join two protein coding regions, in the same reading frame.

The term “vector” is used to describe a polynucleotide that may be engineered to contain a cloned polynucleotide or polynucleotides that may be propagated in a host cell. A vector may include one or more of the following elements: an origin of replication, one or more regulatory sequences (such as, for example, promoters and/or enhancers) that regulate the expression of the polypeptide of interest, and/or one or more selectable marker genes (such as, for example, antibiotic resistance genes and genes that may be used in colorimetric assays, e.g., β-galactosidase). The term “expression vector” refers to a vector that is used to express a polypeptide of interest in a host cell.

A “host cell” refers to a cell that may be or has been a recipient of a vector or isolated polynucleotide. Host cells may be prokaryotic cells or eukaryotic cells. Exemplary eukaryotic cells include mammalian cells, such as primate or non-primate animal cells; fungal cells, such as yeast cells; plant cells; and insect cells. Non-limiting exemplary mammalian cells include, but are not limited to, NSO cells, PER.C6® cells (Crucell), and 293 and CHO cells, and their derivatives, such as 293-6E and DG44 cells, respectively.

As used herein, a “variant” virus refers to an isolate of a virus whose genome sequence differs from that of a reference virus and the difference in the genome sequence confers new phenotypic properties such as increased fitness compared to the reference virus. When referring to a viral species in the present application, such as influenza virus, it is understood that the species encompass variants as well as the reference virus that was first isolated and identified.

As used herein, by “pharmaceutically acceptable” or “pharmacologically compatible” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.

As used herein, “a pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable substrate, composition or vehicle used in the process of drug delivery, which may have one or more ingredients including, but not limited to, excipient(s), binder(s), diluent(s), solvent(s), filler(s), and/or stabilizer(s).

It is understood that embodiments of the invention described herein include “consisting of” and/or “consisting essentially of” embodiments.

Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

As used herein, reference to “not” a value or parameter generally means and describes “other than” a value or parameter.

As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

II. Chimeric Proteins

The present application provides chimeric proteins (such as fusion proteins) comprising: (a) an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa. In some embodiments, the positively charged amino acid residues are selected from the group consisting of lysine, arginine, histidine, ornithine, and combinations thereof. In some embodiments, the positively charged amino acid residues are lysines. In some embodiments, the mucoadhesive peptide fragment is a polylysine peptide having at least about 5 (e.g., about 5 to about 30, such as about 12) lysines (including for example at least about 5 (e.g., about 5 to about 30, such as about 12) contiguous lysines). In some embodiments, the positively charged amino acid residues are histidines. In some embodiments, the mucoadhesive peptide fragment is a polyhistidine peptide having at least about 5 (e.g., about 5 to about 30, such as about 12) histidines (including for example at least about 5 (e.g., about 5 to about 30, such as about 12) contiguous histidines). In some embodiments, the positively charged amino acid residues are arginines. In some embodiments, the mucoadhesive peptide fragment is a polyarginine peptide having at least about 5 (e.g., about 5 to about 30, such as about 12) arginines (including for example at least about 5 (e.g., about 5 to about 30, such as about 12) contiguous arginines). In some embodiments, the positively charged amino acid residues are ornithines. In some embodiments, the mucoadhesive peptide fragment is a polyornithine peptide having at least about 5 (e.g., about 5 to about 30, such as about 12) ornithines (including for example at least about 5 (e.g., about 5 to about 30, such as about 12) contiguous ornithines). In some embodiments, the positively charged amino acid residues are contiguous with each other. In some embodiments, the positively charged amino acid residues are interspersed with non-positively charged amino acid residues. In some embodiments, the mucoadhesive peptide fragment is covalently fused to the antibody moiety. In some embodiments, the mucoadhesive peptide fragment is non-covalently associated with the antibody moiety, e.g., via an oligomerization and/or multimerization domain. In some embodiments, the influenza virus is a Type A influenza virus (IAV), a Type B influenza virus (IBV), a Type C influenza virus (ICV), a Type D influenza virus (IDV), or a variant, subtype, or reassortant thereof. In some embodiments, the component of the influenza virus or variant thereof is a viral surface protein. In some embodiments, the viral surface protein is HA. In some embodiments, the viral surface protein is NA. In some embodiments, the influenza virus or variant thereof causes a respiratory infection. In some embodiments, the mucosa is selected from the group consisting of nasal mucosa, larynx mucosa, trachea mucosa, bronchi mucosa, lung mucosa, eye mucosa, and combinations thereof.

In some embodiments, there is provided a chimeric protein (e.g., fusion protein) comprising: (a) an antibody moiety that specifically binds to a HA protein of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa. In some embodiments, the positively charged amino acid residues are selected from the group consisting of lysine, arginine, histidine, ornithine, and combinations thereof. In some embodiments, the positively charged amino acid residues are lysines. In some embodiments, the mucoadhesive peptide fragment is a polylysine peptide having at least about 5 (e.g., about 5 to about 30, such as about 12) lysines (including for example at least about 5 (e.g., about 5 to about 30, such as about 12) contiguous lysines). In some embodiments, the positively charged amino acid residues are histidines. In some embodiments, the mucoadhesive peptide fragment is a polyhistidine peptide having at least about 5 (e.g., about 5 to about 30, such as about 12) histidines (including for example at least about 5 (e.g., about 5 to about 30, such as about 12) contiguous histidines). In some embodiments, the positively charged amino acid residues are arginines. In some embodiments, the mucoadhesive peptide fragment is a polyarginine peptide having at least about 5 (e.g., about 5 to about 30, such as about 12) arginines (including for example at least about 5 (e.g., about 5 to about 30, such as about 12) contiguous arginines). In some embodiments, the positively charged amino acid residues are ornithines. In some embodiments, the mucoadhesive peptide fragment is a polyornithine peptide having at least about 5 (e.g., about 5 to about 30, such as about 12) ornithines (including for example at least about 5 (e.g., about 5 to about 30, such as about 12) contiguous ornithines). In some embodiments, the positively charged amino acid residues are contiguous with each other. In some embodiments, the positively charged amino acid residues are interspersed with non-positively charged amino acid residues. In some embodiments, the mucoadhesive peptide fragment is covalently fused to the antibody moiety. In some embodiments, the mucoadhesive peptide fragment is non-covalently associated with the antibody moiety, e.g., via an oligomerization and/or multimerization domain. In some embodiments, the influenza virus is a Type A influenza virus (IAV), a Type B influenza virus (IBV), a Type C influenza virus (ICV), a Type D influenza virus (IDV), or a variant, subtype, or reassortant thereof. In some embodiments, the influenza virus comprises a hemagglutinin (HA) antigen, such as an HA antigen selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof. In some embodiments, the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof. In some embodiments, the mucosa is selected from the group consisting of nasal mucosa, larynx mucosa, trachea mucosa, bronchi mucosa, lung mucosa, eye mucosa, and combinations thereof. In some embodiments, the antibody moiety is a full-length antibody (e.g., IgG, IgA, IgM, IgE, or IgD). In some embodiments, the antibody moiety is an antigen-binding fragment selected from the group consisting of a Fab, a Fab′, a (Fab′)₂, an Fv, a single chain Fv (scFv), an scFv-Fc, a disulfide stabilized Fv fragment (dsFv), a (dsFv)₂, an scFv dimer, a domain antibody, a camelized single domain antibody, a bivalent domain antibody, a minibody, and a V_HH.

In some embodiments, there is provided a chimeric protein (e.g., fusion protein) comprising: (a) an antibody moiety that specifically binds to a HA protein of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa, and wherein the antibody moiety comprises any one of the antibodies or antigen binding fragments thereof as described in Table 4A or wherein the antibody moiety comprises any one of the antibodies or antigen binding fragments thereof as described in Table 6. In some embodiments, the antibody moiety binds with a HA antigen, such as an HA antigen selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof. In some embodiments, the mucoadhesive peptide comprises any one of the mucoadhesive peptide fragments as described in Table 8.

In some embodiments, there is provided a chimeric protein (e.g., fusion protein) comprising: (a) an antibody moiety that specifically binds to a NA protein of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa. In some embodiments, the positively charged amino acid residues are selected from the group consisting of lysine, arginine, histidine, ornithine, and combinations thereof. In some embodiments, the positively charged amino acid residues are lysines. In some embodiments, the mucoadhesive peptide fragment is a polylysine peptide having at least about 5 (e.g., about 5 to about 30, such as about 12) lysines (including for example at least about 5 (e.g., about 5 to about 30, such as about 12) contiguous lysines). In some embodiments, the positively charged amino acid residues are histidines. In some embodiments, the mucoadhesive peptide fragment is a polyhistidine peptide having at least about 5 (e.g., about 5 to about 30, such as about 12) histidines (including for example at least about 5 (e.g., about 5 to about 30, such as about 12) contiguous histidines). In some embodiments, the positively charged amino acid residues are arginines. In some embodiments, the mucoadhesive peptide fragment is a polyarginine peptide having at least about 5 (e.g., about 5 to about 30, such as about 12) arginines (including for example at least about 5 (e.g., about 5 to about 30, such as about 12) contiguous arginines). In some embodiments, the positively charged amino acid residues are ornithines. In some embodiments, the mucoadhesive peptide fragment is a polyornithine peptide having at least about 5 (e.g., about 5 to about 30, such as about 12) ornithines (including for example at least about 5 (e.g., about 5 to about 30, such as about 12) contiguous ornithines). In some embodiments, the positively charged amino acid residues are contiguous with each other. In some embodiments, the positively charged amino acid residues are interspersed with non-positively charged amino acid residues. In some embodiments, the mucoadhesive peptide fragment is covalently fused to the antibody moiety. In some embodiments, the mucoadhesive peptide fragment is non-covalently associated with the antibody moiety, e.g., via an oligomerization and/or multimerization domain. In some embodiments, the influenza virus is a Type A influenza virus (IAV), a Type B influenza virus (IBV), a Type C influenza virus (ICV), a Type D influenza virus (IDV), or a variant, subtype, or reassortant thereof. In some embodiments, the influenza virus comprises a neuraminidase (NA) antigen, such as an NA antigen selected from the group consisting of N1, N2, N3, N7, N8, and N9, or a variant or reassortant thereof. In some embodiments, the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof. In some embodiments, the mucosa is selected from the group consisting of nasal mucosa, larynx mucosa, trachea mucosa, bronchi mucosa, lung mucosa, eye mucosa, and combinations thereof. In some embodiments, the antibody moiety is a full-length antibody (e.g., IgG, IgA, IgM, IgE, or IgD). In some embodiments, the antibody moiety is an antigen-binding fragment selected from the group consisting of a Fab, a Fab′, a (Fab′)₂, an Fv, a single chain Fv (scFv), an scFv-Fc, a disulfide stabilized Fv fragment (dsFv), a (dsFv)₂, an scFv dimer, a domain antibody, a camelized single domain antibody, a bivalent domain antibody, a minibody, and a V_HH.

In some embodiments, there is provided a chimeric protein (e.g., fusion protein) comprising: (a) an antibody moiety that specifically binds to a NA protein of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa, and wherein the antibody moiety comprises any one of the antibodies or antigen binding fragments thereof as described in Table 4B or wherein the antibody moiety comprises any one of the antibodies or antigen binding fragments thereof as described in Table 6. In some embodiments, the antibody moiety binds with a NA antigen, such as an NA antigen selected from the group consisting of N1, N2, N3, N7, N8, and N9, or a variant or reassortant thereof. In some embodiments, the mucoadhesive peptide comprises any one of the mucoadhesive peptide fragments as described in Table 8.

In some embodiments, there is provided a chimeric protein (e.g., fusion protein) comprising a full-length antibody comprising: a first antibody heavy chain, a second antibody heavy chain, a first antibody light chain, and a second antibody light chain (e.g., a first, second, third, and fourth polypeptide chain, respectively), wherein the antibody specifically binds to a component of an influenza virus or variant thereof, wherein the chimeric protein comprises: (a) a first polypeptide chain comprising the first antibody heavy chain fused to a first mucoadhesive peptide fragment; (b) a second polypeptide chain comprising the second antibody heavy chain fused to a second mucoadhesive peptide fragment; (c) a third polypeptide chain comprising the first antibody light chain; and (d) the fourth polypeptide chain comprising a second antibody light chain, wherein the first and second mucoadhesive peptide fragments each comprise about at least about 5 positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the first and second mucoadhesive peptide fragments facilitate attachment of the chimeric protein to a mucosa. In some embodiments, the first polypeptide chain comprises from the N-terminus to the C-terminus: the first antibody heavy chain, an optional peptide linker, and the first mucoadhesive peptide fragment. In some embodiments, the second polypeptide chain comprises from the N-terminus to the C-terminus: the second antibody heavy chain, an optional peptide linker, and the second mucoadhesive peptide fragment. In some embodiments, the first mucoadhesive peptide fragment is identical to the second mucoadhesive peptide fragment. In some embodiments, the first mucoadhesive peptide fragment is different from the second mucoadhesive peptide fragment. In some embodiments, the optional linkers of the first and second polypeptide chains are identical. In some embodiments, the optional linkers of the first and second polypeptide chains are different. In some embodiments, the third polypeptide chain and the fourth polypeptide comprise the antibody light chain. In some embodiments, the full-length antibody is a monospecific antibody. In some embodiments, the full-length antibody is a multispecific antibody (e.g., a bispecific antibody). In some embodiments, the influenza virus or variant thereof causes a respiratory infection. In some embodiments, the influenza virus is a Type A influenza virus (IAV), a Type B influenza virus (IBV), a Type C influenza virus (ICV), a Type D influenza virus (IDV), or a variant, subtype, or reassortant thereof. In some embodiments, the influenza virus comprises a HA antigen, such as HA antigen selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof. In some embodiments, the influenza virus comprises an NA antigen, such as an NA antigen selected from the group consisting of N1, N2, N3, N7, N8, and N9, or a variant or reassortant thereof. In some embodiments, the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof. In some embodiments, the mucosa is selected from the group consisting of nasal mucosa, larynx mucosa, trachea mucosa, bronchi mucosa, lung mucosa, eye mucosa, and combinations thereof. In some embodiments, the full-length antibody is IgG, IgA, IgM, IgE, or IgD.

In some embodiments, there is provided a chimeric protein (e.g., fusion protein) comprising a full-length antibody comprising: a first antibody heavy chain, a second antibody heavy chain, a first antibody light chain, and a second antibody light chain (e.g., a first, second, third, and fourth polypeptide chain, respectively), wherein the antibody specifically binds to a HA protein, wherein the chimeric protein comprises: (a) a first polypeptide chain comprising the first antibody heavy chain fused to a first mucoadhesive peptide fragment; (b) a second polypeptide chain comprising the second antibody heavy chain fused to a second mucoadhesive peptide fragment; (c) a third polypeptide chain comprising the first antibody light chain; and (d) the fourth polypeptide chain comprising a second antibody light chain, wherein the first and second mucoadhesive peptide fragments each comprise about at least about 5 positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the first and second mucoadhesive peptide fragments facilitate attachment of the chimeric protein to a mucosa. In some embodiments, the chimeric protein comprises: (1) a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 216, 218-242, and 416-419, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217; (2) a first and a second polypeptide chain each independently having at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 243, 245-258, and 422-425, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244; or (3) a first and a second polypeptide chain each independently having at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 448-486, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447.

In some embodiments, there is provided a chimeric protein (e.g., fusion protein) comprising a full-length antibody comprising: a first antibody heavy chain, a second antibody heavy chain, a first antibody light chain, and a second antibody light chain (e.g., a first, second, third, and fourth polypeptide chain, respectively), wherein the antibody specifically binds to a NA protein, wherein the chimeric protein comprises: (a) a first polypeptide chain comprising the first antibody heavy chain fused to a first mucoadhesive peptide fragment; (b) a second polypeptide chain comprising the second antibody heavy chain fused to a second mucoadhesive peptide fragment; (c) a third polypeptide chain comprising the first antibody light chain; and (d) the fourth polypeptide chain comprising a second antibody light chain, wherein the first and second mucoadhesive peptide fragments each comprise about at least about 5 positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the first and second mucoadhesive peptide fragments facilitate attachment of the chimeric protein to a mucosa. In some embodiments, the chimeric protein comprises: (1) a first and a second polypeptide chains each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 259, 261-274, and 428-431, and a third and a fourth polypeptide chains each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260; or (2) a first and a second polypeptide chains each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 275, 277-290, and 434-437, and a third and a fourth polypeptide chains each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276.

In some embodiments, there is provided a chimeric protein (e.g., fusion protein) comprising: (a) an scFv that specifically binds to a component of an influenza virus or variant thereof; and (b) a mucoadhesive peptide fragment, wherein the mucoadhesive peptide fragment comprises about at least about 5 positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa. In some embodiments, the chimeric protein comprises a polypeptide comprising: from the N-terminus to the C-terminus: the scFv, an optional peptide linker, and the mucoadhesive peptide fragment. In some embodiments, the scFv comprises from the N-terminus to the C-terminus: V_H, an optional linker, and V_L. In some embodiments, the scFv comprises from the N-terminus to the C-terminus: V_L, an optional linker, and V_H. In some embodiments, the chimeric protein further comprises one or more constant domains of an antibody, e.g., CH₁, C_L, CH₂, CH₃, and/or CH₄. In some embodiments, the chimeric protein further comprises an Fc. In some embodiments, the positively charged amino acid residues are selected from the group consisting of lysine, arginine, histidine, ornithine, and combinations thereof. In some embodiments, the positively charged amino acid residues are lysines. In some embodiments, the mucoadhesive peptide fragment is a polylysine peptide having at least about 5 (e.g., about 5-30 such as 12) lysines (including for example at least about 5 (e.g., about 5-30 such as 12) contiguous lysines). In some embodiments, the positively charged amino acid residues are histidines. In some embodiments, the mucoadhesive peptide fragment is a polyhistidine peptide having at least about 5 (e.g., about 5-30 such as 12) histidines (including for example at least about 5 (e.g., about 5-30 such as 12) contiguous histidines). In some embodiments, the positively charged amino acid residues are arginines. In some embodiments, the mucoadhesive peptide fragment is a polyarginine peptide having at least about 5 (e.g., about 5-30 such as 12) arginines (including for example at least about 5 (e.g., about 5-30 such as 12) contiguous arginines). In some embodiments, the positively charged amino acid residues are ornithines. In some embodiments, the mucoadhesive peptide fragment is a polyornithine peptide having at least about 5 (e.g., about 5-30 such as 12) ornithines (including for example at least about 5 (e.g., about 5-30 such as 12) contiguous ornithines). In some embodiments, the positively charged amino acid residues are contiguous with each other. In some embodiments, the positively charged amino acid residues are interspersed with non-positively charged amino acid residues. In some embodiments, the influenza virus is a Type A influenza virus (IAV), a Type B influenza virus (IBV), a Type C influenza virus (ICV), a Type D influenza virus (IDV), or a variant, subtype, or reassortant thereof. In some embodiments, the influenza virus comprises an HA antigen, such as an HA selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof. In some embodiments, the influenza virus comprises a NA antigen, such as an NA selected from the group consisting of N1, N2, N3, N7, N8, and N9, or a variant or reassortant thereof. In some embodiments, the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof. In some embodiments, the component of the influenza virus or variant thereof is a viral surface protein. In some embodiments, the viral surface protein is HA. In some embodiments, the viral surface protein is NA. In some embodiments, the influenza virus or variant thereof causes a respiratory infection. In some embodiments, the mucosa is selected from the group consisting of nasal mucosa, larynx mucosa, trachea mucosa, bronchi mucosa, lung mucosa, eye mucosa, and combinations thereof.

In some embodiments, there is provided a chimeric protein (e.g., fusion protein) comprising: (a) a first scFv and a second scFv that each specifically binds to a component of an influenza virus or a variant thereof; and (b) a first and a second mucoadhesive peptide fragments, wherein the mucoadhesive peptide fragments each comprise at least about 5 positively charged amino acid residues (e.g., about 5 to about 30 positively charged amino acid residues), wherein the mucoadhesive peptide fragments facilitate attachment of the chimeric protein to a mucosa; wherein the chimeric protein comprises: (1) a first polypeptide comprising from the N-terminus to the C-terminus: the first scFv, an optional linker, CH₂ domain, CH₃ domain, an optional linker, and the first mucoadhesive peptide fragment; and (2) a second polypeptide comprising from the N-terminus to the C-terminus: the second scFv, an optional linker, CH₂ domain, CH₃ domain, an optional linker, and the second mucoadhesive peptide fragment. In some embodiments, the first mucoadhesive peptide fragment is identical to the second mucoadhesive peptide fragment. In some embodiments, the first mucoadhesive peptide fragment is different from the second mucoadhesive peptide fragment. In some embodiments, the first scFv and the second scFv specifically bind to the same component of the influenza virus or variant thereof. In some embodiments, the first scFv and the second scFv specifically bind to different variants of the same component, different components of the same influenza virus, or components of different influenza viruses. In some embodiments, the positively charged amino acid residues are selected from the group consisting of lysine, arginine, histidine, ornithine, and combinations thereof. In some embodiments, the positively charged amino acid residues are lysines. In some embodiments, the mucoadhesive peptide fragment is a polylysine peptide having at least about 5 (e.g., about 5-30 such as 12) lysines (including for example at least about 5 (e.g., about 5-30 such as 12) contiguous lysines). In some embodiments, the positively charged amino acid residues are histidines. In some embodiments, the mucoadhesive peptide fragment is a polyhistidine peptide having at least about 5 (e.g., about 5-30 such as 12) histidines (including for example at least about 5 (e.g., about 5-30 such as 12) contiguous histidines). In some embodiments, the positively charged amino acid residues are arginines. In some embodiments, the mucoadhesive peptide fragment is a polyarginine peptide having at least about 5 (e.g., about 5-30 such as 12) arginines (including for example at least about 5 (e.g., about 5-30 such as 12) contiguous arginines). In some embodiments, the positively charged amino acid residues are ornithines. In some embodiments, the mucoadhesive peptide fragment is a polyornithine peptide having at least about 5 (e.g., about 5-30 such as 12) ornithines (including for example at least about 5 (e.g., about 5-30 such as 12) contiguous ornithines). In some embodiments, the positively charged amino acid residues are contiguous with each other. In some embodiments, the positively charged amino acid residues are interspersed with non-positively charged amino acid residues. In some embodiments, the influenza virus is a Type A influenza virus (IAV), a Type B influenza virus (IBV), a Type C influenza virus (ICV), a Type D influenza virus (IDV), or a variant, subtype, or reassortant thereof. In some embodiments, the influenza virus comprises an HA antigen, such as an HA antigen selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof. In some embodiments, the influenza virus comprises a NA antigen, such as an NA selected from the group consisting of N1, N2, N3, N7, N8, and N9, or a variant or reassortant thereof. In some embodiments, the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof. In some embodiments, the component of the influenza virus or variant thereof is a viral surface protein. In some embodiments, the viral surface protein is HA. In some embodiments, the viral surface protein is NA. In some embodiments, the influenza virus or variant thereof causes a respiratory infection. In some embodiments, the mucosa is selected from the group consisting of nasal mucosa, larynx mucosa, trachea mucosa, bronchi mucosa, lung mucosa, eye mucosa, and combinations thereof.

In some embodiments, the half-life of the chimeric protein on the mucosa is at least about n hours, where n hours is selected from 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours 22 hours, 24 hours, 30 hours, 36 hours, and 48 hours, or more. In some embodiments, the half-life of the chimeric protein on the mucosa is at least 12 hours. In some embodiments, the half-life of the chimeric protein on the mucosa is at least 24 hours.

The half-life of the chimeric protein on the mucosa may be determined using known in vitro assays in the art. In view of the size and polar properties of the chimeric protein, mucosal (e.g., nasal) absorption of the chimeric protein is minimal because of low membrane permeability of the chimeric protein. However, mucociliary clearance of the chimeric protein may play a role in the half-life of the chimeric proteins. The mucoadhesive peptide fragment can improve the retention time of the chimeric protein on the mucosa. For example, an in vitro model cell system, such as mucosal epithelial cells, may be used to determine the amount of the chimeric protein remaining on cell/mucin surface by FACS or immunofluorescence. As another example, mucosa related components, such as mucin, could be used to incubate with a chimeric protein and determine the amount of the chimeric protein associated with mucin by ELISA. In both methods, for chimeric proteins comprising an IgG, anti-IgG secondary antibodies can be used as a detection probe.

Exemplary chimeric proteins comprising an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof, and a mucoadhesive peptide fragment comprising at least about 5 (e.g., about 5 to about 30 positively charges amino acid residues) positively charged amino acid residues are provided herein. Table 1 provides the sequences of some exemplary chimeric proteins which comprise antibody light chain (“LC”) polypeptides as well as antibody heavy chain (“HC”) polypeptides fused to mucoadhesive peptide fragments.

TABLE 1
Exemplary anti-influenza chimeric proteins
				SEQ
Chimeric	Anti-	HC /	Sequence	ID
Protein	gen	LC	(mucoadhesive peptide fragment is underlined)	NO
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	216
6H			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKHHHHHH
		LC	DIVMTQSPDSLAVSLGERATINCKSSQSVTFNYKNYLAWYQQK	217
			PGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVA
			VYYCQQHYRTPPTFGQGTKVEIKGQPKANPTVTLFPPSSEELQA
			NKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNN
			KYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	218
12H			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKHHHHHHHHHHHH
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	219
30H			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKHHHHHHHHHHHHHHHHHHHHHHHHH
			HHHHH
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	220
6K			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKKKKKKK
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	221
12K			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKGGGGSKKKKKKKKKKKK
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	222
30K			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKKKKKKKKKKKKKKKKKKKKKKKKKK
			KKKKK
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	223
6R			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKPRRRRRR
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	224
12R			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKRRRRRRRRRRRR
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	225
30R			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKRRRRRRRRRRRRRRRRRRRRRRRRRRR
			RRR
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	226
6O			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSASVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
			SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT
			KVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE
			VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
			RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP
			REPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQP
			ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE
			ALHNHYTQKSLSLSPGKOOOOOO
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	227
12O			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKPOOOOOOOOOOOO
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	228
30O			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKOOOOOOOOOOOOOOOOOOOOOOOOO
			OOOOO
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	229
6X-1			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKHHKKOO
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	230
6X-2			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKHORKHR
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	231
6X-3			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKHKRSOH
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	232
6X-4			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKRRHTHR
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	233
12X-1			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKHHHKKKRRROOO
			“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	234
30X-1			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKHKROHKROHKROHKROHKROHKROHK
			ROHK
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	236
12X-2			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKHHOAKKRCOOQH
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	237
30X-2			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKKOHRSOKRHTORHKAHORKCKROKQR
			KHOS
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	239
12X-3			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKHRKOORKHHRKK
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	240
30X-3			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKKKROSRRHOTOOHHAROKHCKHROQR
			HKKS
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	241
12X-4			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKKRAHOKCORKSH
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	242
30X-4			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKHRKQOHRSOOKTRRRAHROCHHHSRHOTH
			R
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	416
5H			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS
			HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL
			HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP
			SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
			LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS
			LSLSPGKHHHHH
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	417
7X-1			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS
			HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL
			HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP
			SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
			LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS
			LSLSPGKKKKGKKK
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	418
12X-7			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS
			HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL
			HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP
			SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
			LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS
			LSLSPGKKKAHHGKKAHHV
		LC	“HA1” LC	217
HA1-hIgG-	HA	HC	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPG	419
12X-8			KGLEWVAVISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNS
			LRAEDTAVYYCAKDSQLRSLLYFEWLSQGYFDYWGQGTLVTV
			SSTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS
			HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL
			HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP
			SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
			LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS
			LSLSPGKKKARRGKKARRV
		LC	“HA1” LC	217
HA2-hIgG-	HA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	243
6H			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKHHHHHH
		LC	QSVLTQPPSASGTPGQSVTISCSGSRSNIGGNTVNWYQHLPGMA	244
			PKLLIYSSNQRSSGVPDRFSGSKSGTSASLAISGLQSEDDADYYC
			ASWDDSLNGVVFGGGTKLTVLGGQPKAAPSVTLFPPSSEELQA
			NKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNN
			KYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
HA2-hIgG-	HA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	245
12H			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKHHHHHHHHHHHH
		LC	“HA2” LC	244
HA2-hIgG-	HA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	246
30H			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKHHHHHHHHHHHHHHHHHHHHHHHHH
			HHHHH
		LC	“HA2” LC	244
HA2-hIgG-	HA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	247
6K			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKKKKKKK
		LC	“HA2” LC	244
HA2-hIgG-	HA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	248
12K			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKGGGGSKKKKKKKKKKKK
		LC	“HA2” LC	244
HA2-hIgG-	HA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	249
30K			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKKKKKKKKKKKKKKKKKKKKKKKKKK
			KKKKK
		LC	“HA2” LC	244
HA2-hIgG-	HA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	250
6R			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKRRRRRR
		LC	“HA2” LC	244
HA2-hIgG-	HA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	251
12R			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKRRRRRRRRRRRR
		LC	“HA2” LC	244
HA2-hIgG-	HA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	252
30R			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKRRRRRRRRRRRRRRRRRRRRRRRRRRR
			RRR
		LC	“HA2” LC	244
HA2-hIgG-	HA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	253
6O			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKOOOOOO
		LC	“HA2” LC	244
HA2-hIgG-	HA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	254
12O			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKOOOOOOOOOOOO
		LC	“HA2” LC	244
HA2-hIgG-	HA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	255
30O			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKOOOOOOOOOOOOOOOOOOOOOOOOO
			OOOOO
		LC	“HA2” LC	244
HA2-hIgG-	HA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	256
6X-7			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKKKOORR
		LC	“HA2” LC	244
HA2-hIgG-	HA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	257
12X-5			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKKKRROOHHHRRR
		LC	“HA2” LC	244
HA2-hIgG-	HA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	258
30X-1			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKHKROHKROHKROHKROHKROHKROHK
			ROHK
		LC	“HA2” LC	244
HA2-hIgG-	HA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	422
5H			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKHHHHH
		LC	“HA2” LC	244
HA2-hIgG-	HA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	423
7X-1			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKKKKGKKK
		LC	“HA2” LC	244
HA2-hIgG-	HA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	424
12X-7			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKKKAHHGKKAHHV
		LC	“HA2” LC	244
HA2-hIgG-	HA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	425
12X-8			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTV
			SSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS
			GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK
			VDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
			TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
			VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
			EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
			NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA
			LHNHYTQKSLSLSPGKKKARRGKKARRV
		LC	“HA2” LC	244
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	448
hIgG-5H			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTA YMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSS
			KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
			SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC
			TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE
			DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ
			DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR
			DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD
			SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS
			LSPGKHHHHH
		LC	QSALTQPPAVSGTPGQRVTISCSGSDSNIGRRSVNWYQQFPGTA	447
			PKLLIYSNDQRPSVVPDRFSGSKSGTSASLAISGLQSEDEAEYYC
			AAWDDSLKGAVFGGGTQLTVLGQPKANPTVTLFPPSSEELQAN
			KATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNK
			YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	449
hIgG-6H			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKHHHHHH
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	450
hIgG-12H			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKHHHHHHHHHHHH
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	451
hIgG-30H			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	452
hIgG-6K			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKKKKKKK
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	453
hIgG-12K			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GGGGSKKKKKKKKKKKKK
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	454
hIgG-30K			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKK
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	455
hIgG-6R			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKRRRRRR
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	456
hIgG-12R			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKRRRRRRRRRRRR
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	457
hIgG-30R			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	458
hIgG-6O			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKOOOOOO
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	459
hIgG-12O			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKOOOOOOOOOOOO
		LC	HA15 LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	460
hIgG-30O			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	461
hIgG-6X-1			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKHHKKOO
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	462
hIgG-6X-2			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKHORKHR
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	463
hIgG-6X-3			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKHKRSOH
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	464
hIgG-6X-4			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKRRHTHR
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	465
hIgG-6X-5			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKKKHHRR
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	466
hIgG-6X-6			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKOORRHH
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	467
hIgG-6X-7			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKKKOORR
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	468
hIgG-7X-1			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKKKKGKKK
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	469
hIgG-12X-			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
1			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKHHHKKKRRROOO
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	470
hIgG-12X-			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
2			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKHHOAKKRCOOQH
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	471
hIgG-12X-			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
3			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKHRKOORKHHRKK
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	472
hIgG-12X-			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
4			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKKRAHOKCORKSH
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	473
hIgG-12X-			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
5			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKKKRROOHHHRRR
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	474
hIgG-12X-			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
6			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKOOORRRKKKHHH
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	475
hIgG-12X-			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
7			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKKKAHHGKKAHHV
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	476
hIgG-12X-			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
8			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKKKARRGKKARRV
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	477
hIgG-30X-			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
1			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSASVFPLAPSS
			KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS
			SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCT
			CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED
			PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD
			WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
			ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS
			DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL
			SPGKKHKROHKROHKROHKROHKROHKROHKROHK
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	478
hIgG-30X-			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
2			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKKOHRSOKRHTORHKAHORKCKROKQRKHOS
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	479
hIgG-30X-			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
3			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKKKROSRRHOTOOHHAROKHCKHROTRHKKS
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	480
hIgG-30X-			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
4			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSVFPLAPSSKS
			TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
			LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTCP
			PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE
			VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
			NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT
			KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS
			FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
			KHRKQOHRSOOKTRRRAHROCHHHSRHOTHR
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	481
hIgG-35X-			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
1			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKGRHKAKNHIRRPKSRWKKWHKYRKVHRHKVHKGRR
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	482
hIgG-40X-			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
2			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKWRKVHHYKKQHKNRAHGKLKLRAKIHQRSRMHGKQKHYH
			R
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	483
hIgG-42X-			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
1			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKAHHKCRRGHKQKILHRRPHKFHRWKRVHKGRHGKKHRRH
			KHR
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	484
hIgG-45X-			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
1			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKQHRGKAKYHRTHHVKKQRHGRKNHKVHRHARKFHKIRRL
			KCHKKH
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	485
hIgG-50X-			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
1			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKHNKRFKKGRHVRHSRHKSHRRTHKYHHWRHYRKVHRCKK
			AHKSHHRVHHK
		LC	“HA15” LC	447
HA15-	HA	HC	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQ	486
hIgG-50X-			GLDWMGGISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTS
2			EDTAVYFCARHGNYYYYSGMDVWGQGTTVTVSSSVFPLAPSSK
			STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
			GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCTC
			PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP
			EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
			LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
			TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG
			SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
			GKAHGRPHOFKROCKAHOVKHILKRTOSHOYKOVHORNKOAO
			KMRKIRGGHK
		LC	“HA15” LC	447
NA1-hIgG-	NA	HC	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKG	259
6H			LQWIGYIYYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVWGKGTTVTVSSSVFPL
			APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
			VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE
			PKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
			VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT
			VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
			LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
			PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT
			QKSLSLSPGKHHHHHH
		LC	DIQMTQSPSSLSASVRDKVTFVCRASQTISIFLNWYQHKPGEAPK	260
			LLIYAASRLQSGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQQ
			SYSAPWTFGQGTKVEIKGQPKANPTVTLFPPSSEELQANKATLV
			CLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASS
			YLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
NA1-hIgG-	NA	HC	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKG	261
12H			LOWIGYIYYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVWGKGTTVTVSSSVFPL
			APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
			VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE
			PKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
			VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT
			VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
			LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
			PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT
			QKSLSLSPGKHHHHHHHHHHHH
		LC	“NA1” LC	260
NA1-hIgG-	NA	HC	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKG	262
30H			LOWIGYIYYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVWGKGTTVTVSSSVFPL
			APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
			VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE
			PKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
			VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT
			VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
			LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
			PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT
			QKSLSLSPGKHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
		LC	“NA1” LC	260
NA1-hIgG-	NA	HC	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKG	263
6K			LOWIGYIYYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVWGKGTTVTVSSSVFPL
			APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
			VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE
			PKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
			VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT
			VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
			LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
			PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT
			QKSLSLSPGKKKKKKK
		LC	“NA1” LC	260
NA1-hIgG-	NA	HC	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKG	264
12K			LOWIGYIYYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVWGKGTTVTVSSSVFPL
			APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
			VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE
			PKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
			VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT
			VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
			LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
			PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT
			QKSLSLSPGKGGGGSKKKKKKKKKKKK
		LC	“NA1” LC	260
NA1-hIgG-	NA	HC	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKG	265
30K			LQWIGYIYYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVWGKGTTVTVSSSVFPL
			APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
			VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE
			PKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
			VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT
			VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
			LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
			PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT
			QKSLSLSPGKKKKKKKKKKKKKKKKKKKKKKKKKKKKKKK
		LC	“NA1” LC	260
NA1-hIgG-	NA	HC	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKG	266
6R			LOWIGYIYYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVWGKGTTVTVSSSVFPL
			APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
			VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE
			PKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
			VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT
			VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
			LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
			PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT
			QKSLSLSPGKRRRRRR
		LC	“NA1” LC	260
NA1-hIgG-	NA	HC	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKG	267
12R			LQWIGYIYYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVWGKGTTVTVSSSVFPL
			APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
			VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE
			PKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
			VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT
			VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
			LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
			PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT
			QKSLSLSPGKRRRRRRRRRRRR
		LC	“NA1” LC	260
NA1-hIgG-	NA	HC	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKG	268
30R			LQWIGYIYYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVWGKGTTVTVSSSVFPL
			APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
			VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE
			PKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
			VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT
			VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
			LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
			PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT
			QKSLSLSPGKRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR
		LC	“NA1” LC	260
NA1-hIgG-	NA	HC	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKG	269
6O			LQWIGYIYYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVWGKGTTVTVSSSVFPL
			APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
			VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE
			PKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
			VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT
			VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
			LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
			PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT
			QKSLSLSPGKOOOOOO
		LC	“NA1” LC	260
NA1-hIgG-	NA	HC	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKG	270
12O			LOWIGYIYYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVWGKGTTVTVSSSVFPL
			APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
			VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE
			PKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
			VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT
			VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
			LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
			PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT
			QKSLSLSPGKOOOOOOOOOOOO
		LC	“NA1” LC	260
NA1-hIgG-	NA	HC	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKG	271
30O			LOWIGYIYYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVWGKGTTVTVSSSVFPL
			APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
			VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE
			PKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
			VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT
			VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
			LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
			PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT
			QKSLSLSPGKGOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO
		LC	“NA1” LC	260
NA1-hIgG-	NA	HC	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKG	272
6X-5			LQWIGYIYYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVWGKGTTVTVSSSVFPL
			APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
			VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE
			PKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
			VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT
			VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
			LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
			PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT
			QKSLSLSPGKKKHHRR
		LC	“NA1” LC	260
NA1-hIgG-	NA	HC	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKG	273
12X-5			LQWIGYIYYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVWGKGTTVTVSSSVFPL
			APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
			VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE
			PKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
			VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT
			VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
			LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
			PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT
			QKSLSLSPGKKKRROOHHHRRR
		LC	“NA1” LC	260
NA1-hIgG-	NA	HC	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKG	274
30X-1			LQWIGYIYYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVWGKGTTVTVSSSVFPL
			APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
			VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVE
			PKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
			VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT
			VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
			LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
			PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT
			QKSLSLSPGKHKROHKROHKROHKROHKROHKROHKROHK
		LC	“NA1” LC	260
NA1-hIgG-	NA	HC	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKG	428
5H			LQWIGYIYYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVWGKGTTVTVSSSVFPL
			APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
			VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP
			KSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV
			SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL
			HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP
			SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
			LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS
			LSLSPGKHHHHH
		LC	“NA1” LC	260
NA1-hIgG-	NA	HC	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKG	429
7X-1			LQWIGYIYYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVWGKGTTVTVSSSVFPL
			APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
			VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP
			KSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV
			SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL
			HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP
			SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
			LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS
			LSLSPGKKKKGKKK
		LC	“NA1” LC	260
NA1-hIgG-	NA	HC	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKG	430
12X-7			LQWIGYIYYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVWGKGTTVTVSSSVFPL
			APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
			VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP
			KSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV
			SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL
			HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP
			SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
			LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS
			LSLSPGKKKAHHGKKAHHV
		LC	“NA1” LC	260
NA1-hIgG-	NA	HC	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKG	431
12X-8			LQWIGYIYYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVWGKGTTVTVSSSVFPL
			APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
			VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP
			KSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV
			SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL
			HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP
			SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
			LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS
			LSLSPGKKKARRGKKARRV
		LC	“NA1” LC	260
NA2-hIgG-	NA	HC	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQ	275
6H			GLEWVGGIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLR
			SDDTAVYYCARDTVAVYEDFDWSSPYFFYMDVWGKGTTVTVS
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKHHHHHH
		LC	EIVLTQSPATLSLFPGERATLSCRASQSAGSKSLAWYQHKVGQP	276
			PRLLINGASSRATGIPDRESGSGSGPDFNLTISRLEPEDFAVYYCQ
			RYGTSLVTFGGGTKVEIKGQPKANPTVTLFPPSSEELQANKATL
			VCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAAS
			SYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
NA2-hIgG-	NA	HC	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQ	277
12H			GLEWVGGIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLR
			SDDTAVYYCARDTVAVYEDFDWSSPYFFYMDVWGKGTTVTVS
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKHHHHHHHHHHHH
		LC	“NA2” LC	276
NA2-hIgG-	NA	HC	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQ	278
30H			GLEWVGGIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLR
			SDDTAVYYCARDTVAVYEDFDWSSPYFFYMDVWGKGTTVTVS
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKHHHHHHHHHHHHHHHHHHHHHHHHHHHH
			HH
		LC	“NA2” LC	276
NA2-hIgG-	NA	HC	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQ	279
6K			GLEWVGGIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLR
			SDDTAVYYCARDTVAVYEDFDWSSPYFFYMDVWGKGTTVTVS
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKKKKKKK
		LC	“NA2” LC	276
NA2-hIgG-	NA	HC	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQ	280
12K			GLEWVGGIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLR
			SDDTAVYYCARDTVAVYEDFDWSSPYFFYMDVWGKGTTVTVS
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKGGGGSKKKKKKKKKKKK
		LC	“NA2” LC	276
NA2-hIgG-	NA	HC	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQ	281
30K			GLEWVGGIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLR
			SDDTAVYYCARDTVAVYEDFDWSSPYFFYMDVWGKGTTVTVS
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKKKKKKKKKKKKKKKKKKKKKKKKKKKKK
			KK
		LC	“NA2” LC	276
NA2-hIgG-	NA	HC	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQ	282
6R			GLEWVGGIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLR
			SDDTAVYYCARDTVAVYEDFDWSSPYFFYMDVWGKGTTVTVS
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKRRRRRR
		LC	“NA2” LC	276
NA2-hIgG-	NA	HC	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQ	283
12R			GLEWVGGIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLR
			SDDTAVYYCARDTVAVYEDFDWSSPYFFYMDVWGKGTTVTVS
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKRRRRRRRRRRRR
		LC	“NA2” LC	276
NA2-hIgG-	NA	HC	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQ	284
30R			GLEWVGGIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLR
			SDDTAVYYCARDTVAVYEDFDWSSPYFFYMDVWGKGTTVTVS
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR
		LC	“NA2” LC	276
NA2-hIgG-	NA	HC	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQ	285
6O			GLEWVGGIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLR
			SDDTAVYYCARDTVAVYEDFDWSSPYFFYMDVWGKGTTVTVS
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKOOOOOO
		LC	“NA2” LC	276
NA2-hIgG-	NA	HC	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQ	286
12O			GLEWVGGIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLR
			SDDTAVYYCARDTVAVYEDFDWSSPYFFYMDVWGKGTTVTVS
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKOOOOOOOOOOOO
		LC	“NA2” LC	276
NA2-hIgG-	NA	HC	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQ	287
30O			GLEWVGGIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLR
			SDDTAVYYCARDTVAVYEDFDWSSPYFFYMDVWGKGTTVTVS
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKOOOOOOOOOOOOOOOOOOOOOOOOOOOO
			OO
		LC	“NA2” LC	276
NA2-hIgG-	NA	HC	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQ	288
6X-6			GLEWVGGIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLR
			SDDTAVYYCARDTVAVYEDFDWSSPYFFYMDVWGKGTTVTVS
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKOORRHH
		LC	“NA2” LC	276
NA2-hIgG-	NA	HC	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQ	289
12X-6			GLEWVGGIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLR
			SDDTAVYYCARDTVAVYEDFDWSSPYFFYMDVWGKGTTVTVS
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKOOORRRKKKHHH
		LC	“NA2” LC	276
NA2-hIgG-	NA	HC	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQ	290
30X-1			GLEWVGGIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLR
			SDDTAVYYCARDTVAVYEDFDWSSPYFFYMDVWGKGTTVTVS
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKKROHKROHKROHKROHKROHKROHKROHK
		LC	“NA2” LC	276
NA2-hIgG-	NA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	434
5H			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTVS
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKHHHHH
		LC	“NA2” LC	276
NA2-hIgG-	NA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	435
7X-1			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTVS
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKKKKGKKK
		LC	“NA2” LC	276
NA2-hIgG-	NA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	436
12X-7			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTVS
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKKKAHHGKKAHHV
		LC	“NA2” LC	276
NA2-hIgG-	NA	HC	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQG	437
12X-8			LEWMGGIIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYYGLDVWGQGTTVTVS
			SSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
			VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV
			DKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
			VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
			SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
			VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
			KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
			HYTQKSLSLSPGKKKARRGKKARRV
		LC	“NA2” LC	276

Additional chimeric proteins comprising any of the anti-influenza virus (e.g., anti-HA or anti-NA) antibody moieties or variants thereof, the mucoadhesive peptide fragments, and/or linkers provided herein are also contemplated. It should be understood that various other chimeric proteins comprising anti-influenza virus antibody moieties or variants known in the art fused with any of the mucoadhesive peptide fragments and/or linkers provided herein may be encompassed by the scope of this invention.

In some embodiments, the chimeric protein comprises an anti-HA antibody moiety and one or more of the mucoadhesive peptide fragments described herein. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently comprising a heavy chain of a full-length anti-HA antibody, and a third and fourth polypeptide chain each independently comprising a light chain of a full-length anti-HA antibody, such as any of the chimeric proteins provided in Table 1 above, e.g., HA1-hIgG-6H; HA1-hIgG-12H; HA1-hIgG-30H; HA1-hIgG-6K; HA1-hIgG-12K; HA1-hIgG-30K; HA1-hIgG-6R; HA1-hIgG-12R; HA1-hIgG-30R; HA1-hIgG-60; HA1-hIgG-120; HA1-hIgG-300; HA1-hIgG-6X-1; HA1-hIgG-6X-2; HA1-hIgG-6X-3; HA1-hIgG-6X-4; HA1-hIgG-12X-1; HA1-hIgG-30X-1; HA1-hIgG-6X-2; HA1-hIgG-12X-2; HA1-hIgG-30X-2; HA1-hIgG-6X-3; HA1-hIgG-12X-3; HA1-hIgG-30X-3; HA1-hIgG-12X-4; HA1-hIgG-30X-4; HA2-hIgG-6H; HA2-hIgG-12H; HA2-hIgG-30H; HA2-hIgG-6K; HA2-hIgG-12K; HA2-hIgG-30K; HA2-hIgG-6R; HA2-hIgG-12R; HA2-hIgG-30R; HA2-hIgG-60; HA2-hIgG-120; HA2-hIgG-300; HA2-hIgG-6X-7; HA2-hIgG-12X-5; HA2-hIgG-30X-1; HA1-hIgG-5H; HA1-hIgG-7X-1; HA1-hIgG-12X-7; HA1-hIgG-12X-8; HA2-hIgG-5H;HA2-hIgG-7X-1; HA2-hIgG-12X-7; HA2-hIgG-12X-8; HA15-hIgG-5H; HA15-hIgG-6H; HA15-hIgG-12H; HA15-hIgG-30H; HA15-hIgG-6K; HA15-hIgG-12K; HA15-hIgG-30K; HA15-hIgG-6R; HA15-hIgG-12R; HA15-hIgG-30R; HA15-hIgG-60; HA15-hIgG-120; HA15-hIgG-300; HA15-hIgG-6X-1; HA15-hIgG-6X-2; HA15-hIgG-6X-3; HA15-hIgG-6X-4; HA15-hIgG-6X-5; HA15-hIgG-6X-6; HA15-hIgG-6X-7; HA15-hIgG-7X-1; HA15-hIgG-12X-1; HA15-hIgG-12X-2; HA15-hIgG-12X-3; HA15-hIgG-12X-4; HA15-hIgG-12X-5; HA15-hIgG-12X-6; HA15-hIgG-12X-7; HA15-hIgG-12X-8; HA15-hIgG-30X-1; HA15-hIgG-30X-2; HA15-hIgG-30X-3; HA15-hIgG-30X-4; HA15-hIgG-35X-1; HA15-hIgG-40X-2; HA15-hIgG-42X-1; HA15-hIgG-45X-1; HA15-hIgG-50X-1; and HA15-hIgG-50X-2.

In some embodiments, the chimeric protein comprises a heavy chain (HC) polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 414, 420, and 446, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 414, 420, and 446, and a light chain (LC) polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 217, 244, and 447, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 217, 244, and 447.

In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 414, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 414, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 217, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217.

In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 420, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 420, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 244, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244.

In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 446, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 446, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 447, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 216, 218-234, 236, 237, 239-242, and 416-419, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of any one of SEQ ID NOs: 216, 218-234, 236, 237, 239-242, and 416-419, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 216, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 216, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-6H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 218, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 218, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-12H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 219, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 219, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-30H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 220, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 220, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-6K, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 221, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 221, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-12K, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 222, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 222, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-30K, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 223, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 223, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-6R, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 224, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 224, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-12R, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 225, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 225, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-30R, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 226, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 226, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-60, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 227, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 227, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-120, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 228, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 228, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-300, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 229, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 229, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-6X-1, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 230, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 230, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-6X-2, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 231, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 231, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-6X-3, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 232, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 232, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-6X-4, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 233, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 233, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-12X-1, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 234, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 234, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-30X-1, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 236, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 236, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-12X-2, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 237, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 237, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-30X-2, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 239, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 239, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-12X-3, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 240, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 240, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-30X-3, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 241, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 241, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-12X-4, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 242, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 242, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-30X-4, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 416, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 416, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-5H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 417, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 417, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-7X-1, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 418, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 418, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-12X-7, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 419, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 419, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 217. In some embodiments, the chimeric protein is HA1-hIgG-12X-8, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 243, 245-258, and 422-425, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of any one of SEQ ID NOs: 243, 245-258, and 422-425, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 243, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 243, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-6H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 245, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 245, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-12H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 246, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 246, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-30H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 247, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 247, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-6K, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 248, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 248, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-12K, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 249, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 249, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-30K, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 250, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 250, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-6R, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 251, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 251, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-12R, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 252, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 252, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-30R, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 253, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 253, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-60, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 254, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 254, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-120, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 255, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 255, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-300, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 256, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 256, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-6X-7, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 257, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 257, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-12X-5, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 258, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 258, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-30X-1, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 422, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 422, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-5H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 423, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 423, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-7X-1, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 424, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 424, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-12X-7, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 425, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 425, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 244. In some embodiments, the chimeric protein is HA2-hIgG-12X-8, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 448-486, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of any one of SEQ ID NOs: 448-486, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 448, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 448, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-5H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 449, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 449, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 450, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 450, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 451, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 451, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-30H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 452, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 452, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6K, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 453, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 453, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12K, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 454, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 454, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-30K, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 455, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 455, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6R, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 456, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 456, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12R, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 457, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 457, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-30R, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 458, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 458, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-60, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 459, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 459, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-120, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 460, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 460, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-300, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 461, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 461, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6X-1, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 462, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 462, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6X-2, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 463, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 463, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6X-3, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 464, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 464, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6X-4, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 465, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 465, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6X-5, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 466, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 466, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6X-6, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 467, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 467, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-6X-7, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 468, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 468, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-7X-1, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 469, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 469, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12X-1, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 470, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 470, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12X-2, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 471, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 471, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12X-3, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 472, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 472, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12X-4, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 473, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 473, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12X-5, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 474, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 474, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12X-6, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 475, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 475, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12X-7, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 476, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 476, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-12X-8, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 477, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 477, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-30X-1, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 478, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 478, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-30X-2, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 479, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 479, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-30X-3, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 480, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 480, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-30X-4, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 481, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 481, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-35X-1, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 482, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 482, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-40X-2, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 483, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 483, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-42X-1, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 484, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 484, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-45X-1, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 485, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 485, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-50X-1, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 486, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 486, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 447. In some embodiments, the chimeric protein is HA15-hIgG-50X-2, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently comprising a V_H of a full-length anti-NA antibody, and a third and fourth polypeptide chain each independently comprising a V_L of a full-length anti-NA antibody, such as any of the chimeric proteins provided in Table 1 above, e.g., NA1-hIgG-6H; NA1-hIgG-12H; NA1-hIgG-30H; NA1-hIgG-6K; NA1-hIgG-12K; NA1-hIgG-30K; NA1-hIgG-6R; NA1-hIgG-12R; NA1-hIgG-30R; NA1-hIgG-60; NA1-hIgG-120; NA1-hIgG-300; NA1-hIgG-6X-5; NA1-hIgG-12X-5; NA1-hIgG-30X-1; NA2-hIgG-6H; NA2-hIgG-12H; NA2-hIgG-30H; NA2-hIgG-6K; NA2-hIgG-12K; NA2-hIgG-30K; NA2-hIgG-6R; NA2-hIgG-12R; NA2-hIgG-30R; NA2-hIgG-60; NA2-hIgG-120; NA2-hIgG-300; NA2-hIgG-6X-6; NA2-hIgG-12X-6; NA2-hIgG-30X-1; NA1-hIgG-5H; NA1-hIgG-7X-1; NA1-hIgG-12X-7; NA1-hIgG-12X-8; NA2-hIgG-5H; NA2-hIgG-7X-1; NA2-hIgG-12X-7; and NA2-hIgG-12X-8.

In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 426 or 432, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 426 or 432, an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 260 or 276, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260 or 276.

In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 426, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 426, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 260, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260.

In some embodiments, the chimeric protein comprises an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 432, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 432, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 276, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chains each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 259, 261-274, and 428-431, and a third and a fourth polypeptide chains each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chains each independently having the amino acid sequence of any one of SEQ ID NOs: 259, 261-274, and 428-431, and a third and a fourth polypeptide chains each having the amino acid sequence of SEQ ID NO: 260.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 259, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 259, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-6H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 261, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 261, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-12H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 262, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 262, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-30H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 263, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 263, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-6K, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 264, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 264, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-12K, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 265, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 265, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-30K, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 266, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 266, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-6R, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 267, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 267, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-12R, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 268, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 268, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-30R, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 269, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 269, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-60, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 270, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 270, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-120, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 271, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 271, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-300, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 272, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 272, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-6X-5, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 273, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 273, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-12X-5, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 274, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 274, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-30X-1, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 428, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 428, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-5H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 429, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 429, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-7X-1, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 430, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 430, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-12X-7, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 431, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 431, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 260. In some embodiments, the chimeric protein is NA1-hIgG-12X-8, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chains each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 275, 277-290 and 434-437, and a third and a fourth polypeptide chains each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chains each independently having the amino acid sequence of any one of SEQ ID NOs: 275, 277-290, and 434-437, and a third and a fourth polypeptide chains each having the amino acid sequence of SEQ ID NO: 276.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 275, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 275, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-6H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 277, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 277, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-12H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 278, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 278, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-30H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 279, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 279, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-6K, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 280, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 280, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-12K, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 281, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 281, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-30K, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 282, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 282, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-6R, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 283, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 283, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-12R, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 284, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 284, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-30R, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 285, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 285, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-60, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 286, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 286, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-120, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 287, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 287, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-300, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 288, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 288, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-6X-6, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 289, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 289, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-12X-6, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 290, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 290, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-30X-1, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 434, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 434, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-5H, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 435, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 435, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-7X-1, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 436, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 436, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-12X-7, as described in Table 1.

In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 437, and a third and a fourth polypeptide chain each having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein comprises a first and a second polypeptide chain each independently having the amino acid sequence of SEQ ID NO: 437, and a third and a fourth polypeptide chain each having the amino acid sequence of SEQ ID NO: 276. In some embodiments, the chimeric protein is NA2-hIgG-12X-8, as described in Table 1.

Without being bound by any theory or hypothesis, influenza virus infection occurs mainly through respiratory droplets and possible airborne transmission. Upper respiratory surfaces are the dominant and initial sites for influenza virus infection. The nasal epithelium produces a physical glycoprotein barrier to inhaled particles including allergens and pathogens, preventing penetration to the epithelial surface of mucosal tissues. One major component of the mucosal layer of nasal and respiratory tract are mucins, a family of large glycoproteins that coat the surface of the respiratory epithelium. Mucins, the primary non-aqueous component of mucus, are a complex and heterogeneous structure, which carry a highly negative charge. The inventors of the present application, in some embodiments, engineered a tail comprising at least 5 positively charged amino acids (e.g., lysines, histidines, arginines, ornithines, or combinations thereof) which, when covalently linked to an antibody or antibody moiety, confers to the conjugate (i.e., chimeric protein) positive charges. The antibody with its positively charged tail can form a layer of influenza-binding antibody that can line the nasal/respiratory tract and prevent the virus from binding to the viral receptor-expressing epithelial cells. A positively charged antibody could also bind the phospholipid bilayer of cell membranes, also negatively charged. This “sticky” property of polymeric positively charged amino acid chain imparts to the antibody a longer half-life in the respiratory mucosal epithelium, providing a lengthened period of protection. Therefore, the engineered antibody-mucoadhesive polymer conjugate can function as a neutralizing antibody, which can block influenza viral entry into the cells of the respiratory cavity, even if the virus might penetrate the mucosal barrier and reach viral receptor-positive epithelial cells. In other embodiments, the positively charged mucoadhesive amino acids can be interspersed with non-positively charged amino acids without disrupting the mucoadhesive properties of the chimeric protein. Furthermore, the chimeric protein may be expressed as a fusion protein, or the mucoadhesive peptide fragment may be chemically conjugated to antibodies.

The different aspects and embodiments are discussed in various sections below in further detail.

A. Anti-Influenza Antibody Moieties

The chimeric proteins described herein comprise an antibody moiety that specifically binds to a component of an influenza virus (including influenza virus variants), e.g., a HA or NA influenza viral surface protein. Contemplated antibody moieties include, for example, scFv, Fab, Fc fusion protein (e.g., scFv-Fc), full-length antibodies, and multi-specific antibodies.

In some embodiments, the antibody moiety comprises one or more (e.g., 2, 3, 4 or more) polypeptide chains. These one or more polypeptide chains may be bound together, for example, via a disulfide bond (i.e., S—S bond) or multimerization domains.

In some embodiments, the antibody moiety is a full-length antibody or any suitable antigen binding fragments thereof. In some embodiments, the antibody moiety is a full-length antibody. In some embodiments, the antibody moiety is selected from the group consisting of an IgG, an IgA, an IgM, and an IgD. In some embodiments, the antibody moiety is an antigen-binding fragment selected from the group consisting of a Fab, a Fab′, a (Fab′)₂, an Fv, a single chain Fv (scFv), an scFv-Fc, a disulfide stabilized Fv fragment (dsFv), a (dsFv)₂, an scFv dimer, a domain antibody, a camelized single domain antibody, a bivalent domain antibody, a minibody, and a V_HH. In some embodiments, the antibody moiety is an animal, human, humanized, camelid, or chimeric antibody or an antigen-binding fragment thereof.

In some embodiments, the antibody moiety comprises a scFv. In some embodiments, the antibody moiety is a scFv. In some embodiments, the antibody moiety is a scFv-Fc fusion protein. In some embodiments, the antibody moiety is a scFv-CH₃ fusion protein. In some embodiments, the scFv comprises a V_H fused to a V_L via a flexible peptide linker, such as (GGGS)_n, or similar peptides disclosed in Table 9, SEQ ID NOs: 343-348. In some embodiments, the scFv comprises a V_L fused to a V_H via a peptide linker.

In humans, IgA is the major antibody isotype secreted in the upper airways; its presence there correlates with resistance to infection by some respiratory viruses, such as influenza viruses or variants thereof. Antibody delivery to the upper airway mucosal surface, mimicking naturally secreted antibody, can prevent virus from reaching its target or directly neutralize infectious virus, and may prove a very useful strategy for prophylaxis. Indeed, antibodies have been shown to provide protection of the respiratory tract from viral infection when given prophylactically. IgA antibodies have a unique structure and glycosylation pattern that enables binding to mucin molecules in the airway epithelium, resulting in extension of their half-lives in the mucosa. While secretory IgA antibodies are more efficient than IgG antibodies in providing effective viral protection, IgG antibodies have a well-established modality for large-scale manufacturing and characterization, both of which are essential for providing an affordable and scalable source of antibodies for a prophylactic approach.

In some embodiments, the antibody moiety comprises a purification tag, e.g., a His tag, such as DYKDDDDKHHHHHH (Flag-His(6), SEQ ID NO: 342).

In some embodiments, the influenza virus or variant thereof causes respiratory infections.

The component of the influenza virus or variant thereof can be a protein-based molecule, or a non-protein-based molecule (e.g., oligosaccharide). In some embodiments, the component is a glycoprotein.

The component of the influenza virus or variant thereof may be a surface molecule on the influenza virus. For example, the component may be a glycoprotein on the surface of the influenza virus. In some embodiments, the component is a capsid protein, an envelope protein, or a viral membrane fusion protein. In some embodiments, the component is a lipopolysaccharide (LPS). In some embodiments, the component is a viral surface protein or fragment thereof. In some embodiments, the viral surface protein is I-A. In some embodiments, the viral surface protein is NA.

Exemplary influenza viruses and antibody moieties are further described below.

Influenza

The chimeric proteins of the present invention comprise an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof.

In some embodiments, the influenza virus is a Type A influenza virus (IAV), a Type B influenza virus (IBV), a Type C influenza virus (ICV), a Type D influenza virus (IDV), or a variant, subtype, or reassortant thereof. In some embodiments, the influenza virus comprises a HA antigen, such as an HA antigen selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof. In some embodiments, the influenza virus comprises a NA antigen, such as an NA antigen selected from the group consisting of N1, N2, N3, N7, N8, and N9, or a variant or reassortant thereof. In some embodiments, the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof.

In some embodiments, the antibody moiety specifically binds to a component, e.g., HA protein or NA protein, on the surface of an influenza virus or a variant thereof. In some embodiment, the antibody moiety is derived from a subneutralizing or non-neutralizing antibody for a virulent influenza virus or variant thereof.

Influenza viruses are a group of related, yet antigenically and genetically diverse viruses that cause diseases in mammals and birds. In humans, influenza viruses cause respiratory tract infections that can range from mild to lethal. The most common symptoms include: a sudden onset of fever, cough (usually dry), headache, muscle and joint pain, severe malaise (feeling unwell), sore throat and a runny nose. The incubation period of influenza varies between one to four days, with symptoms appearing about two days following exposure to the influenza virus. Complications of influenza viruses can cause pneumonia (either direct viral pneumonia or secondary bacterial pneumonia) and bronchitis (either direct viral bronchitis or secondary bacterial bronchitis).

There are four type of influenza viruses: types A (IAV), B (IBV), C (ICV), and D (IDV). Of the four types of influenza virus, three types (A, B and C) affect humans. Influenza type A viruses, also referred to herein as “influenza A” are the most virulent human pathogens and cause the most severe disease. Influenza A viruses can be categorized based on the different subtypes of major viral surface proteins present, HA and NA. At present, there are 18 different HAs and 11 different NAs present among various influenza A viral strains, resulting in various subtype or strain combinations of the viral surface proteins (e.g., H1N1, H5N1). Type B influenza virus does not usually cause as severe disease as does type A influenza virus, and is more commonly seen in children, long-term care facilities, college campuses, and military camps. Influenza C virus generally causes a mild respiratory illness.

Influenza A and B viruses continuously evolve, generating new variants, a phenomenon known as antigenic drift. Consequently, antibodies produced in response to past viruses may be poorly- or non-protective against new drifted viruses. Therefore, a new vaccine may need to be produced every year against viruses that are predicted to emerge. Tables 2A and 2B show exemplary influenza A (Table 2A) and influenza B (Table 2B) antigens from the 2019 flu season. Table 3 shows exemplary influenza antigens from various flu seasons.

TABLE 2A
Exemplary influenza A HA and NA antigens from the 2019 flu season
		SEQ
Name;		ID
Antigen	Sequence	NO
>QHA30968A/	MKTIIALSCILCLVFAQKIPGNDNSTATLCLGHHAVPNGTIVKTITDDRIEVTN	326
Yokosuka/	ATELVQNSSIGEICDSPHQILDGENCTLIDALLGDPQCDGFQNKKWDLFVERN
NHRC_OID_FD	KAYSNCYPYDVPDYASLRSLVASSGTLEFNNESFNWAGVTQNGTSSSCIRGS
X70722/2019	KSSFFSRLNWLTHLNSKYPALNVTMPNNEQFDKLYIWGVHHPGTDKDQISLY
2019/04/17	AQSSGRITVSTKRSQQAVIPNIGSRPRIRDIPSRISIYWTIVKPGDILLINSTGNLI
HA	APRGYFKIRSGKSSIMRSDAPIGKCKSECITPNGSIPNDKPFQNVNRITYGACP
	RYVKQSTLKLATGMRNVPERQTRGIFGAIAGFIENGWEGLVDGWYGFRHQN
	SEGRGQAADLKSTQAAIDQINGKLNRLIGKTNEKFHQIEKEFSEVEGRIQDLE
	KYVEDTKIDLWSYNAELLVALENQHTIDLTDSEMNKLFEKTKKQLRENAED
	MGNGCFKIYHKCDNACMGSIRNGTYDHNVYRDEALNNRFQIKGVELKSGY
	KDWILWISFAISCFLLCVVLLGFIMWACQKGNIRCNICI
>QHA30980A/	MNPNQKIITIGSICMTIGMANLILQIGNIISIWVSHSIQIGNQSQIETCNKSVITYE	327
Yokosuka/	NNTWVNQTYVNISNTNSAARQSVASVKLAGNSSLCPVSGWAIYSKDNSVRI
NHRC_OID_FD	GSKGDVFVIREPFISCSPLECRTFFLTQGALLNDKHSNGTIKDRSPYRTLMSCPI
X70778/2019	GEVPSPYNSRFESVAWSASACHDGTNWLTIGVSGPDSGAVAVLKYNGIITDTI
2019/05/30	KSWRNNILRTQESECACVNGSCFTIMTDGPSDGQASYKIFRIEKGKIIKSVEM
NA	KAPNYHYEECSCYPDSSEITCVCRDNWHGSNRPWVSFNQNLEYQMGYICSG
	VFGDNPRPNDKTGSCGPVSSNGANGVKGFAFKYGNGVWIGRTKSISSRKGFE
	MIWDPNGWTGTDNKFSKKQDIVGINEWSGYSGSFVQHPELTGLNCIRPCFW
	VELIRGRPEENTIWTSGSSISFCGVDSDIVGWSWPDGAELPFTIDK
>QFG38740A/	VFAQKIPGNDNSTATLCLGHHAVPNGTIVKTITNDRIEVTNATELVQNSSIGEI	328
Thailand/	CDSPHLILDGKNCTLIDALLGDPQCDGFQNKKWDLFVERSKAYSNCYPYDVP
TM-5434_51/	DYASLRSLVASSGTLEFNNESFNWTGVKQNGTSSACIRKSSSSFFSRLNWLTH
2019	LNYTYPALNVTMPNNEQFDKLYIWGVHHPGTDKDQIFLYAQSSGRITVSTKR
2019/04/01	SQQTVIPNIGSRPRIRDIPSRISIYWTIVKPGDILLINSTGNLIAPRGYFKIQSGKS
HA	SIMRSDAPIGKCKSECITPNGSIPNDKPFQNVNRITYGTCPRYVKHSTLKLATG
	MRNVPEKQTRGIFGAIAGFIENGWEGMVDGWYGFRHQNSEGRGQAADLKS
	TQAAIDQINGKLNRLIGKTNEKFHQIEKEFSEVEGRIQDLEKYVEDTKIDLWS
	YNAELLVALENQHTIDLTDSEMNKLFEKTKKQLRENAEDMGNGCFKIYHKC
	DNACIGSIRNGTYDHNVYRDEALNNRFQIKGVELKSGYKDWILWISFAISCFL
	LCVALLGFIMWACQKGN
>QFP41505A/	SLTISTICFFMQIAILITTVTLHFKQYEFNSPPNNQVMLCEPTIIERNITEIVYLTN	329
Thailand/	TTIEKEICLKPAEYRNWSKPQCGITGFAPFSKDNSIRLSAGGDIWVTREPYVSC
TM-5434_51/	DPDKCYQFALGQGTTLNNVHSNNTVRDRTPYRTLLMNELGVPFHLGTKQVC
2019	MAWSSSSCHDGKAWLHVCITGDDKNATASFIYNGRLVDSVVSWSKDILRTQ
2019/04/01	ESECVCINGTCTVVMTDGNATGKADTKILFIEEGKIVHTSKLSGSAQHVEECS
NA	CYPRYPGVRCVCRDNWKGSNRPIVDINIKDHSIVSSYVCSGLVGDTPRKSDSS
	SSSHCLNPNNEEGGHGVKGWAFDDGNDVWMGRTINETSRLGYETFKVVEG
	WSNSKSKLQINRQVIVDRGDRSGYSGIFSVEGKSCINRCFYVELIRGRKEETE
	VLWTSNSIVVFCGTSGTYGT
>QDC19555A/	MKTIIALSCILCLVFAQKIPGNDNSTATLCLGHHAVPNGTIVKTITNDRIEVTN	330
Germany/94	ATELVQNSSIGEICDSPHQILDGENCTLIDALLGDPQCDGFQNKKWDLFVERN
96/2019	KAYSNCYPYDVPDYASLRSLVASSGTLEFNNESFNWAGVTQNGTSSSCIRGS
2019/04/03	KSSFFSRLNWLTHLNSKYPALNVTMPNNEQFDKLYIWGVHHPGTDKDQTSL
HA	YAQSSGRITVSTKRSQQAVIPNIGSRPRIRDIPSRISIYWTIVKPGDILLINSTGNL
	IAPRGYFKIRSGKSSIMKSDAPIGKCKSECITPNGSIPNDKPFQNVNRITYGACP
	RYVKQSTLKLATGMRNVPEKQTRGIFGAIAGFIENGWEGLVDGWYGFRHQN
	SEGRGQAADLKSTQAAIDQINGKLNRLIGKTNEKFHQIEKEFSEVEGRIQDLE
	KYVEDTKIDLWSYNAELLVALENQHTIDLTDSEMNKLFEKTKKQLRENAED
	MGNGCFKIYHKCDNACMGSIRNGTYDHNVYRDEALNNRFQIKGVELKSGY
	KDWILWISFAISCFLLCVVLLGFIMWACQKGNIRCNICI
>QDC19627A/	MNPNQKIITISSVSLTISTICFFMQIAILITTVTLHFKQYEFNPPPNNQVMLCEPT	331
Germany/94	HIERNITEIVYLTNTTIEREICPKPAEYRNWSKPQCGITGFAPFSKDNSIRLSAGG
96/2019	DIWVTREPYVSCDPDKCYQFALGQGTTINNVHSNNTARDRTPHRTLLMSELG
2019/04/03	VPFHLGTKQVCIAWSSSSCHDGKAWLHVCITGDDKNATASFIYNGRLVDSV
NA	VSWSKDILRTQESECVCINGTCTVVMTDGNATGKADTKILFIEEGKIVHTSKL
	SGSAQHVEECSCYPRYPGVRCVCRDNWKGSNRPIVDINIKDHSIVSSYVCSGL
	VGDTPRKTDSSSSSHCLNPNNEKGGHGVKGWAFDDGNDVWMGRTINETSR
	LGYETFKVVEGWSNSKSKLQINRQVIVDRGDRSGYSGIFSVEGKSCINRCFYV
	ELIRGRKEETEVLWTSNSIVVFCGTSGTYGTGSWPDGADLNLMHI
>QIA57890A/	MNPNQKIITIGSICMTIGTANLILQIGNIISIWVSHSIQIGNQSQIETCNKSVITYE	332
Delaware/	NNTWVNQTFVNISNTNSAARQSVASVKLAGNSSLCPVSGWAIYSKDNSVRIG
55/2019	SKGDVFVIREPFISCSPLECRTFFLTQGALLNDKHSNGTIKDRSPYRTLMSCPIG
2019/12/11	EVPSPYNSRFESVAWSASACHDGTNWLTIGISGPDSGAVAVLKYNGIITDTIK
NA	SWRNKILRTQESECACVNGSCFTIMTDGPSDGQASYKIFRIEKGKIIKSVEMK
	APNYHYEECSCYPDSSEITCVCRDNWHGSNRPWVSFNQNLEYQMGYICSGV
	FGDNPRPNDKTGSCGPVSSNGANGVKGFSFKYGNGVWIGRTKSISSRKGFEM
	IWDPNGWTGTDNKFSKKQDIVGINEWSGYSGSFVQHPELTGLNCIRPCFWVE
	LIRGRPEENTIWTSGSSISFCGVDSDIVGWSWPDGAELPFTIDK
>QIA57903A/	MNPNQKIITIGSICMTIGMANLILQIGNIISIWVSHSIQTGNQSQIETCNKNVITY	333
Delaware/	ENNTWVNQTYVNISNTNSAARQSVASVKLAGNSSLCPVSGWAIYSKDNSVRI
56/2019	GSKGDVFVIREPFISCSPLECRTFFLTQGALLNDKHSNGTIKDRSPYRTLMSCPI
2019/12/12	GEVPSPYNSRFESVAWSASACHDGTNWLTIGISGPDSGAVAVLKYNGIITDTI
NA	KSWRNNILRTQESECACVNGSCFTMMTDGPSDGQASYKIFRIEKGKIIKSVEM
	KAPNYHYEECSCYPDSSEITCVCRDNWHGSNRPWVSFNQNLEYQMGYICSG
	VFGDNPRPNDKTGSCGPVSSNGANGVKGFSFKYGNGVWIGRTKSISSRKGFE
	MIWDPNGWTGTDNKFSKKQDIVGINEWSGYSGSFVQHPELTGLNCIRPCFW
	VELIRGRPEENTIWTSGSSISFCGVDSDIVGWSWPDGAELPFTIDK

TABLE 2B
Exemplary influenza B HA and NA antigens from the 2019 flu season
		SEQ
Name;		ID
Antigen	Sequence	NO
>QJA11920B/	MKAIIVLLMVVTSNADRICTGITSSNSPHVVKTATQGEVNVTGVIPLTTTPTKS	334
Alabama/07/	HFANLKGTETRGKLCPKCLNCTDLDVALGRPKCTGKIPSARVSILHEVRPVTS
2020	GCFPIMHDRTKIRQLPNLLRGYEHVRLSTHNVINAEGAPGGPYKIGTSGSCPNI
2020/02/21	TNGNGFFATMAWAVPDKNKTATNPLTIEVPYVCTEGEDQITVWGFHSDNET
HA	QMAKLYGDSKPQKFTSSANGVTTHYVSQIGGFPNQTEDGGLPQSGRIVVDY
	MVQKSGKTGTITYQRGILLPQKVWCAXGRSKVIKGSLPLIGEADCLHEKYGG
	LNKSKPYYTGEHAKAIGNCPIWVKTPLKLANGTKYRPPAKLLKERGFFGAIA
	GFLEGGWEGMIAGWHGYTSHGAHGVAVAADLKSTQEAINKITKNLNSLSEL
	EVKNLQRLSGAMDELHNEILELDEKVDDLRADTISSQIELAVLLSNEGIINSED
	EHLLALERKLKKMLGPSAVEIGNGCFETKHKCNQTCLDKIAAGTFDAGEFSL
	PTFDSLNITAASLNDDGLDNHTILLYYSTAASSLAVTLMIAIFVVYMVSRDNV
	SCSICL
>QJA11911B/	MLPSTIQTLTLFLTSGGVLLSLYVSASLSYLLYSDILLKFSPTEITAPTMPLDCA	335
Alabama/07/	NASNVQAVNRSATKGVILLLPEPEWTYPRLSCPGSTFQKALLISPHRFGETKG
2020	NSAPLIIREPFVACGPNECKHEALTHYAAQPGGYYNGTRGDRNKLRHLISVK
2020/02/21	LGKIPTVENSIFHMAAWSGSACHDGKEWTYIGVDGPDNNALLKIKYGEAYT
NA	DTYHSYANNILRTQESACNCIGGNCYLMITDGSXSGVSECRFLKIREGRIIKEI
	FPTGRVKHTEECTCGFASNKTIECACRDNRYTAKRPFVKLNVETDTAEIRLM
	CTDTYLDTPRPNDGSITGPCESDGDKGSGGIKGGFVHQRMKSKIGRWYSRTM
	SQTERMGMGLYVKYGGDPWADSDALAFSGVMVSMKEPGWYSFGFEIKDK
	KCDVPCIGIEMVHDGGKETWHSAATAIYCLMGSGQLLWDTVTGVDMAL
>QGT76054B/	MKAIIVLLMVVTSNADRICTGITSSNSPHVVKTATQGEVNVTGVIPLTTTPTKS	336
China/b45/	HFANLKGTETRGKLCPKCLNCTDLDVALGRPKCTGKIPSARVSILHEVRPVTS
2019 2019/	GCFPIMHDRTKIRQLPNLLRGYEHVRLSTHNVINAEDAPGGPYKIGTSGSCPNI
01/08	TNGNGFFATMAWAVPKNDKNKTATNPLTIEVPYICTEGEDQITVWGFHSDN
HA	ETQMAKLYGDSKPQKFTSSANGVTTHYVSQIGGFPNQTEDGGLPQSGRIVVD
	YMVQKSGKTGTITYQRGILLPQKVWCASGRSKVIKGSLPLIGEADCLHEKYG
	GLNKSKPYYTGEHAKAIGNCPIWVKTPLKLANGTKYRPPAKLLKERGFFGAI
	AGFLEGGWEGMIAGWHGYTSHGAHGIAVAADLKSTQEAINKITKNLNSLSE
	LEVKNLQRLSGAMDELHNEILELDEKVDDLRADTISSQIELAVLLSNEGIINSE
	DEHLLALERKLKKMLGPSAVEIGNGCFETKHKCNQTCLDRIAAGTFDAGEFS
	LPTFDSLNITAASLNDDGLDNHTILLYYSTAASSLAVTLMIAIFVVYMVSRDN
	VSCSICL
>QGT76183B/	MLPSTIQTLTLFLTSGGVLLSLYVSASLSYLLYSDILLKFSPTEITAPTMPLDCA	337
China/b45/	NASNVQAVNRSATKGATLLLPEPEWTYPRLSCPGSTFQKALLISPHRFGETKG
2019 2019/	NSAPLIIREPFVACGPNECKHEALTHYAAQPGGYYNGTRGDRNKLRHLISVK
01/08	LGKIPTVENSIFHMAAWSGSACHDGKEWTYIGVDGPDNNALLKVKYGEAYT
NA	DTYHSYANNILRTQESACNCIGGNCYLMITDGSASGVSECRFLKIREGRIIKEI
	FPTGRVKHTEECTCGFASNKTIECACRDNRYTAKRPFVKLNVETDTAEIRLM
	CTDTYLDTPRPNDGSITGPCESDGDEGSGGIKGGFVHQRMKSKIGRWYSRTM
	SKTERMGMGLYVKYGGDPWADSDALVFSGVMISMKEPGWYSFGFEIKDKK
	CDVPCIGIEMVHDGGKETWHSAATAIYCLMGSGQLLWDTVTGVDMAL
>QDX11011B/	MKAIIVLLMVVTSNADRICTGITSSNSPHVVKTATQGEVNVTGVIPLTTTPTKS	338
Japan/9830/	HFANLKGTETRGKLCPKCLNCTDLDVALGRPKCTGKIPSARVSILHEVRPVTS
2019 2019/	GCFPIMHDRTKIRQLPNILRGYEHVRLSTHNVINAEDAPGRPYEIGTSGSCPNI
05/22	TNGNGFFATMAWAVPKNKTATNPLTIEVPYICTEGEDQITVWGFHSDNETQ
HA	MAKLYGDSKPQKFTSSANGVTTHYVSQIGGFPNQTEDGGLPQSGRIVVDYM
	VQKSGKTGTITYQRGILLPQKVWCASGRSKVIKGSLPLIGEADCLHEKYGGL
	NKSKPYYTGEHAKAIGNCPIWVKTPLKLANGTKYRPPAKLLKERGFFGAIAG
	FLEGGWEGMIAGWHGYTSHGAHGVAVAADLKSTQEAINKITKNLNSLSELE
	VKNLQRLSGAMDELHNEILELDEKVDDLRADTISSQIELAVLLSNEGIINSEDE
	HLLALERKLKKMLGPSAVEIGNGCFETKHKCNQTCLDRIAAGTFDAGEFSLP
	TFDSLNITAASLNDDGLDNHTILLYYSTAASSLAVTLMIAIFVVYMVSRDNVS
	CSICL
>QDX11015B/	MLPSTIQTLTLFLTSGGVLLSLYVSASLSYLLYSDILLKFSPTEITAPTMPLDCA	339
Japan/9830/	NASNVQAVNRSATKGVTLLLPEPEWTYPRLSCPGSTFQKALLISPHRFGETKG
2019 2019/	NSAPLIIREPFVACGPNECKHEALTHYAAQPGGYYNGTRGDRNKLRHLISVK
05/22	LGKIPTVENSIFHMAAWSGSACHDGKEWTYIGVDGPDNNALLKVKYGEAYT
NA	DTYHSYANNILRTQESACNCIGGNCYLMITDGSASGVSECRFLKIREGRIIKEI
	FPTGRVKHTEECTCGFASNKTIECACRDNKYTAKRPFVKLNVETDTAEIRLM
	CTDTYLDTPRPNDGSITGPCESDGDKGSGGIKGGFVHQRMKSKIGRWYSRTM
	SKTERMGMGLYVKYGGDPWADSDALTFSGVMVSMKEPGWYSFGFEIKDKK
	CDVPCIGIEMVHDGGKETWHSAATAIYCLMGSGQLLWDTVTGVDMAL
>QDA45896B/	MKAIIVLLMVVTSNADRICTGITSSNSPHVVKTATQGEVNVTGVIPLTTTPTKS	340
Moscow/2/	HFANLKGTETRGKLCPKCLNCTDLDVALGRPKCTGKIPSARVSILHEVKPVTS
2019 2019/	GCFPIMHDRTKIRQLPNLLRGYEHVRLSTHNVINAEGAPGGPYKIGTSGSCPNI
02/22	TNGNGFFATMAWAVPDKNKTATNPLTIEVPYICTEGEDQITVWGFHSDNETQ
HA	MAKLYGDSKPQKFTSSANGVTTHYVSQIGGFPNQTEDGGLPQSGRIVVDYM
	VQKSGKTGTITYQRGILLPQKVWCASGRSKVIKGSLPLIGEADCLHEKYGGL
	NKSKPYYTGEHAKAIGNCPIWVKTPLKLANGTKYRPPAKLLKERGFFGAIAG
	FLEGGWEGMIAGWHGYTSHGAHGVAVAADLKSTQEAINKITKNLNSLSELE
	VKNLQRLSGAMDELHNEILELDEKVDDLRADTISSQIELAVLLSNEGIINSEDE
	HLLALERKLKKMLGPSAVEIGNGCFETKHKCNQTCLDKIAAGTFDAGEFSLP
	TFDSLNITAASLNDDGLDNHTILLYYSTAASSLAVTLMIAIFVVYMVSRDNVS
	CSICL
>QDA45899B/	MLPSTIQTLTLFLTSGGVLLSLYVSASLSYLLYSDILLKFSPTEITAPTMPLDCA	341
Moscow/2/	NASNVQAVNRSATKGVTLLLPEPEWTYPRLSCPGSTFQKALLISPHRFGETKG
2019 2019/	NSAPLIIREPFVACGPNECKHEALTHYAAQPGGYYNGTRGDRNKLRHLISVK
02/22	LGKIPTVENSIFHMAAWSGSACHDGKEWTYIGVDGPDNNALLKVKYGEAYT
NA	DTYHSYANNILRTQESACNCIGGNCYLMITDGSASGVSECRFLKIREGRIIKEI
	FPTGRVKHTEECTCGFASNKTIECACRDNRYTAKRPFVKLNVETDTAEIRLM
	CTDTYLDTPRPNDGSITGPCESDGDKGSGGIKGGFVHQRMKSKIGRWYSRTM
	SKTERMGMGLYVKYGGDPWADSNALAFSGVMISMKEPGWYSFGFEIKDKK
	CDVPCIGIEMVHDGGKETWHSAATAIYCLMGSGQLLWDTVTGVDMAL

TABLE 3
Exemplary influenza A HA and NA antigens from various flu seasons
		SEQ
Name;		ID
Antigen	Sequence	NO
>AB745403.1/	AGSGIIISDTPVHDCNTTCQTPKGAINTSLPFQNIHPITIGKCPKYVKSTKLRLA	421
H1N1 A/	TGLRNVPSIQSRGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAADLK
Tottori/	STQNAIDKITNKVNSVIEKMNTQFTAVGKEFNHLEKRIENLNKKVDDGFLDI
YK041/2011	WTYNAELLVLLENERTLDYHDSNVKNLYEKVRNQLKNNAKEIGNGCFEFYH
	KCDNTCMESVKNGTYDYPKYSEEAKLNREEIDGVKLESTRIYQIL
>4058_A/H3A/	RTGKSSIMRSDAPIGTCSSECITPNGSIPNDKPFQNVNKITYGACPKYVKQNTL	427
(H3N2	KLATGMRNVPEKQTRGIFGAIAGFIENGWEGMIDGWYGFRHQNSEGTGQAA
Victoria/3/	DLKSTQAAIDQINGKLNRVIEKTNEKFHQIEKEFSEVEGRIQDLEKYVEDTKID
1975)	LWSYNAELLVALENQHTIDLTDSEMNKLFEKTRRQLRENAEDMGNGCFKIY
	HKCDNACIGSIRNGTYDHDVYRDEALNNRFQIKGVELKSGYKDWI
>O56140/H5	STIMKSELEYGNCNTKCQTPMGAINSSMPFHNIHPLTIGECPKYVKSNRLVLA	444
(H5N1 A/Hong	TGLRNTPQRERRRKKRGLFGAIAGFIEGGWQGMVDGWYGYHHSNEQGSGY
Kong/156/97)	AADKESTQKAIDGVTNKVNSIINKMNTQFEAVGREFNNLERRIENLNKKMED
	GFLDVWTYNAELLVLMENERTLDFHDSNVKNLYDKVRLQLRDNAKELGNG
	CFEFYHKCDNECMESVKNGTYDYPQYSEEARLNREEISGVKLESMGTYQIL
>ARM59253/	LSGESHGRILKTDLNSGNCVVQCQTEKGGLNSTLPFHNISKYAFGDCPKYIGV	495
H7 (H9N2 A/	KSLKLAIGLRNVPARSSRGLFGAIAGFIEGGWPGLVAGWYGFQHSNDQGVG
Egypt/ZU65/	MAADRDSTQKAVDKITSKVNNIVDKMNKQYEIIDHEFSEVETRLNMINNKID
2016)	DQIQDVWAYNAELLVLLENQKTLDEHDANVNNLYNKVKRALGSNAMEDG
	KGCFELYHKCDDQCMETIRNGTYNRRKYMEESRLGRQKIEGVKLESEGTYKIL

Exemplary antibodies against the HA antigen (e.g., human and animal HA antigen) of influenza virus are known in the art, including, for example, FI6V3, F045-092, mAb35490, KPF1, H1H14611N2, FluA-20, H5.28, H5.31, H7-200, 12mab, mAb14303, VIS410, FluAB_MLNS, D7, ATlO_004, CR8001, and CR9114 reported in U.S. Pat. Nos. 10,815,294, 9,605,053, 11,168,129, 11,230,593, 9,611,317, 9,718,874, US 2021/0171612, US 2021/0371505, US 2021/0252150, PCT/US2020/017889, PCT/CN2020/071524, PCT/EP2020/062160, CN111704665 and PCT/EP2012/063637 which are incorporated by reference in their entirety. Exemplary antibodies against the NA protein of influenza virus (e.g., in humans and animals) are also known in the art, including, for example, 1G05, 2E01, IF2, 1F4, 1092A9, 1092B6, 3C05, SEQ 42-43, SEQ 40-41, SEQ 44-45, 2D04, 1D05, 1G03, and 2B04, reported in U.S. Pat. No. 10,079,518, US 2021/0047389, US 2021/0002354, PCT/US2021/016879, and PCT/US2020/035323, which are incorporated by reference in their entirety. Exemplary human antibody sequences against HA and NA of various influenza viruses or variants thereof are shown in Tables 4A-4B, respectively. Exemplary animal anti-HA antibody sequences are shown in Table 6. Exemplary animal anti-NA antibodies targeting the NA protein of zoonotic IAV strain H7N9 have been published in the literature (D3 and 7H2, Xiong, et al., Emerging Microbes & Infections 9(1):78-87 (2020)). Additionally, a camelid antibody directed to another zoonotic strain, IAV H5N1 (N1-V_HH, Cardoso, et al. Journal of Virology, 88(15):8278-96 (2014)) has been described.

New antibodies may be developed against a component (e.g., antibodies against HA and NA antigens, such as human or animal HA and NA antigens) of an influenza virus or variant thereof using art-known techniques, and the variable region sequences of such antibodies, or a fragment thereof, may be used as the antibody moiety of a chimeric protein of the present disclosure. In some embodiments, the influenza virus is a known influenza virus. In some embodiments, the influenza virus is a variant of a known influenza virus. In some embodiments, the influenza virus is a future influenza virus. In some embodiments, the influenza virus is a variant of a future influenza virus.

In some embodiments, the antibody moiety is a derivative of any one of the antibodies against the HA or NA protein of an influenza virus or variant thereof described herein. In some embodiments, the antibodies that compete with any of these art-recognized antibodies for binding to the HA protein or NA of an influenza virus or variant thereof can be used.

HA is the main target of neutralizing antibodies that are induced by infection of an individual by an influenza virus or variant thereof or vaccination against an influenza virus or variant thereof. HA directs the binding the influenza virus to cells with sialic acid on the membranes, such as cells in the upper respiratory tract, e.g., cells of the nasal cavity, the larynx, trachea, bronchi or lung. In addition, HA is responsible for the fusion of the influenza viral envelope with the endosome membrane, allowing the capsid and viral genome to enter and infect the host.

HA is a homotrimeric integral membrane glycoprotein, composed of three identical monomers, each made of an intact HA0 single polypeptide chain comprising HA1 and HA2 regions linked by two disulfide bridges. Each HA2 region adopts an α-helical coiled coil structure and primarily forms the “stem” region of HA, while the HA1 region is a small globular domain comprising a combination of a/P structures (“head” region of HA). The globular HA head region facilitates binding to viral receptors expressed on host cells, which are typically sialic acid-containing glycoproteins, gangliosides, or glycolipid (“sialic acid receptors”), while the HA stem mediates the subsequent fusion between the viral and cellular membranes. While the highly variable and immunodominant HA globular head domain undergoes constant antigenic drift, the HA stem region is fairly conserved among influenza subtypes. Current influenza vaccines generally induce an immune response against the HA head region. (see, e.g., Kirkpatrick et al., Nat Sci Rep, 8:10432 (2018)). Therefore, a particular influenza vaccine usually confers protection for no more than a few years and annual re-development of influenza vaccines is required.

Recently, a new class of influenza-neutralizing antibodies that target conserved sites in the HA stem were developed as influenza virus therapeutics. These antibodies targeting the stem region of HA are usually broader neutralizing compared to antibodies targeting the head region of HA. An overview over broadly neutralizing influenza A antibodies is provided in Corti and Lanzavecchia, Annu Rev Immunol, 31:705-742 (2013).

The other major surface glycoprotein of influenza A and B viruses is NA, which is absent in influenza C virus. NA is a receptor-destroying enzyme that is responsible for cleaving terminal sialic acid residues from N-linked glycans present on cell surfaces and progeny virions. This activity is important for releasing incoming influenza viruses trapped by glycans of host natural defense proteins on mucosal surfaces, and for releasing of nascent influenza viruses budding from infected host cells. Anti-NA antibodies can block this cleavage activity by directly binding to the enzymatic active site of NA or by sterically hindering interactions between NA and its substrate.

NA is a homotetrameric transmembrane glycoprotein made of four identical subunits. NA protein is made of four main regions: a cytoplasmic tail domain, a hydrophobic transmembrane domain, a stalk region, and a globular head domain containing the enzyme active site. The structure of each NA individual subunit consists of six topologically identical 4-stranded antiparallel β-sheets arranged. The enzyme active site (19 amino acids) is located at the center of each subunit. The active site is a deep pocket made of amino acids that are highly conserved in all strains of influenza virus. Antibody-binding sites are located on the surface loops that surround the enzyme active site. Additional description of NA can be found in, for example, Jagadesh et al., Arch Virol, 161:2087-2094 (2016). As described above, influenza viruses can mutate the antigenic sites in HA (particularly in the HA stem region) at a high rate, whereas NA has been shown to exhibit a slower antigenic drift, resulting in a broader cross-reactivity of anti-NA antibodies compared with that of anti-HA antibodies.

In some embodiments, provided herein is a chimeric protein comprising an antibody or an antigen binding fragment thereof that binds an epitope on HA or NA on the surface of an influenza virus or variant thereof. In some embodiments, the antibody or an antigen binding fragment thereof binds an epitope on HA. In some embodiments, the HA epitope is from an HA antigen, such as an HA antigen of the HA1, HA2, HA3, HA4, HA5, HA6, HA7, HA8, HA9, HA10, HA11, HA12, HA13, HA14, HA15, HA16, HA17, or HA18 subtype, or a combination thereof. In some embodiments, the antibody or an antigen binding fragment thereof binds an epitope on two or more HA subtypes (e.g., HA1, HA2, HA3, HA4, HA5, HA6, HA7, HA8, HA9, HA10, HA1 l, HA12, HA13, HA14, HA15, HA16, HA17, HA18). In some embodiments, the antibody or an antigen binding fragment thereof binds an epitope on NA. In some embodiments, the NA epitope is from an NA antigen, such as an NA antigen of the N1, N2, N3, N4, N5, N6, N7, N8, N9, N10, or N11 subtype, or a combination thereof. In some embodiments, the antibody or an antigen binding fragment thereof binds an epitope on two or more NA types (e.g., N1, N2, N3, N4, N5, N6, N7, N8, N9, N10, N11). In some embodiments, the chimeric protein treats or prevents infection by two or more types of influenza virus, e.g., H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or variants or reassortants thereof.

Anti-HA and Anti-NA Antibodies and Antigen Binding Fragments Thereof

The present application provides chimeric proteins comprising antibodies or antigen binding fragments thereof that specifically bind to a HA or NA surface protein of an influenza virus (including influenza virus variants) (also referred to as “anti-HA or anti-NA antibodies”). The anti-HA and NA antibodies described herein can be of any suitable full-length antibody or antigen-binding fragment format. Any of the anti-HA or anti-NA antibodies or antigen binding fragments thereof may be used as the antibody moiety in a chimeric protein described herein, or the anti-HA or anti-NA antibody moiety in an anti-HA or anti-NA antibody construct described herein.

In some embodiments, the anti-HA or anti-NA antibody is a full-length antibody or an immunoglobulin derivative. In some embodiments, the anti-HA or anti-NA antibody is an IgG, an IgA, an IgD, an IgE, or an IgM. Full-length antibodies comprise two heavy chains and two light chains. IgG, IgA, and IgD's heavy chains each comprise V_H, CH₁, CH₂, and CH₃, while IgM and IgE's heavy chains each comprise the additional CH₄, with pairs of the CH₂CH₃ fragment or the CH₂CH₃CH₄ fragment forming the Fc domain. Light chains each comprise V_L and C_L. V_H and V_L pair up to form a variable region of an antibody, while CH₁ and C_L pair up as a part of the constant region of an antibody. The complete constant region of a full-length antibody comprises two CH₁—C_L pairs and one pair of the CH₂CH₃ fragment or the CH₂CH₃CH₄ fragment.

In some embodiments, the anti-HA or anti-NA antibody is an antigen-binding fragment, for example, an antigen-binding fragment selected from the group consisting of a Fab, a Fab′, a F(ab′)2, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv)₂, an scFv dimer, a domain antibody, a bivalent domain antibody, a single-chain Fv (scFv), a scFv-Fc fusion protein, and a minibody (i.e., a scFv-CH3 fusion protein). In some embodiments, the anti-HA or anti-NA antibody is a scFv. In some embodiments, the anti-HA or anti-NA antibody is a fusion protein comprising a scFv fused to an Fc region. In some embodiments, the anti-HA or anti-NA antibody is a fusion protein comprising a scFv fused to a CH₃ domain.

In some embodiments, the anti-HA or anti-NA antibody is chimeric, animal, human, partially humanized, fully humanized, or semi-synthetic. In some embodiments, the anti-HA or anti-NA antibody is a semi-synthetic antibody comprising fully human sequences and one or more synthetic regions. In some embodiments, the synthetic HC-CDR3 is from about 5 to about 19 (such as about n, where n is selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, and 19) amino acids in length. In some embodiments, the anti-HA or anti-NA antibody is a semi-synthetic antibody comprising human CDRs and non-human framework sequences. Non-human framework sequences include, in some embodiments, any sequence that can be used for generating synthetic heavy and/or light chain variable regions using one or more human CDR sequences as described herein, including, e.g., mammals, such as mouse, rat, rabbit, pig, bovine (e.g., cow, bull, buffalo), deer, sheep, goat, chicken, cat, dog, ferret, primate (e.g., marmoset, rhesus monkey), etc. In some embodiments, the anti-HA or anti-NA antibody is generated by grafting one or more human CDR sequences as described herein onto a non-human framework sequence (e.g., a mouse or chicken framework sequence).

The anti-HA or anti-NA antibody, in some embodiments, comprises specific sequences or certain variants of such sequences. In some embodiments, the amino acid substitutions in the variant sequences do not substantially reduce the ability of the anti-HA or anti-NA antibody to specifically recognize an HA protein or an NA protein, respectively, of an influenza virus or variant thereof. For example, alterations that do not substantially reduce HA or NA binding affinity may be made. Alterations that substantially improve HA or NA binding affinity or affect some other property, such as specificity and/or cross-reactivity with related variants of the HA or NA protein, are also contemplated.

Exemplary human antibody sequences are shown in Tables 4A-4B, and exemplary animal antibody sequences are shown in Table 6.

Exemplary Human Anti-HA Antibodies

In some embodiments, there is provided a chimeric protein comprising an anti-HA antibody or antigen binding fragment thereof (e.g., an anti-HA antibody moiety) that specifically binds to a human HA antigen. In some embodiments, the anti-HA antibody or antigen fragment thereof is a human anti-HA antibody or antigen fragment thereof.

Exemplary anti-HA antibodies are provided in Table 4A.

TABLE 4A
CDR and VH/VL sequences of exemplary human anti-HA antibodies
					SEQ
Antibody	Antibody	Target			ID
code	Name	strain	Sequence	Type	NO
HA1	FI6V3	IAV	QVQLVESGGGVVQPGRSLRLSCAASGFTFS	VH	76
Reference:		group 1	TYAMHWVRQAPGKGLEWVAVISYDANY
WO2013011347		and 2: H1,	KYYADSVKGRFTISRDNSKNTLYLQMNSL
		H5, H9,	RAEDTAVYYCAKDSQLRSLLYFEWLSQGY
		H3, H7	FDYWGQGTLVTVSS
		IAV	DIVMTQSPDSLAVSLGERATINCKSSQSVT	VL	77
		group 1:	FNYKNYLAWYQQKPGQPPKLLIYWASTRE
		H1, H5,	SGVPDRFSGSGSGTDFTLTISSLQAEDVAV
		H9	YYCQQHYRTPPTFGQGTKVEIK
		IAV	GFTFSTYA	HC-CDR1	1
		group 2:	ISYDANYK	HC-CDR2	2
		H3, H7	AKDSQLRSLLYFEWLSQGYFDY	HC-CDR3	3
			QSVTFNYKNY	LC-CDR1	4
			WAS	LC-CDR2
			QQHYRTPPT	LC-CDR3	6
HA2	F045-092	IAV	EVQLVESGAEVKKPGSSVKVSCRASGTFY	VH	78
Reference:		group 1:	KYAINWVRQAPGQGLEWMGGIIPFFGTTN
WO2012029997		H1, H3	YAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYY
			GLDVWGQGTTVTVSS
			QSVLTQPPSASGTPGQSVTISCSGSRSNIGG	VL	79
			NTVNWYQHLPGMAPKLLIYSSNQRSSGVP
			DRFSGSKSGTSASLAISGLQSEDDADYYCA
			SWDDSLNGVVFGGGTKLTVLG
			KYAIN	HC-CDR1	7
			GIIPFFGTTNYAQKFQG	HC-CDR2	8
			PSITESHYCLDCAAKDYYYGLDV	HC-CDR3	9
			SGSRSNIGGNTVN	LC-CDR1	235
			SSNQRSS	LC-CDR2	238
			ASWDDSLNG	LC-CDR3	415
HA3	mAb35490	IBV	EVQLVESGGDLVQPGGSLRLSCAASGFTVS	VH	80
Reference:			SNYMSWVRQVPGKGLDWVSVTYSGGNTY
WO2021086899			YADSVKGRFTISRHNSKNTLYLQMNSLRIE
			DTAVYYCATVPSFHGMDVWGQGTTVTVS
			S
			DIQMTQSPSSLSASVGDRVTITCRASQSISS	VL	81
			YLNWYQQKPGKAPKLLIYAASSLQSGVPS
			RFSGSGSGTDFTLTISSLQPEDFATYYCQQS
			YSTPPITFGQGTRLEIK
			GFTVSSNY	HC-CDR1	10
			TYSGGNT	HC-CDR2	11
			ATVPSFHGMDV	HC-CDR3	12
			QSISSY	LC-CDR1	13
			AAS	LC-CDR2
			QQSYSTPPIT	LC-CDR3	15
HA4	KPF1	IAV	EVQLLESGGGLVQPGGSLRISCAASGSTFG	VH	82
Reference:		group 1:	DFAMSWVRQSPGRGLEWVSVTSAGGDRT
WO2018213097		H1	YYADSVKGRFTISRDNSKNTLYLQMNSLR
			GEDTAMYYCARLDSSGFHYGRPGRNWGQ
			GTLVTVSS
			DIQMTHSPPSLSASVGDRITITCQASQDISY	VL	83
			YLIWYQQKPGKAPKPLIYDASNLEAGVPSR
			FSASGSGTDFTLTISSLQPEDLATYYCQQY
			KSLPYTFGQGTKLEIK
			GSTFGDFA	HC-CDR1	16
			TSAGGDRT	HC-CDR2	17
			ARLDSSGFHYGRPGRN	HC-CDR3	18
			QDISYY	LC-CDR1	19
			DAS	LC-CDR2
			QQYKSLPYT	LC-CDR3	21
HA5	H1H14611	IAV	EVQLVESGGGLVKPGGSLRLSCAASGFTFS	VH	84
Reference:	N2	group 2:	GFSMNWVRQVPGKGLEWVSSISTSGNYM
WO2019147867		H3, H4,	YYADSVKGRFTISRDNAKKSFSLQMNSLR
		H10, H14,	AEDSAIYYCARGGGYNWNLFDYWGQGSL
		H15	VTVSS
			EIVLTQSPGTLSLSPGERATLSCRASQSLNS	VL	85
			NYLAWYQQKPGQAPRLLIYGASSRATGIP
			DRFSGSGSGTDFTLTITRLESEDFAVYYCQ
			QYGNSPLTFGGGTKVEIK
			GFTFSGFS	HC-CDR1	22
			ISTSGNYM	HC-CDR2	23
			ARGGGYNWNLFDY	HC-CDR3	24
			QSLNSNY	LC-CDR1	25
			GAS	LC-CDR2
			QQYGNSPLT	LC-CDR3	27
HA6	FluA-20	Pan IAV	QVQLQESGPGLVKPSETLSLTCSVSGVSVT	VH	86
Reference:			SDIYYWTWIRQPPGKGLEWIGYIFYNGDTN
WO2020041540			YNPSLKSRVTMSIDTSKNEFSLRLTSVTAA
			DTAVYFCARGTEDLGYCSSGSCPNHWGQ
			GTLVTVSS
			DIQMTQSPSSLSASIGDRVTITCRPSQNIRSF	VL	87
			LNWFQHKPGKAPKLLIYAASNLQSGVPSR
			FSGSGSGTEFTLTIRSLQPEDFATYYCQQSY
			NTPPTFGQGTKVEIK
			GVSVTSDIYY	HC-CDR1	28
			IFYNGDT	HC-CDR2	29
			ARGTEDLGYCSSGSCPNH	HC-CDR3	30
			QNIRSF	LC-CDR1	31
			AAS	LC-CDR2
			QQSYNTPPT	LC-CDR3	33
HA7	H5.28	Pan IAV	EVQLVESGGGLVQPGGSLRLSCAASGFTFS	VH	88
Reference:			TYWMTWVRQAPGKGLEWVANINQDGGE
WO2020041540			KYFVDSVKGRFTISRDNAKNSLFLQMNTL
			RAEDTAVYYCARGFLERLLLGRQGAYYY
			GMDVWGQGTTVTVSS
			DIQMTQSPSSLSASVGDRVSMTCRASQIISS	VL	89
			SLNWYQQKPGKAPKLLIYAASNLQSGVPS
			RFSGSGSGTDFTLTISSLQPEDFATYYCQQS
			YSTPPELTFGGGTKVEIK
			GFTFSTYW	HC-CDR1	34
			INQDGGEK	HC-CDR2	35
			ARGFLERLLLGRQGAYYYGMDV	HC-CDR3	36
			QIISSS	LC-CDR1	37
			AAS	LC-CDR2
			QQSYSTPPELT	LC-CDR3	39
HA8	H5.31	Pan IAV	EVQLVQSGGGLVQPGGSLRLSCEASRFTSS	VH	90
Reference:			SYWITWVRQAPGKGLEWVANIKQDGSEK
WO2020041540			YFVDSVKGRFTISRDNASNSLYLQMSSLRA
			EDTAVYYCARGFLERLLLGRQGAYYYGM
			DVWGQGTTVTVSS
			DIQMTQSPSSLSASVGDRVTMTCRASQSIS	VL	91
			SSLNWYQQKPGKAPKLLIYAASNLQSGVP
			SRFSGSGSGTDFTLTISSLQPEDFATYYCQQ
			SYTMPPELTFGGGTKVQIK
			RFTSSSYW	HC-CDR1	40
			IKQDGSEK	HC-CDR2	41
			ARGFLERLLLGRQGAYYYGMDV	HC-CDR3	42
			QSISSS	LC-CDR1	43
			AAS	LC-CDR2
			QQSYTMPPELT	LC-CDR3	45
HA9	H7-200	Pan IAV	QVQLVESGPGLVKPSQTLSLTCTVSGGSIN	VH	92
Reference:			SSHSFWSWIRQPAGKGLEWIGRIYSTGNSN
WO2020041540			YNPSLKSRVTISLDTSKNQFSLKLSSVTAA
			DTAVYYCARESLWNPDYYYYMDVWGKG
			TLVTVSS
			DIVMTQSPSSLSASVGDRVTITCRASQSFSS	VL	93
			HLNWYQQKPGRAPDLLIYAASSLHSGVPS
			RFSGSGSGTDFTLTISSLQPEDFAVYYCQQS
			YSVPYTFGQGTKLQIK
			GGSINSSHSF	HC-CDR1	46
			IYSTGNS	HC-CDR2	47
			ARESLWNPDYYYYMDV	HC-CDR3	48
			QSFSSH	LC-CDR1	49
			AAS	LC-CDR2
			QQSYSVPYT	LC-CDR3	51
HA10	12mab	IAV	EVQLVESGGGLVQPGGSLRLSCAASGFTFS	VH	94
Reference:		group 1:	TYNMNWVRQAPGKGLEWLSYISTSSNTIY
WO2020143799		H1	YADSVKGRFTISRDNAKNSLFLQMNSLRD
		IAV	EDTAVYYCARDRGCSSTNCYVVGYYFYG
		group 2:	MDVWGQGTTVTVSS
		H3, H4,	DIQMTQSPSSVSASVGDRVTITCRASQGISS	VL	95
		H7, H10,	YLAWYQLKPGRAPKLLIYGATRLQSGVPS
		H14, H15	RFSGSGSGTDFTLTISGLQPEDFATYHCQQ
			ADSFPLTFGQGTRLEIK
			GFTFSTYN	HC-CDR1	52
			ISTSSNTI	HC-CDR2	53
			ARDRGCSSTNCYVVGYYFYGMDV	HC-CDR3	54
			QGISSY	LC-CDR1	55
			GAT	LC-CDR2
			QQADSFPLT	LC-CDR3	57
HA11	mAb14303	IAV H1	QVHLVQSGPEVKKPGSSVKVSCKASGVTFI	VH	96
Reference:			SHAISWVRQAPGQGLEWVGGIIAIFGTTNY
WO2020167919			AQKFQGRVTVTTDKSTNTVYMELSRLRSE
			DTAIYYCARGETYYEGNFDFWGQGTLVTV
			SS
			DIQMTQSPSSLSASVGDRVTITCRASQSISS	VL	97
			YLNWYQQKPGKAPKLLIYAASSLQSGVPS
			RFSGSGSGTDFTLTISSLQPEDFATYYCQQS
			YSTPPITFGQGTRLEIK
			GVTFISHA	HC-CDR1	58
			IIAIFGTT	HC-CDR2	59
			ARGETYYEGNFDF	HC-CDR3	60
			QSISSY	LC-CDR1	61
			AAS	LC-CDR2
			QQSYSTPPIT	LC-CDR3	63
HA12	VIS410	IAV:	QVQLLETGGGLVKPGQSLKLSCAASGFTFT	VH	98
Reference:		H1N1,	SYAMHWVRQPPGKGLEWVAVVSYDGNY
WO2020198329		H1N2,	KYYADSVQGRFTISRDNSKNTLYLQMNSL
		H2N2,	RAEDTAVYYCAKDSRLRSLLYFEWLSQGY
		H3N2,	FNPWGQGTTLTVSS
		H5N1,	DIQMTQSPSSLSASVGDRVTITCRSSQSITF	VL	99
		H6N1,	DYKNYLAWYQQKPGKAPKLLIYWGSYLE
		H7N2,	SGVPSRFSGSGSGTDFTLTISSLQPEDFATY
		H7N3,	YCQQHYRTPPSFGQGTKVEIK
		H7N7,	SYAMH	HC-CDR1	64
		H7N9,	VVSYDGNYKYYADSVQG	HC-CDR2	65
		H9N2,	DSRLRSLLYFEWLSQGYFNP	HC-CDR3	66
		H10N7	WGSYLES	LC-CDR1	67
			QQHYRTPPS	LC-CDR2	68
			QSITFDYKNYLA	LC-CDR3	69
HA13	FluAB_ML	IAV:	QVQLQQSGPGLVKPSQTLSLTCAISGDSVS	VH	100
Reference:	NS	H1N1	SYNAVWNWIRQSPSRGLEWLGRTYYRSG
WO2020221908			WYNDYAESVKSRITINPDTSKNQFSLQLNS
			VTPEDTAVYYCARSGHITVFGVNVDAFDM
			WGQGTMVTVSS
			DIQMTQSPSSLSASVGDRVTITCRTSQSLSS	VL	101
			YTHWYQQKPGKAPKLLIYAASSRGSGVPS
			RFSGSGSGTDFTLTISSLQPEDFATYYCQQS
			RTFGQGTKVEIK
			SYNAVWN	HC-CDR1	70
			RTYYRSGWYNDYAESVKS	HC-CDR2	71
			SGHITVFGVNVDAFDM	HC-CDR3	72
			RTSQSLSSYTH	LC-CDR1	73
			AASSRGS	LC-CDR2	74
			QQSRT	LC-CDR3	75
HA14	D7	IAV	PDSVIRTQQRQTTMESVLSWVFLVAILQGE	VH	102
Reference:		group 1:	VQLVESGGDLVKPGGSLRLSCVASGFTFSD
CN111704665		H2	FDMSWVRQAPGKGLQWVAAIAYDGSSTY
		IAV	YTDAVKGRFTISRDNARNTVYLQMDNSLR
		group 2:	AEDTAVYYCASPTTVPTIDWFYYWGQGTL
		H3	VTVS
			MLWIPGSTGEAVMTQTPLSLAVTPGELATI	VL	103
			SCRANQSLLRSDGKSYLWYLQKPGPQTPR
			PLIYEASKRFSGVSGRFSGSGTDFTKITRVE
			ADEVGYYCQQGLHFPPFQGTKVEI
HA15	CR9114	IAV	QVQLVQSGAEVKKPGSSVKVSCKSSGGTS	VH	438
Reference:		group 1	NNYAISWVRQAPGQGLDWMGGISPIFGST
WO13007770		H1, H2,	AYAQKFQGRVTISADIFSNTAYMELNSLTS
		H5, H6,	EDTAVYFCARHGNYYYYSGMDVWGQGT
		H8, H9	TVTVSS
		IAV	QSALTQPPAVSGTPGQRVTISCSGSDSNIGR	VL	442
		group 2:	RSVNWYQQFPGTAPKLLIYSNDQRPSVVP
		H3, H4,	DRFSGSKSGTSASLAISGLQSEDEAEYYCA
		H7, H10	AWDDSLKGAVFGGGTQLTVL
			GGTSNNYA	HC-CDR1	439
			ISPIFGST	HC-CDR2	440
			ARHGNYYYYSGMDV	HC-CDR3	441
			DSNIGRRS	LC-CDR1	443
			SND	LC-CDR2
			AAWDDSLKGAV	LC-CDR3	445
HA16	MEDI8852	Pan IAV	QVQLQQSGPGLVKPSQTLSLTCAISGDSVS	VH	487
Reference:			SYNAVWNWIRQSPSRGLEWLGRTYYRSG
WO17123685			WYNDYAESVKSRITINPDTSKNQFSLQLNS
			VTPEDTAVYYCARSGHITVFGVNVDAFDM
			WGQGTMVTVSS
			DIQMTQSPSSLSASVGDRVTITCRTSQSLSS	VL	491
			YTHWYQQKPGKAPKLLIYAASSRGSGVPS
			RFSGSGSGTDFTLTISSLQPEDFATYYCQQS
			RTFGQGTKVEIK
			SYAMH	HC-CDR1	488
			VVSYDGNYKYYADSVQG	HC-CDR2	489
			DSRLRSLLYFEWLSQGYFNP	HC-CDR3	490
			WGSYLES	LC-CDR1	492
			QQHYRTPPS	LC-CDR2	493
			QSITFDYKNYLA	LC-CDR3	494

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises an HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of any one of antibodies HA1-HA16 of Table 4A. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H and V_L of any one of antibodies HA1-HA16 of Table 4A. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises an HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of antibody HA1 of Table 4A. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H and V_L of antibody HA1 of Table 4A. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises an HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of antibody HA2 of Table 4A. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H and V_L of antibody HA2 of Table 4A. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises an HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of antibody HA15 of Table 4A. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H and V_L of antibody HA15 of Table 4A.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L Comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of WAS, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 6, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, an LC-CDR2 comprising the amino acid sequence of WAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 6.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 1, 2, and 3; and a V_L comprising the amino acid sequences of WAS and SEQ ID NOs: 4 and 6. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 76 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 77. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 76, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 76, and a V_L comprising the amino acid sequence of SEQ ID NO: 77, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 77.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L Comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 235, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 238, or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 415, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 235, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 238, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 415.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 7, 8, and 9; and a V_L comprising the amino acid sequences of SEQ ID NOs: 235, 238, and 415. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 78 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 79. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 78, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 78, and a V_L comprising the amino acid sequence of SEQ ID NO: 79, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 79.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L Comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 13, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of AAS, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 13, an LC-CDR2 comprising the amino acid sequence of AAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 15.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 10, 11, and 12; and a V_L comprising the amino acid sequences of AAS and SEQ ID NOs: 13 and 15. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 80 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 81. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 80, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 80, and a V_L comprising the amino acid sequence of SEQ ID NO: 81, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 81.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 16, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 17, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 18, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L Comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 19, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of DAS, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 21, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 16, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 18; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 19, an LC-CDR2 comprising the amino acid sequence of DAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 21.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 16, 17, and 18; and a V_L comprising the amino acid sequences of DAS and SEQ ID NOs: 19 and 21. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 82 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 83. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 82, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 82, and a V_L comprising the amino acid sequence of SEQ ID NO: 83, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 83.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 24, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L Comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of GAS, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 24; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, an LC-CDR2 comprising the amino acid sequence of GAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 22, 23, and 24; and a V_L comprising the amino acid sequences of GAS and SEQ ID NOs: 25 and 27. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 84 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 85. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 84, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 84, and a V_L comprising the amino acid sequence of SEQ ID NO: 85, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 85.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 28, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L Comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of AAS, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises i) a V_H Comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 28, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 29, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 30; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LC-CDR2 comprising the amino acid sequence of AAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 33.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 28, 29, and 30; and a V_Lcomprising the amino acid sequences of AAS and SEQ ID NOs: 31 and 33. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 86 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 87. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 86, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 86, and a V_L comprising the amino acid sequence of SEQ ID NO: 87, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 87.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 34, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 36, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L Comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of AAS, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 36; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, an LC-CDR2 comprising the amino acid sequence of AAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 34, 35, and 36; and a V_L comprising the amino acid sequences of AAS and SEQ ID NOs: 37 and 39. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 88 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 89. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 88, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 88, and a V_L comprising the amino acid sequence of SEQ ID NO: 89, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 89.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 40, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 41, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 42, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L Comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 43, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of AAS, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 45, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 40, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 41, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 42; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 43, an LC-CDR2 comprising the amino acid sequence of AAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 45.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 40, 41, and 42; and a V_L comprising the amino acid sequences of AAS and SEQ ID NOs: 43 and 45. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 90 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 91. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 90, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 90, and a V_L comprising the amino acid sequence of SEQ ID NO: 91, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 91.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 46, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 47, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 48, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L Comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 49, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of AAS, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 51, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 46, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 47, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 48; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 49, an LC-CDR2 comprising the amino acid sequence of AAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 51.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 46, 47, and 48; and a V_L comprising the amino acid sequences of AAS and SEQ ID NOs: 49 and 51. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 92 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 93. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 92, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 92, and a V_L comprising the amino acid sequence of SEQ ID NO: 93, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 93.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 52, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 53, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 54, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L Comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of GAT, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 53, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 54; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, an LC-CDR2 comprising the amino acid sequence of GAT, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 57.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 52, 53, and 54; and a V_L comprising the amino acid sequences of GAT and SEQ ID NOs: 55 and 57. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 94 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 95. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 94, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 94, and a V_L comprising the amino acid sequence of SEQ ID NO: 95, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 95.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 58, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 59, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 60, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of AAS, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 63, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 58, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 59, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 60; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, an LC-CDR2 comprising the amino acid sequence of AAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 63.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 58, 59, and 60; and a V_L comprising the amino acid sequences of AAS and SEQ ID NOs: 61 and 63. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 96 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 97. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 96, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 96, and a V_L comprising the amino acid sequence of SEQ ID NO: 97, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 97.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 64, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 65, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 66, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L Comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 67, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 68, or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 69, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 64, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 65, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 66; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 67, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 68, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 69.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 64, 65, and 66; and a V_L comprising the amino acid sequences of SEQ ID NOs: 67, 68, and 69. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H Comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 98 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 99. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 98, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 98, and a V_L comprising the amino acid sequence of SEQ ID NO: 99, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 99.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 70, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 71, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 72, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L Comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 73, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 74, or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 75, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 70, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 71, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 72; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 73, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 74, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 75.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 70, 71, and 72; and a V_L comprising the amino acid sequences of SEQ ID NOs: 73, 74, and 75. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H Comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 100 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 101. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 100, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 100, and a V_L comprising the amino acid sequence of SEQ ID NO: 101, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 101.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 102 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 103. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H Comprising the amino acid sequence of SEQ ID NO: 102, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 102, and a V_L comprising the amino acid sequence of SEQ ID NO: 103, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 103.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 439, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 440, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 441, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 443, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SND, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 445, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 439, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 440, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 441; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 443, an LC-CDR2 comprising the amino acid sequence of SND, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 445.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 439, 440, and 441; and a V_L comprising the amino acid sequences of SND and SEQ ID NOs: 443 and 445. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 438 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 442. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 438, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 438, and a V_L comprising the amino acid sequence of SEQ ID NO: 442, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 442.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 488, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 489, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 490, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 492, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 493, or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 493, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 488, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 489, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 490; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 492, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 493, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 494.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 488, 489, and 490; and a V_L comprising the amino acid sequences of SEQ ID NOs: 492, 493, and 494. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 487 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 491. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 487, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 487, and a V_L comprising the amino acid sequence of SEQ ID NO: 491, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 491.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof specifically binds to the HA protein of an influenza virus or a variant thereof. In some embodiments, the anti-HA antibody or antigen binding fragment thereof specifically binds to the HA1 region (e.g., the globular “head” region) of the HA protein. In some embodiments, the binding of the anti-HA antibody or antigen binding fragment thereof to the HA1 region of the HA protein prevents binding of an influenza virus or variant thereof to a sialic acid receptor. In some embodiments, the anti-HA antibody or antigen binding fragment thereof specifically binds to the HA2 region (e.g., the “stem” region) of the HA protein. In some embodiments, binding of the anti-HA antibody or antigen binding fragment thereof to the HA2 region of the HA protein prevents fusion of an influenza virus or variant thereof viral membrane with that of a host cell. In some embodiments, the anti-HA antibody or antigen binding fragment thereof is a neutralizing antibody.

In some embodiments, the anti-HA antibody or antigen binding fragment thereof specifically binds to the HA protein of an influenza virus or variant thereof with a K_D of no more than about any one of 100 nM, 50 nM, 20 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.75 nM, 0.5 nM, 0.2 nM, 0.1 nM, 0.05 nM, 0.01 nM, or less, including any values and ranges in between these values. In some embodiments, the anti-HA antibody or antigen binding fragment thereof specifically binds to the HA protein of an influenza virus or variant thereof with a K_D of about any one of 0.01 nM to 0.1 nM, 0.1 nM to 1 nM, 1 nM to 5 nM, 5 nM to 10 nM, 10 nM-100 nM, 0.01 nM to 1 nM, 0.5 nM to 10 nM, 0.1 nM to 1 nM, 0.1 nM to 10 nM, or 0.01 nM to 100 nM.

In some embodiments, the antibody moiety can be an anti-HA antibody that competes for binding to an HA protein of an influenza virus or variant thereof with a second anti-HA antibody according to any of the anti-HA antibodies described herein. In some embodiments, the anti-HA antibody can bind to the same, or substantially the same, epitope as the second anti-HA antibody. In some embodiments, binding of the anti-HA antibody to an HA protein of an influenza virus or variant thereof can inhibit the binding of a second anti-HA antibody to the same HA protein of an influenza virus or variant by at least about 70% (such as by at least about any of 75%, 80%, 85%, 90%, 95%, 98% or 99%), or vice versa. In some embodiments, the anti-HA antibody and the second anti-HA antibody can cross-compete for binding to the HA protein of an influenza virus or variant, i.e., each of the anti-HA antibody moieties can compete with the other for binding to the HA protein of an influenza virus or variant.

Exemplary Human Anti-NA Antibodies

In some embodiments, there is provided a chimeric protein comprising an anti-NA antibody or antigen binding fragment thereof (e.g., an anti-NA antibody moiety) that specifically binds to a human NA antigen. In some embodiments, the anti-HA antibody or antigen fragment thereof is a human anti-NA antibody or antigen fragment thereof.

Exemplary anti-NA antibodies are provided in Table 4B.

TABLE 4B
CDR and VH/VL sequences of exemplary human anti-NA antibodies
					SEQ
Antibody	Antibody	Target			ID
code	Name	strain	Sequence	Type	NO
NA1	1G05	IBV	QVQLQESGPGLVRPSETLSLTCTVSGDSIG	VH	188
Reference:			GSYWNWIRQPPGKGLQWIGYIYYTGITNY
WO2021158960			NPSLKSRVTMSLDTSKNQISLKMDSVTAA
			DTALYFCARGDYSGYDRDVQVELMDVW
			GKGTTVTVSS
			DIQMTQSPSSLSASVRDKVTFVCRASQTISI	VL	189
			FLNWYQHKPGEAPKLLIYAASRLQSGVPS
			RFSGSGSGTDFTLTISGLQPEDFATYYCQQS
			YSAPWTFGQGTKVEIK
			GDSIGGSY	HC-CDR1	104
			IYYTGIT	HC-CDR2	105
			ARGDYSGYDRDVQVELMDV	HC-CDR3	106
			QTISIF	LC-CDR1	107
			AAS	LC-CDR2
			QQSYSAPWT	LC-CDR3	109
NA2	2E01	IBV	EVQLVESGAEVKKPGSSVKVSCRASGTFY	VH	190
Reference:			KYAINWVRQAPGQGLEWMGGIIPFFGTTN
WO2021158960			YAQKFQGRLTITADGSTNTAYMQLDSLRS
			EDTAVYYCAGPSITESHYCLDCAAKDYYY
			GLDVWGQGTTVTVSS
			QSVLTQPPSASGTPGQSVTISCSGSRSNIGG	VL	191
			NTVNWYQHLPGMAPKLLIYSSNQRSSGVP
			DRFSGSKSGTSASLAISGLQSEDDADYYCA
			SWDDSLNGVVFGGGTKLTVLG
			GYTFINHA	HC-CDR1	110
			IIPIFGLA	HC-CDR2	111
			ARDTVAVYEDFDWSSPYFFYMDV	HC-CDR3	112
			QSAGSKS	LC-CDR1	113
			GAS	LC-CDR2
			QRYGTSLVT	LC-CDR3	115
NA3	IF2	IBV:	QVHLQQSGPEVARPGASVKLSCKASGYTF	VH	192
Reference:		Victoria,	TDYYLNWVKQRPRQGLEWIGQIHPGSTNT
WO2018187706		Yamagata	YYNEKFKGKATLTADKSSSTAYMQLSSLT
		lineages	FEDSAVYFCAISLGDGYYVYAMVCWGQG
			TAVTVSS
			DIVMTQSQKFMSTSVGDRVSVTCKASQNV	VL	193
			VTNVVWYQQKPGQSPKPLIYSASYRYSGV
			PDRFTGSGSGTDFTLTISNV
			GYTFTDYY	HC-CDR1	116
			IHPGSTNT	HC-CDR2	117
			AISLGDGYYVYAMVC	HC-CDR3	118
			QNVVTN	LC-CDR1	119
			SAS	LC-CDR2
			QQYHSYPFT	LC-CDR3	121
NA4	IF4	IBV:	QVHLQQSGSELRSPGSSVKLSCKDFDSEVF	VH	194
Reference:		Victoria,	PIVYMRWIRQKPGHGFEWIGDILPSFGRTIY
WO2018187706		Yamagata	GEKFEDKATLDADTVSNTAYLELNSLTSE
		lineages	DSAIYYCARGDHGNWLAYWGQGTLVTVS
			A
			DIVMTQSHKFMSTSVGDRVTITCKASQDV	VL	195
			STNVAWYQQKPGQSPKLLIYWASTRHTGV
			PNRFTGIISGTDYTLTISSVQAEDRALYYCQ
			QHYSAPWTFGGGTKLEIK
			DSEVFPIVY	HC-CDR1	122
			ILPSFGRT	HC-CDR2	123
			ARGDHGNWLAY	HC-CDR3	124
			QDVSTN	LC-CDR1	125
			WAS	LC-CDR2
			QQHYSAPWT	LC-CDR3	127
NA5	1092A9	IBV	EVQLLQSGGGLVQPGGSLRLSCAASGLTFS	VH	196
Reference:			GYAMSWVRQVPGKGPECVSGIIASGGSTY
WO2019213384			FADSVKGRFTISRDNSKNTLDLEMNSLRAE
			DTAVYYCAQHTKSHYYSGMGVWGQGTT
			VTVSS
			DIQMTQSPSSLSASVGDRVTITCQASQDISN	VL	197
			YLNWYQQRPGKAPKLLIYDAANLETGVPS
			RFSGSGSATQFTFTISGLQPEDFATYYCQQ
			YDNLPLTFGGGTKVEIK
			GLTFSGYA	HC-CDR1	128
			IIASGGST	HC-CDR2	129
			AQHTKSHYYSGMGV	HC-CDR3	130
			QDISNY	LC-CDR1	131
			DAA	LC-CDR2
			QQYDNLPLT	LC-CDR3	133
NA6	1092B6	IBV	QVQLVQSGAEVRKPGASVKVSCKVSRYNI	VH	198
Reference:			IELSMDWVRQAPGKGLEWMGGIDPDDSER
WO2019213384			IYAQKLQGRVTMTEDTSTDTAYMELSGLR
			SEDTAIYYCAAARRPIRGEYHYALDVWGQ
			GTAVTVSS
			EIVLTQSPGTLSLSPGERATLSCRASQSVSS	VL	199
			SYLGWYQQKPGQAPRLLIYRASSRATGIPH
			RFSGSGSGTEFTLTITRLEPEDFA VYYCHH
			YAKVFGQGTKVEIK
			RYNIIELS	HC-CDR1	134
			IDPDDSER	HC-CDR2	135
			AAARRPIRGEYHYALDV	HC-CDR3	136
			QSVSSSY	LC-CDR1	137
			RAS	LC-CDR2
			HHYAKV	LC-CDR3	139
NA7	3C05	IAV	QVQLQQWGAGLLKPSETLSLTCAVYGGSF	VH	200
Reference:			GGYYWNWIRQPPGKGLEWIGEINHSGSTN
WO2020251834			YNPSLKSRVTLSVDTSKNQVSLNVSSVTAA
			DTAVYYCARGRGGYATYYYYYYVDVWG
			KGTTVTVSS
			EIVLTQSPATLSLSPGERATLSCRASQSVSS	VL	201
			YLAWYQQKPGQAPRLLIYDASKRATGIPA
			RFSGSGSGTDFTLTISSLEPEDFAVYYCQQR
			SNWLTFGGGTKVELE
			GGSFGGYY	HC-CDR1	140
			INHSGST	HC-CDR2	141
			ARGRGGYATYYYYYYVDV	HC-CDR3	142
			QSVSSY	LC-CDR1	143
			DAS	LC-CDR2
			QQRSNWLT	LC-CDR3	145
NA8	SEQ 42-43	pan-NA	EVQLVESGGRVVRPGGSLRLSCAASGFTFD	VH	202
Reference:			DYGMSWVRQPPGKGLEFVSGLNWNGDIT
WO2020243572			AFTDSVKGRETISRDNVKSSLYLQMNSLRA
			DDTAFYYCARVRTWGDYTTGEEIINSWYF
			DLWGRGTLVTVSS
			DIQLTQSPSFLSASVGDRVTITCRASQDISS	VL	203
			YLAWYQQKPGNAPKVLIYAASLLSGVPSR
			FSAFGSGTEFTLTISSLQPEDFATYYCQHLK
			SYPLETFGPGTKVDIK
			GFTFDDYGM	HC-CDR1	146
			LNWNGDITA	HC-CDR2	147
			TWGEYTTREEPINSWY	HC-CDR3	148
			DISSFL	LC-CDR1	149
			SLL	LC-CDR2
			LNSYPLETF	LC-CDR3	151
NA9	SEQ 40-41	pan-NA	EVQLVESGGRVVRPGGSLRLSCAASGFTFD	VH	204
Reference:			DYGMSWVRQAPGKGLEFVSGLNWNGDIT
WO2020243572			AFTDSVKGRETISRDNAKSSLYLQMNSLRA
			DDTAFYYCARVRTWGEYTTREEPIHSWYF
			DLWGRGTLVTVSS
			DIQLTQSPSFLSASVGDRVTITCRASQDISS	VL	205
			YLAWYQQKPGNAPKLLIYAASLLSGVPSR
			FSAFGSGTEFTLTISSLQPEDFATYYCQHLK
			SYPLETFGPGTKVDIK
			GFTFDDYGM	HC-CDR1	152
			LNWNGDITA	HC-CDR2	153
			TWGDYTTGEEIINSWY	HC-CDR3	154
			DISSYL	LC-CDR1	155
			SLL	LC-CDR2
			LKSYPLETF	LC-CDR3	157
NA10	SEQ 44-45	pan-NA	EVQLVESGGRALRPGGSLRLSCAASGFKFD	VH	206
Reference:			DYAMSWVRQVPGKGLEFVSGLNWNGDIT
WO2020243572			AYTDSVKGRETVSRDNAKNSLYLHINSPKP
			EDTALYYCARTSSWGDYTRGPEPKITWYF
			DLWGRGTLVTVSS
			DIQLTQSPSFLSASVGDRITITCRASQGIDG	VL	207
			YLAWYQQRPGKAPNLLIYAASLLSGVPSR
			FSGSGYGTEFTLTISSLQPEDFATYYCQHLD
			SYPLETFGPGTKVDIK
			GFKFDDYAM	HC-CDR1	158
			LNWNGDITA	HC-CDR2	159
			SWGDYTRGPEPKITWY	HC-CDR3	160
			GIDGYL	LC-CDR1	161
			SLL	LC-CDR2
			LDSYPLETF	LC-CDR3	163
NA11	2D04	IAV: N1,	EVQLVESGGGLVKPGQSLRLSCAASGFTFT	VH	208
Reference:		N2, N3,	NAWMSWVRQAPGKGLEWVGRIKTKTEGE
WO2019169231		N4, N5,	TVDYAAPVKGRITISRDDSKNMVYLQLKS
		N6, N7,	LKIEDAAVYYCTTGLTRSSLGGFVDYWGP
		N8, N9,	GTLVTVSS
		N10, N11	DIVMTQSPDSLTVSLGERATINCRSSQTVLS	VL	209
			SSNNENFLAWYQQKSGQPPNLLIYWASTR
			ASGVPDRFSGSGSGTDFTLTISSLQTEDVA
			VYYCLQYLTTPRTFGQGTKVEIK
			NAWMS	HC-CDR1	164
			RIKTKTEGETVDYAAPVKG	HC-CDR2	165
			TTGLTRSSLGGFVDY	HC-CDR3	166
			RSSQTVLSSSNNENFLA	LC-CDR1	167
			WASTRAS	LC-CDR2	168
			LQYLTTPRT	LC-CDR3	169
NA12	1D05	IAV: N1,	VQLVESGGGLVKPGGSLRLSCAASGFTFSD	VH	210
Reference:		N2, N3,	YYMSWIRQAPGKGLEWISYISSSSTYTDYA
WO2019169231		N4, N5,	DSVKGRFTVSRDNAKNSLYLQMNNLRAE
		N6, N7,	DTAVYYCATVADTAYSRGRPQITHFDNW
		N8, N9,	GQGTLVTVSS
		N10, N11	SYELTQPPSMSVSPGQTATITCFGDKLGEK	VL	211
			YAYWYQQKPGQSPLLVIYQDTKRPSGIPER
			FSGSNSGNTATLTISGTQAMDEADYYCQT
			WDSTLVFFGGGTKLTVL
			DYYMS	HC-CDR1	170
			YISSSSTYTDYADSVKG	HC-CDR2	171
			ATVADTAYSRGRPQITHEDN	HC-CDR3	172
			FGDKLGEKYAY	LC-CDR1	173
			QDTKRPS	LC-CDR2	174
			QTWDSTLVF	LC-CDR3	175
NA13	1G03	IAV: N1,	VQLVESGGGVVQPGGSLRLSCAVSGLTIN	VH	212
Reference:		N2, N3,	DLVIHWVRQPPDKGLEWVAVMGYDGGN
WO2019169231		N4, N5,	KDYAESVKGRFSISGDNPQNTLYLQINSLR
		N6, N7,	VEDTAVYYCARASYFGELRDEYYSFAMD
		N8, N9,	VWGQGTTVTVSS
		N10, N11	EIVLTQSPGTLSLSPGERGTLSCRASQSVSR	VL	213
			SYLAWYQQKPGQAPRLLIYGASSRATGIPD
			RFSGSGSGTDFTLTISRLEPEDFALYYCQLY
			GTSPPYTFGQGTKVEIK
			DLVIH	HC-CDR1	176
			VMGYDGGNKDYAESVKG	HC-CDR2	177
			ARASYFGELRDEYYSFAMDV	HC-CDR3	178
			RASQSVSRSYLA	LC-CDR1	179
			GASSRAT	LC-CDR2	180
			QLYGTSPPYT	LC-CDR3	181
NA14	2B04	IAV: N1,	EVQLVESGGGLVKPGGSLRLSCAASGFTVS	VH	214
Reference:		N2, N3,	NAWMSWVRQAPGKGLEWVGRIKKESEGG
WO2019169231		N4, N5,	TIDYGAPVKGRFTISRDESKNILYLHMKSLI
		N6, N7,	TDDTAVYYCTIPNPQIVVVTTTPHSHWGQ
		N8, N9,	GTLVTVSS
		N10, N11	SYELTQPPSVSVAPGKTARITCGGNNIGSK	VL	215
			NVHWYQQKPGQAPVLVIYYDSDRPSAIPE
			RFSGSNSGNTATLTISRVEAGDEADYYCQV
			WDSSSDHWVFGGGTKLAVL
			NAWMS	HC-CDR1	182
			RIKKESEGGTIDYGAPVKG	HC-CDR2	183
			TIPNPQIVVVTTTPHSH	HC-CDR3	184
			GGNNIGSKNVH	LC-CDR1	185
			YDSDRPS	LC-CDR2	186
			QVWDSSSDHWV	LC-CDR3	187

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises an HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of any one of antibodies NA1-NA14 of Table 4B. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H and V_L of any one of antibodies NA1-NA14 of Table 4B. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises an HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of antibody NA1 of Table 4B. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H and V_L of antibody NA1 of Table 4B. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises an HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of antibody NA2 of Table 4B. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H and V_L of antibody NA2 of Table 4B.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 104, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 106, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 107, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of AAS, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 109, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 104, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 106; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 107, an LC-CDR2 comprising the amino acid sequence of AAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 109.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 104, 105, and 106; and a V_L comprising the amino acid sequences of AAS and SEQ ID NOs: 107 and 109. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 188 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 189. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 188, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 188, and a V_L comprising the amino acid sequence of SEQ ID NO: 189, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 189.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 110, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 111, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 112, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 113, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of GAS, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 115, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 110, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 111, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 112; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 113, an LC-CDR2 comprising the amino acid sequence of GAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 115.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 110, 111, and 112; and a V_L comprising the amino acid sequences of GAS and SEQ ID NOs: 113 and 115. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 190 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 191. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 190, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 190, and a V_L comprising the amino acid sequence of SEQ ID NO: 191, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 191.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 116, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 117, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 118, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 119, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SAS, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 121, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 116, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 117, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 118; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 119, an LC-CDR2 comprising the amino acid sequence of SAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 121.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 116, 117, and 118; and a V_L comprising the amino acid sequences of SAS and SEQ ID NOs: 119 and 121. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 192 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 193. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 192, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 192, and a V_L comprising the amino acid sequence of SEQ ID NO: 193, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 193.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 122, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 124, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 125, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of WAS, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 127, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 122, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 124; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 125, an LC-CDR2 comprising the amino acid sequence of WAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 127.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 122, 123, and 124; and a V_L comprising the amino acid sequences of WAS and SEQ ID NOs: 125 and 127. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 194 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 195. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 194, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 194, and a V_L comprising the amino acid sequence of SEQ ID NO: 195, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 195.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 130, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 131, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence DAA, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 133, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 128, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 129, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 130; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 131, an LC-CDR2 comprising the amino acid sequence of DAA, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 133.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 128, 129, and 130; and a V_L comprising the amino acid sequences of DAA and SEQ ID NOs: 131 and 133. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 196 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 197. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 196, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 196, and a V_L comprising the amino acid sequence of SEQ ID NO: 197, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 197.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 134, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 137, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of RAS, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 139, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 134, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 135, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 136; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 137, an LC-CDR2 comprising the amino acid sequence of RAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 139.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 134, 135, and 136; and a V_L comprising the amino acid sequences of RAS and SEQ ID NOs: 137 and 139. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 198 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 199. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 198, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 198, and a V_L comprising the amino acid sequence of SEQ ID NO: 199, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 199.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 141, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 142, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 143, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of DAS, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 145, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 140, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 141, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 142; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 143, an LC-CDR2 comprising the amino acid sequence of DAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 145.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 140, 141, and 142; and a V_L comprising the amino acid sequences of DAS and SEQ ID NOs: 143 and 145. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 200 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 201. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 200, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 200, and a V_L comprising the amino acid sequence of SEQ ID NO: 201, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 201.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 146, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 147, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 148, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 149, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SLL, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 151, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 146, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 147, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 148; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 149, an LC-CDR2 comprising the amino acid sequence of SLL, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 151.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 146, 147, and 148; and a V_L comprising the amino acid sequences of SLL and SEQ ID NOs: 149 and 151. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 202 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 203. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 202, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 202, and a V_L comprising the amino acid sequence of SEQ ID NO: 203, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 203.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 154, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 155, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SLL, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 157, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 152, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 153, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 154; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 155, an LC-CDR2 comprising the amino acid sequence of SLL, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 157.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 152, 153, and 154; and a V_L comprising the amino acid sequences of SLL and SEQ ID NOs: 155 and 157. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 204 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 205. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 204, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 204, and a V_L comprising the amino acid sequence of SEQ ID NO: 205, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 205.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 158, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 159, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 160, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SLL, or a variant thereof comprising about 1 or about 2 amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 163, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 158, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 159, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 160; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an LC-CDR2 comprising the amino acid sequence of SLL, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 163.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 158, 159, and 160; and a V_L comprising the amino acid sequences of SLL and SEQ ID NOs: 161 and 163. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 206 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 207. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 206, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 206, and a V_L comprising the amino acid sequence of SEQ ID NO: 207, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 207.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 164, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 165, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 166, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 167, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 168, or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 169, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 164, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 165, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 166; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 167, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 168, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 169.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 164, 165, and 166; and a V_L comprising the amino acid sequences of SEQ ID NOs: 167, 168, and 169. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 208 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 209. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 208, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 208, and a V_L comprising the amino acid sequence of SEQ ID NO: 209, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 209.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 170, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 171, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 172, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 173, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 174, or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 175, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 170, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 171, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 172; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 173, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 174, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 175.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 170, 171, and 172; and a V_L comprising the amino acid sequences of SEQ ID NOs: 173, 174, and 175. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 210 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 211. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 210, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 210, and a V_L comprising the amino acid sequence of SEQ ID NO: 211, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 211.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 176, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 177, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 178, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 179, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 180, or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 181, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 176, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 177, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 178; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 179, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 180, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 181.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 176, 177, and 178; and a V_L comprising the amino acid sequences of SEQ ID NOs: 179, 180, and 181. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 212 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 213. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 212, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 212, and a V_L comprising the amino acid sequence of SEQ ID NO: 213, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 213.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 182, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 183, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 184, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 185, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 186, or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 187, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 182, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 183, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 184; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 185, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 186, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 187.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 182, 183, and 184; and a V_L comprising the amino acid sequences of SEQ ID NOs: 185, 186, and 187. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 214 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 215. In some embodiments, the anti-NA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 214, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 214, and a V_L comprising the amino acid sequence of SEQ ID NO: 215, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 215.

In some embodiments, the anti-NA antibody or antigen binding fragment thereof specifically binds to the NA protein of an influenza virus or a variant thereof. In some embodiments, the anti-NA antibody prevents the cleavage of terminal sialic acid residues from N-linked glycans present on host cell surfaces and progeny virions of the influenza virus or variant thereof. In some embodiments, the anti-NA antibody or antigen binding fragment thereof specifically binds to the enzymatic active site of the NA protein. In some embodiments, binding of the enzymatic active site of the NA protein by the anti-NA antibody prevents the cleavage of terminal sialic acid residues from N-linked glycans present on host cell surfaces and progeny

In some embodiments, the anti-NA antibody or antigen binding fragment thereof specifically binds to the NA protein of an influenza virus or variant thereof with a K_D of no more than about any one of 100 nM, 50 nM, 20 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.75 nM, 0.5 nM, 0.2 nM, 0.1 nM, 0.05 nM, 0.01 nM, or less, including any values and ranges in between these values. In some embodiments, the anti-NA antibody or antigen binding fragment thereof specifically binds to the NA protein of an influenza virus or variant theoefor with a K_D of about any one of 0.01 nM to 0.1 nM, 0.1 nM to 1 nM, 1 nM to 5 nM, 5 nM to 10 nM, 10 nM-100 nM, 0.01 nM to 1 nM, 0.5 nM to 10 nM, 0.1 nM to 1 nM, 0.1 nM to 10 nM, or 0.01 nM to 100 nM.

In some embodiments, the antibody moiety can be an anti-NA antibody that competes for binding to an NA protein of an influenza virus or variant thereof with a second anti-NA antibody, according to any of the anti-NA antibodies described herein. In some embodiments, the anti-NA antibody can bind to the same, or substantially the same, epitope as the second anti-NA antibody. In some embodiments, binding of the anti-NA antibody to an NA protein of an influenza virus or variant thereof can inhibit the binding of a second anti-NA antibody to the same NA protein of an influenza virus or variant by at least about 70% (such as by at least n %, where n % is selected from 75%, 80%, 85%, 90%, 95%, 98%, and 99%), or vice versa. In some embodiments, the anti-NA antibody and the second anti-NA antibody can cross-compete for binding to the NA protein of an influenza virus or variant, i.e., each of the anti-NA antibody moieties can compete with the other for binding to the NA protein of an influenza virus or variant.

Exemplary Animal Anti-HA and Anti-NA Antibodies

In some embodiments, there is provided a chimeric protein comprising an animal anti-HA or an animal anti-NA antibody or antigen binding fragment thereof (e.g., an animal anti-HA or an animal anti-NA antibody moiety) that specifically binds to an animal HA or NA antigen, respectively.

Exemplary animal HA and NA antigens are provided in Table 5 below.

TABLE 5
Exemplary animal HA and NA antigens
Antigen;
Animal;		SEQ
Reference;		ID
Strain	Sequence	NO
HA;	MKTIIVLSYLFCLALSQDYSENNNSTATLCLGHHAVPNGTVVKTITDDQI	349
Bird;	EVTNATELVQSSSTGKICNNPHRILDGRDCTLIDALLGDPHCDVFQDETW
QDX47284.1;	DLYVERSSAFSNCYPYDVPDYASLRSLVASSGTLEFITEGFTWTGVTQNG
H3N8	GSSACKRGPASGFFSRLNWLTKSGSAYPVLNVTMPNNDNFDKLYVWGV
	HHPSTNQEQTNLYVQASGRVTVSTRKSQQTIIPNIGSRPWVRGQSGRISIY
	WTIVKPGDVLVINSNGNLIAPRGYFKMRTGKSSIMRSDAPIDTCISECITPN
	GSIPNDKPFQNVNKITYGACPKYVKQSTLKLATGMRNVPEKQTRGLFGA
	IAGFIENGWEGMIDGWYGFRHQNSEGTGQAADLKSTQAAIDQINGKLNR
	VIEKTNEKFHQIEKEFSEVEGRIQDLEKYVEDTKIDLWSYNAELLVALEN
	QHTIDLTDSEMNKLFEKTRRQLRENAEDMGNGCFKIYHKCDNACIESIRN
	GTYDHDIYRDEALNNRFQIKGVELKSGYKDWILWISFAISCFLLCVVLLG
	FIMWACQRGNIRCNICI
NA;	MNPNQKIITIGSICMAIGIMSLVLQIGNIISIWVSHSIQTESKSPETCNQSVIT	350
Bird;	YENNTWVNQTYLNISNTNLIVEQIVAPVTLAGNSSLCPISGWAIYSKDNGI
QDX47725.1;	RIGSKGDVFVIREPFISCSHLECRTFFLTQGALLNDKHSNGTVKDRSPYRT
H3N8	LMSCPVGEAPSPYNSRFESVAWSASACHDGISWLTIGISGPDNGAVAVLK
	YNGIITDTVKSWRNNILRTQESECACINGSCFTIMTDGPSNGQASYKIFKIE
	KGKVVKSVELNAPNYHYEECSCYPDASEVMCVCRDNWHGSNRPWVSF
	NQDLEYQIGYICSGVFGDNPRPNDGTGSCGPVSSNGAYGVKGFSFRYGN
	GVWIGRTKSTSSRSGFEMIWDPNGWTETDNSFSVKQDIVAITDWSGYSG
	SFVQHPELTGLDCVRPCFWVELIRGRPKENTIWTSGSSISFCGVNSDTVG
	WSWPDGAELPFTIDK
HA;	MRTVIALSYIFCLAFGQNLKGNENNAATLCLGHHAVPNGTMVKTITSDQI	351
Cat;	EVTNATEQVQNSSTGKICNNPHKILDGRDCTLIDALLGDPHCDVFQNET
AFI61906.1;	WDLFVERSNAFSNCYPYDVQDYASLRSIVASSGTLEFITEGFTWAGVTQN
H3N2	GGSGACKRGPANGFFSRLNWLTKSGNTYQVLNVTMPNNNNFDKLYIWG
	VHHPSTNQEQTSLYIQASGRVTVSTRRSKQTIILNIESRPLVRCQSGRISVY
	WTIVKPGVILVINSNGNLIAPRGYFKMHIGKSTIMRSDAPVDTCISECITPN
	GSIPNEKPFQNVNKITYGACPKYVKQNTLKLSTGMRNVPERQTRGLFGAI
	AGFIENGWEGMVDGWYGFRHQNSEGTGQAADLKSTQAAIDQINGKLNR
	VIEKTNEKFHQIEKEFSEVEGRIQDLERYVEDTKVDLWSYNAELLVALEN
	QNTIDLTDSEMNKLFEKTRRQLRENAEDMGNGCFKIYHKCDNACIESIRN
	GTYDHNIYRDEAVNNRFQIKGVELKSGYKDLILWISFAISCFLLCVVLLGF
	IMWACQRGNIRCNICI
NA;	MNPNQKIIAIGSVSLIIATVCFLLQIAILATNVTLYFKQNECNIPSNSQVVPC	352
Cat;	KPIIIERNITEVVYLNNTTIEKEIYSVVLEYRNWSKPQCQITGFAPFSKDNSI
ANW47171.1;	RLSAGGDIWVTREPYVSCDPSKCYQFALGQGTTLNNKHSNGTIHDRISHR
H3N2	TLLMNELGVPFHLGTKQVCIAWSSSSCHDGKAWLHVCVTGDDKNATAS
	FVYNGMLVDSIGSWSRNILRTQESECVCINGTCTVVMTDGSASGRADTRI
	LFIREGKIVHISPLSGSAQHIEECSCYPRYPNVRCVCRDNWKGSNRPVIDI
	NMADYSIDSSYVCSGLVGDTPRNDDSFSSSNCRDPNNERGNPGVKGWAF
	DNENDVWMGRTISKDLRSGYETFKVIGCRTTANSKSQVNRQVIVDNNN
	WSGYSGIFSVEGKSCVNRCFYVELIRGGPQETRVWWTSNSIVVFCGTSGT
	YGAGSWPDGANINFMPI
HA;	MKTVIALSYIFCLAFGQNLLGNENNAATLCLGHHAVPNGTMVKTITDDQ	353
Dog;	IEVTNATELVQNSSTGKICNNPHKILDGRDCTLIDALLGDPHCDVFQNET
QBQ33923.2;	WDLFVERSNAFSNCYPYDVPDYASLRSIVASSGTLEFITEGFTWAGVTQN
H3N2	GGSGACKRGPANSFFSRLNWLTKSGNTYPVLNVTMPNNNNFDKLYIWG
	VHHPSTDQEQTSLYIQASGRVTVSTRKSQQTIIPNIGSRPLVRGQSGRISVY
	WTIVEPGDILVINSNGNLIAPRGYFKMHIGKSSIMRSDAPIDTCISECITPNG
	SIPTEKPFQNVNKITYGACPKYVKQNTLKLATGMRNVPERQTRGLFGAX
	AGFIENGWEGMVDGWYGFRHQNSEGTGQAADLKSTQAAIDQINGKLNR
	VIEKTNEKFHQIEKEFSEVEGRIQDLERYVEDTKIDLWSYNAELLVALEN
	QNTIDLTDSEMNKLFEKTRRQLRENAEDMGNGCFKIYHKCDNACIESIRN
	GTYDHNIYRDEAVNNRFQIKGVELKSGYKDWILWISFAISCFLLCVVLLG
	FIMWACQRGNIRCNICI
NA;	MNPNQKIIAIGSVSLAIATVCFLLQIATLATTVTLYFKQNECNIPSNSQIVP	354
Dog;	CKPIIIERNITEVVHLNNTTIEKEIYSVVLEYRNWSKPQCQITGFAPFSKDN
QBQ33992.2;	SIRLSAGGDIWVTREPYVSCDPSKCYQFALGQGTTLNNKHSNSTIHDRTS
H3N2	YRTLLMNELGVPXHLGTKQVCIAWSSSSCHDGKAWLHVCVTGDDRNAT
	ASFVYNGMLVDSIGSWSRNILRTQESECVCINGTCTVVMTDGSASGKAD
	TRILFIKEGKIIHISPLSGSAQHIEECSCYPQYPNVRCVCRDNWKGSNRPVI
	DINMADYNINSSYVCSGLVGDTPRNDDSSSSSNCKDPNNERGNPGVKGW
	AFDNDNDVWMGRTISKDLRSGYETFKVIGGWTTANSKSQVNRQVIVDN
	NNWSGYSGIFSVEGKSCVNRCFYVELIRGGPQETRVWWTSNSIVVFCGTS
	GTYGTGSWPDGANINFMPI
NA;	MNPNQKIITIGTASLGILIINVILHVVSIIVTVLVLNNNETGLNCKGTIIREY	355
Horse;	NETVRVEKITQWHNTSAIKYIERPPNEYYMNNTEPLCEAQGFAPFSKDNG
AIZ95447.1;	IRIGSRGHVFVIREPFVSCSPSECRTFFLTQGSLLNDKHSNGTVKDRSPYRT
H3N8	LMSVKIGQSPNVYQARFESVAWSATACHDGKKWMTIGVTGPDNQAIAV
	VNYGGIPVDIINSWEGDILRTQESSCTCIKGNCYWVMTDGPANRQAKYRI
	FKAKDGRVIGQTDISFNGGHIEECSCYPNEGKVECICRDNWTGTNRPILVI
	SSDLSYTVGYLCAGIPTDTPRGEDSQFTGSCTSPLGNKGYGVKGFGFRQG
	TDVWAGRTISRTSRSRFEIIKIRNGWTQNSKDQIRRQVIIDDPNWSGYSGS
	FTLPVELTKKGCLVPCFWVEMIRGKPEETTIWTSSSSIVMCGVDHKIASW
	SWHDGAILPFDIDKM
HA;	MKTTTIFIFILLTHWAYSQNPISNNNTATLCLGHHAVANGTLVKTISDDQI	356
Horse;	EVTNATELVQSISMGKICNNSYRILDGRNCTLIDAMLGDPHCDVFQYEN
AXQ87682.1;	WDLFIERSSAFSNCYPYDIPDYASLRSIVASSGTLEFTAEGFTWTGVTQNG
H3N8	RSGACKRGSTDSFFSRLNWLTKSGNSYPTLNVTMPNNKNFDKLYIWGIH
	HPSSNQEQTKLYIQGSGRVTVSTKRSQQTIIPNIGSRPWVRGQSGRISIYW
	TIVKPGDILMINSNGNLVAPRGYFKLKTGKSSVMRSDVPIDICVSECITPN
	GSISNDKPFQNVNKVTYGKCPKYIRQNTLKLATGMRNVPEKQIRGIFGAI
	AGFIENGWEGMVDGWYGFRYQNSEGTGQAADLKSTQTAIDQINEKLNR
	VIERTNEKFHQIEKEFSEVEGRIQDLEKYVEDTKIDLWSYNAELLVALEN
	QHTIDLTDAEMNKLFEKTRRQLRENAEDMGGGCFKIYHKCDNACIGSIR
	NGTYDHYIYRDEALNNRFQIKGVELKSGYKDWILWISFAISCFLICVVLL
	GFIMWACQKGNIRCNICI
HA;	MKAILLVLLYTFVPTNADTLCIGYHANNSTDTVDTILERNVTVTHSVNLL	357
Pig;	EDKHNGRLCKLGGIAPLHLGKCNIAGWLLGNPECESLFTVSSWSYIVETS
AEA29582.1;	NSYNGTCYPGDFINYEELREQLSSVSSFERFEIFPKASSWPNHETNKGVTA
H1N1	ACSHAGTKSFYRNLIWLVKKGNSYPNISKSYFNNKGNEVLVLWGIHHPS
	TNNDQQTLYQNADTYVFVGTSKYNKKFKPEIAIRPKVRDQEGRMNYYW
	TLVEPGDKITFEATGNLVVPRYAFAMERNAGSGIIISDTPVHDCNTTCQTP
	KGAINTSLPFQNIHPTTIGKCPKYVKSTKLRLATGLRNVPSIQSRGLFGAIA
	GFIEGGWTGMVDGWYGYHHQNEQGSGYAADQKSTQNAIDGITNKVNS
	VIEKMNTQFTAVGKEFNHLEKRIENLNKKVDDGFLDVWTYNAELLILLE
	NERTLDFHDSNVKNLYEKARRQLKNNAKEIGNGCFEFYHKCDNACMES
	VKNGTYDYPKYSEESRLNREEISGVKLDSTRIYQILAIYSTVASSSVLLVS
	LGAISFWMCSNGSLQCRICI
NA;	MNTNQRIITIGTVCLTVGIISLLLQIGNIVSLWISHSIQTGGKNHTEMCNKN	358
Pig;	VITYVNNTWVNRTYVNISNTKIVNVQDVVSVILTGNSSLCPISGWAIYSK
AHB21162.1;	DNSIRIGSKGDIFVIREPFISCSHLECRTFFLTQGALLNDKHSNGTVKDRSP
H1N1	YRTLMSCPIGEAPSPYNSRFESVAWSASACHDGMGWLTIGISGPDNGAV
	AVLKYNGIITDTIKSWRNKILRTQESECVCMNGSCFTVLTDGPSNGQASY
	KIFKMEKGKIIKSIELDAPNYHYEECSCYPDAGKVMCVCRDNWHASNRP
	WVSFDQNLDYQIGYICSGVFGDNPRSNDGKGNCGPVHSNGANGVKGFS
	YRYGNGVWIGRTKSINSRSGFEMIWDPNGWTGTDSSFSMKQDIIALTDW
	SGYSGSFVQHPELTGMNCIRPCFWVELIRGQPKENTIWASGSSISFCGVN
	GETASWSWPDGADLPFTIDK

Exemplary animal HA and NA antigens, such as SEQ ID NOs: 349-358 of Table 5, may be bound (e.g., targeted) by a chimeric protein described herein (e.g., a chimeric protein comprising an antibody moiety that specifically binds to an animal HA protein or an animal NA protein of an influenza virus or a variant thereof). It should be understood that the chimeric proteins of the present invention may bind additional animal HA and NA influenza antigens and variants thereof, such as known animal HA and NA influenza antigen or variants thereof, or future animal HA and NA influenza antigen or variants thereof, all of which are encompassed by the scope of the present invention.

Exemplary animal anti-HA antibodies are provided in Table 6.

TABLE 6
CDR and VH/VL sequences of exemplary animal anti-HA antibodies
Antibody
Name;
Reference;
Target				SEQ
Species;	Target			ID
Ab Source	Strain	Sequence	Type	NO
G126;	H1	QSLEESGGDLVKPGASLTLTCTASGFSFSS	VH	383
QJD38416		SYWICWVRQAPGKGLEWIACIYAGSSGS
QJD38411;		AYFASWAKGRFTISETSSTTVTLQMTSLT
Swine;		AADTATYFCARAPSYTYGYAGYAYAYS
Rabbit		YYFNLWGPGTLVTVSS
		VMTQTPASVEVTMGGTVTINCQASQSIN	VL	384
		NELCWYQQKPGQRPKLLIYDASDLASGV
		PSRFKGSGSGTEFTLTISDLECADAATYYC
		QQDYSTNNVDNLFGGGTEVVVK
		SGFSFSSSY	HC-CDR1	359
		LEWIACIYAGSSGSAYF	HC-CDR2	360
		APSYTYGYAGYAYAYSYYEN	HC-CDR3	361
		QSINN	LC-CDR1	362
		PKLLYDASDLA	LC-CDR2	363
		DYSTNN	LC-CDR3	364
FY-UCA-VH;	H5	QVQLQQSGPGLVKPSQTLSLTCAISGDSV	VH	385
ANT83586		SSNNAVWNWIRQSPSRGLEWLGRTYYRS
ANT83603;		KWYNDYAESVKSRITINPDTSKNQFSLQL
Pan_IAV;		NSVTPEDTAVYYCARSGHITVFGVNVDA
Human		FDMWGQGTMVTVSS
		DIQMTQSPSSLSASVGDRVTITCRTSQSLS	VL	386
		SYTHWYQQKPGKAPKLLIYAASSRGSGV
		PSRFSGSGSGTDFTLTISSLQPEDFATYYC
		QQSRTFGQGTKVEIK
		SNNAVWN	HC-CDR1	365
		RTYYRSKWYNDYAESVKS	HC-CDR2	366
		SGHITVFGVNVDAFDM	HC-CDR3	367
		TRSQSLSSYLH	LC-CDR1	368
		AASSLQS	LC-CDR2	369
		QQSRT	LC-CDR3	370
AT10_004;	H1	EVQLVESGGGLIQPGGSLRLSCAASGFTV	VH	387
WO10130636;		SSNYVSWVRQAPGKGLEWLSLIYTGGTT
Cat;		YYADSVKGRFTISRDNSKNTVFLQMNSL
Human		RAEDAAMYYCARVSALRFLQWPNYAMD
		V
	H3	QSALTQPASVSGSPGRSITISCSGTRSDVG	VL	388
		GHNYVSWYQQHPGKAPKLMIYEVSHRPS
		GVSNRFSGSKSGSTASLTISGLQSEDEADY
		YCSSYTGEGPLGV
	H5	LIYTGGTTYYADSVKG	HC-CDR1	371
		VSALRFLQWPNYAMDV	HC-CDR2	372
		SGTRSDVGGHNYVS	HC-CDR3	373
		EVSHRPS	LC-CDR1	374
		SSYTGEGPLGV	LC-CDR2	375
		SYWMS	LC-CDR3	376
CR8001;	H1	QVQLVQSGAEVRKPGASVKVSCKASGYT	VH	389
WO13081463;		FTRHGISWVRQAPGQGLEWMGWISAYTG
Bird/Pig;		DTDYAQKFQGRVTMTTDTSTNTAYMEL
Human		RSLRSDDAAVYYCARLRLQGEVVVPPSQ
		SNWFDPWGQGTLVTVSS
	H3	EIVLTQSPATLSLYPGERATLSCRASQSVS	VL	390
		RYLAWYQQKPGQAPRLLIYDASNRATGI
		PARFSGSGSGTDFTLTISSLEPEDFAVYYC
		CDRQQRSNWLKITFGQGTRLEIKGTV
	H5	RHGIS	HC-CDR1	377
	H7	WISAYTGDTDYAQKFQG	HC-CDR2	378
	H9	GWGAVTSPFDF	HC-CDR3	379
		GWGAVTSPFDF	LC-CDR1	380
		DASNRAT	LC-CDR2	381
		QQRSNWLK	LC-CDR3	382

In some embodiments, the antibody moiety of a chimeric protein comprises animal anti-HA or anti-NA antibody or antigen binding fragment thereof that comprises an HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3 of any one of the antibodies of Table 6. In some embodiments, the antibody moiety comprises an animal anti-HA antibody or antigen binding fragment thereof that comprises a V_H and V_L of any one of the antibodies of Table 6.

In some embodiments, the antibody moiety comprises an animal anti-HA antibody or antigen binding fragment thereof comprising: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 359, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 360, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 361, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 362, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 363, or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 364, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the animal anti-HA antibody or antigen binding fragment thereof comprises i) a V_H Comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 359, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 360, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 361; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 362, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 363, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 364.

In some embodiments, the animal anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 359, 360, and 361; and a V_L comprising the amino acid sequences of SEQ ID NOs: 362, 363, and 364. In some embodiments, the animal anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 383 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 384. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 383, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 383, and a V_L comprising the amino acid sequence of SEQ ID NO: 384, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 384.

In some embodiments, the antibody moiety comprises an animal anti-HA antibody or antigen binding fragment thereof comprising: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 365, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 366, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 367, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 368, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 369, or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 370, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the animal anti-HA antibody or antigen binding fragment thereof comprises i) a V_H Comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 365, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 366, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 367; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 368, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 369, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 370.

In some embodiments, the animal anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 365, 366, and 367; and a V_L comprising the amino acid sequences of SEQ ID NOs: 368, 369, and 370. In some embodiments, the animal anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 385 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 386. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 385, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 385, and a V_L comprising the amino acid sequence of SEQ ID NO: 386, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 386.

In some embodiments, the antibody moiety comprises an animal anti-HA antibody or antigen binding fragment thereof comprising: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 371, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 372, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 373, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 374, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 375, or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 376, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the animal anti-HA antibody or antigen binding fragment thereof comprises i) a V_H Comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 371, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 372, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 373; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 374, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 375, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 376.

In some embodiments, the animal anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 371, 372, and 373; and a V_L comprising the amino acid sequences of SEQ ID NOs: 374, 375, and 376. In some embodiments, the animal anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 387 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 388. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 387, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 387, and a VL comprising the amino acid sequence of SEQ ID NO: 388, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 389.

In some embodiments, the antibody moiety comprises an animal anti-HA antibody or antigen binding fragment thereof comprising: i) a V_H comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 377, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 378, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 379, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 380, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 381, or a variant thereof comprising up to about 3 (such as about any of 1, 2, or 3) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 382, or a variant thereof comprising up to about 5 (such as about n, where n is selected from 1, 2, 3, 4, and 5) amino acid substitutions. In some embodiments, the animal anti-HA antibody or antigen binding fragment thereof comprises i) a V_H Comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 377, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 378, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 379; and ii) a V_L comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 380, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 381, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 382.

In some embodiments, the animal anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequences of SEQ ID NOs: 377, 378, and 379; and a V_L comprising the amino acid sequences of SEQ ID NOs: 380, 381, and 382. In some embodiments, the animal anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 of the amino acid sequence of SEQ ID NO: 389 and a V_L comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 of the amino acid sequence of SEQ ID NO: 390. In some embodiments, the anti-HA antibody or antigen binding fragment thereof comprises a V_H comprising the amino acid sequence of SEQ ID NO: 389, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 389, and a V_L comprising the amino acid sequence of SEQ ID NO: 390, or a variant thereof comprising at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of SEQ ID NO: 390.

In some embodiments, the animal anti-HA antibody or antigen binding fragment thereof specifically binds to the HA protein of an influenza virus or a variant thereof. In some embodiments, the animal anti-HA antibody or antigen binding fragment thereof specifically binds to the HA1 region (e.g., the globular “head” region) of the HA protein. In some embodiments, the binding of the animal anti-HA antibody or antigen binding fragment thereof to the HA1 region of the HA protein prevents binding of an influenza virus or variant thereof to a sialic acid receptor. In some embodiments, the animal anti-HA antibody or antigen binding fragment thereof specifically binds to the HA2 region (e.g., the “stem” region) of the HA protein. In some embodiments, binding of the animal anti-HA antibody or antigen binding fragment thereof to the HA2 region of the HA protein prevents fusion of an influenza virus or variant thereof viral membrane with that of a host cell. In some embodiments, the animal anti-HA antibody or antigen binding fragment thereof is a neutralizing antibody.

In some embodiments, the animal anti-HA antibody or antigen binding fragment thereof specifically binds to the HA protein of an influenza virus or variant thereof with a K_D of no more than about n, where n is selected from 100 nM, 50 nM, 20 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.75 nM, 0.5 nM, 0.2 nM, 0.1 nM, 0.05 nM, and 0.01 nM, or less, including any values and ranges in between these values. In some embodiments, the animal anti-HA antibody or antigen binding fragment thereof specifically binds to the HA protein of an influenza virus or variant thereof with a K_D of about 0.01 nM to about 0.1 nM, about 0.1 nM to about 1 nM, about 1 nM to about 5 nM, about 5 nM to about 10 nM, about 10 nM to about 100 nM, about 0.01 nM to about 1 nM, about 0.5 nM to about 10 nM, about 0.1 nM to about 1 nM, about 0.1 nM to about 10 nM, or about 0.01 nM to about 100 nM.

In some embodiments, the antibody moiety can comprise an animal anti-HA antibody that competes for binding to an HA protein of an influenza virus or variant thereof with a second anti-HA antibody according to any of the anti-HA antibodies described herein. In some embodiments, the animal anti-HA antibody can bind to the same, or substantially the same, epitope as the second anti-HA antibody. In some embodiments, binding of the animal anti-HA antibody to an HA protein of an influenza virus or variant thereof can inhibit the binding of a second animal anti-HA antibody to the same HA protein of an influenza virus or variant by at least about 70% (such as at least about n %, where n % is selected from 75%, 80%, 85%, 90%, 95%, 98%, and 99%), or vice versa. In some embodiments, the animal anti-HA antibody and the second animal anti-HA antibody can cross-compete for binding to the HA protein of an influenza virus or variant, i.e., each of the animal anti-HA antibody moieties can compete with the other for binding to the HA protein of an influenza virus or variant.

Animal anti-NA antibodies or antigen binding fragments thereof are also contemplated. Exemplary animal anti-NA antibodies targeting the NA protein of zoonotic IAV strain H7N9 have been published in the literature (D3 and 7H2, Xiong, et al., Emerging Microbes & Infections 9(1):78-87) (2020). Additionally, a camelid antibody directed to another zoonotic strain, IAV H5N1 (N1-V_HH, Cardoso, et al. Journal of Virology, 88(15):8278-96 (2014)) has been described.

In some embodiments, the animal anti-NA antibody or antigen binding fragment thereof specifically binds to the NA protein of an influenza virus or a variant thereof. In some embodiments, the animal anti-NA antibody prevents the cleavage of terminal sialic acid residues from N-linked glycans present on host cell surfaces and progeny virions of the influenza virus or variant thereof. In some embodiments, the animal anti-NA antibody or antigen binding fragment thereof specifically binds to the enzymatic active site of the NA protein. In some embodiments, binding of the enzymatic active site of the NA protein by the animal anti-NA antibody prevents the cleavage of terminal sialic acid residues from N-linked glycans present on host cell surfaces and progeny.

In some embodiments, the animal anti-NA antibody or antigen binding fragment thereof specifically binds to the NA protein of an influenza virus or variant thereof with a K_D of no more than about n, where n is selected from 100 nM, 50 nM, 20 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.75 nM, 0.5 nM, 0.2 nM, 0.1 nM, 0.05 nM, and 0.01 nM, or less, including any values and ranges in between these values. In some embodiments, the animal anti-NA antibody or antigen binding fragment thereof specifically binds to the NA protein of an influenza virus or variant theoefor with a K_D of about 0.01 nM to about 0.1 nM, about 0.1 nM to about 1 nM, about 1 nM to about 5 nM, about 5 nM to about 10 nM, about 10 nM to about 100 nM, about 0.01 nM to about 1 nM, about 0.5 nM to about 10 nM, about 0.1 nM to about 1 nM, about 0.1 nM to about 10 nM, or about 0.01 nM to about 100 nM.

In some embodiments, the antibody moiety can comprise an animal anti-NA antibody that competes for binding to an NA protein of an influenza virus or variant thereof with a second anti-NA antibody according to any of the anti-NA antibodies described herein. In some embodiments, the animal anti-NA antibody can bind to the same, or substantially the same, epitope as the second anti-NA antibody. In some embodiments, binding of the animal anti-HA antibody to an NA protein of an influenza virus or variant thereof can inhibit the binding of a second animal anti-NA antibody to the same NA protein of an influenza virus or variant by at least about 70% (such as at least about n %, where n % is selected from 75%, 80%, 85%, 90%, 95%, 98%, and 99%), or vice versa. In some embodiments, the animal anti-NA antibody and the second animal anti-NA antibody can cross-compete for binding to the NA protein of an influenza virus or variant, i.e., each of the animal anti-NA antibody moieties can compete with the other for binding to the HA protein of an influenza virus or variant.

B. Fc Region

The antibodies, e.g., the antibody moiety of the chimeric proteins described herein, in some embodiments comprise an Fc region. The term “Fc region,” “Fc domain” or “FC” refers to a C-terminal non-antigen binding region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native Fc regions and variant Fc regions. In some embodiments, a human IgG heavy chain Fc region extends from Cys226 to the carboxyl-terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present, without affecting the structure or stability of the Fc region. Unless otherwise specified herein, numbering of amino acid residues in the IgG or Fc region is according to the EU numbering system for antibodies, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991).

In some embodiments, the Fc fragment comprises an immunoglobulin IgG heavy chain constant region comprising a hinge region (starting at Cys226), an IgG CH2 domain and CH3 domain. The term “hinge region” or “hinge sequence” as used herein refers to the amino acid sequence located between the linker and the CH2 domain. In some embodiments, the fusion protein comprises an Fc fragment comprising a hinge region. In some embodiments, the fusion protein comprises an Fc fragment that does not comprise the hinge region.

In some embodiments, the anti-HA or anti-NA antibody comprises an Fc fragment selected from the group consisting of Fc fragments from IgG, IgA, IgD, IgE, IgM, and combinations and hybrids thereof. IgG's, IgA's and IgD's Fc fragments comprise CH₂ and CH₃, while IgE's and IgM's Fc fragments comprise CH₂, CH₃, and CH₄. In some embodiments, the Fc fragment is derived from a human IgG. In some embodiments, the Fc fragment comprises the Fc region of human IgG₁, IgG₂, IgG₃, IgG4, or a combination or hybrid IgG. In some embodiments, the Fc fragment is an IgG₁ Fc fragment. In some embodiments, the Fc fragment comprises the CH₂ and CH₃ domains of IgG₁. In some embodiments, the Fc fragment is an IgG₄ Fc fragment. In some embodiments, the Fc fragment comprises the CH₂ and CH₃ domains of IgG₄. IgG₄ Fc is known to exhibit less effector activity than IgG₁ Fc, and thus may be desirable for some applications. In some embodiments, the Fc fragment is derived from of a mouse immunoglobulin.

In some embodiments, the IgG CH₂ domain starts at Ala231. In some embodiments, the CH₃ domain starts at Gly341. It is understood that the C-terminus Lys residue of human IgG can be optionally absent. It is also understood that conservative amino acid substitutions of the Fc region without affecting the desired structure and/or stability of Fc is contemplated within the scope of the invention.

In some embodiments of the chimeric proteins disclosed herein, especially the embodiments wherein the chimeric protein comprises an Fc region or a fragment thereof such as CH₂, the chimeric protein binds to or recruits a component of the complement system, known as the C1 complex (C1qC1r2C1s2). Such recruitment can initiate a cleavage cascade involving C2, C3, C4, and C5, and subsequently trigger microbial clearance. The microbial clearance can result from the so-called “classical complement pathway,” which depends on further downstream complement components, e.g., the membrane attack complex (MAC), thereby killing the microbial targets, e.g., bacterial cells or enveloped viruses. See Mellors et al., 2020. Microbial clearance may also be achieved through a C1- and C4-dependent antiviral mechanism that is independent of downstream complement components. With assistance from C1, which is recruited by Fc or just CH₂ (a fragment of Fc), C4 directly inactivates the virus capsid and neutralizes viruses. See Bottermann et al., Cell Host & Microbe, 25:617-629 (2019). As used herein, the term “activation of the complement pathway” includes activation of the classical complement pathway and/or the C4-dependent antiviral pathway.

Additionally, anti-HA or anti-NA antibodies comprising any of the Fc variants known in the art, or combinations thereof, are contemplated. In some embodiments, the Fc fragment comprises sequence that has been altered or otherwise changed so that it has enhanced antibody dependent cellular cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC) effector function.

In some embodiments, each chain of the Fc fragment is fused to the same entity. In some embodiments, the anti-HA or anti-NA antibody comprises two identical anti-HA or anti-NA antibody moieties described herein, each fused with one chain of the Fc fragment. In some embodiments, the two chains of the Fc fragment are identical. In some embodiments, the anti-HA or anti-NA antibody comprising the Fc fragment is a homodimer.

In some embodiments, each chain of the Fc fragment is fused to a different entity. In some embodiments, the anti-HA or anti-NA antibody comprises two different anti-HA or anti-NA antibody moieties, each fused to one chain of the Fc fragment. In some embodiments, the two anti-HA or anti-NA antibody moieties are different, but both specifically recognize an HA or NA protein, respectively. In some embodiments, the anti-HA or anti-NA antibody is monovalent, i.e., only one anti-HA or anti-NA antibody moiety is fused to one chain of the Fc fragment, and the second chain of the Fc fragment is not fused to an anti-HA or anti-NA antibody moiety, respectively. In some embodiments, the anti-HA or anti-NA antibody comprising the Fc fragment is a heterodimer.

Heterodimerization of non-identical polypeptides in the anti-HA or anti-NA antibody can be facilitated by methods known in the art, including without limitation, heterodimerization by the knob-into-hole technology. The structure and assembly method of the knob-into-hole technology can be found in, e.g., U.S. Pat. Nos. 5,821,333, 7,642,228, US 2011/0287009, and PCT/US2012/059810, hereby incorporated by reference in their entireties. This technology was developed by introducing a “knob” (or a protuberance) by replacing a small amino acid residue with a large one in the CH₃ domain of one Fc and introducing a “hole” (or a cavity) in the CH₃ domain of the other Fc by replacing one or more large amino acid residues with smaller ones. In some embodiments, one chain of the Fc fragment in the fusion protein comprises a knob, and the second chain of the Fc fragment comprises a hole.

The preferred residues for the formation of a knob are generally naturally occurring amino acid residues and are preferably selected from arginine (R), phenylalanine (F), tyrosine (Y) and tryptophan (W). Most preferred are tryptophan and tyrosine. In one embodiment, the original residue for the formation of the knob has a small side chain volume, such as alanine, asparagine, aspartic acid, glycine, serine, threonine or valine. Exemplary amino acid substitutions in the CH₃ domain for forming the knob include without limitation the T366W, T366Y or F405W substitution.

The preferred residues for the formation of a hole are usually naturally occurring amino acid residues and are preferably selected from alanine (A), serine (S), threonine (T) and valine (V). In one embodiment, the original residue for the formation of the hole has a large side chain volume, such as tyrosine, arginine, phenylalanine or tryptophan. Exemplary amino acid substitutions in the CH₃ domain for generating the hole include without limitation the T366S, L368A, F405A, Y407A, Y407T and Y407V substitutions. In certain embodiments, the knob comprises T366W substitution, and the hole comprises the T366S/L368A/Y407V substitutions. It is understood that other modifications to the Fc region known in the art that facilitate heterodimerization are also contemplated and encompassed by the instant application.

C. Variants

In some embodiments, amino acid sequence variants of the anti-HA or anti-NA antibody moieties of the chimeric proteins, and amino acid sequence variants of the chimeric proteins provided herein (e.g., in the peptide linker and/or in the mucoadhesive peptide fragment), are contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody moieties. Amino acid sequence variants of an antibody moiety (e.g., an anti-HA or anti-NA antibody or antigen-binding fragment thereof) may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody moiety, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antibody moiety (e.g., an anti-HA or anti-NA antibody or antigen-binding fragment thereof). Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., target-binding.

In some embodiments, variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include the HVRs and FRs of antibody moieties. Amino acid substitutions may be introduced into an antibody moiety of interest (e.g., an anti-HA or anti-NA antibody or antigen-binding fragment thereof) and the products screened for a desired activity, e.g., retained/improved target binding or decreased immunogenicity.

Conservative substitutions are shown in Table B below.

TABLE B
Conservative amino acid substitutions
	Original	Exemplary	Preferred
	Residue	Substitutions	Substitutions
	Ala (A)	Val; Leu; Ile	Val
	Arg (R)	Lys; Gln; Asn	Lys
	Asn (N)	Gln; His; Asp, Lys; Arg	Gln
	Asp (D)	Glu; Asn	Glu
	Cys (C)	Ser; Ala	Ser
	Gln (Q)	Asn; Glu	Asn
	Glu (E)	Asp; Gln	Asp
	Gly (G)	Ala	Ala
	His (H)	Asn; Gln; Lys; Arg	Arg
	Ile (I)	Leu; Val; Met; Ala; Phe; Norleucine	Leu
	Leu (L)	Norleucine; Ile; Val; Met; Ala; Phe	Ile
	Lys (K)	Arg; Gln; Asn	Arg
	Met (M)	Leu; Phe; Ile	Leu
	Phe (F)	Trp; Leu; Val; Ile; Ala; Tyr	Tyr
	Pro (P)	Ala	Ala
	Ser (S)	Thr	Thr
	Thr (T)	Val; Ser	Ser
	Trp (W)	Tyr; Phe	Tyr
	Tyr (Y)	Trp; Phe; Thr; Ser	Phe
	Val (V)	Ile; Leu; Met; Phe; Ala; Norleucine	Leu

Amino acids may be grouped into different classes according to common side-chain properties:

• • a. hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile;
  • b. neutral hydrophilic: Cys, Ser, Thr, Asn, Gln;
  • c. acidic: Asp, Glu;
  • d. basic: His, Lys, Arg;
  • e. residues that influence chain orientation: Gly, Pro;
  • f. aromatic: Trp, Tyr, Phe.

Non-conservative substitutions will entail exchanging a member of one of these classes for another class.

An exemplary substitutional variant is an affinity matured antibody moiety, which may be conveniently generated, e.g., using phage display-based affinity maturation techniques. Briefly, one or more CDR residues are mutated and the variant antibody moieties displayed on phage and screened for a particular biological activity (e.g., binding affinity). Alterations (e.g., substitutions) may be made in HVRs, e.g., to improve antibody moiety affinity. Such alterations may be made in HVR “hotspots,” i.e., residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and/or specificity determining residues (SDRs), with the resulting variant VH or VL being tested for binding affinity. Affinity maturation by constructing and reselecting from secondary libraries has been described, e.g., in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001).)

In some embodiments of affinity maturation, diversity is introduced into the variable genes chosen for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody moiety variants with the desired affinity. Another method to introduce diversity involves HVR-directed approaches, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding may be specifically identified, e.g., using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 in particular are often targeted.

In some embodiments, substitutions, insertions, or deletions may occur within one or more HVRs so long as such alterations do not substantially reduce the ability of the antibody moiety to bind antigen. For example, conservative alterations (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity may be made in HVRs. Such alterations may be outside of HVR “hotspots” or SDRs. In some embodiments of the variant VH and VL sequences provided above, each HVR either is unaltered, or contains no more than one, two or three amino acid substitutions.

A useful method for identification of residues or regions of an antibody moiety that may be targeted for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham and Wells Science, 244:1081-1085 (1989). In this method, a residue or group of target residues (e.g., charged residues such as arg, asp, his, lys, and glu) are identified and replaced by a neutral or negatively charged amino acid (e.g., alanine or polyalanine) to determine whether the interaction of the antibody moiety with its target is affected. Further substitutions may be introduced at the amino acid locations demonstrating functional sensitivity to the initial substitutions. Alternatively, or additionally, a crystal structure of an antibody moiety-target complex can be determined to identify contact points between the antibody moiety and the target. Such contact residues and neighboring residues may be targeted or eliminated as candidates for substitution. Variants may be screened to determine whether they contain the desired properties.

Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antibody moiety with an N-terminal methionyl residue. Other insertional variants of the antibody moiety include the fusion to the N- or C-terminus of the antibody moiety to an enzyme (e.g., for ADEPT) or a polypeptide which increases the serum half-life of the antibody moiety.

D. Mucoadhesive Peptide Fragments

The chimeric proteins described herein comprise one or more (e.g., 1, 2, 3, 4 or more) mucoadhesive peptide fragments.

In some embodiments, the antibody moiety comprises the same number of polypeptide chains as the number of mucoadhesive peptide fragment(s) in the chimeric protein. In some embodiments, the antibody moiety comprises more polypeptide chains than the number of mucoadhesive peptide fragment(s) in the chimeric protein. In some embodiments, each polypeptide chain of the antibody moiety is coupled to (e.g., fused to) a mucoadhesive peptide fragment. In some embodiments, the antibody moiety comprises polypeptide chains that are not coupled (e.g., fused to) a mucoadhesive peptide fragment.

In some embodiments, the mucoadhesive peptide fragment is fused to any position in the antibody moiety that does not interference with binding of the antibody moiety to the component of an influenza virus or variant thereof. In some embodiments, the mucoadhesive peptide fragment is fused to a site that is distal from the antibody-binding site. In some embodiments, the mucoadhesive peptide fragment is fused to the C-terminus of an antibody heavy chain in the antibody moiety. In some embodiments, the mucoadhesive peptide fragment is fused to the C-terminus of an antibody light chain in the antibody moiety.

In some embodiments, the chimeric protein comprises a single polypeptide chain comprising the antibody moiety and a mucoadhesive peptide fragment.

In some embodiments, the chimeric protein comprises: (a) a first polypeptide comprising a first polypeptide chain of the antibody moiety and a first mucoadhesive peptide fragment; and (b) a second polypeptide comprising a second polypeptide of antibody moiety and a second mucoadhesive peptide fragment. In some embodiments, the antibody moiety further comprises polypeptide chains that are not coupled to (e.g., fused to) a mucoadhesive peptide fragment.

In some embodiments, the mucoadhesive peptide fragments comprises (including for example consisting of or consisting essentially of) about 10 to about 600 amino acid residues (e.g., positively charged amino acid residues plus non-positively charged amino acid residues).

In some embodiments, the mucoadhesive peptide fragment comprises (including for example consisting of or consisting essentially of) about 10 to about 20 amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises (including for example consisting of or consisting essentially of) about 22 to about 30 amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises (including for example consisting of or consisting essentially of) about 32 to about 40 amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises (including for example consisting of or consisting essentially of) about 42 to about 50 amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises (including for example consisting of or consisting essentially of) about 52 to about 60 amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises (including for example consisting of or consisting essentially of) about 16 to about 50 amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises (including for example consisting of or consisting essentially of) about 20 to about 44 amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises (including for example consisting of or consisting essentially of) about 24 to about 40 amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises (including for example consisting of or consisting essentially of) about 28 to about 36 amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises (including for example consisting of or consisting essentially of) about n amino acid residues, where n is selected from 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 300, 400, 500, and 600, or more. In some embodiments, the mucoadhesive peptide fragment comprises (including for example consisting of or consisting essentially of) between about n amino acid residues, where n is selected from 10-20, 21-30, 31-40, 41-50, 51-60, 61-70, 71-80, 81-90, 91-100, 101-110, 111-120, 121-130, 131-140, 141-150, 151-160, 161-170, 171-180, 181-190, 191-200,201-210,211-220,221-230,231-240,241-250,251-260,261-270, 271-280, 281-290, 291-300, 301-310, 311-320, 321-330, 331-340, 341-350, 351-360, 361-370, 371-380, 381-390, 391-400, 401-410, 411-420, 421-430, 431-440, 441-450, 451-460, 461-470, 471-480, 481-490, 491-500, 501-510, 511-520, 521-530, 531-540, 541-550, 551-560, 561-570, 571-580, 581-590, 591-600, 10-30, 10-40, 10-50, 16-30, 16-40, 16-50, 20-40, 20-50, 24-40, 24-50, 30-50-30-60, 10-60, 12-60, and 10-100. In some embodiments, the mucoadhesive peptide fragment comprises (including for example consisting of or consisting essentially of) at least about n amino acid residues, where n is selected from 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 300, 400, 500, and 600, or more. In some embodiments, the mucoadhesive peptide fragment comprises (including for example consisting of or consisting essentially of) no more than about about n amino acid residues, where n is selected from 600, 500, 400, 300, 200, 180, 160, 140, 120, 100, 90, 80, 70, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, and 10.

In some embodiments, the mucoadhesive peptide fragment comprises about 5 to about 300 positively charged amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises about 5 to about 10 positively charged amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises about 11 to about 15 positively charged amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises about 16 to about 20 positively charged amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises about 21 to about 25 positively charged amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises about 26 to about 30 positively charged amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises about 8 to about 25 positively charged amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises about 10 to about 22 positively charged amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises about 12 to about 20 positively charged amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises about 14 to about 18 positively charged amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises about n positively charged amino acid residues, where n is selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, and 300, or more. In some embodiments, the mucoadhesive peptide fragment comprises between about n positively charged amino acid residues, where n is selected from 5-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, 96-100, 101-110, 111-120, 121-130, 131-140, 141-150, 151-160, 161-170, 171-180, 181-190, 191-200,201-210,211-220,221-230,231-240,241-250,251-260,261-270, 271-280, 281-290, 291-300, 5-15, 5-20, 5-25, 8-15, 8-20, 8-25, 10-20, 10-25, 12-20, 12-25, 15-25, 15-30, 5-30, 6-30, and 5-50. In some embodiments, the mucoadhesive peptide fragment comprises at least about n positively charged amino acid residues, where n is selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, and 300, or more. In some embodiments, the mucoadhesive peptide fragment comprises no more than about n positively charged amino acid residues, where n is selected from 300, 290, 280, 270, 260, 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 10, 9, 8, 7, 6, and 5.

In some embodiments, the mucoadhesive peptide fragment comprises at least about 5 positively charged amino acid residues (e.g., lysines, arginines, histidines, ornithines, and combinations thereof). In some embodiments, the mucoadhesive peptide fragment comprises at least about 5 positively charged amino acid residues (e.g., lysines, arginines, histidines, ornithines, and combinations thereof). In some embodiments, the mucoadhesive peptide fragment comprises at least about 6 positively charged amino acid residues (e.g., lysines, arginines, histidines, ornithines, and combinations thereof). In some embodiments, the mucoadhesive peptide fragment comprises about 5 to about 50 positively charged amino acid residues (e.g., lysines, arginines, histidines, ornithines, and combinations thereof). In some embodiments, the mucoadhesive peptide fragment comprises about 5 to about 30 positively charged amino acid residues (e.g., lysines, arginines, histidines, ornithines, and combinations thereof). In some embodiments, the mucoadhesive peptide fragment comprises about 5, 6, 12, 18, 24, or 30 positively charged amino acid residues (e.g., lysines, arginines, histidines, ornithines, and combinations thereof).

In some embodiments, the chimeric protein comprises two or more mucoadhesive peptide fragments. In some embodiments, each of the two or more mucoadhesive peptide fragments comprises about 5 to about 300 positively charged amino acid residues. In some embodiments, each of the two or more mucoadhesive peptide fragments comprises about 5 to about 10 positively charged amino acid residues. In some embodiments, each of the two or more mucoadhesive peptide fragments comprises about 11 to about 15 positively charged amino acid residues. In some embodiments, each of the two or more mucoadhesive peptide fragments comprises about 16 to about 20 positively charged amino acid residues. In some embodiments, each of the two or more mucoadhesive peptide fragments comprises about 21 to about 25 positively charged amino acid residues. In some embodiments, each of the two or more mucoadhesive peptide fragments comprises about 26 to about 30 positively charged amino acid residues. In some embodiments, each of the two or more mucoadhesive peptide fragments comprises about 8 to about 25 positively charged amino acid residues. In some embodiments, each of the two or more mucoadhesive peptide fragments comprises about 10 to about 22 positively charged amino acid residues. In some embodiments, each of the two or more mucoadhesive peptide fragments comprises about 12 to about 20 positively charged amino acid residues. In some embodiments, each of the two or more mucoadhesive peptide fragments comprises about 14 to about 18 positively charged amino acid residues. In some embodiments, each of the two or more mucoadhesive peptide fragments comprises about n positively charged amino acid residues, where n is selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, and 300, or more. In some embodiments, each of the two or more mucoadhesive peptide fragments comprises between about n positively charged amino acid residues, where n is selected from 5-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, 96-100, 101-110, 111-120, 121-130, 131-140, 141-150, 151-160, 161-170, 171-180, 181-190, 191-200,201-210,211-220,221-230,231-240,241-250,251-260, 261-270, 271-280, 281-290, 291-300, 5-15, 5-20, 5-25, 8-15, 8-20, 8-25, 10-20, 10-25, 12-20, 12-25, 15-25, 15-30, 5-30, 6-30, and 5-50. In some embodiments, each of the two or more mucoadhesive peptide fragments comprises at least about n positively charged amino acid residues, where n is selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, and 300, or more. In some embodiments, each of the two or more mucoadhesive peptide fragments comprises no more than about about n positively charged amino acid residues, where n is selected from 300, 290, 280, 270, 260, 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 10, 9, 8, 7, 6, and 5.

In some embodiments, the total number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) in the chimeric protein is about 5 to about 600. In some embodiments, the total number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) in the chimeric protein is about 5 to about 20. In some embodiments, the total number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) in the chimeric protein is about 11 to about 30. In some embodiments, the total number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) in the chimeric protein is about 16 to about 40. In some embodiments, the total number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) in the chimeric protein is about 21 to about 50. In some embodiments, the total number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) in the chimeric protein is about 26 to about 60. In some embodiments, the total number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) in the chimeric protein is about 8 to about 50. In some embodiments, the total number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) in the chimeric protein is about 10 to about 44. In some embodiments, the total number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) in the chimeric protein is about 12 to about 40. In some embodiments, the total number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) in the chimeric protein is about 14 to about 36. In some embodiments, the total number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) in the chimeric protein is about n positively charged amino acid residues, where n is selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 550, and 600, or more. In some embodiments, the total number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) in the chimeric protein is between about n positively charged amino acid residues, where n is selected from 5-10, 11-15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71-75, 76-80, 81-85, 86-90, 91-95, 96-100, 101-110, 111-120, 121-130, 131-140, 141-150, 151-160, 161-170, 171-180, 181-190, 191-200,201-210,211-220,221-230,231-240,241-250,251-160,261-270,271-280,281-290, 291-300, 301-310, 311-320, 321-330, 331-340, 341-350, 351-360, 361-370, 371-380, 381-390, 391-400, 401-410, 411-420, 421-430, 431-440, 441-450, 451-460, 461-470, 471-480, 481-490, 491-500, 501-510, 511-520, 521-530, 531-540, 541-550, 551-560, 561-570, 571-580, 581-590, 591-600, 5-15, 5-20, 5-25, 8-15, 8-20, 8-25, 10-20, 10-25, 12-20, 12-25, 15-25, 15-30, 5-30, 6-30, and 5-50. In some embodiments, the total number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) in the chimeric protein is at least about n positively charged amino acid residues, where n is selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, and 600, or more. In some embodiments, the total number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) in the chimeric protein is no more than about n positively charged amino acid residues, where n is selected from 600, 590, 580, 570, 560, 550, 540, 530, 520, 510, 500, 490, 480, 470, 460, 450, 440, 430, 420, 410, 400, 390, 380, 370, 360, 350, 340, 330, 320, 310, 300, 290, 280, 270, 260, 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 10, 9, 8, 7, 6, and 5.

In some embodiments, the number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) per antibody moiety is about 5 to about 30. In some embodiments, the number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) per antibody moiety is about 8 to about 25. In some embodiments, the number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) per antibody moiety is about 10 to about 22. In some embodiments, the number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) per antibody moiety is about 12 to about 20. In some embodiments, the number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) per antibody moiety is about 14 to about 18. In some embodiments, the number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) per antibody moiety is about n positively charged amino acid residues, where n is selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30, or more. In some embodiments, the number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) per antibody moiety is between about about n positively charged amino acid residues, where n is selected from 5-10, 11-15, 16-20, 21-25, 26-30, 5-15, 5-20, 5-25, 8-15, 8-20, 8-25, 10-20, 10-25, 12-20, 12-25, 15-25, 15-30, 5-30, and 6-30. In some embodiments, the number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) per antibody moiety is at least about about n positively charged amino acid residues, where n is selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, and 30, or more. In some embodiments, the number of positively charged amino acid residues in the mucoadhesive peptide fragment(s) per antibody moiety is no more than about n positively charged amino acid residues, where n is selected from 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 10, 9, 8, 7, 6, and 5.

The mucoadhesive peptide fragment(s) may comprise any suitable positively charged amino acid residues at physiological pH of the mucosa, including naturally occurring and synthetic amino acid residues such as lysine, arginine, histidine, ornithine, and combinations thereof. In some embodiments, the mucoadhesive peptide fragment comprises lysines only. In some embodiments, the mucoadhesive peptide fragment comprises arginines only. In some embodiments, the mucoadhesive peptide fragment comprises histidines only. In some embodiments, the mucoadhesive peptide fragment comprises ornithines only.

In some embodiments, the mucoadhesive peptide fragment comprises both lysines and arginines. In some embodiments, the mucoadhesive peptide fragment comprises an equal number of lysines and arginines. In some embodiments, the mucoadhesive peptide fragment comprises unequal numbers of lysines and arginines. In some embodiments, the mucoadhesive peptide fragment comprises both lysines and histidines. In some embodiments, the mucoadhesive peptide fragment comprises an equal number of lysines and histidines. In some embodiments, the mucoadhesive peptide fragment comprises unequal numbers of lysines and histidines. In some embodiments, the mucoadhesive peptide fragment comprises both lysines and ornithines. In some embodiments, the mucoadhesive peptide fragment comprises an equal number of lysines and ornithines. In some embodiments, the mucoadhesive peptide fragment comprises unequal numbers of lysines and ornithines. In some embodiments, the mucoadhesive peptide fragment comprises both arginines and ornithines. In some embodiments, the mucoadhesive peptide fragment comprises an equal number of arginines and ornithines. In some embodiments, the mucoadhesive peptide fragment comprises an unequal number of arginines and ornithines. In some embodiments, the mucoadhesive peptide fragment comprises both arginines and histidines. In some embodiments, the mucoadhesive peptide fragment comprises an equal number of arginines and histidines. In some embodiments, the mucoadhesive peptide fragment comprises an unequal number of ornithines and histidines. In some embodiments, the mucoadhesive peptide fragment comprises both ornithines and histidines. In some embodiments, the mucoadhesive peptide fragment comprises an equal number of ornithines and histidines. In some embodiments, the mucoadhesive peptide fragment comprises an unequal number of ornithines and histidines. In some embodiments, the mucoadhesive peptide fragment comprises lysines, arginines, and ornithines. In some embodiments, the mucoadhesive peptide fragment comprises an equal number of lysines, arginines, and ornithines. In some embodiments, the mucoadhesive peptide fragment comprises unequal numbers of lysines, arginines, and ornithines. In some embodiments, the mucoadhesive peptide fragment comprises histidines, arginines, and ornithines. In some embodiments, the mucoadhesive peptide fragment comprises an equal number of histidines, arginines, and ornithines. In some embodiments, the mucoadhesive peptide fragment comprises unequal numbers of histidines, arginines, and ornithines. In some embodiments, the mucoadhesive peptide fragment comprises lysines, histidines, and ornithines. In some embodiments, the mucoadhesive peptide fragment comprises an equal number of lysines, histidines, and ornithines. In some embodiments, the mucoadhesive peptide fragment comprises unequal numbers of lysines, histidines, and ornithines. In some embodiments, the mucoadhesive peptide fragment comprises lysines, arginines, and histidines. In some embodiments, the mucoadhesive peptide fragment comprises an equal number of lysines, arginines, and histidines. In some embodiments, the mucoadhesive peptide fragment comprises unequal numbers of lysines, arginines, and histidines. In some embodiments, the mucoadhesive peptide fragment comprises lysines, arginines, histidines, and ornithines. In some embodiments, the mucoadhesive peptide fragment comprises an equal number of lysines, arginines, histidines, and ornithines. In some embodiments, the mucoadhesive peptide fragment comprises unequal numbers of lysines, arginines, histidines, and ornithines. In some embodiments, the mucoadhesive peptide fragment(s) comprises one or more non-naturally occurring amino acid residues that are positively charged at physiological pH of the mucosa.

In some embodiments, the mucoadhesive peptide fragment has an isoelectric point (pI) higher than the pH of the mucosa. The pH values of various mucosa in human are known. For example, the human nasal mucosa may have a pH range of about 5.5 to about 6.5, about 5.5 to about 6.6, about 6.44 to about 6.91, about 6.4 to about 7.9, or about 6.4 to about 6.5. In some examples, the human nasal mucosa may have a pH of about 6.6. In other examples, the human tracheal mucosa may have a pH range of about 6.1 to about 7.9, or a pH of about 6.71. In further examples, the human bronchial mucosa may have a pH range of about 5.7 to about 6.6 or about 7 to about 7.5. In some examples, the human bronchial mucosa may have a pH of about 6.7, about 7.1, about 6.25, about 6.78, or about 6.58. In some examples, the human mucosa may be diseased. In such examples, smokers may have a sputum mucosa pH of about 7.25 or about 6.82. In other examples, patients suffering with chronic bronchitis may have a sputum mucoid pH of about 7.59 and/or a sputum purulent pH of about 7.83. In other examples, patients suffering with rhinitis may have a nasal mucosa pH range of about 7.2 to about 8.3. In other examples still, patients suffering with the common cold may have a mucosa pH range of about 7.2 to about 8.3.

In some embodiments, at nasal pH (e.g., ˜6.5), the various properties (e.g., pI, net charge, and molecular weight) of polycationic peptides described herein may be calculated. In some examples, at nasal pH (e.g., ˜6.5), the equivalent of a 20-mer polypeptide may be calculated. The 20-mer polypeptide will be linear, and the size of each polypeptide will be proportional to the molecular weight. The pI and molecular weight of various exemplary 20-mer polypeptides at nasal pH were calculated and are listed in Table 7. The interactions between the positively charged polypeptides and mucosal cells or mucin may primarily occur by charge.

TABLE 7
Exemplary amino acid and corresponding 20-mer
polypeptides properties at nasal pH
Amino acid		Net	Molecular
or polypeptide	pI	charge	weight (Da)
Lysine (K)	8.8	+1	146.2
Arginine (R)	10.0	+1	174.2
Histidine (H)	7.2	+0.5	155.2
K-20	11.3	+20	2581.5
R-20	13.3	+20	3141.8
H-20	8.1	+10	2760.8

In some embodiments, the pI range of the mucoadhesive peptide fragment is at least about n, where n is selected from 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11, 11.5, 12, 12.5, and 13, or more. In some embodiments, the pI range of the mucoadhesive peptide fragment is about 8 to about 14. In some embodiments, the range of pI values of the mucoadhesive peptide fragment is about 8.8 to about 10.0. In some embodiments, the range of pI values of the mucoadhesive peptide fragment is about 11.3 to about 13.3. In some embodiments, the range of pI values of the chimeric protein is at least about n, where n is selected from 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11, 11.5, 12, 12.5, and 13, or more, including, 8-8.3, 8.3-8.5, 8.5-8.7, 8.7-8.9, 8.9-9.1, 9.1-9.3, 9.3-9.4, 9.4-10, 8-10, 8-9, 9-10, 8-11, 8.5-9.5, 8.76-9.44, 8.77-9.61, and 8.32-9.33.

In some embodiments, the mucoadhesive peptide fragment is a polylysine peptide. In some embodiments, the mucoadhesive peptide fragment is a polylysine peptide having about n contiguous lysines, where n is selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30. In some embodiments, the mucoadhesive peptide fragment is a polylysine peptide having between about n contiguous lysines, where n is selected from 5-10, 10-15, 15-20, 20-25, 25-30, 30-40, 40-50, 5-15, 5-20, 5-25, 8-15, 8-20, 8-25, 10-20, 10-25, 12-20, 12-25, 15-25, 15-30, 5-30, 6-30, and 5-50.

In some embodiments, the mucoadhesive peptide fragment is a polyhistidine peptide. In some embodiments, the mucoadhesive peptide fragment is a polyhistidine peptide having about n contiguous histidines, where n is selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30. In some embodiments, the mucoadhesive peptide fragment is a polyhistidine peptide having between about n contiguous histidines, where n is selected from 5-10, 10-15, 15-20, 20-25, 25-30, 30-40, 40-50, 5-15, 5-20, 5-25, 8-15, 8-20, 8-25, 10-20, 10-25, 12-20, 12-25, 15-25, 15-30, 5-30, 6-30, and 5-50.

In some embodiments, the mucoadhesive peptide fragment is a polyarginine peptide. In some embodiments, the mucoadhesive peptide fragment is a polyarginine peptide having any about n contiguous arginines, where n is selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30. In some embodiments, the mucoadhesive peptide fragment is a polyarginine peptide having between about n contiguous arginines, where n is selected from 5-10, 10-15, 15-20, 20-25, 25-30, 30-40, 40-50, 5-15, 5-20, 5-25, 8-15, 8-20, 8-25, 10-20, 10-25, 12-20, 12-25, 15-25, 15-30, 5-30, 6-30, and 5-50.

In some embodiments, the mucoadhesive peptide fragment is a polyornithine peptide. In some embodiments, the mucoadhesive peptide fragment is a polyornithine peptide having about n contiguous ornithines, where n is selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30. In some embodiments, the mucoadhesive peptide fragment is a polyornithine peptide having between about n contiguous ornithines, where n is selected from 5-10, 10-15, 15-20, 20-25, 25-30, 30-40, 40-50, 5-15, 5-20, 5-25, 8-15, 8-20, 8-25, 10-20, 10-25, 12-20, 12-25, 15-25, 15-30, 5-30, 6-30, and 5-50.

In some embodiments, the mucoadhesive peptide fragment comprises a continuous stretch of positively charged amino acid residues. In some embodiments, the mucoadhesive peptide fragment comprises about n positively charged amino acid residues, such as arginines, histidines, lysines, or ornithines, or combinations thereof, where n is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30. In some embodiments, the mucoadhesive peptide fragment comprises between n contiguous positively charged amino acid residues, such as arginines, histidines, lysines, or ornithines, or combinations thereof, where n is selected from 2-5, 5-10, 10-15, 15-20, 20-25, 25-30, 30-40, 40-50, 2-15, 2-20, 2-25, 8-15, 8-20, 8-25, 10-20, 10-25, 12-20, 12-25, 15-25, 15-30, 2-30, 6-30, and 2-50. In some embodiments, all positively charged amino acid residues are contiguous with respect to each other.

In some embodiments, the mucoadhesive peptide fragment comprises one or more non-positively charged amino acid residues. In some embodiments, the non-positively charged amino acid residues are non-polar amino acids or polar uncharged amino acids. In some embodiments, the mucoadhesive peptide fragment comprises isoleucine, valine, alanine, tryptophan, leucine, glycine, methionine, proline, phenylalanine, threonine, cysteine, tyrosine, glutamine, serine, asparagine, or combinations thereof. In some embodiments, the mucoadhesive peptide fragment comprises one or more alanine, threonine, cysteine, serine, glutamine, asparagine, or combinations thereof. In some embodiments, the mucoadhesive peptide fragment comprises a combination of one or more isoleucines, valines, alanines, tryptophans, leucines, glycines, methionines, prolines, phenylalanines, threonines, cysteines, tyrosines, glutamines, serines, or asparagines. In some embodiments, the mucoadhesive peptide fragment comprises a combination of one or more alanines, threonines, cysteines, serines, glutamines, or asparagines. In some embodiments, the mucoadhesive peptide fragment(s) comprises one or more non-naturally occurring amino acid residues that are non-positively charged at physiological pH of the mucosa.

In some embodiments, the positively charged amino acid residues are interspersed with non-positively charged amino acid residues. In some embodiments, the positively charged amino acid residues are present in every other position in the mucoadhesive peptide fragment. In some embodiments, the positively charged amino acid residues are present in every third position in the mucoadhesive peptide fragment. In some embodiments, the positively charged amino acid residues are present in every fourth position in the mucoadhesive peptide fragment. In some embodiments, the positively charged amino acid residues are randomly dispersed in the mucoadhesive peptide fragment. In some embodiments, the positive charged residues are present in one or more clusters within the mucoadhesive peptide fragment.

In some embodiments, at least about n % of the amino acid residues in the mucoadhesive peptide fragment are positively charged amino acid residues, where n % is selected from 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, and 99%, or more. In some embodiments, all amino acid residues in the mucoadhesive peptide fragment are positively charged. In some embodiments, no more than about n % of the amino acid residues in the mucoadhesive peptide fragment are positively charged amino acid residues, where n % is selected from 99%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, and 10%. In some embodiments, between about n % of the amino acid residues in the mucoadhesive peptide fragment are positively charged amino acid residues, where n % is selected from 10%-99%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-80%, 10%-100%, 10%-30%, 30%-60%, 60%-90%, 20%-50%, and 50%-100%. In some embodiments, at least about 50% of the amino acid residues in the mucoadhesive peptide fragment are positively charged amino acid residues.

In some embodiments, at least about n % of the amino acid residues in the mucoadhesive peptide fragment are non-positively charged amino acid residues, where n % is selected from 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, and 50%, or more. In some embodiments, all amino acid residues in the mucoadhesive peptide fragment are positively charged. In some embodiments, no more than about n % of the amino acid residues in the mucoadhesive peptide fragment are non-positively charged amino acid residues, where n % is selected from 50%, 40%, 30%, 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, and 1%. In some embodiments, between about n % of the amino acid residues in the mucoadhesive peptide fragment are non-positively charged amino acid residues, where n % is selected from 1%-5%, 5%-10%, 10%-25%, 25%-50%, 1%-10%, 5%-15%, 10%-20%, 15%-25%, 20%-30%, 25%-35%, 30%-40%, 35%-45%, and 40%-50%. In some embodiments, no more than about 50% of the amino acid residues in the mucoadhesive peptide fragment are non-positively charged amino acid residues.

In some embodiments, the mucoadhesive peptide fragment is no more than about 15 kD. In some embodiments, the mucoadhesive peptide fragment is about 0.5 kD to about 50 kD. In some embodiments, the mucoadhesive peptide fragment is about 0.5 kD to about 15 kD. In some embodiments, the mucoadhesive peptide fragment is about 2 kD to about 12 kD. In some embodiments, the mucoadhesive peptide fragment is about 4 kD to about 10 kD. In some embodiments, the mucoadhesive peptide fragment is about 6 kD to about 14 kD. In some embodiments, the mucoadhesive peptide fragment is about n kD, where n kD is selected from a 0.5 kD, 1 kD, 2 kD, 3 kD, 4 kD, 5 kD, 6 kD, 7 kD, 8 kD, 9 kD, 10 kD, 11 kD, 12 kD, 13 kD, 14 kD, 15 kD, 20 kD, 25 kD, 30 kD, 35 kD, 40 kD, 45 kD, and 50 kD, or more. In some embodiments, the mucoadhesive peptide fragment is between about n kD, where n kD is selected from 0.5-1 kD, 1-2 kD, 2-3 kD, 4-5 kD, 5-6 kD, 6-7 kD, 8-9 kD, 9-10 kD, 10-11 kD, 11-12 kD, 12-13 kD, 13-14 kD, 14-15 kD, 15-20 kD, 20-25 kD, 25-30 kD, 30-35 kD, 35-40 kD, 40-45 kD, 45-50 kD, or more. In some embodiments, the mucoadhesive peptide fragment at least about n kD, where n kD is selected from 0.5 kD, 1 kD, 2 kD, 3 kD, 4 kD, 5 kD, 6 kD, 7 kD, 8 kD, 9 kD, 10 kD, 11 kD, 12 kD, 13 kD, 14 kD, 15 kD, 20 kD, 25 kD, 30 kD, 35 kD, 40 kD, 45 kD, 50 kD, or more. In some embodiments, the mucoadhesive peptide fragment is no more than about n kD, where n kD is selected from 50 kD, 45 kD, 40 kD, 35 kD, 30 kD, 25 kD, 20 kD, 15 kD, 14 kD, 13 kD, 12 kD, 11 kD, 10 kD, 9 kD, 8 kD, 7 kD, 6 kD, 5 kD, 4 kD, 3 kD, 2 kD, 1 kD, and 0.5 kD.

In some embodiments, the mucoadhesive peptide fragment does not facilitate penetration of the chimeric protein into a cell of the mucosa. In some embodiments, the mucoadhesive peptide fragment does not comprises a motif in a cell penetrating peptide. In some embodiments, the mucoadhesive peptide is not a cell penetrating peptide.

In some embodiments, the mucoadhesive peptide fragment is not a histidine tag. In some embodiments, the mucoadhesive peptide fragment is not a peptide consisting of, or consisting essentially of, six histidines.

In some embodiments, the mucoadhesive peptide fragment does not disrupt folding of the chimeric protein within a host cell expressing the chimeric protein. In some embodiments, at least about n % of chimeric protein expressed in a mammalian host cell is properly folded, where n % is selected from 20%, 30%, 40%, 50%, 60%, 70%, 80%, and 90%, or more.

In some embodiments, the mucoadhesive peptide fragment does not block secretion of the chimeric protein from a host cell expressing the chimeric protein. In some embodiments, at least about n % of chimeric protein expressed in a mammalian host cell is secreted, where n % is selected from 20%, 30%, 40%, 50%, 60%, 70%, 80%, and 90%, or more. Without being bound by any theory or hypothesis, proteins with positively charged fragments tend to be trapped in the Golgi apparatus of cells expressing the proteins. The chimeric proteins described herein are readily expressed and secreted by host cells, and do not get trapped in the Golgi apparatus.

In some embodiments, the mucoadhesive peptide fragment does not interfere with the specific binding between the antibody moiety and the component of an influenza virus or variant thereof. In some embodiments, the mucoadhesive peptide fragment reduces binding between the antibody moiety and the component of an influenza virus or variant thereof by no more than about n %, where n % is selected from 50%, 40%, 30%, 20%, and 10%, or less.

Exemplary mucoadhesive peptide fragments for incorporation into a chimeric protein of the present disclosure are provided herein and are shown in Table 8.

TABLE 8
Exemplary mucoadhesive peptides
	Percentage
Mucoadhesive	Positively		SEQ
Peptide	Charged		ID
Fragment	AA Residues	Sequence	NO
5H	100	HHHHH	407
6H	100	HHHHHH	291
12H	100	HHHHHHHHHHHH	292
30H	100	HHHHHHHHHHHHHHHHHHHHHHHHHHHHHH	293
6K	100	KKKKKK	294
12K	100	KKKKKKKKKKKK	295
30K	100	KKKKKKKKKKKKKKKKKKKKKKKKKKKKKKK	296
6R	100	RRRRRR	297
12R	100	RRRRRRRRRRRR	298
30R	100	RRRRRRRRRRRRRRRRRRRRRRRRRRRRRR	299
60	100	OOOOOO	300
120	100	OOOOOOOOOOOO	301
300	100	OOOOOOOOOOOOOOOOOOOOOOOOOOOOOO	302
6X-1	100	HHKKOO	303
6X-2	100	HORKHR	304
6X-3	83.3	HKRSOH	305
6X-4	83.3	RRHTHR	306
6X-7	100	KKOORR	307
6X-5	100	KKHHRR	308
6X-6	100	OORRHH	309
7X-1	85.7	KKKGKKK	408
12X-1	100	HHHKKKRRROOO	310
12X-2	75	HHOAKKRCOOQH	311
12X-3	100	HRKOORKHHRKK	312
12X-4	75	KRAHOKCORKSH	313
12X-5	100	KKRROOHHHRRR	314
12X-6	100	OOORRRKKKHHH	315
12X-7	66.7	KKAHHGKKAHHV	409
12X-8	66.7	KKARRGKKARRV	410
12X-9	58	KLIHKKARVRGK	411
15X-1	60	ILRRKAHHGKIKKVR	412
15X-2	57	GHRVKKAVRHIKRL	413
30X-1	100	HKROHKROHKROHKROHKROHKROHKROHK	316
30X-2	80	KOHRSOKRHTORHKAHORKCKROKQRKHOS	317
30X-3	80	KKROSRRHOTOOHHAROKHCKHROTRHKKS	318
30X-4	80	HRKQOHRSOOKTRRRAHROCHHHSRHOTHR	319
35X-1	65.7	GRHKAKNHIRRPKSRWKKWHKYRKVHRHKV	320
		HKGRR
40X-2	57.5	WRKVHHYKKQHKNRAHGKLKLRAKIHQRSR	321
		MHGKQKHYHR
42X-1	71.4	AHHKCRRGHKQKILHRRPHKFHRWKRVHKGR	322
		HGKKHRRHKHR
45X-1	67	QHRGKAKYHRTHHVKKQRHGRKNHKVHRHA	323
		RKFHKIRRLKCHKKH
50X-1	70	HNKRFKKGRHVRHSRHKSHRRTHKYHHWRHYRKVHRC	324
		KKAHKSHHRVHHK
50X-2	60	AHGRPHOFKROCKAHOVKHILKRTOSHOYKOVHQRNKO	325
		AOKMRKIRGGHK

It should be understood that additional mucoadhesive peptide fragments comprising similar percentages of positively charged and/or non-positively charged amino acid residues are also within the scope of the invention.

In some embodiments, the mucoadhesive peptide fragment comprises an amino acid sequence having at least about 90% sequence identity (such as at least about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 291-325 and 407-413. In some embodiments, mucoadhesive peptide fragment comprises the amino acid sequence of any one of SEQ ID NOs: 291-325 and 407-413, or a variant thereof comprising about 1, about 2, or about 3 amino acid substitutions. In some embodiments, the mucoadhesive peptide fragment comprises the amino acid sequence of any one of SEQ ID NOs: 291-325 and 407-413.

E. Linkers

In some aspects, the antibody moiety is linked to the mucoadhesive peptide fragment via a linker (such as a peptide linker, also referred herein as a connecting peptide). In some embodiments, the antibody moiety is not covalently linked to the mucoadhesive peptide fragment. In some embodiments, the mucoadhesive peptide fragment is chemically conjugated to the antibody moiety, i.e., via a chemical linker.

In some embodiments, the peptide linker is located between the antibody moiety and the mucoadhesive peptide fragment of the chimeric protein. In some embodiments, the peptide linker is fused to a polypeptide chain of the antibody moiety. In some embodiments, the linker is fused to the mucoadhesive peptide fragment.

In some embodiments, the mucoadhesive peptide fragment is fused to a polypeptide chain of the antibody moiety via a peptide linker. In some embodiments, the linker is about 1 to 20 amino acid residues. In some embodiments, the linker is a glycine-serine linker. In some embodiments, the linker has the amino acid sequence of GGGGS (SEQ ID NO: 344).

The length, the degree of flexibility and/or other properties of the linker may have some influence on properties, including but not limited to the affinity, specificity or avidity for one or more targets of the fusion protein (e.g., bispecific immune cell engager or engineered receptor) described herein. For example, longer linkers may be selected to ensure that two adjacent binding moieties (e.g., the influenza virus HA or NA protein, or fragment thereof, and the effector protein or fragment thereof) do not sterically interfere with one another. In some embodiments, a linker (such as peptide linker) comprises flexible residues (such as glycine and serine) so that the adjacent binding moieties are free to move relative to each other. For example, a glycine-serine doublet can be a suitable peptide linker. In some embodiments, the linker is a non-peptide linker. In some embodiments, the linker is a peptide linker. In some embodiments, the linker is a non-cleavable linker. In some embodiments, the linker is a cleavable linker.

Other linker considerations include the effect on physical or pharmacokinetic properties of the resulting fusion protein (e.g., bispecific immune cell engager or engineered receptor), such as solubility, lipophilicity, hydrophilicity, hydrophobicity, stability (more or less stable as well as planned degradation), rigidity, flexibility, immunogenicity, modulation of antibody moiety binding, the ability to be incorporated into a micelle or liposome, and the like.

Any one or all of the linkers described herein can be accomplished by any chemical reaction that will bind the two molecules so long as the components or fragments retain their respective activities. This linkage can include many chemical mechanisms, for instance covalent binding, affinity binding, intercalation, coordinate binding and complexation. In some embodiments, the binding is covalent binding. Covalent binding can be achieved either by direct condensation of existing side chains or by the incorporation of external bridging molecules. Many bivalent or polyvalent linking agents are useful in coupling protein molecules, such as an Fc fragment. For example, representative coupling agents can include organic compounds such as thioesters, carbodiimides, succinimide esters, diisocyanates, glutaraldehyde, diazobenzenes and hexamethylene diamines. This listing is not intended to be exhaustive of the various classes of coupling agents known in the art but, rather, is exemplary of the more common coupling agents (see Killen and Lindstrom, Jour. Immun. 133:1335-2549 (1984); Jansen et al., Immunological Reviews 62:185-216 (1982); and Vitetta et al., Science 238:1098 (1987)).

Linkers that can be applied in the present application are described in the literature (see, for example, Ramakrishnan, S. et al., Cancer Res. 44:201-208 (1984) describing use of MBS (M-maleimidobenzoyl-N-hydroxysuccinimide ester)). In some embodiments, non-peptide linkers used herein include: (i) EDC (1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride; (ii) SMPT (4-succinimidyloxycarbonyl-alpha-methyl-alpha-(2-pridyl-dithio)-toluene (Pierce Chem. Co., Cat. (21558G); (iii) SPDP (succinimidyl-6 [3-(2-pyridyldithio) propionamido]hexanoate (Pierce Chem. Co., Cat. #21651G); (iv) Sulfo-LC-SPDP (sulfosuccinimidyl 6 [3-(2-pyridyldithio)-propianamide]hexanoate (Pierce Chem. Co. Cat. #2165-G); and (v) sulfo-NHS (N-hydroxysulfo-succinimide: Pierce Chem. Co., Cat. #24510) conjugated to EDC.

The linkers described above contain components that have different attributes, thus leading to fusion proteins with different physio-chemical properties. For example, sulfo-NHS esters of alkyl carboxylates are more stable than sulfo-NHS esters of aromatic carboxylates. NHS-ester containing linkers are less soluble than sulfo-NHS esters. Further, the linker SMPT contains a sterically hindered disulfide bond, and can form fusion protein with increased stability. Disulfide linkages, are in general, less stable than other linkages because the disulfide linkage is cleaved in vitro, resulting in less fusion protein available. Sulfo-NHS, in particular, can enhance the stability of carbodimide couplings. Carbodimide couplings (such as EDC) when used in conjunction with sulfo-NHS, forms esters that are more resistant to hydrolysis than the carbodimide coupling reaction alone.

Any one or all of the linkers described herein can be peptide linkers. The peptide linker may have a naturally occurring sequence, or a non-naturally occurring sequence. For example, a sequence derived from the hinge region of heavy chain only antibodies may be used as the linker. See, for example, WO1996/34103.

The peptide linker can be of any suitable length. In some embodiments, the peptide linker is at least about n amino acids (aa) long, where n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 100, or more. In some embodiments, the peptide linker is no more than about n aa long, where n is selected from a 100, 75, 50, 40, 35, 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, and 5, or fewer. In some embodiments, the length of the peptide linker is any of about 1 aa to about 10 aa, about 1 aa to about 20 aa, about 1 aa to about 30 aa, about 5 aa to about 15 aa, about 10 aa to about 25 aa, about 5 aa to about 30 aa, about 10 aa to about 30 aa, about 30 aa to about 50 aa, about 50 aa to about 100 aa, or about 1 aa to about 100 aa.

In some embodiments, the peptide linker is a stable linker, which is not cleavable by a protease. In some embodiments, the peptide linker is cleavable by a protease.

In some embodiments, the peptide linker tends not to adopt a rigid three-dimensional structure, but rather provide flexibility to a polypeptide. In some embodiments, the peptide linker is a flexible linker. Exemplary flexible linkers include glycine polymers (G)_n, where n≥1, glycine-serine polymers (including, for example, GS(GS)_n, where n≥0 (SEQ ID NO: 345), (GSGGS)_n, where n≥1 (SEQ ID NO: 346), (GGGGS)_n, where n≥1 (SEQ ID NO: 347), and (GGGS)_n, where n≥1 (SEQ ID NO: 348), where n is an integer of at least one), glycine-alanine polymers, alanine-serine polymers, and other flexible linkers known in the art. Glycine and glycine-serine polymers are relatively unstructured, and therefore may be able to serve as a neutral tether between components. Glycine accesses significantly more phi-psi space than even alanine and is much less restricted than residues with longer side chains (see Scheraga, Rev. Computational Chem., 11 173-142 (1992)). The ordinarily skilled artisan will recognize that design of a fusion protein can include linkers that are all or partially flexible, such that the linker can include a flexible linker portion as well as one or more portions that confer less flexible structure to provide a desired fusion protein structure.

Natural linkers adopt various conformations in secondary structure, such as helical, β-strand, coil/bend and turns, to exert their functions. Linkers in an α-helix structure might serve as rigid spacers to effectively separate protein domains, thus reducing their unfavorable interactions. Non-helical linkers with Pro-rich sequence could increase the linker rigidity and function in reducing inter-domain interference.

Additional linkers may be used in the chimeric proteins of the present application for purposes of stability. For example, in some embodiments, the linker stabilizes the chimeric protein. In some embodiments, the linker increases, the serum half-life of the chimeric protein in vivo, the avidity of the chimeric protein to the component of the influenza virus or variant thereof in vitro, the number of chimeric proteins in vitro, and/or the effective amount of the chimeric protein delivered to a nasal cavity in vivo. In some embodiments, the linker comprises an oligomerization or multimerization domain. In some embodiments, the oligomerization or multimerization domain is from a naturally occurring protein. In some embodiments, the oligomerization or multimerization domain is from a non-naturally occurring protein. Exemplary linkers (e.g., peptide linkers and domains to be included in linkers) are shown in Table 9.

TABLE 9
Exemplary peptide linkers and linker domains
Linker or			SEQ
Multimerization		Exemplary	ID
Domain	Cluster	Sequence	NO	Reference
Immunoglobulin	Dimer	TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE	391	Lobner et al.,
Fc region		VTCVVVDVSHEDPEVKFNWYVDGVEVHNAK		Immunol. Rev.,
(CH2CH3)		TKPREEQYNSTYRVVSVLTVLHQDWLNGKEY		270(1)113-31
		KCKVSNKALPAPIEKTISKAKGQPREPQVYTLP		(2016)
		PSRDELTKNQVSLTCLVKGFYPSDIA VEWESN
		GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR
		WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
Immunoglobulin	Dimer	PPKVSVFVPPRDGFFGNPRKSKLICQATGFSPR	406	pir||S37768
Fc region		QIQVSWLREGKQVGSGVTTDQVQAEAKESGP
(CH2CH3CH4)		TTYKVTSTLTIKESDWLSQSMFTCRVDHRGLT
		FQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKS
		TKLTCLVTDLTTYDSVTISWTRQNGEAVKTHT
		NISESHPNATFSAVGEASICEDDWNSGERFTCT
		VTHTDLPSPLKQTISRPKGVALHRPDVYLLPPA
		REQLNLRESATITCLVTGFSPADVFVQWMQRG
		QPLSPEKYVTSAPMPEPQAPGRYFAHSILTVSE
		EEWNTGETYTCVVAHEALPNRVTERTVDKST
		GKPTLYNVSLVMSDTAGTCY
Immunoglobulin	Dimer	GQPKANPTVTLFPPSSEELQANKATLVCLISDF	392
CL	(pairing	YPGAVTVAWKADGSPVKAGVETTKPSKQSNN
	with CH1)	KYAASSYLSLTPEQWKSHRSYSCQVTHEGSTV
		EKTVAPTECS
Immunoglobulin	Dimer	ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF	393
CH1	(pairing	PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS
	with CL)	SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRV
		EPKSC
Immunoglobulin	Dimer	TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE	394
CH2	(pairing	VTCVVVDVSHEDPEVKFNWYVDGVEVHNAK
	with CH2)	TKPREEQYNSTYRVVSVLTVLHQDWLNGKEY
		KCKVSNKALPAPIEKTISKAKGQPRE
Immunoglobulin	Dimer	PQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA	395
CH3	(pairing	VEWESNGQPENNYKTTPPVLDSDGSFFLYSKL
	with CH3)	TVDKSRWQQGNVFSCSVMHEALHNHYTQKSL
		SLSPGK
Immunoglobulin	Dimer	PDVYLLPPAREQLNLRESATITCLVTGFSPADV	396	pir||S37768
CH4	(pairing	FVQWMQRGQPLSPEKYVTSAPMPEPQAPGRY
	with CH4)	FAHSILTVSEEEWNTGETYTCVVAHEALPNRV
		TERTVDKSTGK
Alkaline	Dimer	MWWRLWWLLLLLLLLWGSSASAAIIPVEEEN	397	BBD75655.1
phosphatase		PDFWNREAAEALGAAKKLQPAQTAAKNLIIFL
		GDGMGVSTVTAARILKGQKKDKLGPEIPLAM
		DRFPYVALSKTYNVDKHVPDSGATATAYLCG
		VKGNFQTIGLSAAARFNQCNTTRGNEVISVMN
		RAKKAGKSVGVVTTTRVQHASPAGTYAHTVN
		RNWYSDADVPASARQEGCQDIATQLISNMDID
		VILGGGRKYMFRMGTPDPEYPDDYSQGGTRL
		DGKNLVQEWLAKRQGARYVWNRTELMQASL
		DPSVTHLMGLFEPGDMKYEIHRDSTLDPSLME
		MTEAALRLLSRNPRGFFLFVEGGRIDHGHHES
		RAYRALTETIMFDDAIERAGQLTSEEDTLSLVT
		ADHSHVFSFGGYPLRGSSIFGLAPGKARDRKA
		YTVLLYGNGPGYVLKDGARPDVTESESGSPEY
		RQQSAVPLDEETHAGEDVAVFARGPQAHLVH
		GVQEQTFIAHVMAFAACLEPYTACDLAPPAGT
		TDAAHPGYSRVGAAGRFEQT
Glutathione-s-	Dimer	MKLVGSYTSPFVRKLSILLLEKGITFEFINELPY	398	WP_000779792
transferase		NADNGVAQFNPLGKVPVLVTEEGECWFDSPII
		AEYIELMNVAPAMLPRDPLESLRVRKIEALAD
		GIMDAGLVSVREQARPAAQQSEDELLRQREKI
		NRSLDVLEGYLVDGTLKTDTVNLATIAIACAV
		GYLNFRRVAPGWCVDRPHLVKLVENLFSRESF
		ARTEPPKA
bHLH-Leucine	Trimer	LENHSRRLEMTNKQLWLRIQEL	399	Napolitano and
Zipper				Ballabio, J.
				Cell Sci.,
				129(13):2475-81
				(2016)
Leucine/	Trimer	LSIIAICLGSLGLILIILLSVVVWKLL	400	Branttie and
Isoleucine				Dutch, J. Gen
Zipper				Virol.,
				101(5):467-472
				(2020)
Collagen-like	Trimer	GPP(GPP)n, where n ≥ 0	401	Fan et al.,
Peptide				FASEB J.,
				22:3795-3804
				(2008).
p53	Tetramer	EYFTLQIRGRERFEMFRELNEALELKDAQAG	402	Gencel-Augusto
Tetramerization				et al., Genes
Domain				Dev., 34(17-
				18):1128-1146
				(2020)
Streptavidin	Tetramer	MAEAGITGTWYNQLGSTFIVTAGADGALTGT	403	Chivers et al.,
(SA)		YESAVGNAEGDYVLTGRYDSAPATDGSGTAL		Biochem J.,
		GWTVAWKNNYRNAHSATTWSGQYVGGAEA		435(Pt 1):55-63
		RINTQWLLTSGTTEANAWKSTLVGHDTFTKV		(2011)
		KPSAAS
T4 Fibritin	Trimer	GYIPEAPRDGQAYVRKDGEWVLLSTFL	404	Yang et al., J.
				Virol.,
				76(9):4634-42
				(2002)
COMP (cartilage	Pentamer	GPQMLRELGETNAALQDVRELLRQQVREITFL	405	Holler et al.,
oligomeric		KNTVMECDAC		J. Immunol.
matrix protein)				Methods,
				237:159-173
				(2000)
Dextramers + SA	3, 6 or 13	Dextran polymer scaffold	N/A	Dolton et al.,
	SA per			Clin. Exp.
	Dextramer			Immunol.,
				177(1):47-63
				(2014)
DMGS + SA	Octamers	Di-maleimide-di-glycine-serine	N/A	Guillaume et al.,
				J. Biol. Chem.,
				278:P4500-4509
				(2003)
Linker A	N/A	SRGGGGSGGGGSGGGGSLEMA	343	N/A
Linker 1	N/A	GGGGS	344	N/A
Linker 2	N/A	GS(GS)n, where n ≥ 0	345	N/A
Linker 3	N/A	(GSGGS)n, where n ≥ 1	346	N/A
Linker 4	N/A	(GGGGS)n, where n ≥ 1	347	N/A
Linker 5	N/A	(GGGS)n, where n ≥ 1	348	N/A

Any of the linkers described in Table 9 are compatible with the chimeric proteins provided herein. In some embodiments, the mucoadhesive peptide fragment is fused to a polypeptide chain of the target-binding moiety via any of the linkers provided in Table 9, or variants thereof. In some embodiments, the mucoadhesive peptide fragment is fused to a polypeptide chain of the target-binding moiety via a linker comprising at least about 90% sequence identity (such as about n % sequence identity, where n % is selected from 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99%) to the amino acid sequence of any one of SEQ ID NOs: 343-348 and 391-406. In some embodiments, the linker comprises the amino acid sequence of any one of SEQ ID NOs: 343-348 and 391-406. It should be understood that the linkers provided in Table 9 are exemplary, and other linkers with similar properties would similarly be compatible with the chimeric proteins provided herein.

In some embodiments, the peptide linker comprises a constant region of a full-length antibody, or a fragment thereof. In some embodiments, the peptide linker comprises the complete constant region of a full-length antibody. In some embodiments wherein the full-length antibody is IgG, IgA, or IgD, the peptide linker comprises the CH₁, CH₂, and CH₃ domains. In some embodiments wherein the full-length antibody is IgE or IgM, the peptide linker comprises the CH₁, CH₂, CH₃, and CH₄ domains. In some embodiments, the peptide linker comprises a fragment of a constant region of a full-length antibody. In some embodiments, the peptide linker comprises a CH₁ domain or a fragment thereof. In some embodiments, the peptide linker comprises a CH₂ domain or a fragment thereof. In some embodiments, the peptide linker comprises a CH₃ domain or a fragment thereof. In some embodiments, the peptide linker comprises a CH₄ domain or a fragment thereof. In some embodiments, the peptide linker comprises a CL domain or a fragment thereof.

Immunoglobulin Fc regions, or fragments thereof, may be used as the peptide linker or a portion thereof. Fc region may facilitate dimerization and retain antibody-like properties, including physicochemical characteristics for expression, purification and storage, and long serum half-life in vivo. Such properties would be advantageous to the chimeric proteins provided herein. In some embodiments, the peptide linker comprises an Fc region or a fragment thereof. In some embodiments, the Fc region comprises a CH₂ and CH₃ domain. In some embodiments, the Fc region comprises a CH₂, CH₃, and CH₄ domain.

In some embodiments, the peptide linker comprises an enzymatic tag, such as a detectable enzymatic tag. In some embodiments, the enzymatic tag functions as a dimer. In some embodiments, the enzymatic tag is an alkaline phosphatase. In some embodiments, the enzymatic tag is a glutathione-s-transferase (GST).

Additional peptide linkers or useful domains to be included in linkers described herein may be used to facilitate stable protein:protein interactions in the chimeric proteins of the present invention. In some embodiments, the linker comprises a domain that facilitates protein:protein interactions. In some embodiments, the linker comprises one or more heptad repeats. The term “heptad repeat” as used herein refers to a structural motif that consists of a repeating pattern of seven amino acids. In some embodiments, the heptad repeat comprises the repeating pattern: “H P P H C P C”, wherein “H” represents a hydrophobic amino acid residue, “C” typically represents a charged amino acid residue, and “P” represents a polar (hydrophilic) amino acid residue. In some embodiments, the linker comprises the heptad repeats of a basic helix-loop-helix leucine zipper (bZIP) domain. In some embodiments, the linker comprises the heptad repeats of a basic isoleucine bZIP domain. In some embodiments, the heptad repeat forms a protein trimer.

Glycine-X-Y repeats (e.g., GPP(GPP)_n, where n≥0) have been shown not to interfere with the functionality or safety profile of fusion proteins (e.g., chimeric proteins). In some embodiments, the linker comprises one or more (GPP)_n, where n≥1, motifs. In some embodiments, the linker comprises a collagen-like protein. In some embodiments, the collagen-like protein forms a protein trimer.

Other, higher order, multimerization domains may be incorporated in the linkers provided herein. In some embodiments, the multimerization domains may form self-assembling complexes. In some embodiments, the linker comprises an affinity moiety. In some embodiments, the linker comprises a streptavidin (SA) protein. In some embodiments, the streptavidin protein forms a tetramer with biotin molecules. In some embodiments, the linker comprises a dextran scaffold domain. In some embodiments, the linker comprises a SA protein and a dextran scaffold domain. In some embodiments, the linker comprises one or more maleimide polymers (DMGS). In some embodiments, the linker comprises one or more malemide polymers and a SA protein. In some embodiments, the linker comprises a p53 tetramerization domain. In some embodiments, the linker comprises a bacteriophage T7 fibritin protein, or a portion thereof. In some embodiments, the linker comprises the C-terminal 27 amino acids of the bacteriophage T7 fibritin protein. In some embodiments, the C-terminal 27 amino acids of the bacteriophage T7 fibritin protein forms a trimeric complex. In some embodiments, the linker comprises one or more coiled-coil structural domains. In some embodiments, the linker comprises a cartilage oligomeric matrix protein (COMP), or a portion thereof. In some embodiments, the liner comprises a coiled-coil domain of the COMP. In some embodiments, the coiled-coil domain of the COMP forms a pentameric complex.

III. Methods of Prevention and Treatment, Methods of Killing a Virus, Methods of Neutralizing a Virus, Methods of Activating Complement Pathway

The present application further provides methods of preventing or treating an infection caused by an influenza virus or variant thereof in an individual, comprising administering to the individual an effective amount of any one of the chimeric proteins described herein, or a cocktail composition of chimeric proteins described herein. In some embodiments, the method comprises administering to the individual a pharmaceutical composition, such as any of the pharmaceutical compositions provided herein, comprising an effective amount of any one of the chimeric proteins described herein, or a cocktail composition of chimeric proteins described herein. In some embodiments, the method is for preventing an infection caused by an influenza virus or variant thereof in an individual (e.g., a human or an animal). In some embodiments, the method is for treating an infection caused by influenza virus or variant thereof in an individual. In some embodiments, the influenza virus comprises an HA antigen, such as an HA antigen selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof. In some embodiments, the influenza virus comprises an NA antigen, such as an NA antigen selected from the group consisting of N1, N2, N3, N7, N8, and N9, or a variant or reassortant thereof. In some embodiments, the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof. In some embodiments, the method is for activation of complement pathway in an individual. In some embodiments, the method is an in vitro method for killing or neutralizing an influenza virus. In some embodiments, the method is for killing or neutralizing an influenza virus in an individual. In some embodiments, the method is for preventing, treating, or reducing infection caused by an influenza virus in an individual, wherein at least one virus is killed or neutralized on the mucosa. Use of the chimeric in prevention or treatment of an infection, for activating the complement pathway, or for killing or neutralizing a virus, and use of the chimeric proteins in the preparation of a medicament for preventing or treating an infection, for activating the complement pathway, or for killing or neutralizing a virus, are also provided. Methods of veterinary use are also contemplated herein.

In some embodiments, there is provided a method of preventing or treating an infection caused by an influenza virus or variant thereof that infects through a mucosa in an individual, comprising administering to the individual an effective amount of a chimeric protein comprising: (a) an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa.

In some embodiments, there is provided a method of activating the complement pathway in an individual infected with a virus (e.g., an influenza virus or variant thereof), comprising administering to the individual an effective amount of a chimeric protein comprising administering to the individual an effective amount of a chimeric protein comprising: (a) an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa. In some embodiments, at least one virus is killed or neutralized on the mucosa. In some embodiments, the virus is an influenza virus.

In some embodiments, there is provided a method of killing or neutralizing a virus (e.g., an influenza virus or variant thereof) in an individual, comprising administering to the individual an effective amount of a chimeric protein comprising: (a) an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa. In some embodiments, at least one virus is killed or neutralized on the mucosa. In some embodiments, the killing or neutralization is via activation of the complement pathway. In some embodiments, the virus is an influenza virus.

In some embodiments, there is provided an in vitro method of killing or neutralizing a virus (e.g., an influenza virus or variant thereof), comprising contacting the virus with a chimeric protein comprising: (a) an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa, in the presence of at least one component of the complement system. In some embodiments, the at least one component of the complement system is C1, C4, or membrane attack complex (MAC). In some embodiments, the at least one component of the complement system is CL. In some embodiments, the at least one component of the complement system is C4. In some embodiments, the C4 is involved in the neutralization of the virus. In some embodiments, the at least one component of the complement system is MAC. In some embodiments, the MAC is involved in the killing of the virus. In some embodiments, at least one virus is killed or neutralized on the mucosa. In some embodiments, the killing or neutralization is via activation of the complement pathway. In some embodiments, the virus is an influenza virus.

In some embodiments, there is provided a method of preventing, treating, or reducing infection caused by a virus (e.g., an influenza virus or variant thereof) in an individual, comprising administering to the individual a chimeric protein comprising: (a) an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa, wherein at least one virus is killed or neutralized on the mucosa. In some embodiments, the chimeric protein induces an immune response in the individual. In some embodiments, the chimeric protein activates the complement pathway in the individual. In some embodiments, the at least one virus is killed or neutralized on the mucosa via activation of the complement pathway. In some embodiments, the virus is an influenza virus.

In some embodiments, the chimeric protein is administered to the individual before the individual is exposed to the influenza virus or variant thereof. In some embodiments, the chimeric protein is administered to the individual within about any one of n hours from exposure of the individual to the influenza virus or variant thereof, where n hours is selected from 72 hours, 48 hours, 36 hours, 24 hours, 12 hours, 6 hours, 4 hours, or less. In some embodiments, administration of the chimeric protein to the individual protects the individual from infection by the pathogen for about n days, where n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more. In some embodiments, the chimeric protein is administered topically to the mucosa. In some embodiments, the chimeric protein is administered via a nasal spray, an inhaler, a nebulizer, or an eye drop. In some embodiments, the chimeric protein is administered to both nostrils of the individual. In some embodiments, the chimeric protein is administered once every two days, once daily, or twice daily.

In some embodiments, the individual is a mammal (e.g., human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc.). In some embodiments, the individual is a human. In some embodiments, the individual is a clinical patient, a clinical trial volunteer, an experimental animal, etc. In some embodiments, the individual is younger than about 60 years old (such as younger than about n years old, where n years old is selected from 50, 40, 30, 25, 20, 15, and 10 years old). In some embodiments, the individual is about 60 years old or older (such as older than about n years old, where n years old is selected from 70, 80, 90, and 100 years old). In some embodiments, the individual has not been exposed to the influenza virus or variant thereof. In some embodiments, the individual is diagnosed with influenza, such as H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof. In some embodiments, the individual is diagnosed with an influenza variant. In some embodiments, the individual is at a risk of developing severe symptoms of the influenza infection. In some embodiments, the individual has an underlying medical condition, such as cardiovascular disease, diabetes, chronic respiratory disease, and/or cancer.

In some embodiments, the method is for preventing or treating infection by one or more influenza variants. In some embodiments, the method prevents or treats infection by a plurality (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) of influenza variants.

In some embodiments, there is provided a method of treating or preventing infection of an individual by a plurality of influenza variants, comprising administering to the individual an effective amount of a pharmaceutical composition (e.g., a cocktail composition) comprising a plurality of chimeric proteins, wherein the plurality of chimeric proteins each comprises: (a) an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa. In some embodiments, the plurality of chimeric proteins each comprise a different antibody moiety that specifically recognize different influenza variants. In some embodiments, the antibody moiety is derived from a neutralizing antibody that specifically binds to an viral surface protein, such as HA or NA, of an influenza virus, e.g., an anti-HA or anti-NA antibody. For example, the pharmaceutical composition may comprise a cocktail of chimeric proteins each comprising an antibody fragment derived from a different anti-HA or anti-NA antibody described herein or known in the art. In some embodiments, the mucoadhesive peptide fragment comprises at least 5 positively charged amino acid residues interspersed with one or more non-positively charged amino acid residues. In some embodiments, the chimeric protein is administered via a nasal spray.

In some embodiments, there is provided a method of treating or preventing infection of an individual by a plurality of influenza variants, comprising administering to the individual an effective amount of a chimeric protein comprising: (a) an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa of the individual. In some embodiments, the antibody moiety is derived from a neutralizing antibody that specifically binds to a HA protein of an influenza virus or variant thereof, e.g., an anti-HA antibody. In some embodiments, the antibody moiety is derived from a neutralizing antibody that specifically binds to a NA protein of an influenza virus or variant thereof, e.g., an anti-NA antibody. In some embodiments, the positively charged amino acid residues are interspersed with non-positively charged amino acid residues. In some embodiments, the chimeric protein is administered via a nasal spray.

In some embodiments, the chimeric protein, e.g., any of the anti-HA or anti-NA chimeric proteins or other constructs of the present application, is administered as a single agent, or in combination with a second, third, or fourth agent (including, e.g., anti-viral drugs, convalescent plasma, anti-inflammatory drugs etc.) to treat the infection, kill the virus, neutralize the virus, and/or activate the complement pathway.

Efficacy of the treatments can be evaluated, for example, by viral load (e.g., via detection of viral DNA), duration of survival, quality of life, viral protein expression and/or activity, detection of serological antibodies against the influenza virus or variant thereof, assessment of respiratory functions, and/or Computerized Tomography (CT) imaging.

IV. Nucleic Acids and Methods of Preparation

Nucleic acid molecules encoding the chimeric proteins described herein are contemplated. In some embodiments, the nucleic acid molecules encode the anti-HA or anti-NA chimeric proteins described herein. In some embodiments, there is provided a nucleic acid (such as an isolated nucleic acid) encoding any of the chimeric proteins described herein. In some embodiments, the nucleic acid (such as an isolated nucleic acid) encodes the complete amino acid sequence or sequences of any of the chimeric proteins described herein. In some embodiments, there is provided a set of nucleic acids (such as a set of isolated nucleic acids) encoding any of the chimeric proteins described herein. For example, different polypeptides of a chimeric protein, such as any of the chimeric proteins described herein, may be encoded by different nucleic acids (such as isolated nucleic acids) within the set of nucleic acids (such as a set of isolated nucleic acids). Nucleic acid molecules may be constructed using recombinant DNA techniques conventional in the art. In some embodiments, a nucleic acid molecule is an expression vector that is suitable for expression in a selected host cell.

Vectors comprising polynucleotides that encode the chimeric proteins described herein are also provided. In some embodiments, the vectors comprise polynucleotides encoding the anti-HA or anti-NA chimeric proteins described herein. In some embodiments, the vectors comprise a nucleic acid encoding any of the chimeric proteins described herein. In some embodiments, a vector comprises a nucleic acid sequence encoding the complete amino acid sequence or sequences of any of the chimeric proteins described herein. In some embodiments, there is provided a set of vectors comprising different nucleic acids encoding different polypeptides of any of the chimeric proteins described herein. Such vectors include, but are not limited to, DNA vectors, phage vectors, viral vectors, retroviral vectors, etc.

In various embodiments, the chimeric proteins described herein may be expressed in prokaryotic cells, such as bacterial cells; or in eukaryotic cells, such as fungal cells (such as yeast cells), plant cells, insect cells, and mammalian cells. In some embodiments, the anti-HA or anti-NA chimeric proteins described herein may be expressed in prokaryotic cells, such as bacterial cells; or in eukaryotic cells, such as fungal cells (such as yeast cells), plant cells, insect cells, and mammalian cells. In some embodiments, a nucleic acid encoding any of the chimeric proteins described herein may be expressed in prokaryotic cells, such as bacterial cells; or in eukaryotic cells, such as fungal cells (such as yeast cells), plant cells, insect cells, and mammalian cells. In some embodiments, a set of nucleic acids encoding any of the chimeric proteins described herein may be expressed in prokaryotic cells, such as bacterial cells; or in eukaryotic cells, such as fungal cells (such as yeast), plant cells, insect cells, and mammalian cells. Such expression may be carried out, for example, according to procedures known in the art. Exemplary eukaryotic cells that may be used to express polypeptides include, but are not limited to, COS cells, including COS 7 cells; 293 cells, including 293-6E cells; CHO cells, including CHO—S, DG44. Lec13 CHO cells, and FUT8 CHO cells; PER.C6® cells (Crucell); and NSO cells.

Introduction of one or more nucleic acids into a desired host cell may be accomplished by any method, including but not limited to, calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, etc. Non-limiting exemplary methods are described, e.g., in Sambrook et al., Molecular Cloning, A Laboratory Manual, 3^rd ed. Cold Spring Harbor Laboratory Press (2001). Nucleic acids may be transiently or stably transfected in the desired host cells, according to any suitable method.

The invention also provides host cells comprising any of the nucleic acids or vectors described herein. In some embodiments, the invention provides a host cell comprising a chimeric protein described herein. In some embodiments, the invention provides a host cell comprising the anti-HA or anti-NA chimeric proteins described herein. In some embodiments, the invention provides a host cell comprising a nucleic acid encoding any of the chimeric proteins described herein. In some embodiments, the nucleic acid encodes the complete amino acid sequence or sequences of any of the chimeric proteins described herein. In some embodiments, the invention provides a host cell comprising a set of nucleic acids encoding any of the chimeric proteins described herein. In some embodiments, the invention provides a host cell comprising a vector that contains a nucleic acid encoding any of the chimeric proteins described herein. In some embodiments, the vector comprises a nucleic acid sequence encoding the complete amino acid sequence or sequences of any of the chimeric proteins described herein. In some embodiments, the invention provides a host cell comprising a set of vectors comprising different nucleic acids encoding different polypeptides of any of the chimeric proteins described herein. Any host cells capable of over-expressing heterologous DNAs can be used for the purpose of isolating the genes encoding the antibody, polypeptide or protein of interest. Non-limiting examples of mammalian host cells include but not limited to COS, HeLa, and CHO cells. Suitable non-mammalian host cells include prokaryotes (such as E. coli or B. subtilis) and yeast (such as S. cerevisae, S. pombe; or K. lactis).

The chimeric proteins described herein, the anti-HA or anti-NA chimeric proteins described herein, an isolated nucleic acid encoding any of the chimeric proteins described herein, and/or a set of isolated nucleic acids encoding any of the chimeric proteins described herein may be purified by any suitable method. Such methods include, but are not limited to, the use of affinity matrices or hydrophobic interaction chromatography. Suitable affinity ligands include ligands that bind antibody constant regions. For example, a Protein A, Protein G, Protein A/G, or an antibody affinity column may be used to bind the constant region and to purify a chimeric protein or anti-HA or anti-NA antibody comprising an Fc region. Hydrophobic interactive chromatography, for example, a butyl or phenyl column, may also be suitable for purifying some polypeptides such as antibodies. Ion exchange chromatography (e.g., anion exchange chromatography and/or cation exchange chromatography) may be also suitable for purifying some polypeptides such as antibodies. Mixed-mode chromatography (e.g., reversed phase/anion exchange, reversed phase/cation exchange, hydrophilic interaction/anion exchange, hydrophilic interaction/cation exchange, etc.) may also be suitable for purifying some polypeptides such as antibodies. Many methods of purifying polypeptides are known in the art.

V. Pharmaceutical Compositions, Kits, and Articles of Manufacture

A. Pharmaceutical Composition

One aspect of the present application provides compositions (e.g., pharmaceutical compositions) comprising any one of the chimeric proteins described herein. In some embodiments, the pharmaceutical composition is suitable for nasal administration. In some embodiments, the pharmaceutical composition is suitable for respiratory (e.g., upper respiratory airway) administration. In some embodiments, the pharmaceutical composition is suitable for administration by inhalation. In some embodiments, the pharmaceutical composition is a nasal spray formulation.

In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a citrate-buffered saline carrier. In some embodiments, the pharmaceutical composition comprises a stabilizing agent, a viscosity enhancing agent, a surfactant, and/or a preservative. In some embodiments, the pharmaceutical composition comprises 25 mM citrate buffer, pH 6.5, 100 mM NaCl, 0.1% methionine, 0.02% polysorbate 80, and 0.1% potassium sorbate. In some embodiments, the pharmaceutical composition comprises 25 mM citrate buffer, pH 6.5, 125 mM NaCl, 5% glycerin, 0.1% methionine, 0.02% polysorbate 80, and 0.1% potassium sorbate.

In some embodiments, the pharmaceutical composition comprises a single type of chimeric protein. In some embodiments, the pharmaceutical composition comprises at least two chimeric proteins, wherein the two chimeric proteins have different antibody moieties. In some embodiments, the pharmaceutical composition comprises a plurality (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or more) of chimeric proteins, wherein the antibody moieties of the chimeric proteins are different from each other. In some embodiments, the pharmaceutical composition comprises a cocktail of chimeric proteins that target different component of the same influenza virus and/or the same component of different variants (e.g., strains) of an influenza virus. In some embodiments, the chimeric proteins in the cocktail composition each comprise the same mucoadhesive peptide fragment(s). In some embodiments, the chimeric proteins in the cocktail composition each comprise different mucoadhesive peptide fragment(s).

In some embodiments, the pharmaceutical composition is formulated for topical administration to a mucosa, such as nasal mucosa, larynx mucosa, trachea mucosa, bronchi mucosa, lung mucosa, eye mucosa, and combinations thereof. In some embodiments, the pharmaceutical composition is formulated for administration via a nasal spray, an inhaler, a nebulizer, or an eye drop.

In some embodiments, there is provided a pharmaceutical composition comprising: (a) a chimeric protein comprising an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof, and a mucoadhesive peptide fragment comprising at least about 5 (e.g., about 5 to about 30 such as about 12) positively charged amino acid residues (e.g., lysine, histidine, arginine, ornithine, or combinations thereof), wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa, (b) a stabilizing agent that maintains the weak reducing environment in nasal area, (c) a buffering agent, and (d) an osmolality adjusting agent, wherein the pharmaceutical composition has a pH of about 4.5 to about 7.5 (e.g., about 6.0 to about 7.0), and wherein the pharmaceutical composition has an osmolality of about 230 to about 330 Osm/kg (e.g., about 250 to about 300 Osm/kg). In some embodiments, the antibody specifically binds an influenza virus viral surface protein or fragment thereof, and/or an influenza virus variant viral surface protein or fragment thereof. In some embodiments, the viral surface protein is HA. In some embodiments, the viral surface protein is NA. In some embodiments, the antibody moiety is any one of the anti-influenza (e.g., anti-HA or anti-NA) antibody moieties as described in Section II. In some embodiments, the chimeric protein is any one of the chimeric proteins described in Section II. In some embodiments, the positively charged amino acid residues are interspersed with one or more non-positively charged amino acid residues. In some embodiments, the pharmaceutical composition further comprises a viscosity-enhancing agent. In some embodiments, the pharmaceutical composition further comprises a surfactant. In some embodiments, the formulation further comprises a preservative.

In some embodiments, there is provided a pharmaceutical composition for nasal administration comprising: (a) a chimeric protein comprising an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof, and a mucoadhesive peptide fragment comprising at least about 5 (e.g., about 5 to about 30 such as about 12) positively charged amino acid residues (e.g., lysine, histidine, arginine, ornithine, or combinations thereof), wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa, (b) a methionine, (c) a buffering agent, (d) an osmolality adjusting agent, (e) a viscosity enhancing agent, (f) a surfactant, and (g) a preservative, wherein the pharmaceutical composition has a pH of about 4.5 to about 7.5 (e.g., about 6.0 to about 7.0), and wherein the pharmaceutical composition has an osmolality of about 230 to about 330 Osm/kg (e.g., about 250 to about 300 Osm/kg). In some embodiments, the antibody specifically binds an influenza virus viral surface protein or fragment thereof, and/or an influenza virus variant viral surface protein or fragment thereof. In some embodiments, the viral surface protein is HA. In some embodiments, the viral surface protein is N A. In some embodiments, the antibody moiety anti-influenza (e.g., anti-HA or anti-NA) antibody moieties as described in Section II. In some embodiments, the chimeric protein is any one of the chimeric proteins described in Section II. In some embodiments, the positively charged amino acid residues are interspersed with one or more non-positively charged amino acid residues.

In some embodiments, there is provided a pharmaceutical composition for nasal administration comprising: (a) a chimeric protein comprising an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof, and a mucoadhesive peptide fragment comprising at least about 5 (e.g., about 5 to about 30 such as about 12) positively charged amino acid residues (e.g., lysine, histidine, arginine, ornithine, or combinations thereof), wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa, (b) a methionine, (c) a citrate buffer, and (d) NaCl, wherein the pharmaceutical composition has a pH of about 4.5 to about 7.5 (e.g., about 6.0 to about 7.0), and wherein the pharmaceutical composition has an osmolality of about 230 to about 330 Osm/kg (e.g., about 250 to about 300 Osm/kg). In some embodiments, the antibody specifically binds an influenza virus viral surface protein or fragment thereof, and/or an influenza virus variant viral surface protein or fragment thereof. In some embodiments, the viral surface protein is I A. In some embodiments, the viral surface protein is NA. In some embodiments, the antibody moiety anti-influenza (e.g., anti-HA or anti-NA) antibody moieties as described in Section II. In some embodiments, the chimeric protein is any one of the chimeric proteins described in Section II. In some embodiments, the positively charged amino acid residues are interspersed with one or more non-positively charged amino acid residues. In some embodiments, the pharmaceutical composition further comprises a viscosity-enhancing agent (e.g., glycerin). In some embodiments, the pharmaceutical composition further comprises a surfactant (e.g., polysorbate 80). In some embodiments, the pharmaceutical composition further comprises a preservative (e.g., potassium sorbate).

In some embodiments, there is provided a pharmaceutical composition for nasal administration comprising: (a) a chimeric protein comprising an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof, and a mucoadhesive peptide fragment comprising at least about 5 (e.g., about 5 to about 30 such as about 12) positively charged amino acid residues (e.g., lysine, histidine, arginine, ornithine, or combinations thereof), wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa at a concentration of about 0.6 mg/mL to about 1 mg/mL (e.g., about 1 mg/mL to about 3 mg/mL), (b) a methionine at about 0.05% to 0.2% (e.g., about 0.075% to about 0.125%) (w/w), (c) a citrate buffer at about 20 mM to about 50 mM (e.g., about 20 mM to about 30 mM), (d) NaCl at about 100 mM to about 150 mM (e.g., about 110 mM to about 130 mM), (e) glycerin at about 1% to about 10% (e.g., about 2.5% to about 7.5%) (w/w), (f) polysorbate 80 at about 0.01% to about 0.1% (e.g., about 0.01% to about 0.05%) (w/w), and (g) potassium polysorbate at about 0.05% to 0.2% (e.g., about 0.075% to about 0.125%) (w/w), wherein the pharmaceutical composition has a pH of about 4.5 to about 7.5 (e.g., about 6.0 to about 7.0). In some embodiments, the pharmaceutical composition comprises about 25 mM citrate at pH 6.5, about 125 mM NaCl, about 5% glycerin, about 0.1% methionine, about 0.02% polysorbate 80, and about 0.1% potassium sorbate. In some embodiments, the antibody specifically binds an influenza virus viral surface protein or fragment thereof, and/or an influenza virus variant viral surface protein or fragment thereof. In some embodiments, the viral surface protein is HA. In some embodiments, the viral surface protein is NA. In some embodiments, the antibody moiety anti-influenza (e.g., anti-HA or anti-NA) antibody moieties as described in Section II. In some embodiments, the chimeric protein is any one of the chimeric proteins described in Section II. In some embodiments, the positively charged amino acid residues are interspersed with one or more non-positively charged amino acid residues.

In some embodiments, the pharmaceutical composition described herein is for administration via a nasal spray. In some embodiments, the pharmaceutical composition is for prophylactic use. In some embodiments, the pharmaceutical composition maintains the stability (including physical and chemical stability) of the antibody at 37° C. for at least about n days, where n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more days, including any values and ranges in between these values. In some embodiments, the pharmaceutical composition promotes adhesion of the antibody to a mucosa, such as nasal mucosa. In some embodiments, the pharmaceutical composition prolongs the residence time of the antibody in nostrils and other upper respiratory tract areas, for example, by at least about n compared to the antibody in PBS, where n is selected from 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, or more. In some embodiments, the pharmaceutical composition is neutral and gentle to the nasal surfaces. In some embodiments, the pharmaceutical composition is a solution of the antibody. In some embodiments, the pharmaceutical composition is an aqueous solution.

Nasal spray pharmaceutical composition parameters and excipients have been described, for example, in Kulkami and Shaw, Inhalation, 10-11 (2021); Thorat, Scholars Journal of Applied Medical Sciences (SJAMS), 4(8D):2976-2985 (2016), which are incorporated by reference in their entirety. Commonly used excipients for a nasal spray pharmaceutical composition include, but are not limited to, a tonicity agent or osmolality adjustment agent, buffering agent, purging agent, preservative, surfactant, chelating agent, suspending agent, co-solvent, antioxidant, and humectant. Antibody pharmaceutical compositions for various routes of administration, including nasal pharmaceutical composition, have been described, for example, in Cui Y. et al., Drug Development and Industrial Pharmacy, 11:28 (2017), which is incorporated herein by reference. Any excipients compatible with the FDA guideline for nasal spray pharmaceutical composition and/or antibody pharmaceutical composition may be used here.

In some embodiments, the pharmaceutical composition has a pH that is compatible with the nasal environment. The average baseline human nasal pH is about 6.3. The optimal pH of the pharmaceutical composition also depends on factors, including, for example, pI of the antibody (including positively charged mucoadhesive peptide), protein stability, net charge of the antibody, etc. In some embodiments, the pharmaceutical composition has a pH of about 4.5 to about 7.5, such as about n, where n is selected from 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, and 7.5, including any values or ranges in between the values. In some embodiments, the pharmaceutical composition has a pH of between about n, where n is selected from 4.5-5.0, 5.0-5.5, 5.5-6.0, 6.0-6.5, 4.5-5.5, 5.5-6.5, 5.0-6.5, 4.5-6.0, 6.5-7.0, 7.0-7.5, 6.0-7.5, 5.5-7, 6-7, and 6.5-7.5. In some embodiments, the pharmaceutical composition has a pH of about 6.5.

For adjusting and buffering pH value, physiologically acceptable acids, bases, salts, and combinations of these may be used. Suitable excipients for lowering the pH value or as acidic components of a buffer system are strong mineral acids, in particular, sulfuric acid and hydrochloric acid. Moreover, inorganic and organic acids of medium strength as well as acidic salts may be used, for example, phosphoric acid, citric acid, tartaric acid, succinic acid, fumaric acid, methionine, acidic hydrogen phosphates with sodium or potassium, lactic acid, glucuronic acid etc. Suitable for raising the pH value or as basic component for buffer system are, in particular, mineral bases such as sodium hydroxide or other alkali and alkaline earth hydroxides and oxides such as, in particular, magnesium hydroxide and calcium hydroxide, ammonium hydroxide and basic ammonium salts such as ammonium acetate, as well as basic amino acids such as lysine, carbonates such as sodium or magnesium carbonate, sodium hydrogen carbonate, citrates such as sodium citrate etc.

In some embodiments, the pharmaceutical composition comprises a citrate buffer. In some embodiments, the citrate buffer contains citric acid and sodium citrate. The citrate buffer has a pKa of about 6.4. In some embodiments, the citrate buffer is present a concentration of about 20 mM to about 50 mM, such as about n mM, where n is selected from 20, 25, 30, 35, 40, 45, and 50, including any values or ranges in between these values. In some embodiments, the citrate buffer is present a concentration of about between about n mM, where n is selected from 20-30, 30-40, 40-50, 25-50, 25-35, and 25-40. In some embodiments, the pharmaceutical composition comprises a citrate buffer at about 25 mM.

In some embodiments, the pharmaceutical composition comprises a phosphate buffer. The phosphate buffer has a pKa of about 7.2.

In some embodiments, the pharmaceutical composition has an osmolality that is close to the nasal environment. In some embodiments, the pharmaceutical composition has an osmolality that facilitates adhesion of the antibody to a mucosa (e.g., nasal mucosa). In some embodiments, the pharmaceutical composition minimizes penetration of the antibody into blood stream. In some embodiments, the pharmaceutical composition has an osmolality of about 230 Osm/kg to about 330 Osm/kg, such as about n Osm/kg, where n is selected from 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, and 330, including any values or ranges in between these values. In some embodiments, the pharmaceutical composition has an osmolality of between about n Osm/kg, where n is selected from 230-250, 250-270, 270-290, 290-310, 310-330, 230-275, 275-300, 300-330, 230-280, 280-330, and 260-320. In some embodiments, the pharmaceutical composition has an osmolality of about 280 Osm/kg. A skilled person in the art could readily convert these osmolality values to osmolality.

In some embodiments, the pharmaceutical composition comprises an osmolality adjusting agent. Exemplary osmolality adjusting agents or tonicity agents include, but are not limited to, sodium, calcium or magnesium chloride, sulfate or phosphate. In some embodiments, the osmolality adjusting agent is sodium chloride. Calcium and magnesium salts may have a positive or auxiliary influence in the inhalation of active agent solutions, possibly because they themselves counteract the local irritations caused by the administration. Alternatively, physiologically safe organic compounds may be used as the osmolality adjusting agent. Particularly suitable are water-soluble substances with a relatively low molecular weight, for example, with a molecular weight of less than 300 or, better still, less than 200 and with a correspondingly high osmotic activity. Examples for such excipients are sugars and sugar alcohols, in particular, trehalose, mannitol, sorbitol and isomalt.

In some embodiments, the pharmaceutical composition comprises about 100 mM to about 150 mM NaCl, such as about n mM NaCl, where n is selected from 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, and 150, including any values or ranges in between these values. In some embodiments, the pharmaceutical composition comprises between about n nM NaCl, where n is selected from 100-120, 120-140, 100-125, 125-150, 130-150, and 110-130. In some embodiments, the pharmaceutical composition comprises about 125 mM NaCl.

In some embodiments, the pharmaceutical composition comprises one or more stabilizing agents. In some embodiments, the stabilizing agent maintains the weak reducing environment in nasal areas. In some embodiments, the one or more stabilizing agents comprises methionine. In some embodiments, the one or more stabilizing agents comprise glycerin. In some embodiments, the one or more stabilizing agents comprise trehalose, e.g., 10% trehalose. In some embodiments, the pharmaceutical composition comprises about 0.05% to about 0.2% (w/w) methionine, such as about n % (w/w) methionine, where n % (w/w) is selected from 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, and 0.2%, including any values or ranges in between these values. In some embodiments, the pharmaceutical composition comprises between about n % (w/w) methionine, where n % (w/w) is selected from any one of 0.05%-0.1%, 0.75%-1.25%, 0.1%-0.15%, 0.15%-0.2%, 0.1%-0.2%, 0.125-0.175%, 0.8%-1.6%, and 0.5%-0.15%. In some embodiments, the pharmaceutical composition comprises about 0.1% (w/w) methionine.

In some embodiments, the pharmaceutical composition comprises a viscosity-enhancing agent. In some embodiments, the viscosity-enhancing agent is selected from the group consisting of glycerin, dextran and hydroxyethylcellulose. In some embodiments, the viscosity-enhancing agent is glycerin. In some embodiments, the pharmaceutical composition comprises about 1% (w/w) to about 10% (w/w) glycerin, such as about n % (w/w) glycerin, where n % (w/w) is selected from 1%, 2%, 3%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, and 10% (w/w), including any values or ranges in between these values. In some embodiments, the pharmaceutical composition comprises between about n % (w/w) glycerin, where n % (w/w) is selected from 1%-4%, 2%-6%, 3%-7%, 5%-8%, 7%-10%, 2.5%-7.5%, 4%-6%, 1%-2.5%, 2.5%-5%, 5%-7.5%, and 7.5%-10% (w/w). In some embodiments, the pharmaceutical composition comprises about 5% (w/w) glycerin.

In some embodiments, the pharmaceutical composition comprises surfactant. In some embodiments, the surfactant allows the antibody to cross a mucosa (e.g., nasal mucosa) and/or allows absorption of the antibody across the mucosa. Suitable surfactants include, in particular, those that are to be considered safe for oral or nasal inhalation or mucosal administration. Examples of surfactants with particularly good physiological compatibility include tyloxapol, polysorbates (such as polysorbate 20, polysorbate 80), PEG400, PEG3500, polyoxyl 400 stearate, vitamin E-TPGS, and macrogol hydroxystearates such as macrogol-15-hydroxystearate. In some embodiments, the surfactant is polysorbate 80. In some embodiments, the pharmaceutical composition comprises about 0.01% (w/w) to about 0.1% (w/w) polysorbate 80, such as about n % (w/w) polysorbate 80, where n % (w/w) is selected from 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, and 0.1% (w/w), including any values or ranges in between these values. In some embodiments, the pharmaceutical composition comprises between about n % (w/w) polysorbate 80, where n % (w/w) is selected from 0.01%-0.02%, 0.02%-0.05%, 0.05%-0.1%, 0.01%-0.05%, 0.02%-0.04%, 0.04%-0.08%, 0.02%-0.08%, and 0.02%-0.1% (w/w). In some embodiments, the pharmaceutical composition comprises about 0.02% (w/w) polysorbate 80.

In some embodiments, the pharmaceutical composition comprises a preservative. In some embodiments, the preservative maintains sterility of the pharmaceutical composition. Exemplary preservatives include, but are not limited to, benzyl alcohol, benzalkonium chloride, chlorobutanol, methylparaben, phenylethyl alcohol, propylparaben, and potassium sorbate. In some embodiments, the preservative is potassium sorbate. In some embodiments, the pharmaceutical composition comprises about 0.05% to about 0.2% (w/w) potassium polysorbate, such as about any one of 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19% or 0.2% (w/w), including any values or ranges in between these values. In some embodiments, the pharmaceutical composition comprises about any one of 0.05%-0.1%, 0.75%-1.25%, 0.1%-0.15%, 0.15%-0.2%, 0.1%-0.2%, 0.125-0.175%, 0.8%-1.6%, or 0.5%-0.15% (w/w) potassium sorbate. In some embodiments, the pharmaceutical composition comprises about 0.1% potassium sorbate.

In some embodiments, the antibody is present in the pharmaceutical composition at a concentration of about 0.6 mg/mL to about 6 mg/mL, such as about n mg/mL, where n is selected from 0.6, 0.8, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, and, including about any values or ranges in between these values. In some embodiments, the antibody is present in the pharmaceutical composition at a concentration of between about n mg/mL, where n is selected from 0.6-1, 1-2, 2-3, 3-4, 4-5, 5-6, 0.6-2.5, 2.5-5, 2-4, 4-6, 0.6-3, 3-6, and 2-5.

A nasal spray containing IgG antibodies can be used as a complement to vaccines, therapeutics and other preventive measures against the spread of influenza. Human IgG antibody nasal sprays have many advantages. One advantage of using antibodies or chimeric proteins comprising antibodies in a prophylaxis nasal spray is the well-established manufacturing process and scale-up capacity for antibodies. More than two dozen IgG antibodies have been approved by the U.S. Food and Drug Administration (FDA) for human use. The IgG antibody manufacturing process, from cell line development to large-scale bioreactor culture, has been optimized to produce high quality and yield for use in humans. In addition, the effectiveness of IgG antibodies against influenza has already been demonstrated in patients in a therapeutic setting. An IgG in a nasal spray application also has the advantage of a much lower dosage requirement (approximately 10,000 times lower) than an IgG therapeutic. This will significantly lower the cost and make it affordable for wider use. Furthermore, use of a human IgG antibody significantly reduces the risk of immunogenicity, which is an important consideration for a prophylactic nasal spray pharmaceutical composition subject to long-term repeated use. The long-term stability of the modified IgG antibody at room temperature in the nasal spray pharmaceutical composition makes it easy for daily use and storage.

In some embodiments, the pharmaceutical composition (e.g., nasal spray pharmaceutical composition or eye drop pharmaceutical composition) is administered at a dosage of about 0.1 mg to about 1 mg of the antibody, e.g., per nostril or per eye. In some embodiments, about 100 □L of the pharmaceutical composition (e.g., nasal spray pharmaceutical composition or eye drop pharmaceutical composition) is administered at a time, e.g., to both nostrils of an individual (e.g., 100 □L per nostril or per eye).

Suitable pharmaceutical compositions are obtained by mixing the chimeric protein(s), anti-HA or anti-NA antibody or construct described herein having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 23rd edition, Adejare, A. Ed. (2020)), in the form of lyophilized pharmaceutical compositions or aqueous solutions. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

The pharmaceutical composition herein may also contain one or more active compounds in addition to the compositions described herein as necessary for the infection being treated, preferably those with complementary activities that do not adversely affect each other. Such molecules are suitably present in combination in amounts that are effective for the purpose intended. The effective amount of such other agents depends on the amount of the composition described herein present in the pharmaceutical composition, the type and severity of infection in the treatment, and other factors discussed above. These are generally used in the same dosages and with administration routes as described herein or from about 1% to about 99% of the heretofore employed dosages.

The pharmaceutical compositions to be used for in vivo administration must be sterile. This is readily accomplished by, e.g., filtration through sterile filtration membranes.

Further provided are methods and use of the pharmaceutical compositions described herein for preventing or treating an infection, e.g., influenza infection.

B. Kits and Articles of Manufacture

In some embodiments, there is provided an article of manufacture comprising materials useful for the prevention or treatment of a microbial infection (e.g., infection by an influenza virus or variant thereof). The article of manufacture can comprise a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, etc. The containers may be formed from a variety of materials such as glass or plastic. Generally, the container holds a composition, which is effective for treating a microbial infection, described herein, and may have a sterile access port. In some embodiments, the article of manufacture is a nasal spray, an inhaler, a nebulizer, or an eye drop. Package insert refers to instructions customarily included in commercial packages of therapeutic products that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products. In some embodiments, the package insert indicates that the composition is used for treating a microbial infection. The label or package insert may further comprise instructions for administering the composition to a patient.

Additionally, the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

In some embodiments, there is provided an article of manufacture (e.g., a nasal spray) comprising a pharmaceutical composition comprising any one of the chimeric proteins described herein, and a spray device for applying the formulation to a nostril of a subject. In some embodiments, the nasal spray provides a uniform plume with droplets having a diameter of 10 □m or more. In some embodiments, the device sprays a volume of about 100 □L at a time. In some embodiments, the spray device is for an adult patient. In some embodiments, the spray device is for a pediatric patient. In some embodiments, the article of manufacture comprises a single dose of the active agent. In some embodiments, the article of manufacture comprises at least about n doses of the active agent, where n is selected from 2, 5, 10, 20, 30, 40, and 50, or more.

Kits are also provided that are useful for various purposes, e.g., for prevention or treatment of a microbial infection described herein, optionally in combination with the articles of manufacture. Kits of the invention include one or more containers comprising any one of the compositions described herein (or unit dosage form and/or article of manufacture). In some embodiments, the kit further comprises other agents and/or instructions for use in accordance with any of the methods described herein. The kit may further comprise a description of selection of individuals suitable for prevention or treatment. Instructions supplied in the kits of the invention are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.

For example, in some embodiments, the kit comprises a chimeric protein comprising: (a) an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about 5 (e.g., about 5 to about 30 such as about 12) positively charged amino acid residues (e.g., lysine, histidine, arginine, ornithine, or combinations thereof), wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa. In some embodiments, the component is a HA or NA viral surface protein.

The kits of the invention are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. Kits may optionally provide additional components such as buffers and interpretative information. The present application thus also provides articles of manufacture, which include vials (such as sealed vials), bottles, jars, flexible packaging, and the like.

The containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses. Kits may also include multiple unit doses of the pharmaceutical compositions and instructions for use and packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies.

EXEMPLARY EMBODIMENTS

The following exemplary embodiments are provided herein:

• • Embodiment 1. A chimeric protein comprising: (a) an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof; and (b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa.
  • Embodiment 2. The chimeric protein of embodiment 1, comprising a single polypeptide chain.
  • Embodiment 3. The chimeric protein of embodiment 1, comprising two or more polypeptide chains.
  • Embodiment 4. The chimeric protein of embodiment 3, wherein the chimeric protein comprises two or more mucoadhesive peptide fragments.
  • Embodiment 5. The chimeric protein of embodiment 4, wherein each of the two or more mucoadhesive peptide fragments comprises at least about 5 positively charged amino acid residues.
  • Embodiment 6. The chimeric protein of any one of embodiments 1-5, wherein the mucoadhesive peptide fragment comprises at least about 6 positively charged amino acid residues.
  • Embodiment 7. The chimeric protein of any one of embodiments 1-6, wherein the positively charged amino acid residues are selected from the group consisting of lysine, arginine, histidine, ornithine, and combinations thereof.
  • Embodiment 8. The chimeric protein of embodiment 7, wherein the positively charged amino acid residues comprise lysines.
  • Embodiment 9. The chimeric protein of embodiment 8, wherein the mucoadhesive peptide fragment comprises about 5, about 6, about 12, or about 30 lysines.
  • Embodiment 9a. The chimeric protein of embodiment 9, wherein the mucoadhesive peptide fragment comprises about 5 lysines.
  • Embodiment 10. The chimeric protein of embodiment 7, wherein the positively charged amino acid residues comprise arginines.
  • Embodiment 11. The chimeric protein of embodiment 10, wherein the mucoadhesive peptide fragment comprises about 6, about 12, or about 30 arginines.
  • Embodiment 12. The chimeric protein of embodiment 7, wherein the positively charged amino acid residues comprise histidines.
  • Embodiment 13. The chimeric protein of embodiment 12, wherein the mucoadhesive peptide fragment comprises about 6, about 12, or about 30 histidines.
  • Embodiment 14. The chimeric protein of embodiment 7, wherein the positively charged amino acid residues comprise ornithines.
  • Embodiment 15. The chimeric protein of embodiment 14, wherein the mucoadhesive peptide fragment comprises about 6, about 12, or about 30 ornithines.
  • Embodiment 16. The chimeric protein of any one of embodiments 1-15, wherein the mucoadhesive peptide fragment comprises at least 5 contiguous positively charged amino acids.
  • Embodiment 17. The chimeric protein of any one of embodiments 1-15, wherein the positively charged amino acid residues are interspersed with one or more non-positively charged amino acid residues.
  • Embodiment 18. The chimeric protein of embodiment 17, wherein the non-positively charged amino acid residues are non-polar amino acids or polar uncharged amino acids.
  • Embodiment 19. The chimeric protein of embodiment 17 or 18, wherein the non-positively charged amino acid residues are selected from the group consisting of isoleucine, valine, alanine, tryptophan, leucine, glycine, methionine, proline, phenylalanine, threonine, cysteine, tyrosine, glutamine, serine, and asparagine, and combinations thereof.
  • Embodiment 20. The chimeric protein of any one of embodiments 17-19, wherein at least 50% of the amino acid residues in the mucoadhesive peptide fragment are positively charged amino acid residues.
  • Embodiment 21. The chimeric protein of any one of embodiments 1-20, wherein the mucoadhesive peptide fragment is no more than about 15 kD.
  • Embodiment 22. The chimeric protein of any one of embodiments 1-21, wherein the mucoadhesive peptide fragment has an isoelectric point (pI) higher than the pH of the mucosa.
  • Embodiment 23. The chimeric protein of any one of embodiments 1-22, wherein the half-life of the chimeric protein on the mucosa is at least 12 hours.
  • Embodiment 24. The chimeric protein of any one of embodiments 1-23, wherein the mucoadhesive peptide fragment does not facilitate penetration of the chimeric protein into a cell of the mucosa.
  • Embodiment 25. The chimeric protein of any one of embodiments 1-24, wherein the mucoadhesive peptide fragment does not disrupt folding of the chimeric protein within a host cell expressing the chimeric protein.
  • Embodiment 26. The chimeric protein of any one of embodiments 1-25, wherein the mucoadhesive peptide fragment does not block secretion of the chimeric protein from a host cell expressing the chimeric protein.
  • Embodiment 27. The chimeric protein of any one of embodiments 1-26, wherein the mucoadhesive peptide fragment does not interfere with the binding between the antibody moiety and the component of the influenza virus or variant thereof.
  • Embodiment 28. The chimeric protein of any one of embodiments 1-27, wherein the mucoadhesive peptide fragment comprises an amino acid sequence of any one of SEQ ID NOs: 291-325 and 407-413, or variants thereof comprising up to about 3 amino acid substitutions.
  • Embodiment 29. The chimeric protein of any one of embodiments 1-28, wherein the mucoadhesive peptide fragment is fused to the antibody moiety.
  • Embodiment 30. The chimeric protein of any one of embodiments 1-29, wherein the mucoadhesive peptide fragment is fused to the antibody moiety via a bond.
  • Embodiment 31. The chimeric protein of any one of embodiments 1-29, wherein the mucoadhesive peptide fragment is fused to the antibody moiety via a peptide linker.
  • Embodiment 32. The chimeric protein of embodiment 31, wherein the peptide linker comprises one or more oligomerization and/or multimerization domains.
  • Embodiment 33. The chimeric protein of embodiment 31 or 32, wherein the peptide linker comprises the constant region of a heavy chain of a full-length antibody or a fragment thereof, or the constant region of a light chain of a full-length antibody or a fragment thereof.
  • Embodiment 34. The chimeric protein of any one of embodiments 31-33, wherein the peptide linker comprises an CH₁, CH₂, CH₃, CH₄, and/or C_L domain or fragments thereof.
  • Embodiment 35. The chimeric protein of any one of embodiments 31-33, wherein the peptide linker comprises an Fc region or a fragment thereof.
  • Embodiment 36. The chimeric protein of any one of embodiments 31-35, wherein the peptide linker comprises a detectable enzymatic tag, optionally wherein the enzymatic tag is an alkaline phosphatase and/or a glutathione-s-transferase.
  • Embodiment 37. The chimeric protein of any one of embodiments 31-36, wherein the peptide linker comprises:
    • (i) a basic helix-loop-helix leucine zipper (bZIP) domain, bZIP isoleucine zipper domain, and/or bZIP-leucine/isoleucine zipper domain;
    • (ii) a collagen-like peptide;
    • (iii) a p53 tetramerization domain;
    • (iv) a streptavidin (SA) protein, optionally wherein the linker further comprises a dextran scaffold or one or more maleimide polymers (DMGS);
    • (v) a bacteriophage T7 fibritin protein or a portion thereof; and/or
    • (vi) a cartilage oligomeric matrix protein (COMP) protein.
  • Embodiment 38. The chimeric protein of any one of embodiments 1-37, wherein the antibody moiety is a full-length antibody.
  • Embodiment 39. The chimeric protein of embodiment 38, wherein the antibody moiety is selected from the group consisting of an IgG, an IgA, an IgM, and an IgD.
  • Embodiment 40. The chimeric protein of any one of embodiments 1-37, wherein the antibody moiety is an antigen-binding fragment selected from the group consisting of a Fab, a Fab′, a (Fab′)₂, an Fv, a single chain Fv (scFv), an scFv-Fc, a disulfide stabilized Fv fragment (dsFv), a (dsFv)₂, an scFv dimer, a domain antibody, a camelized single domain antibody (sdAb), a bivalent domain antibody, a minibody, and a V_HH.
  • Embodiment 41. The chimeric protein of any one of embodiments 1-40, wherein the antibody moiety is animal, human, humanized, camelid, or chimeric.
  • Embodiment 42. The chimeric protein of any one of embodiments 1-41, wherein the mucoadhesive peptide fragment is fused to a C-terminus of the antibody moiety.
  • Embodiment 43. The chimeric protein of any one of embodiments 1-39, 41, and 42, wherein the antibody moiety is a full-length antibody, and wherein:
    • (1) the mucoadhesive peptide fragment is fused to the C-terminus of a heavy chain of the full-length antibody via a first optional peptide linker; and/or
    • (2) the mucoadhesive peptide fragment is fused to the C-terminus of a light chain of the full-length antibody via a second optional peptide linker.
  • Embodiment 44. The chimeric protein of embodiment 43, wherein the chimeric protein comprises: i) a first and a second polypeptide chain each comprising from the N-terminus to the C-terminus: the heavy chain of the full-length antibody, the first optional peptide linker, and the mucoadhesive peptide fragment; and ii) a third and a fourth polypeptide chain each comprising the light chain of the full-length antibody.
  • Embodiment 45. The chimeric protein of any one of embodiments 1-44, wherein the influenza virus is a Type A influenza virus (IAV), a Type B influenza virus (IBV), a Type C influenza virus (ICV), a Type D influenza virus (IDV), or a variant, subtype, or reassortant thereof.
  • Embodiment 46. The chimeric protein of any one of embodiments 1-45, wherein the influenza virus comprises a hemagglutinin (HA) antigen selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof.
  • Embodiment 47. The chimeric protein of any one of embodiments 1-46, wherein the influenza virus comprises an neuraminidase (NA) antigen selected from the group consisting of N1, N2, N3, N7, N8, and N9, or a variant or reassortant thereof.
  • Embodiment 48. The chimeric protein of any one of embodiments 1-47, wherein the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof.
  • Embodiment 49. The chimeric protein of any one of embodiments 1-48, wherein the component of the influenza virus or variant thereof is a viral surface protein or fragment thereof.
  • Embodiment 50. The chimeric protein of embodiment 49, wherein the viral surface protein is HA.
  • Embodiment 50a. The chimeric protein of embodiment 50, wherein the chimeric protein comprises:
    • (i) a heavy chain complementarity determining region (HC-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region (LC-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 4, an LC-CDR2 comprising the amino acid sequence of WAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 6;
    • (ii) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 235, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 238, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 415; or
    • (iii) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 439, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 440, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 441, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 443, an LC-CDR2 comprising the amino acid sequence of SND, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 445.
  • Embodiment 50b. The chimeric protein of embodiment 50 or 50a, wherein the chimeric protein comprises:
    • (i) a heavy chain variable domain (V_H) comprising the amino acid sequence of SEQ ID NO: 76, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 76, and a light chain variable domain (V_L) comprising the amino acid sequence of SEQ ID NO: 77, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 77;
    • (ii) a V_H comprising the amino acid sequence of SEQ ID NO: 78, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 78, and a V_L comprising the amino acid sequence of SEQ ID NO: 79, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 79; or
    • (iii) a V_H comprising the amino acid sequence of SEQ ID NO: 438, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 438, and a V_L comprising the amino acid sequence of SEQ ID NO: 442, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 443;
  • Embodiment 50c. The chimeric protein of any one of embodiments 50-50b, wherein the chimeric protein comprises:
    • (i) a heavy chain (HC) polypeptide comprising the amino acid sequence of SEQ ID NO: 414, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 414, and a light chain (LC) polypeptide comprising the amino acid sequence of SEQ ID NO: 217, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 217;
    • (ii) an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 420, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 420, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 244, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 244; or
    • (iii) an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 446, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 446, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 447, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 447.
  • Embodiment 51. The chimeric protein of any one of embodiments 50-50c, wherein the chimeric protein comprises:
    • (i) a first and a second polypeptide chain each independently comprising the amino acid sequence of any one of SEQ ID NOs: 216, 218-234, 236, 237, 239-242, and 416-419, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 216, 218-234, 236, 237, 239-242, and 416-419, and a third and a fourth polypeptide chain each independently comprising the amino acid sequence of SEQ ID NO: 217, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 217;
    • (ii) a first and a second polypeptide chain each independently comprising the amino acid sequence of any one of SEQ ID NOs: 243, 245-258, and 422-425, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 243, 245-258, and 422-425, and a third and a fourth polypeptide chain each independently comprising the amino acid sequence of SEQ ID NO: 244, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 244; or
    • (iii) a first and a second polypeptide chain each independently comprising the amino acid sequence of any one of SEQ ID NOs: 448-468, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 448-468, and a third and a fourth polypeptide chain each independently comprising the amino acid sequence of SEQ ID NO: 447, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 447.
  • Embodiment 52. The chimeric protein of embodiment 49, wherein the component of the viral surface protein is NA.
  • Embodiment 52a. The chimeric protein of embodiment 52, wherein the chimeric protein comprises:
    • (i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 104, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 106, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 107, an LC-CDR2 comprising the amino acid sequence AAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 109; or
    • (ii) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 110, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 111, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 112, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 113, an LC-CDR2 comprising the amino acid sequence GAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 115.
  • Embodiment 52b. The chimeric protein of embodiment 52 or 52a, wherein the chimeric protein comprises:
    • (i) a V_H comprising the amino acid sequence of SEQ ID NO: 188, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 188, and a V_L comprising the amino acid sequence of SEQ ID NO: 189, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 189; or
    • (ii) a V_H comprising the amino acid sequence of SEQ ID NO: 190, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 190, and a V_L comprising the amino acid sequence of SEQ ID NO: 191, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 191.
  • Embodiment 52c. The chimeric protein of any one of embodiments 52-52b, wherein the chimeric protein comprises:
    • (i) an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 426, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 426, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 260, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 260; or
    • (ii) an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 432, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 432, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 276, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 276.
  • Embodiment 53. The chimeric protein of any one of embodiments 52-52c, wherein the chimeric protein comprises:
    • (i) a first and a second polypeptide chain each independently comprising the amino acid sequence of any one of SEQ ID NOs: 259, 261-274, and 428-431, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 259, 261-274, and 428-431, and a third and a fourth polypeptide chains each independently comprising the amino acid sequence of SEQ ID NO: 260, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 260; or
    • (ii) a first and a second polypeptide chain each independently comprising the amino acid sequence of any one of SEQ ID NOs: 275, 277-290, and 434-437, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 275, 277-290, and 434-437, and a third and a fourth polypeptide chains each independently comprising the amino acid sequence of SEQ ID NO: 276, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 276.
  • Embodiment 54. The chimeric protein of any one of embodiments 1-53, wherein the mucosa is selected from the group consisting of nasal mucosa, larynx mucosa, trachea mucosa, bronchi mucosa, lung mucosa, eye mucosa, and combinations thereof.
  • Embodiment 55. A pharmaceutical composition comprising the chimeric protein of any one of embodiments 1-54, and a pharmaceutically acceptable carrier.
  • Embodiment 56. The pharmaceutical composition of embodiment 55, wherein the pharmaceutical composition comprises a plurality of the chimeric proteins, and wherein at least two of the plurality of the chimeric proteins are different from each other.
  • Embodiment 57. The pharmaceutical composition of embodiment 55 or 56, wherein the pharmaceutically acceptable carrier:
    • (i) comprises about 0.05% to about 0.2% (w/w) methionine;
    • (ii) has a pH of about 4.5 to about 7.5;
    • (iii) comprises about 20 mM to about 50 mM citrate;
    • (iv) comprises about 100 mM to about 150 mM NaCl;
    • (v) comprises about 0.01% to about 0.1% (w/w) polysorbate 80;
    • (vi) comprises about 1% to about 10% (w/w) glycerin; and/or
    • (vii) comprises about 0.05% to about 0.2% (w/w) potassium sorbate.
  • Embodiment 58. The pharmaceutical composition of any one of embodiments 55-57, wherein the pharmaceutical composition is formulated for intranasal administration, intraocular administration, and/or intrabronchial administration.
  • Embodiment 59. An isolated nucleic acid or a set of isolated nucleic acids encoding the chimeric protein of any one of embodiments 1-54.
  • Embodiment 60. A vector or a set of vectors comprising the nucleic acid or the set of nucleic acids of embodiment 59.
  • Embodiment 61. A host cell comprising the chimeric protein of any one of embodiments 1-54, the nucleic acid or set of nucleic acids of embodiment 59, the vector or set of vectors of embodiment 60.
  • Embodiment 62. A method of preparing a chimeric protein, comprising:
    • (a) culturing a host cell of embodiment 61 under a condition effective to express the chimeric protein; and
    • (b) obtaining the expressed chimeric protein from the host cell.
  • Embodiment 63. A method of preventing or treating an infection caused by an influenza virus or a variant thereof in an individual, comprising administering to the individual an effective amount of the chimeric protein of any one of embodiments 1-54, or the pharmaceutical composition of any one of embodiments 55-58.
  • Embodiment 64. The method of embodiment 63, wherein the chimeric protein or the pharmaceutical composition is administered to the individual before the individual is exposed to the influenza virus or variant thereof.
  • Embodiment 65. The method of embodiment 63, wherein the chimeric protein or the pharmaceutical composition is administered to the individual within about 72 hours after the individual is exposed to the influenza virus or variant thereof.
  • Embodiment 66. The method of any one of embodiments 63-65, wherein the chimeric protein or the pharmaceutical composition is administered topically onto the mucosa.
  • Embodiment 67. The method of embodiment 66, wherein the chimeric protein or the pharmaceutical composition is administered via a nasal spray, an inhaler, a nebulizer, or an eye drop.
  • Embodiment 68. The method of any one of embodiments 63-67, wherein the chimeric protein or the pharmaceutical composition is administered once daily.
  • Embodiment 69. An in vitro method of killing or neutralizing a virus, comprising contacting a virus with the chimeric protein of any one of embodiments 1-54 in the presence of at least one component of the complement system, optionally wherein the at least one component of the complement system is C1, C4, or membrane attack complex (MAC).
  • Embodiment 70. A method of killing or neutralizing a virus in an individual, comprising administering to the individual an effective amount of the chimeric protein of any one of embodiments 1-54, or the pharmaceutical composition of any one of embodiments 55-58.
  • Embodiment 71. A method of activating the complement pathway in an individual, comprising administering to the individual an effective amount of the chimeric protein of any one of embodiments 1-54, or the pharmaceutical composition of any one of embodiments 55-58.
  • Embodiment 72. The method of embodiment 70 or 71, wherein at least one virus is killed or neutralized on the mucosa.
  • Embodiment 73. A method of preventing, treating, or reducing infection caused by a virus in an individual, comprising administering to the individual an effective amount of the chimeric protein of any one of embodiments 1-54, or the pharmaceutical composition of any one of embodiments 55-58, wherein at least one virus is killed or neutralized on the mucosa.
  • Embodiment 74. The method of any one of embodiments 63-73, wherein the chimeric protein activates the complement pathway in the individual.
  • Embodiment 75. The method of any one of embodiments 63-74, wherein the killing or neutralization is via activation of the complement pathway.
  • Embodiment 76. The method of any one of embodiments 62-75, wherein the virus is an influenza virus.
  • Embodiment 77. The method of embodiment 76, wherein the influenza virus is selected from the group consisting of a Type A influenza virus (IAV), a Type B influenza virus (IBV), a Type C influenza virus (ICV), a Type D influenza virus (IDV), or a variant, subtype, or reassortant thereof.
  • Embodiment 78. The method of embodiment 76 or 77, wherein the influenza virus comprises an HA antigen selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof.
  • Embodiment 79. The method of any one of embodiments 76-78, wherein the influenza virus comprises an NA antigen selected from the group consisting of N1, N2, N3, N7, N8, and N9, or a variant or reassortant thereof.
  • Embodiment 80. The method of any one of embodiments 76-79, wherein the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof.
  • Embodiment 81. The chimeric protein of any one of embodiments 1-54, or the pharmaceutical composition of any one of embodiments 55-58, for use in a method of preventing or treating an infection caused by an influenza virus or a variant thereof in an individual, the method comprising administering to the individual an effective amount of the chimeric protein of or the pharmaceutical composition.
  • Embodiment 82. The chimeric protein or pharmaceutical composition for use of embodiment 81, wherein the chimeric protein or the pharmaceutical composition is administered to the individual before the individual is exposed to the influenza virus or variant thereof.
  • Embodiment 83. The chimeric protein or pharmaceutical composition for use of embodiment 81, wherein the chimeric protein or the pharmaceutical composition is administered to the individual within about 72 hours after the individual is exposed to the influenza virus or variant thereof.
  • Embodiment 84. The chimeric protein or pharmaceutical composition for use of any one of embodiments 81-83, wherein the chimeric protein or the pharmaceutical composition is administered topically onto the mucosa.
  • Embodiment 85. The chimeric protein or pharmaceutical composition for use of embodiment 84, wherein the chimeric protein or the pharmaceutical composition is administered via a nasal spray, an inhaler, a nebulizer, or an eye drop.
  • Embodiment 86. The chimeric protein or pharmaceutical composition for use of any one of embodiments 81-85, wherein the chimeric protein or the pharmaceutical composition is administered once daily.
  • Embodiment 87. The chimeric protein of any one of embodiments 1-54, or the pharmaceutical composition of any one of embodiments 55-58, for use in a method of killing or neutralizing a virus in an individual, the method comprising administering to the individual an effective amount of the chimeric protein or the pharmaceutical composition.
  • Embodiment 88. The chimeric protein of any one of embodiments 1-54, or the pharmaceutical composition of any one of embodiments 55-58, for use in a method of activating the complement pathway in an individual, the method comprising administering to the individual an effective amount of the chimeric protein or the pharmaceutical composition.
  • Embodiment 89. The chimeric protein or pharmaceutical composition for use of embodiment 87 or 88, wherein at least one virus is killed or neutralized on the mucosa.
  • Embodiment 90. The chimeric protein of any one of embodiments 1-54, or the pharmaceutical composition of any one of embodiments 55-58, for use in a method of preventing, treating, or reducing infection caused by a virus in an individual, wherein at least one virus is killed or neutralized on the mucosa, the method comprising administering to the individual an effective amount of the chimeric protein or the pharmaceutical composition.
  • Embodiment 91. The chimeric protein or pharmaceutical composition for use of any one of embodiments 81-90, wherein the chimeric protein activates the complement pathway in the individual.
  • Embodiment 92. The chimeric protein or pharmaceutical composition for use of any one of embodiments 81-91, wherein the killing or neutralization is via activation of the complement pathway.
  • Embodiment 93. The chimeric protein or pharmaceutical composition for use of any one of embodiments 81-92, wherein the virus is an influenza virus.
  • Embodiment 94. The chimeric protein or pharmaceutical composition for use of embodiment 93, wherein the influenza virus is selected from the group consisting of a Type A influenza virus (IAV), a Type B influenza virus (IBV), a Type C influenza virus (ICV), a Type D influenza virus (IDV), or a variant, subtype, or reassortant thereof.
  • Embodiment 95. The chimeric protein or pharmaceutical composition for use of embodiment 93 or 94, wherein the influenza virus comprises an HA antigen selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof.
  • Embodiment 96. The chimeric protein or pharmaceutical composition for use of any one of embodiments 93-95, wherein the influenza virus comprises an NA antigen selected from the group consisting of N1, N2, N3, N7, N8, and N9, or a variant or reassortant thereof.
  • Embodiment 97. The chimeric protein or pharmaceutical composition for use of any one of embodiments 93-96, wherein the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof.
  • Embodiment 98. The use of chimeric protein of any one of embodiments 1-54, or the pharmaceutical composition of any one of embodiments 55-58, in the manufacture of a medicament for preventing or treating an infection caused by an influenza virus or a variant thereof in an individual.
  • Embodiment 99. The use according to embodiment 98, wherein the chimeric protein or the pharmaceutical composition is administered to the individual before the individual is exposed to the influenza virus or variant thereof.
  • Embodiment 100. The use according to embodiment 98, wherein the chimeric protein or the pharmaceutical composition is administered to the individual within about 72 hours after the individual is exposed to the influenza virus or variant thereof.
  • Embodiment 101. The use according to any one of embodiments 98-100, wherein the chimeric protein or the pharmaceutical composition is administered topically onto the mucosa.
  • Embodiment 102. The use according to embodiment 101, wherein the chimeric protein or the pharmaceutical composition is administered via a nasal spray, an inhaler, a nebulizer, or an eye drop.
  • Embodiment 103. The use according to any one of embodiments 98-102, wherein the chimeric protein or the pharmaceutical composition is administered once daily.
  • Embodiment 104. The use of the chimeric protein of any one of embodiments 1-54, or the pharmaceutical composition of any one of embodiments 55-58, in the manufacture of a medicament for killing or neutralizing a virus in an individual.
  • Embodiment 105. The use of the chimeric protein of any one of embodiments 1-54, or the pharmaceutical composition of any one of embodiments 55-58, in the manufacture of a medicament for activating the complement pathway in an individual.
  • Embodiment 106. The c use according to embodiment 104 or 105, wherein at least one virus is killed or neutralized on the mucosa.
  • Embodiment 107. The use chimeric protein of any one of embodiments 1-54, or the pharmaceutical composition of any one of embodiments 55-58, in the manufacture of a medicament for preventing, treating, or reducing infection caused by a virus in an individual, wherein at least one virus is killed or neutralized on the mucosa.
  • Embodiment 108. The use according to any one of embodiments 98-107, wherein the chimeric protein activates the complement pathway in the individual.
  • Embodiment 109. The use according to any one of embodiments 98-108, wherein the killing or neutralization is via activation of the complement pathway.
  • Embodiment 110. The use according to any one of embodiments 98-109, wherein the virus is an influenza virus.
  • Embodiment 111. The use according to embodiment 110, wherein the influenza virus is selected from the group consisting of a Type A influenza virus (IAV), a Type B influenza virus (IBV), a Type C influenza virus (ICV), a Type D influenza virus (IDV), or a variant, subtype, or reassortant thereof.
  • Embodiment 112. The use according to embodiment 110 or 111, wherein the influenza virus comprises an HA antigen selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof.
  • Embodiment 113. The use according to any one of embodiments 110-112, wherein the influenza virus comprises an NA antigen selected from the group consisting of N1, N2, N3, N7, N8, and N9, or a variant or reassortant thereof.
  • Embodiment 114. The use according to any one of embodiments 110-113, wherein the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof.

EXAMPLES

The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.

Example 1. Exemplary Anti-HA hIgG Antibodies

Several antibodies directed to the hemagglutinin (HA) protein of influenza types A and B are disclosed in Table 4A, along with their variable region and CDR sequences.

Several animal antibodies directed to the HA protein of influenza types A and B are disclosed in Table 6, along with their variable region and CDR sequences.

Example 2. Exemplary Anti-NA hIgG Antibodies

Several antibodies directed to the neuraminidase (NA) protein of influenza types A and B are disclosed in Table 4B, along with their variable region and CDR sequences.

Antibodies directed to animal NA proteins from influenza type A strains are also disclosed.

Example 3. Characterization of Anti-HA IgG Antibodies

Example 3A. Human Anti-HA Antibodies Bind the IAV HA Glycoprotein

This Example demonstrates that exemplary anti-HA-hIgG antibodies (HA1, HA2, HA15 and the other antibodies from Table 4A) bind to HEK293F cell surface expressed HA when co-expressed with influenza NA and M2 (ion channel) proteins according to McKay et al. Gene Therapy 13:715-724 (2006). In that study, the ability to produce lentiviral vectors pseudotyped with fowl plague virus HA was improved by co-expression of influenza virus NA and further improved by co-expressing the Influenza Virus M2 proton channel in transfected HEK293 cells. We first test whether HA expression is easily detected in HEK293F cells transfected with an Influenza Virus type A (IAV) HA and Influenza Virus type B (IVB) NA and Influenza M2 expressed from a eukaryotic expression vector.

HEK293F (FreeStyle™ 293-F Cells, ThermoFisher Scientific) cells are transfected with an expression vector carrying the IAV HA gene, the IBV NA gene and the M2 ion channel gene and a stable cell line is established and designated HEK293-HNM. The HEK293-HNM cells are tested for membrane HA expression. HEK293-HNM cells are harvested and washed with 1% ice-cold BSA in PBS (bovine serum albumin, phosphate buffered saline). The cells (0.1 million for each concentration) are stained for 30 min using the exemplary anti-HA antibodies shown in Table 4A, including HA1, HA2 and HA15, or with negative control antibodies such as anti-PSMA. The cells are then washed three times in 1% ice-cold BSA in PBS, and incubated with 5 μg/mL of goat anti-Human IgG (H+L) secondary antibody (PE/Cy7, Novus Biologicals) for 30 min. The cells are washed three times with 1% ice-cold BSA in PBS and resuspended into 100 μL of washing buffer for flow cytometry analysis. Flow cytometry data are collected using BD FACSCanto™ II system using the FlowJo™ v10.6.1 software package. All the anti-HA antibodies tested detect IAV HA proteins on the surface of HEK293-HNM cells. However, negative control antibodies (anti-PSMA) do not bind (data not shown).

Example 3B. Binding of Chimeric Proteins Comprising Anti-HA-hIgG Human Antibodies to HA

The binding of exemplary chimeric proteins comprising anti-HA antibodies (Table 4A), including HA1, HA2, and HA15, to IAV HA are measured by Bio-Layer Interferometry (BLI) on a ForteBio Octet KQ with a Sensor Chip CAP. Binding of the human IgG antibodies is demonstrated using the following protocol: 20 μg/mL biotinylated target HA protein in kinetics buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.05% (v/v) Surfactant P20) is loaded onto a streptavidin biosensor. After washing off excess antigen, anti-HA antibody is added at 10 μg/mL in kinetics buffer for a 300 s period of association and a 300 s period of dissociation.

Example 3C. Characterization of Animal Anti-HA Antibodies

Exemplary animal anti-HA antibodies shown in Table 6 are also characterized using the same methods of Examples 3A-3B. Briefly, the animal anti-HA antibodies are evaluated for binding to the IAV HA glycoproteins, and are able to detect IAV HA proteins on the surface of HEK293-HNM cells. The binding of exemplary animal anti-HA antibodies is measured by BLI on a ForteBio Octet KQ with a Sensor Chip CAP, which shows that the animal anti-HA antibodies are able to bind HA proteins from IAV strains.

Example 4. Characterization of Anti-NA hIgG Antibodies

Example 4A. Human Anti-NA Antibodies Bind the IBV NA Glycoprotein

This Example demonstrates that exemplary anti-NA-hIgG antibodies (NA1, NA2 and the other antibodies from Table 4B) bind to HEK293F cell surface expressed NA when co-expressed with influenza HA and M2 (ion channel) proteins, as cited in the previous Example. We first test whether NA expression is easily detected in HEK293F cells transfected with an Influenza Virus type B (IBV) NA and Influenza Virus type A (IAV)-HA and Influenza M2 expressed from a eukaryotic expression vector.

HEK293F (FreeStyle™ 293-F Cells, ThermoFisher Scientific) cells are transfected with an expression vector carrying the IBV NA gene, the IAV HA gene and the M2 ion channel gene and a stable cell line is established and designated HEK293-HNM. The HEK293-HNM cells are tested for membrane NA expression. HEK293-HNM cells are harvested and washed with 1% ice-cold BSA in PBS. The cells (0.1 million for each concentration) are stained for 30 min using exemplary anti-NA antibodies shown in Table 4B, including NA1 and NA2, or with negative control antibodies such as □PSMA. The cells are then washed three times in 1% ice-cold BSA in PBS, and incubated with 5 μg/ml of goat anti-Human IgG (H+L) secondary antibody (PE/Cy7, Novus Biologicals) for 30 min. The cells are washed three times with 1% ice-cold BSA in PBS and resuspended into 100 μL of washing buffer for flow cytometry analysis. Flow cytometry data are collected using BD FACSCanto™ II system using the FlowJo™ v10.6.1 software package. All of the anti-NA antibodies tested detect IBV NA proteins on the surface of HEK293-HNM cells, however, negative control antibodies (anti-PSMA) do not bind.

Example 4B. Binding of Human Anti-NA-hIgG Antibodies to NA

The binding of exemplary anti-NA antibodies (Table 4B) including NA1 and NA2 to IBV NA is measured by BLI on a ForteBio Octet KQ with a Sensor Chip CAP. Binding of the human IgG antibodies is demonstrated using the following protocol: 20 μg/mL biotinylated target NA protein in kinetics buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.05% (v/v) Surfactant P20) is loaded onto a streptavidin biosensor. After washing off excess antigen, anti-HA antibody is added at 10 μg/mL in kinetics buffer for a 300 s period of association and a 300 s period of dissociation. The association and dissociation graphs confirm binding of the anti-NA antibody to NA proteins from IBV strains.

Example 4C. Characterization of Animal Anti-NA Antibodies

Exemplary animal anti-NA antibodies, targeting the NA protein of zoonotic IAV strain H7N9 have been published in the literature (D3 and 7H2, Xiong, et al., Emerging Microbes & Infections, 9(1):78-87 (2020)). Additionally, a camelid antibody directed to another zoonotic strain, IAV H5N1 (N1-V_HH, Cardoso, et al. Journal of Virology, 88(15):8278-96 (2014)) has been described. Such exemplary animal anti-NA antibodies, and other animal anti-NA antibodies, are also characterized using the same methods of Examples 4A-4B. Briefly, the animal anti-NA antibodies are evaluated for binding to IBV NA glycoproteins and are able to detect IAB-NA proteins on the surface of HEK293-HNM cells. The binding of exemplary animal anti-NA antibodies is measured by BLI on a ForteBio Octet KQ with a Sensor Chip CAP, which shows that the animal anti-NA antibodies are able to bind NA proteins from IBV strains.

Example 5. Blocking of Pseudoviral Infection by Anti-HA IgGs In Vitro

Example 5A. Production of HA-Pseudotyped Lentiviruses

Lentiviruses containing HA, NA and M2 proteins are produced by transfection of IAV HA, IBV NA and M2 expressing HEK293F cells using the lentiviral expression vector pCDH-EF1-MCS (System Biosciences) that carries the HA, NA and M2 expression constructs on a single vector under the control of the E1F promoter. Helper plasmids which encode the proteins required in trans for the production of infectious pseudotyped virus are simultaneously co-transfected.

Concentrated lentiviruses are applied to engineered HEK293-HNM cells in 96-well plates for 48 hours. In some experiments, HEK293-HNM cells are mock-transduced (no DNA added) or transduced with empty lentiviral vectors. Repeat flow cytometry analyses are done on day 5. Transduction efficiencies of HEK cells are assessed by flow cytometry using a goat anti-human PE-conjugated anti-HA antibody (Jackson Immuno, Cat #109-116-097). Flow cytometry data are collected using a BD LSR FORTESSA™ and analyzed using the FlowJo™ v10.6.1 software package (data not shown).

Example 5B. Pseudovirus Blocking Assay

This Example demonstrates that anti-HA IgG antibodies are able to block IAV HA pseudovirus infection in HEK293F cells expressing Influenza type A HA. Briefly, exemplary anti-HA antibodies shown in Table 4A, including HA1, HA2, and HA15 hIgG, are incubated with HA-pseudotyped lentivirus. The pseudotyped virus contains the EF1-α-driven luciferase and GFP reporter genes separated by a P2A self-cleaving peptide. Following a 30 min incubation of the anti-HA hIgG antibody with HA-pseudotyped lentivirus, the lentivirus is added to HEK293-HNM cells expressing IAV HA, IBV NA and M2 proteins. Cells are cultured in 5% CO₂ at 37° C. for 48 h. The degree of cellular infection with the pseudotyped virus is determined by detecting the luciferase level of the infected cells (Promega Luciferase Assay) or by detecting GFP-positive cells using fluorescence microscopy. A low quantity of each anti-HA antibody shown in Table 4A, including HA1, HA2, and HA15 human IgG antibody, is a sufficient antibody concentration to completely block the infection of HEK293-HNM cells expressing IAV HA.

Example 5C. Pseudovirus Blocking by Animal Anti-HA Antibodies

Exemplary animal anti-HA antibodies shown in Table 6 are analyzed for the ability to block IAV HA pseudovirus infection using the same methods of Example 5B. A low quantity of each exemplary animal anti-HA antibodies is sufficient to completely block the infection of HEK293-HNM cells expressing IAV.

Example 6. Blocking of Pseudoviral Infection by Anti-NA IgGs In Vitro

Example 6A. Production of NA-Pseudotyped Lentiviruses

Lentiviruses containing HA, NA and M2 proteins are produced by transfection of IAV HA, IBV NA and M2 expressing HEK293F cells using the lentiviral expression vector pCDH-EF1-MCS (System Biosciences) as in the previous Example.

Concentrated lentiviruses are applied to engineered HEK293-HNM cells in 96-well plates for 48 hours. In some experiments, HEK293-HNM cells are mock-transduced (no DNA added) or transduced with empty lentiviral vectors. Repeat flow cytometry analyses are done on day 5. Transduction efficiencies of HEK cells are assessed by flow cytometry using a goat anti-human PE-conjugated anti-HA antibody (Jackson Immuno, 109-116-097). Flow cytometry data are collected using a BD LSR FORTESSA™ and analyzed using the FlowJo™ v10.6.1 software package (data not shown).

Example 6B. Pseudovirus Blocking Assay

This Example demonstrates that anti-NA IgG antibodies are able to block IBV NA pseudovirus infection in HEK293F cells expressing influenza type B NA. Briefly, exemplary anti-NA antibodies shown in Table 4B, including NA1 and NA2 hIgG, are incubated with NA-pseudotyped lentivirus, as in the previous Example. Following a 30 min incubation of the anti-NA hIgG antibody with NA-pseudotyped lentivirus, the lentivirus is added to HEK293-HNM cells expressing influenza proteins. Cells are cultured in 5% CO2 at 37° C. for 48 h. The degree of cellular infection with the pseudotyped virus is determined by detecting the luciferase level of the infected cells or by detecting GFP-positive cells using fluorescence microscopy. A low quantity of NA1 or NA2 human IgG antibody is a sufficient antibody concentration to completely block the infection of HEK293-HNM cells expressing IBV.

Example 6C. Pseudovirus Blocking by Animal Anti-NA Antibodies

Exemplary animal anti-NA antibodies, including those disclosed in Xiong et al., 2020, Cardoso et al., 2014, and Murphy et al., 1972, N Engl J Med; 286:1329-1332, and other animal anti-NA antibodies, fused to any of the mucoadhesive peptides disclosed in Table 8, are able to block pseudovirus infection of HEK293-HNM cells in vitro using the methods described in Example 6B.

Example 7. Expression and Purification of Anti-HA Chimeric Mucoadhesive Proteins

Example 7A. Chimeric Proteins Comprising Anti-HA Antibodies and Mucoadhesive Polylysine and Polyhistidine Peptides

Chimeric proteins comprising HA1 hIgG, HA2 hIgG, or HA15 hIgG heavy chains fused to various lengths of polylysine or polyhistidine peptide fragments are generated. Specifically, DNA fragments encoding a polylysine-modified HA1, HA2, or HA15 IgG heavy chain (added to the C-terminus of the IgG heavy chain) and an unmodified HA1 or HA2 light chain were cloned into a single mammalian expression vector and used to transfect HEK293F cells as described in the previous Examples. Chimeric proteins HA1-hIgG-12K, HA2-hIgG-12K, and HA15-hIgG-12K were expressed from the transfected HEK293F cells and purified. Additionally, other proteins whose sequences are shown in Table 1 are also generated, including HA1-hIgG-12H, HA2-hIgG-12H and HA15-hIgG-12H.

The chimeric protein HA1-hIgG-12K has two HA1-hIgG heavy chains each fused to a 12 residue polylysine peptide and two unmodified HA1-hIgG light chains. The chimeric protein HA1-hIgG-12H has two HA1-hIgG heavy chains each fused to a 12 residue polyhistidine peptide and two unmodified HA1-hIgG light chains. These polylysine and polyhistidine peptides are examples of mucoadhesive peptide fragments which facilitate the attachment of the exemplary chimeric proteins to the upper respiratory mucosa.

Exemplary chimeric proteins comprising exemplary anti-HA antibodies disclosed in Table 4A with their heavy chains fused to 6K, 12K, or 30K and 6H, 12H, or 30H peptides are also expressed and purified.

Example 7B. Chimeric Proteins Comprising Anti-HA Antibodies with Other Mucoadhesive Polycationic Peptides

Additional mucoadhesive chimeric proteins comprising HA1, HA2, or HA15, or any of the other anti-HA antibodies shown in Table 4A fused to other cationic (positively charged) peptides, produced using the cationic amino acids arginine (R) or ornithine (O). The mucoadhesive antibodies with ornithine-containing peptides are produced by a method described in Mordhorst et al., Angewandte Chemie 59:21442-21447 (2020). In addition, these cationic peptides have been further modified to contain either all cationic amino acids or cationic amino acids interspersed with neutral amino acids as shown in Table 8.

Exemplary cationic peptides listed in Table 8 include peptides consisting of only K, only H, only R or only O ranging from 5 to 30 residues, mixed cationic peptides consisting of mixtures of K, H, R and O ranging from 6 to 30 amino acids, and cationic plus neutral amino acid peptides from 6 to 30 amino acids. Examples of various HA1, HA2, and HA15 mucoadhesive proteins are listed in Table 1. Other antibodies shown in Table 4A are modified with cationic peptides of Table 8 and are made and tested for expression of anti-HA mucoadhesive chimeric proteins in HEK293F cells as described above.

Example 7C. Chimeric Anti-HA Mucoadhesive Proteins Expressed in HEK293F Cells

Vectors comprising DNA fragments encoding the chimeric proteins described in Examples 7A and B are used to transfect host HEK293F cells. After 7 days of culture at 37° C., culture medium is harvested, and the chimeric proteins are isolated or purified from culture supernatants using a HiTrap® Protein A HP column (Cytiva) on an ÄKTA FPLC system (GE Healthcare).

Example 7D. Expression and Purification of Animal Anti-HA Chimeric Proteins

Chimeric proteins comprising exemplary animal anti-HA antibodies shown in Table 6 and polylysine or polyhistidine mucoadhesive peptides (e.g., 6K, 12K, or 30K and 6H, 12H, or 30H) are also produced using the methods of Example 7A. Additional mucoadhesive chimeric proteins comprising any of the exemplary animal anti-HA antibodies shown in Table 6 are fused to other cationic (positively charged) peptides, produced using the cationic amino acids arginine (R) or ornithine (O), according to the methods of Example 7B. The resulting chimeric animal anti-HA mucoadhesive proteins are expressed in HEK293F cells using the methods of Example 7C.

Example 8. Design and Expression of Anti-NA Chimeric Proteins Comprising Mucoadhesive Peptide Fragments

Example 8A. Chimeric Proteins Comprising Anti-NA Antibodies and Mucoadhesive Polylysine and Polyhistidine Peptides

Chimeric proteins comprising NA1 hIgG or NA2 hIgG heavy chains fused to various lengths of polylysine or polyhistidine peptide fragments are generated. Specifically, DNA fragments encoding a polylysine-modified NA1 or NA2 IgG heavy chain (added to the C-terminus of the IgG heavy chain) and an unmodified NA1 or NA2 light chain were cloned into a single mammalian expression vector and used to transfect HEK293F cells as described in previous Examples. Chimeric proteins NA1-hIgG-12K and NA2-hIgG-12K were expressed from the transfected HEK293F cells and purified. Additionally, exemplary proteins whose sequences are shown in Table 1 are also generated, including NA1-hIgG-12H and NA2-hIgG-12H.

The chimeric protein NA1-hIgG-12K has two NA1-hIgG heavy chains each fused to a 12 residue polylysine peptide and two unmodified NA1-hIgG light chains. The chimeric protein NA1-hIgG-12H has two NA1-hIgG heavy chains each fused to a 12 residue polyhistidine peptide and two unmodified NA1-hIgG light chains. The polylysine and polyhistidine peptides are Examples of mucoadhesive peptide fragments which facilitate the attachment of the exemplary chimeric proteins to the upper respiratory mucosa.

Exemplary chimeric proteins comprising the anti-NA antibodies disclosed in Table 4B with their heavy chains fused to 6K, 12K, or 30K, and 6H, 12H, or 30H peptides are also expressed and purified.

Example 8B. Chimeric Proteins Comprising Anti-NA Antibodies with Other Mucoadhesive Polycationic Peptides

Additional mucoadhesive chimeric proteins comprising NA1 or NA2 and the anti-NA antibodies shown in Table 4B are fused to other cationic (positively charged) peptides, produced using the cationic amino acids arginine (R) or ornithine (O). In addition, these cationic peptides have been further modified to contain either all cationic amino acids or cationic amino acids interspersed with neutral amino acids as shown in Table 8. Exemplary cationic peptides listed in Table 8 include peptides consisting of only K, only H, only R or only O ranging from 5 to 30 residues, mixed cationic peptides consisting of mixtures of K, H, R and O ranging from 6 to 30 amino acids, and cationic plus neutral amino acid peptides from 6 to 30 amino acids.

Examples of various NA mucoadhesive proteins are listed in Table 1. Other antibodies shown in Table 4B are modified with cationic peptides of Table 8 and are made and tested for expression of chimeric mucoadhesive NA proteins in HEK293F cells as described above.

Example 8C. Chimeric Anti-NA Mucoadhesive Proteins Expressed in HEK293F Cells

Vectors comprising DNA fragments encoding the chimeric proteins described in Examples 8A and 8B are used to transfect host HEK293F cells. After 7 days of culture at 37° C., culture medium is harvested, and the chimeric proteins are isolated or purified from culture supernatants using a HiTrap® Protein A HP column (Cytiva) on an AKTA FPLC system (GE Healthcare).

Example 8D. Expression and Purification of Animal Anti-NA Chimeric Proteins

Chimeric proteins comprising exemplary animal anti-NA antibodies, including those disclosed in Xiong et al., 2020, Cardoso et al., 2014, and Murphy et al., 1972, N Engl J Med; 286:1329-1332, and other animal anti-NA antibodies, and polylysine or polyhistidine mucoadhesive peptides (e.g., 6K, 12K, or 30K, or 6H, 12H, or 30H) are also produced using the methods of Example 8A. Additional mucoadhesive chimeric proteins comprising any of the exemplary animal anti-NA antibodies are fused to other cationic (positively charged) peptides, produced using the cationic amino acids arginine (R) or ornithine (O), according to the methods of Example 8B. The resulting chimeric animal anti-HA mucoadhesive proteins are expressed in HEK293F cells using the methods of Example 8C.

Example 9. Characterization of Anti-HA Chimeric Proteins Comprising Mucoadhesive Peptide Fragments

Example 9A. Non-Specific Cell Surface Binding of Mucoadhesive Chimeric Proteins to Cell Surface Glycoproteins In Vitro

This Example demonstrates that exemplary chimeric proteins described in Example 7, including chimeric proteins comprising HA1, HA2, or HA15 hIgG antibodies or the antibodies of Table 4A fused to various cationic or mixed peptides of Table 8, are able to nonspecifically bind to the HEK293F cell surface.

Chimeric proteins comprising hIgG fused to cationic peptides (30 nM) are combined with 2×10⁵ HEK293F cells which have been transfected to express HA or NA and incubated for 1 h at room temperature (RT). PE-conjugated goat anti-human IgG Fc is added, and the mixture is incubated for another 30 min at RT. Unmodified hIgG is used as a negative control. Cells are washed once with FACS buffer (2% FBS, 2 mM EDTA in 1× DPBS), and the binding of HA1, HA2 or HA15 hIgG chimeric proteins is assessed by flow cytometry. All tested chimeric proteins, including HA1, HA2 and HA15 hIgG and exemplary proteins listed in Table 4A fused to 5, 6, 12, or 30 K, H, R, or O mucoadhesive peptides are able to nonspecifically bind to the HEK293F cell surface, while unmodified hIgGs are not.

Nonspecific binding to the HEK293F cell surface by exemplary chimeric proteins of varying lengths comprising anti-HA hIgG1 antibody fused to peptides with mixed cationic residues or mixed cationic and neutral residues are also tested using the same method as described above. HA1, HA2 and HA15-hIgG-6X, 12X, and 30X chimeric proteins are also able to nonspecifically bind to the HEK293T cell surface. The nonspecific binding is confirmed for chimeric proteins comprising the antibodies or fragments thereof as disclosed in Table 4A fused to mucoadhesive peptides exemplified in Table 8 to HEK293F cells, but not for their unmodified counterparts.

Example 9B. In Vitro Binding of Mucoadhesive Chimeric Proteins to Mucin

Mucin glycoproteins produced by mucus-producing cells in the respiratory epithelium or submucosal glands are the major macromolecular constituent of mucus. Binding to mucin can potentially extend the retention time of an antibody in the mucus of the respiratory tract.

This Example demonstrates that anti-HA mucoadhesive proteins modified at the C termini of their heavy chains with peptides comprising various numbers of cationic residues (peptides as shown in Table 8) have increased binding to mucin compared to unmodified anti-HA antibodies.

To test the ability of the various mucoadhesive chimeric proteins to bind mucin, 96-well plates are coated with 50 μg/mL mucin (Sigma, M3895) for 2 hr at room temperature. The plates are blocked with 3% BSA overnight at 4° C. 5 μg/mL antibodies in 25 mM HEPES (pH 6.5) is added to the plates and incubated for 1 h at room temperature. After a wash with washing buffer (25 mM HEPES, NaCl, pH 6.5), plates are stained with HRP-conjugated goat anti-human IgG and developed using 3,3′,5,5′-Tetramethylbenzidine (TMB). Absorbance at an optical density at 450 nm (OD₄₅₀) is measured using a standard plate reader.

Example 9C. Binding of Mucoadhesive hIgG Chimeric Proteins to HA

To determine whether the binding of the HA1-hIgG-12K chimeric protein to purified HA was unaffected by the mucoadhesive cationic peptide, association of the chimeric protein to HA was examined by BLI. The assay was conducted on a ForteBio Octet KQ with an anti-human IgG (anti-hFC) capture biosensor. Binding of the HA1-hIgG1-12K chimeric protein was measured using the following protocol. 20 μg/mL biotinylated target HA1-hIgG-12K protein in kinetics buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.05% (v/v) Surfactant P20) was loaded onto an anti-hFC capture biosensor. After washing off excess antibody, the HA protein from the H1N1 or H3N2 isolate was added at 10 μg/mL in kinetics buffer for a 300 s period of association and a 300 s period of dissociation. FIGS. 1 and 2 show mucoadhesive chimeric proteins bind well to HA from the H1N1 or H3N2 strain, unaffected by the presence of polycationic moieties.

Other exemplary anti-HA chimeric proteins shown in Table 1 and other anti-HA mucoadhesive chimeric proteins (those comprising any of the other antibodies shown in Table 4A fused to any of the cationic peptides shown in Table 8) are tested for binding to HA using the protocol outlined above, and binding of these exemplary chimeric mucoadhesive proteins to HA is detected. For example, the binding of the HA1-hIgG-12H chimeric protein is tested for binding to HA using the protocol outlined above, and the binding of the HA1-hIgG-12H chimeric mucoadhesive protein to HA is confirmed.

Example 9D. Characterization of Animal Anti-HA Chimeric Proteins Comprising Mucoadhesive Peptide Fragments

Exemplary animal anti-HA chimeric proteins comprising mucoadhesive peptide fragments described in Example 7D, including exemplary animal anti-HA antibodies shown in Table 6 fused with any of the mucoadhesive peptide fragments shown in Table 8, are also characterized using the same methods of Examples 9A-9C. Binding of these animal chimeric mucoadhesive proteins to HA is detected using BLI, as above.

Example 10. Characterization of Anti-NA Chimeric Proteins Comprising Mucoadhesive Peptide Fragments

Example 10A. Non-Specific Cell Surface Binding of Mucoadhesive Chimeric Proteins to Cell Surface Glycoproteins In Vitro

This Example demonstrates that exemplary chimeric proteins described in previous Examples, including chimeric proteins comprising NA1 or NA2 hIgG antibodies or exemplary antibodies of Table 4B fused to various cationic or mixed peptides of Table 8, are able to nonspecifically bind to the HEK293F cell surface.

Chimeric proteins comprising hIgG fused to cationic peptides (30 nM) are combined with 2×10⁵ HEK293F cells which have been transfected to express NA and incubated for 1 h at room temperature (RT). PE-conjugated goat anti-human IgG Fc is added, and the mixture is incubated for another 30 min at RT. Unmodified hIgG is used as a negative control. Cells are washed once with FACS buffer (2% FBS, 2 mM EDTA in 1× DPBS), and the binding of NA1 or NA2 hIgG chimeric proteins is assessed by flow cytometry. All tested chimeric proteins, including NA1 and NA2 hIgG and exemplary proteins listed in Table 4B fused to 5, 6, 12, or 30 K, H, R, or O mucoadhesive peptides are able to nonspecifically bind to the HEK293F cell surface, while unmodified hIgGs are not.

Nonspecific binding to the HEK293F cell surface by exemplary chimeric proteins of varying lengths comprising anti-NA hIgG1 antibody fused to peptides with mixed cationic residues or mixed cationic and neutral residues are also tested using the same method as described above. All tested chimeric proteins, including NA1 and NA2 hIgG and exemplary proteins listed in Table 4B fused to 5, 6, 12, or 30 K, H, R, or O mucoadhesive peptides are able to nonspecifically bind to the HEK293F cell surface, while unmodified hIgGs are not.

Example 10B. In Vitro Binding of Mucoadhesive Chimeric Proteins to Mucin

Mucin glycoproteins produced by mucus-producing cells in the respiratory epithelium or submucosal glands are the major macromolecular constituent of mucus. Binding to mucin can potentially extend the retention time of an antibody in the mucus of the respiratory tract.

This Example demonstrates that anti-NA mucoadhesive proteins modified at the C termini of their heavy chains with peptides comprising various numbers of cationic residues (peptides as shown in Table 8) have increased binding to mucin compared to unmodified anti-NA antibodies.

To test the ability of the various mucoadhesive chimeric proteins to bind mucin, 96-well plates are coated with 50 μg/mL mucin (Sigma, M3895) for 2 hrs at room temperature. The plates are blocked with 3% BSA overnight at 4° C. 5 μg/mL antibodies in 25 mM HEPES (pH 6.5) are added to the plates and incubated for 1 h at room temperature. After a wash with washing buffer (25 mM HEPES, 50 mM NaCl, pH 6.5), plates are stained with HRP-conjugated goat anti-human IgG and developed using TMB. Absorbance at OD₄₅₀ is measured.

Example 10C. Binding Affinity of Mucoadhesive hIgG Chimeric Proteins to NA

To determine whether the binding of the NA1-hIgG-12K chimeric protein to purified NA was unaffected by presence of the mucoadhesive peptide, association of the chimeric protein to NA was examined by BLI. The assay was conducted on a ForteBio Octet KQ with an anti-hFC capture biosensor Binding of the NA1-hIgG1 chimeric protein was measured using the following protocol. 20 μg/mL biotinylated target NA1-hIgG-12K protein in kinetics buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.05% (v/v) Surfactant P20) was loaded onto an anti-hFC capture biosensor. After washing off excess antibody, the NA protein from an influenza B isolate was added at 10 μg/mL in kinetics buffer for a 300 s period of association and a 300 s period of dissociation. FIG. 3 shows mucoadhesive chimeric protein binds well to NA from the IBV strain, unaffected by the presence of polycationic moieties.

Exemplary chimeric proteins of Table 1 and mucoadhesive variants of proteins in Table 4B are tested for binding to NA using the protocol outlined above and binding of exemplary chimeric mucoadhesive proteins to NA is presented. For example, the binding of the NA1-hIgG-12H chimeric protein is tested for binding to NA using the protocol outlined above, and the binding of the NA2-hIgG-12H chimeric mucoadhesive protein to NA is also confirmed.

Example 10D. Characterization of Animal Anti-NA Chimeric Proteins

Exemplary animal anti-NA chimeric proteins comprising mucoadhesive peptide fragments described in Example 8D, including exemplary animal anti-NA antibodies disclosed in Xiong et al., 2020, Cardoso et al., 2014, and Murphy et al., 1972, and other animal anti-NA antibodies, fused with any of the mucoadhesive peptide fragments shown in Table 8, are also characterized using the same methods of Examples 10A-10C. Binding of these animal chimeric mucoadhesive proteins to NA is detected.

Example 11. Protective Effects of Anti-HA Mucoadhesive Chimeric Proteins in a Mouse Model of Infection

Example 11A. Protective Effects of Human Anti-HA Mucoadhesive Chimeric Protein in a Mouse Model of Infection

In a study by Yan et al., Proc. Nat. Sci. USA, 115 (5):1081-1086 (2017), it was shown that greater than 10⁴ RNA copies and up to 103 infectious virus particles (per 30 min) are contained in the aerosolized droplets from exhalations of infected persons when speaking.

In the experiments described here, we challenge mice with HA-NA pseudovirus by directly dropping at least 10⁶ pseudovirus particles into the nostrils of the mice. Inhibition of viral infection is achieved by pre-administration of HA1-IgG-12K, HA2-IgG-12K, HA15-IgG-12K, HA15-IgG-6K, HA1-IgG-12H, HA2-IgG-12H, HA15-IgG-12H, or other exemplary mucoadhesive chimeric proteins comprising any of the antibodies disclosed in Table 4A fused with any of the mucoadhesive peptide fragments disclosed in Table 8. Inhibition against this high viral titer shows the promise of a nasal spray protection even in a worst-case scenario and could provide a large cushion of protection in most common situations where a healthy person encounters an infected individual.

To test if chimeric proteins comprising anti-HA antibodies fused to various mucoadhesive or polycationic peptide fragments can block infectious influenza viruses or pseudoviruses in vivo, and to determine the role of the polycationic peptide fragment in the potential blocking of influenza infection, the HA1, HA2, and HA15 hIgG chimeric proteins (sequences shown in Table 1; e.g., HA1-hIgG-12K or HA1-IgG-12H) are compared to the unmodified HA1, HA2 and HA15 hIgG antibodies lacking the C-terminal mucoadhesive peptide modification, respectively, in an in vivo pseudovirus protection assay. Seven groups of 4-week-old young adult CD-1® IGS or BALB/c mice (Charles River) (A1 through A7) are pretreated with an HA1, HA2 or HA15 hIgG chimeric protein (e.g., HA1-IgG-12K or HA1-IgG-12H) or unmodified HA1, HA2 or HA15 hIgG. Doses of 25 μg (A2 and A3), 75 μg (A4 and A5) or 200 g (A6 and A7) per nostril of an HA1, HA2, or HA15 chimeric protein (A2, A4, A6) or an unmodified HA1, HA2, or HA15 antibody (A3, A5, A7) are each delivered to 3 groups of mice through nasal administration. A control group (A1) receives no pretreatment with any antibody.

10 hours after nasal administration of the mucoadhesive proteins or antibodies, all groups are dosed with HA-NA pseudotyped lentivirus. Animals are closely monitored after nasal administration of the pseudovirus; on day 3, day 5 and day 7 following pseudoviral application, bioluminescence and body weight are measured for each mouse. After the day 7 measurement, the lungs are dissected and imaged.

The mice pretreated with each of the HA1, HA2, or HA15 hIgG chimeric proteins tested (e.g., HA1-IgG-12K or HA1-IgG-12H) are free of signs of infection as measured by bioluminescent imaging, whereas the mice receiving the HA1, HA2, or HA15 antibody lacking the polylysine or polyhistidine peptide fragment and the control group with no antibody show obvious signs of infection. The mice pretreated with unmodified HA1, HA2, or HA15 hIgG also show signs of pseudoviral infection in their lung tissues, whereas the mice pretreated with the HA1, HA2 or HA15 hIgG chimeric proteins are free of signs of lung involvement after Day 7.

Each of the HA1, HA2, or HA15 hIgG chimeric proteins when tested (e.g., HA1-hIgG-12K or HA1-IgG-12H) is able to block nasal infection by influenza pseudoviruses in mice, and the polycationic peptide fragments play an essential role in the blocking of infection. Each of the HA1, HA2, or HA15 hIgG chimeric proteins is superior to the unmodified HA1, HA2, or HA15 antibody in protecting mice from virus infection when the chimeric proteins or unmodified antibodies are administered 10 hours prior to virus dosing. Thus, the mucin-binding modification (i.e., addition of the cationic peptide fragment) of the HA1, HA2, and HA15 mucoadhesive chimeric proteins makes it possible for these modified proteins to protect mice against nasal infection by influenza pseudoviruses.

Other anti-HA mucoadhesive chimeric proteins, e.g., those using each of antibodies HA3-HA16 (as disclosed in Table 4A) fused with each mucoadhesive peptide fragment disclosed in Table 8, are also compared to their corresponding unmodified HA antibodies in the mouse nasal infection experiments as described in this Example. The protective effect provided by the mucoadhesive proteins tested and each of the HA3-HA16 chimeric proteins is determined by their ability to block nasal infection by influenza pseudoviruses in mice, compared to their unmodified counterpart antibodies.

Example 11B. Protective Effects of Animal Anti-HA Mucoadhesive Chimeric Protein in a Mouse Model of Infection

Chimeric proteins comprising the exemplary animal anti-HA antibodies shown in Table 6 fused with each mucoadhesive peptide fragment disclosed in Table 8 are also characterized for protective effects in a mouse model of influenza pseudovirus infection using the same methods of Example 11A. The protective effect provided by the animal anti-HA chimeric proteins is determined by their ability to block nasal infection by influenza pseudoviruses in mice, compared to their unmodified counterpart antibodies.

Example 12. Protective Effects of Anti-NA Mucoadhesive Chimeric Proteins in a Mouse Model of Infection

Example 12A. Protective Effects of Human Anti-NA Mucoadhesive Chimeric Protein in a Mouse Model of Infection

In the experiments described here, we challenge mice with HA-NA pseudovirus by directly dropping at least 10⁶ pseudovirus particles into the nostrils of the mice. Inhibition of viral infection is achieved by pre-administration of NA1-IgG-12K, NA2-IgG-12K, NA1-IgG-12H, NA2-IgG-12H, or other exemplary mucoadhesive chimeric proteins comprising any of the antibodies disclosed in Table 4A against this high viral titer illustrates the promise of a nasal spray protection even in a worst-case scenario and could provide a large cushion of protection in most common situations where a healthy person encounters an infected individual.

To test if chimeric proteins comprising anti-NA fused to various mucoadhesive or polycationic peptide fragments can block infectious influenza viruses or pseudoviruses in vivo, and to determine the role of the polycationic peptide fragment in the potential blocking of influenza infection, the NA1 and NA2 hIgG chimeric proteins (sequences shown in Table 1; e.g., NA1-hIgG-12K or NA1-IgG-12H) are compared to the unmodified NA1 and NA2 antibodies lacking the C-terminal mucoadhesive peptide modification, respectively, in an in vivo pseudovirus protection assay. Seven groups of 4-week-old young adult CD-1® IGS or BALB/c mice (Charles River) (A1 through A7) are pretreated with an NA1 or NA2 hIgG chimeric protein (e.g., NA1-IgG-12K or NA1-IgG-12H) or unmodified NA1 or NA2 hIgG. Doses of 25 μg (A2 and A3), 75 μg (A4 and A5) or 200 μg (A6 and A7) per nostril of an NA1 or NA2 chimeric protein (A2, A4, A6) or an unmodified NA1 or NA2 antibody (A3, A5, A7) are each delivered to 3 groups of mice through nasal administration. A control group (A1) receives no pretreatment with any antibody.

10 hours after nasal administration of the mucoadhesive proteins and unmodified antibodies, all groups are dosed with HA-NA pseudotyped lentivirus. Animals are closely monitored after nasal administration of the pseudovirus; on day 3, day 5 and day 7 following pseudoviral application, bioluminescence and body weight are measured for each mouse. After the day 7 measurement, the lungs are dissected and imaged.

The mice pretreated with each of the NA1 or NA2 hIgG chimeric proteins tested (e.g., NA1-IgG-12K or NA1-IgG-12H) are free of signs of infection as measured by bioluminescent imaging, whereas the mice receiving the NA1 or NA2 antibody lacking the polylysine peptide fragment and the control group with no antibody show obvious signs of infection. The mice pretreated with unmodified NA1 or NA2 hIgG also show signs of pseudoviral infection in their lung tissues, whereas the mice pretreated with the NA1 or NA2 hIgG chimeric proteins are free of signs of lung involvement after Day 7, as measured by bioluminescent imaging.

Each of the NA1 or NA2 hIgG chimeric proteins tested (e.g., NA1-hIgG-12K or NA1-IgG-12H) is tested for the ability to block nasal infection by influenza pseudoviruses in mice; the polycationic peptide fragments play an essential role in such blocking of infection. Each of the NA1 or NA2 hIgG chimeric proteins is superior to the unmodified NA1 or NA2 antibody in protecting mice from virus infection when the chimeric proteins or unmodified antibodies are administered 10 hours prior to virus dosing. Thus, the mucin-binding modification (i.e., addition of the cationic peptide fragment) of the NA1 and NA2 antibodies makes it possible for the modified chimeric proteins to protect mice against nasal infection by influenza pseudoviruses.

Other anti-HA mucoadhesive chimeric proteins, e.g., those using each of antibodies NA3-NA14 (as disclosed in Table 4B) fused with each mucoadhesive peptide fragment disclosed in Table 8, are also compared to their corresponding unmodified NA antibody proteins in the mouse nasal infection experiments as described in this Example. The protective effect provided by the mucoadhesive proteins tested and each of the NA3-NA14 chimeric proteins is determined by their ability to block nasal infection by Influenza pseudoviruses in mice compared to their unmodified counterpart antibodies.

Example 12B. Protective Effects of Animal Anti-NA Mucoadhesive Chimeric Protein in a Mouse Model of Infection

Chimeric proteins comprising exemplary animal anti-NA antibodies, including those disclosed in Xiong et al., 2020, Cardoso et al., 2014, and Murphy et al., 1972, and other animal anti-NA antibodies fused with mucoadhesive peptide fragments disclosed in Table 8 are also characterized for protective effects in a mouse model of influenza pseudovirus infection using the same methods as in Example 12A. The protective effect provided by the animal anti-NA chimeric proteins is determined by their ability to block nasal infection by influenza pseudoviruses in mice, compared to their unmodified counterpart antibodies. Antibodies D3 and 7H2 from Xiong, et al. 2020 and N1-V_HH from Cardozo, et al. 2014 are tested for their ability to block pseudoviral infection of HEK293-HNM cells as described; in this Example, chimeric mucoadhesive proteins derived from these antibodies (fused to mucoadhesive peptides), along with the unmodified antibodies are tested for their ability to protect mice from pseudoviral infection. Mucoadhesive variants of anti-NA antibodies D3, 7H2, or N1-V_HH are capable of protecting mice from pseudoviral infection compared to their unmodified counterparts.

Example 13. Protection from Influenza Pseudoviral Infection by Anti-HA Mucoadhesive Proteins in a Nasal Spray Formulation

Example 13A. Anti-HA-IgG-12K and Anti-HA-IgG-12H Chimeric Proteins Stored in NS Buffer Maintain Binding Affinity to HA Protein

An accelerated antibody stability assay is performed to confirm that the formulation buffer does not affect the antigen binding ability of HA1-hIgG when modified with (fused to) the 12K or 12H peptide fragment. Neither does the formulation buffer affect the antigen binding ability of the other exemplary anti-HA chimeric proteins (chimeric proteins comprising any of the antibodies disclosed in Table 4A fused with any of the peptides disclosed in Table 8, other than HA1-hIgG-12K and HA1-IgG-12H). Briefly, HA1-hIgG-12K and HA1-IgG-12H chimeric proteins are stored in NS buffer (25 mM citrate buffer, pH 6.5, 125 mM NaCl, 5% glycerin, 0.1% methionine, 0.02% polysorbate 80, and 0.1% potassium sorbate) at 37° C. over a maximum period of 14 days, which is equivalent to about 1.5 years at 4° C. The binding of HA1-hIgG-12K and HA1-IgG-12H towards antigens is determined using a ForteBio Octet instrument with anti-hFC capture biosensor and the data is acquired by Octet Data Acquisition software 9.0. The binding curves of HA1-hIgG-12K and HA1-IgG-12H in NS buffer at different time points are compared to the binding curve of a sample of the unmodified HA1-hIgG antibody stored in PBS at 4° C. Graphs are obtained which show the binding (association and dissociation) of HA1-hIgG-12K and HA1-IgG-12H to HA protein after storage in the nasal spray formulation for 0, 1, 3, 5 7, or 14 days. The stability of binding to HA of other exemplary anti-HA mucoadhesive chimeric proteins in NS buffer are also tested for up to 14 days at 37° C. Mucoadhesive chimeric proteins stored in NS buffer are able to maintain binding affinity to HA protein as measured in this in vitro assay.

Example 13B. Anti-HA-IgG-12K and Anti-HA-IgG-12H Chimeric Proteins Stored in NS Buffer Maintain Monomeric Form

During the 7-day storage period, the degree of aggregation of the HA1-hIgG-12K, HA1-hIgG-12H, or the other exemplary anti-HA chimeric proteins in NS buffer is assayed using size exclusion chromatography (SEC)-HPLC. Briefly, 5 μL of 1 μg/μL antibody in PBS is loaded onto a Waters™ XBridge™ protein BEH 200A SEC column, 3.5 μm, 7.2×300 mm on an Agilent 1260 Infinity HPLC system. The chimeric proteins are eluted using DPBS (Dulbecco's PBS) buffer, pH 7.0 at a flow rate of 0.5 mL/min. A UV reading of the elution flow is monitored. The elution profiles of the mucoadhesive chimeric proteins and the unmodified antibodies stored for 14 days are compared. The accelerated antibody stability test at 37° C. demonstrates the stability of the modified chimeric proteins in NS formulation buffer, remaining precipitate-free over time.

Example 13C. Anti-HA-IgG-12K and Anti-HA-IgG-12H Chimeric Proteins Stored in NS Buffer Maintain the Ability to Block Sialic Acid Glycan Binding

The receptor determinant of influenza A and B viruses are sialic acids, comprised mostly of N-acetyl-neuraminic acid (Neu5Ac). A Neu5Ac (Sigma Aldrich)-coated microplate ELISA assay is used to test antibody blocking ability at varying (antibody) concentrations. HA proteins are incubated with anti-HA1-hIgG-12K or HA1-hIgG-12H chimeric proteins in a series of diluted concentrations for 30 mins. The HA protein and chimeric protein solutions are added into each well of the sialic acid-coated microplate. After 30 mins of incubation, the plate is washed three times in TBST (Tris-Buffered Saline, 0.1% Tween®20). Horseradish peroxidase conjugated (HRP) anti-His Tag (ThermoFisher Scientific) secondary antibody is added to each well for 30 mins, and the plate is washed five times in TBST. Chromogen solution is used as the substrate, and absorbance at 450 nm is measured using a standard microplate reader. HA1-hIgG-12K or HA1-hIgG-12H stored in NS buffer retains the ability to block HA protein binding to sialic acid glycan moieties in vitro. The other exemplary anti-HA chimeric proteins perform similarly in exemplary ELISA assays.

Example 13D. Anti-HA-IgG-12K and Anti-HA-IgG-12H Chimeric Proteins Stored in NS Buffer Maintain the Ability to Block Pseudoviral Infection of HEK-HNM Cells

A luciferase assay is performed as described in Example 5. The HA-NA-pseudotyped lentivirus is added into HA1-hIgG-12K, anti-HA-IgG-12H, or the other exemplary anti-HA chimeric proteins in NS buffer for 30 min at room temperature. The mixture is then added into HEK293F-HNM cells (see Materials and Methods) in culture media. The assay is performed using 3.3 nM, 10 nM or 30 nM HA1-12K hIgG or HA1-12H hIgG chimeric protein stored in NS buffer at 37° C. over a period of 7 days. After 48 hours of incubation, the degree of infection is determined by monitoring luciferase levels in infected cells using a Promega Luciferase Assay or imaged for GFP using fluorescence microscopy, demonstrating the protective effects of the mucoadhesive proteins on HEK-293 cell infection.

Example 13E. Protection from Influenza Pseudoviral Infection by Animal Anti-HA Mucoadhesive Proteins in a Nasal Spray Formulation

Exemplary animal anti-HA mucoadhesive proteins comprising any of the animal anti-HA antibodies shown in Table 6 are also evaluated for protection from influenza pseudoviral infection using the same methods of Examples 13A-13D.

Briefly, an accelerated antibody stability assay is performed using the methods of Example 13A to confirm that the formulation buffer does not affect the antigen binding ability of animal anti-HA mucoadhesive chimeric proteins when modified with (fused to) the mucoadhesive peptide fragments. Animal anti-HA mucoadhesive chimeric proteins stored in NS buffer are able to maintain binding affinity to HA protein as measured in this in vitro assay. The degree of aggregation of the exemplary animal anti-HA chimeric proteins in NS buffer is assayed using SEC-HPLC, using the methods of Example 13B. The modified chimeric proteins in NS formulation buffer remain precipitate-free over time. A Neu5Ac (Sigma Aldrich)-coated microplate ELISA assay is used to test antibody blocking ability at varying (antibody) concentrations, using the same methods of Example 13C, showing that the exemplary animal anti-HA mucoadhesive proteins stored in NS buffer retain the ability to block HA protein binding to sialic acid glycan moieties in vitro. A luciferase assay is performed as described in Example 5, using the methods of Example 13D. The exemplary animal anti-HA chimeric proteins stored in NS buffer maintain the ability to block pseudoviral infection of HEK-HNM cells.

Example 14. In Vitro Characterization of Modified NA Mucoadhesive Proteins in a Nasal Spray Formulation

Example 14A. NA-12K hIgG and NA-12H hIgG Chimeric Proteins Stored in NS Buffer Maintain Binding Affinity to NA Protein

An accelerated antibody stability assay is performed to confirm that the formulation buffer does not affect the binding ability of the NA1-hIgG-12K or NA1-hIgG-12H mucoadhesive proteins (or other exemplary chimeric proteins using the antibodies disclosed in Table 4B fused with the peptides disclosed in Table 8) to the NA protein. Briefly, NA1-hIgG-12K chimeric proteins were stored in NS buffer (25 mM citrate buffer, pH 6.5, 125 mM NaCl, 5% glycerin, 0.1% methionine, 0.02% polysorbate 80, and 0.1% potassium sorbate) at 37° C. over a maximum period of 14 days, which is equivalent to about 1.5 years at 4° C. The binding of antibodies towards antigens is determined using a ForteBio Octet instrument with an anti-hFC capture biosensor and the data is acquired by Octet Data Acquisition software 9.0. The binding curves of the mucoadhesive proteins in NS buffer at different time points are compared to the binding curve of a sample of the unmodified NA1-hIgG antibody stored in PBS at 4° C. FIG. 3 shows the binding (association and dissociation) of the NA1-hIgG-12K to NA protein after storage in the nasal spray formulation for 0, 1, 3, 5, 7, or 14 days. The stability of binding to NA of exemplary mucoadhesive proteins derived from the antibodies from Table 4B in NS buffer, including NA1-hIgG-12H, are also tested for up to 14 days at 37° C. Mucoadhesive chimeric proteins stored in NS buffer are able to maintain binding affinity to NA protein as measured in this in vitro assay.

Example 14B. NA1-IgG-12K and NA1-IgG-12H Chimeric Protein Stored in NS Buffer Maintains its Monomeric Form

During the 14 day storage period, the degree of aggregation of the NA-IgG-12K hIgG or NA-IgG-12H hIgG protein or exemplary modified antibodies of Table 4B in NS buffer is assayed using SEC-HPLC. Briefly, 5 μL of 1 μg/μL antibody in PBS is loaded onto a Waters™ XBridge™ protein BEH 200 Å SEC column, 3.5 μm, 7.2×300 mm on an Agilent 1260 Infinity HPLC system. The antibody is eluted using DPBS (Dulbecco's PBS) buffer, pH 7.0 at a flow rate of 0.5 mL/min. A UV reading of the elution flow is monitored. The elution profiles of the mucoadhesive proteins and the unmodified antibodies stored for 14 days are compared. The accelerated antibody stability test at 37° C. shows how stable the mucoadhesive proteins in NS formulation buffer remain precipitate-free over time.

Example 14C. Anti-NA-12K hIgG and Anti-NA-12H hIgG Chimeric Proteins Stored in NS Buffer Maintain Ability to Block Sialic Acid Glycan Binding

A Neu5Ac (Sigma Aldrich)-coated microplate ELISA assay is used to test antibody blocking ability at varying (antibody) concentrations. NA proteins are incubated with anti-NA-12K hIgG or anti-NA-12H hIgG chimeric proteins in a series of diluted concentrations for 30 mins. The NA protein and antibody solutions are added into each well of the sialic acid-coated microplate. After 30 mins of incubation, the plate is washed three time in TBST (Tris-Buffered Saline, 0.1% Tween®20). HRP anti-His Tag (ThermoFisher Scientific) secondary antibody is added to each well for 30 mins, and the plate is washed five times in TBST.

Chromogen solution is used as the substrate, and absorbance at 450 nm is measured using a standard microplate reader. The NA1-hIgG-12K or NA1-hIgG-12H proteins stored in NS buffer retain the ability to block NA protein binding to sialic acid glycan moieties in vitro. Exemplary mucoadhesive proteins derived from the antibodies of Table 4B perform similarly in comparable ELISA assays.

Example 14D. NA-IgG-12K or NA-IgG-12H Modified Proteins Stored in NS Buffer Maintain the Ability to Block Pseudoviral Infection of HEK-HNM Cells

A luciferase assay is performed as described in Example 5. The HA-NA-pseudotyped lentivirus is added into NA1-hIgG-12K or NA1-hIgG-12H proteins (or other exemplary antibodies disclosed in Table 4B fused with the peptides disclosed in Table 8) in NS buffer for 30 min at room temperature. The mixture is then added into HEK293F-HNM cells in culture media. The assay is performed using 3.3 nM, 10 nM or 30 nM NA1-12K hIgG or NA1-12H hIgG chimeric proteins stored in NS buffer at 37° C. over a period of 14 days. After 48 hours of incubation, the degree of infection is determined by monitoring luciferase levels in infected cells using a Promega Luciferase Assay or imaged for GFP using fluorescence microscopy. Exemplary mucoadhesive chimeric proteins from Table 4B in NS buffer are also tested for up to 14 days.

Example 14E. In Vitro Characterization of Modified NA Mucoadhesive Proteins in a Nasal Spray Formulation

Exemplary animal anti-NA mucoadhesive proteins comprising any of the animal anti-NA antibodies described in Xiong et al., 2020, Cardoso et al., 2014, and Murphy et al., 1972, and other animal anti-NA antibodies, are also evaluated for protection from influenza pseudoviral infection using the same methods of Examples 14A-14D.

Briefly, an accelerated antibody stability assay is performed using the methods of Example 14A to confirm that the formulation buffer does not affect the antigen binding ability of animal anti-NA mucoadhesive chimeric proteins when modified with (fused to) the mucoadhesive peptide fragments. Animal anti-NA mucoadhesive chimeric proteins stored in NS buffer are able to maintain binding affinity to NA protein as measured in this in vitro assay. The degree of aggregation of the exemplary animal anti-NA chimeric proteins in NS buffer is assayed using SEC-HPLC, using the methods of Example 14B. The modified chimeric proteins in NS formulation buffer remain precipitate-free over time. A Neu5Ac (Sigma Aldrich)-coated microplate ELISA assay is used to test antibody blocking ability at varying (antibody) concentrations, using the same methods of Example 13C, showing that the exemplary animal anti-NA mucoadhesive proteins stored in NS buffer retain the ability to block NA protein binding to sialic acid glycan moieties in vitro. A luciferase assay is performed as described in Example 5, and using the methods of Example 14D. The exemplary animal anti-NA chimeric proteins stored in NS buffer maintain the ability to block pseudoviral infection of HEK-HNM cells.

Example 15. Protection from Pseudoviral Infection by Anti-HA Mucoadhesive Chimeric Proteins in a Nasal Spray Formulation In Vivo

Example 15A. Mucoadhesive Human Anti-HA Chimeric Proteins Stored in NS Buffer Prevent Pseudovirus Infection in a Mouse Model

Demonstration of the ability of anti-HA mucoadhesive proteins including HA1-hIgG-12K, HA2-hIgG-12K, HA 1-hIgG-12H, HA2-hIgG-12H, and exemplary modified forms of antibodies disclosed in Table 4A stored in NS buffer to prevent HA-NA pseudovirus infection in a mouse model is described in this Example. In experiments conducted previously (not shown), the most effective length of the mucoadhesive amino acid fragments required to effectively adhere the chimeric proteins to the nasal cavity was shown to be 12 residues when chimeric proteins are administered 10 hours prior to pseudoviral administration, as measured by the protective effect in mice.

4-week-old young adult CD-1® IGS or BALB/c mice (Charles River) are nasally administered the HA1-hIgG-12K or HA1-hIgG-12H chimeric protein stored in NS buffer at various concentrations (25 μg to 200 μg total in 20 μL instilled per nostril), with the same amount of unmodified HA1-hIgG in a second group of mice, and NS buffer alone in control mice. 10 hours after chimeric protein or buffer administration, HA-NA pseudovirus is administered to mice intranasally (20 μL instilled per nostril).

The bioluminescent signal in treated mice in both nose and lung areas up to 7 days is monitored in mice following the pseudoviral dosage. Measurement of luciferase activity is used to assess the degree of infection on days 3, 5 and 7. After the day 7 measurement, the lungs are dissected and imaged. Measurement of bioluminescence in the nasal cavity or lung areas demonstrate the protective effects of the HA1-hIgG-12K- or HA1-hIgG-12H-treated mice up to 7 days after the viral dosage and are reflected in these measurements.

Other exemplary anti-HA chimeric proteins using the antibodies disclosed in Table 4A fused with the peptides disclosed in Table 8 are stored in NS buffer and tested in the mouse pseudovirus infection model as described in this Example. The bioluminescent values and imaging results are obtained for each group. Pre-treating mice nasally with HA1-IgG-12K, HA2-IgG-12K, HA1-IgG-12H, HA2-IgG-12H, or the other exemplary anti-HA chimeric proteins in the nasal spray formulation protect the mice against the influenza pseudovirus infection, at least in the nasal cavities or lungs.

Example 15B. In Vivo Protection from Different Influenza Strains in a Mouse Model

A series of pseudovirus preparations made from the HA and NA proteins of different strains of influenza viruses (variant HA and NA proteins are listed in Tables 2A-B and 3) are used to infect mice pretreated with anti-HA mucoadhesive chimeric proteins described in Example 15A or unmodified anti-HA antibodies, using the methods described in Example 15A. The protective effects of HA1-hIgG-12K or HA1-hIgG-12H and other exemplary modified chimeric proteins to infection with pseudoviruses prepared from several HA strains are examined. Bioluminescent imaging and measurement of luciferase activity taken from the nasal cavities and lungs of pseudovirus-treated mice are obtained, and the degree of protection provided by the mucoadhesive chimeric proteins is calculated using the methods described in previous Examples. The anti-HA mucoadhesive chimeric proteins tested are able to protect the mice against infection by influenza pseudovirus made with the various HA and NA proteins listed in Tables 2A-B and 3.

Example 15C. Protection from Pseudoviral Infection by Animal Anti-HA Mucoadhesive Chimeric Proteins in a Nasal Spray Formulation In Vivo

Exemplary animal anti-HA mucoadhesive proteins comprising any of the animal anti-HA antibodies shown in Table 6, in NS buffer are also evaluated for protection from influenza pseudoviral infection using the methods detailed in Examples 15A-15B. Mucoadhesive animal anti-HA chimeric proteins stored in NS buffer prevent pseudovirus infection in a mouse model, in contrast to their unmodified anti-HA counterparts. The animal anti-HA mucoadhesive chimeric proteins tested are able to protect the mice against infection by influenza pseudovirus made with the various HA and NA proteins listed in Tables 2A-B and 3, as determined using the same methods of Example 15B.

Example 16. Protection from Pseudoviral Infection by Anti-NA Mucoadhesive Chimeric Proteins in a Nasal Spray Formulation In Vivo

Example 16A. Mucoadhesive Human Anti-NA Chimeric Proteins Stored in NS Buffer Prevents Pseudovirus Infection in a Mouse Model

Demonstration of the ability of anti-NA mucoadhesive proteins including modified NA1-IgG-12K, NA2-IgG-12K, NA1-IgG-12H, NA2-IgG-12H, and exemplary modified forms of antibodies disclosed in Table 4A stored in NS buffer to prevent HA-NA pseudovirus infection in a mouse model is described in this Example. 4-week-old young adult CD-1® IGS or BALB/c mice (Charles River) are nasally administered the NA1-hIgG1-12K chimeric protein stored in NS buffer at various concentrations (25 μg to 200 μg total in 20 μL instilled per nostril), with the same amount of unmodified NA1-hIgG in a second group of mice, and NS buffer alone in control mice. 10 hours after chimeric protein or buffer administration, HA-NA pseudovirus is administered to mice intranasally (20 μL instilled per nostril).

The bioluminescent signal in treated mice in both the nose and lung areas up to 7 days is monitored in mice following the pseudoviral dosage. Measurement of luciferase activity is used to assess the degree of infection on days 3, 5 and 7. After the day 7 measurement, the lungs are dissected and imaged. Measurement of bioluminescence in the nasal cavity or lung areas demonstrate the protective effects of the NA1-hIgG1-12K or NA1-hIgG1-12H antibody-treated mice up to 7 days after the viral dosage and are reflected in these measurements.

Other exemplary anti-NA chimeric proteins using the antibodies disclosed in Table 4B fused with the peptides disclosed in Table 8 are stored in NS buffer and tested in the mouse pseudovirus infection model as described in this Example. The bioluminescent values and imaging results are obtained for each group. Pre-treating mice nasally with NA1-IgG-12K, NA2-IgG-12K, NA1-IgG-12H, NA2-IgG-12H, or the other exemplary anti-NA chimeric proteins in the nasal spray formulation protect the mice against the influenza pseudovirus infection, at least in the nasal cavities or lungs.

Example 16B. In Vivo Protection from Different Influenza Strains in a Mouse Model

A series of pseudovirus preparations made from the HA and NA proteins of different strains of influenza viruses (variant HA and NA proteins are listed in Tables 2A-B and 3) are used to infect mice pretreated with anti-NA mucoadhesive chimeric proteins or unmodified anti-NA antibodies as described in Example 15A. The protective effects of NA1-hIgG-12K or NA1-hIgG-12H and the other exemplary chimeric proteins against infection with pseudoviruses prepared from several NA strains are examined. Measurements of luciferase activity taken from the nasal cavities and lungs of pseudovirus-infected mice are obtained, and the degree of protection provided by the mucoadhesive chimeric proteins is calculated using the methods described in previous examples.

Example 16C. Protection from Pseudoviral Infection by Animal Anti-NA Mucoadhesive Chimeric Proteins in a Nasal Spray Formulation In Vivo

Exemplary animal anti-NA mucoadhesive proteins comprising any of the animal anti-NA antibodies disclosed in Xiong et al., 2020, Cardoso et al., 2014, and Murphy et al., 1972, or other animal anti-NA antibodies, in NS buffer are also evaluated for protection from influenza pseudoviral infection using the methods of Examples 16A-16B. Mucoadhesive animal anti-NA chimeric proteins stored in NS buffer prevent pseudovirus infection in a mouse model, in contrast to their unmodified counterparts. The animal anti-NA mucoadhesive chimeric proteins tested are able to protect the mice against infection by influenza pseudovirus made with the various HA and NA proteins listed in Tables 2A-B and 3, as determined using the same methods of Example 16B.

Example 17. Protective Effect and In Vivo Characterization of Anti-Canine HA Mucoadhesive Chimeric Proteins in a Nasal Spray Formulation Using a Mouse Model

The incidence of canine influenza (CIV) has become a concern for pet owners, dog breeders and veterinary practitioners in the North America and China over the past several years (Li et al. Viruses. 2021 Nov. 15; 13(11):2279). Two of the canine influenza virus strains circulating in China and in North America are of avian origin (H3N2); additionally, an American strain (H3N8), is of equine origin (Parrish and Voorhees, Vet Clin North Am Small Anim Pract. 2019 Jul.; 49(4):643-649). All are highly contagious, transmitted from dog to dog, and though often resulting in asymptomatic or mild indications, can cause more severe disease resulting in tracheal bronchitis, pneumonia or death. Influenza virus infections have been most notably found in birds and pigs, but are also found in domestic cats, and horses and in wild animals such as bats and seals.

To investigate the feasibility of a mucoadhesive antibody which could be administered in a veterinary setting, we used antibodies based on an endemic strain of canine influenza in the US, H3N2. Monoclonal antibody D7 (Xie et al., Veterinary Research 46:33 (2015)) was identified as a neutralizing antibody providing protection against CIV H3N2 virus stains Canine/Jiangsu/06/2010 (JS/10) and A/Canine/Guangdong/12/2012 (GD/12).

Using the methods described in Examples 11 and 15, a mucoadhesive chimeric protein comprising the D7 monoclonal antibody fused to a polylysine peptide fragment, D7-IgG-12K, or fused to a polyhistidine peptide fragment, D7-IgG-12H, is produced in HEK293F cells (as described in Example 7) and used to determine the protective effect in mice from canine influenza pseudovirus infection. Pseudovirus particles decorated with the CIV HA3 and N2 proteins are prepared according to Example 5.

Using methods described in Xie et al., the mucoadhesive chimeric protein D7-IgG-12K, D7-IgG-12H, or unmodified D7 antibody in NS buffer is instilled in the nasal passages of CD1 or Balb/c mice at various concentrations (25 μg to 200 μg total in 20 μL instilled per nostril) and the HA3-NA2 pseudovirus is introduced 10 hours later. The mice are monitored for weight and luciferase activity, measured on Day 3, 5 and 7. Demonstration of a protective effect of the D7-IgG-12K or D7-IgG-12H mucoadhesive chimeric protein compared to unmodified antibody are provided by the measurement of luciferase activity in the nasal cavities and lungs of mice challenged with pseudovirus. D7-IgG-12K or D7-IgG-12H protects mice against CIV pseudovirus infection.

Other mucoadhesive chimeric proteins comprising D7-IgG fused to the peptides disclosed in Table 8 are also generated and tested to be protective against CIV pseudovirus infection in mice.

Example 18. Various Peptide Linker Fragments as an Optional Part of the Mucoadhesive Chimeric Proteins

In some instances, it may be necessary to stabilize the mucoadhesive chimeric proteins, with the inclusion of peptide linker fragments, to increase the protein half-life or increase the avidity or number of mucoadhesive proteins in vitro to more easily detect or measure the signal or in vivo to increase the effective amount being delivered to the nasal cavity in a single dose. For this purpose, various types of peptide linker fragments, especially oligomerization or multimerization domains from natural proteins, are used in various embodiments of the mucoadhesive chimeric proteins. In the previous Examples of this application, mucoadhesive modifications of full-length antibodies are described in detail as the main possible embodiments and are tested for functionality. In those embodiments, the peptide linker fragments comprise the complete constant region of a full-length antibody's heavy chain, which is composed of CH₁, CH₂, and CH₃ if the antibody is IgG, IgA, or IgD, or CH₁, CH₂, CH₃, and CH₄ if the antibody is IgE or IgM. In other embodiments of mucoadhesive chimeric proteins, the peptide linker fragments can comprise only parts of the constant region of a full-length antibody's heavy chain or a part of the constant region of an antibody's light chain, e.g., CH_i, CH₂, CH₃, and CH₄, and/or C_L. Some exemplary chimeric proteins comprise Immunoglobulin Fc regions as the peptide linker fragments or a part of the peptide linker fragments, which are comprised of CH₂ and CH₃ domains or CH₂, CH₃, and CH₄ domains. Fc regions act as dimerizing agents and retain some antibody-like properties, such as good physicochemical characteristics for expression, purification and storage, and long serum half-life in vivo see, Lobner et al., Immunol. Rev., 270(1)113-31 (2016). Exemplary sequences of Fc as well as CH_i, CH₂, CH₃, and CH₄, and C_L are shown in Table 9.

Other possible peptide linker fragments or useful domains to be included in peptide linker fragments which can be used to induce stable protein:protein interactions in the mucoadhesive chimeric proteins are shown in Table 9, and include the detectable enzymatic tags alkaline phosphatase and glutathione-s-transferase (GST), both functioning as dimers. In particular, alkaline phosphatase (513 amino acids (aa)) dimerization contacts are formed by patches of discrete aa sequences from at N-terminus: aa27-42, aa68-76, aa83-85, aa94-98 and aa103-105; and the C-terminus: 382-391 and 397-410. GST (217aa) homodimerizes as two monomers: monomer 1 (aal-84): monomer 2 (aa85-217). Alkaline phosphate and GST fusion proteins are highly soluble, easily detected using their enzymatic functions, and they do not seem to interfere with the fusion partner's activity. The enzymatic domains and protein interaction domains are embodied in the whole molecule.

In Table 9, we list exemplary full-length linkers or protein:protein interaction domains which are able to induce multimerization in their fusion partners and may also serve to increase the overall strength or avidity of binding. One often-used example includes the heptad repeats of the basic helix-loop-helix leucine zipper domains (bZIP) or isoleucine zipper domains, which form stable protein trimers see, Napolitano and Ballabio, J. Cell Sci., 129(13):2475-81 (2016); and Branttie and Dutch, J. Gen Virol., 101(5):467-472 (2020). Collagen-like proteins form trimers of great binding strength due to the presence of repeated Glycine-X-Y repeats (GPP)_n and have been shown not to interfere with the fusion protein's functionality or safety profile see, (Fan et al., FASEB J., 22:3795-3804 (2008). Higher order multimerization domains have been used extensively as well; the streptavidin protein is able to tightly bind biotin molecules forming tetrameric units that are easily detectable see Chivers et al., Biochem J., 435(Pt 1):55-63 (2011). However, the streptavidin fusion moiety is large, and perhaps too bulky for some applications; the p53 tetramerization domain is only 31 amino acids long see, Gencel-Augusto et al., Genes Dev., 34(17-18):1128-1146 (2020). The C-terminal 27 amino acids of the bacteriophage T7 fibritin protein (also called folden; see, Yang et al., J. Virol., 76(9):4634-42 (2002)) forms stable soluble trimeric complexes. The coiled-coil domain of the COMP protein (cartilage oligomeric matrix protein, see Holler et al., J. Immunol. Methods, 237:159-173 (2000)) is able to form self-assembling pentameric complexes. Further protein-protein interaction domains can be found in the literature and higher-order complexes can be formed using dextran scaffolds or maleimide polymers (DMGS) (see Dolton et al., Clin. Exp. Immunol., 177(1):47-63 (2014); and Guillaume et al., J. Biol. Chem., 278: P4500-4509 (2003).

Example 19. Anti-HA Mucoadhesive Chimeric Proteins Comprising Various Peptide Linker Fragments

In addition to the exemplary anti-HA mucoadhesive chimeric proteins described in previous Examples in this application, other exemplary anti-HA chimeric proteins are generated using the variable regions of any of the antibodies disclosed in Table 4A, including HA1, HA2, and other human anti-HA antibodies, as well as animal anti-HA antibodies disclosed in Table 6, and other animal anti-HA antibodies, to fuse with any of the linkers or domains disclosed in Table 9, and further fused with any of the mucoadhesive peptides disclosed in Table 8. These other exemplary anti-HA mucoadhesive chimeric proteins are tested for various functions and capabilities as described in previous Examples. They specifically bind to the HA antigens, nonspecifically bind to mucin, and block influenza pseudovirus infection and real virus infection in vitro and in vivo.

Example 20. Anti-NA Mucoadhesive Chimeric Proteins Comprising Various Peptide Linker Fragments

In addition to the exemplary anti-NA mucoadhesive chimeric proteins described in previous Examples in this application, other exemplary anti-NA chimeric proteins are generated using the variable regions of any of the antibodies disclosed in Table 4B, including NA1, NA2, and other human anti-NA antibodies, as well as animal anti-NA antibodies including those disclosed in Xiong et al., 2020, Cardoso et al., 2014, and Murphy et al., 1972, and other animal anti-NA antibodies, to fuse with any of the linkers or domains disclosed in Table 9, and further fused with any of the mucoadhesive peptides disclosed in Table 8. These other exemplary anti-NA mucoadhesive chimeric proteins are tested for various functions and capabilities as described in previous Examples. They specifically bind to the NA antigens, nonspecifically bind to mucin, and block influenza pseudovirus infection and real virus infection in vitro and in vivo.

Example 21. Production of HA-Pseudotyped Lentiviruses

Lentiviruses containing HA, NA and M2 proteins were produced by transfection of HA, NA and M2 expressing HEK293T cells (HEK293-HNM cells) using the lentiviral expression vector pCDH-EF1-MCS (System Biosciences) that carries the HA, NA and M2 expression constructs on a single vector under the control of the E1Fa promoter. A transgene that carries GFP and luciferase markers was also introduced into the lentiviral vector. Helper plasmids which encode the proteins required in trans for the production of infectious pseudotyped virus were simultaneously co-transfected. To evaluate the functional titer of the lentivirus produced, concentrated lentiviruses were applied to HEK293-HNM cells in 96-well plates for 48 hours. Control groups included mock-transduced (no DNA added) HEK293-HNM cells or HEK293-HNM cells transduced with empty lentiviral vectors. Flow cytometry analyses were done on day 3. Transduction efficiencies of the HEK293-HNM cells were assessed by measuring the GFP signal with flow cytometry. Flow cytometry data were collected using a BD LSR FORTESSA™ and analyzed using the FlowJo™ v10.6.1 software package, and pseudoviral titers of greater than 1×10⁶ H3N2 pseudovirus per mL were achieved (data not shown).

Example 22. Expression and Purification of Anti-HA Chimeric Mucoadhesive Proteins

Chimeric proteins comprising HA1 hIgG or HA15 hIgG heavy chains fused to various lengths of polylysine peptide fragments were generated. Specifically, DNA fragments encoding a polylysine-modified HA1 or HA15 IgG heavy chain (added to the C-terminus of the IgG heavy chain) and an unmodified HA1 or HA15 light chain were cloned into a single mammalian expression vector and used to transfect HEK293T cells as described in the previous Examples. Chimeric proteins HA1-hIgG-12K and HA15-hIgG-6K and HA15-hIgG-12K were expressed from the transfected HEK293T cells and purified.

The chimeric protein HA1-hIgG-12K has two HA1-hIgG heavy chains each fused to a 12-residue polylysine peptide and two unmodified HA1-hIgG light chains. The chimeric proteins HA15-hIgG-6K and HA15-hIgG-12K have two HA1-hIgG heavy chains each fused to a 6 or 12-residue polylysine peptide and two unmodified HA1-hIgG light chains. These polylysine peptides are examples of mucoadhesive peptide fragments which facilitate the attachment of the exemplary chimeric proteins to the upper respiratory mucosa.

Example 23. Characterization of Anti-HA Chimeric Proteins Comprising Mucoadhesive Peptide Fragments

Example 23A. In Vitro Binding of Mucoadhesive Chimeric Proteins to Mucin

This Example demonstrates that anti-HA mucoadhesive proteins modified at the C termini of their heavy chains with peptides comprising various numbers of cationic residues (peptides as shown in Table 8) have increased binding to mucin compared to unmodified anti-HA antibodies.

To test the ability of the anti-HA-IgG mucoadhesive chimeric proteins to bind mucin, 96-well plates were coated with 50 μg/mL mucin (Sigma, M3895) for 2 hr at room temperature. The plates were blocked with 3% BSA overnight at 4° C. 5 μg/mL anti-HA1-IgG-12K, anti-HA15-IgG-6K or anti-HA15-IgG-12K chimeric antibodies in 25 mM HEPES (pH 6.5) was added and the plates were incubated for an hour at room temperature. After a wash with washing buffer (25 mM HEPES, mM NaCl, pH 6.5), plates were stained with HRP-conjugated goat anti-human IgG and developed using 3,3′,5,5′-Tetramethylbenzidine (TMB). Absorbance at an optical density at 450 nm (OD₄₅₀) was measured using a standard plate reader. FIG. 4 shows that the addition of either the 6K or 12K cationic moiety significantly increased the antibody binding to mucin-coated plates compared to antibodies that lack mucoadhesive peptides.

Example 23B. Binding of Human Anti-HA-hIgG Human Chimeric Mucoadhesive Antibodies to HA

To determine whether the binding of the HA1-hIgG-12K chimeric protein to purified HA was unaffected by the mucoadhesive cationic peptide, association of the chimeric protein to HA was examined by BLI. The binding of exemplary anti-HA chimeric antibodies HA1 and HA15, to H1N1 or H3N2 HA was measured by Bio-Layer Interferometry (BLI) on a ForteBio Octet KQ with an anti-human IgG (anti-hFC) Capture biosensor. Binding of the human IgG antibodies was demonstrated using the following protocol: 20 μg/mL biotinylated anti-HA1-IgG-12K or anti-HA15-IgG-12K protein in kinetics buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.05% (v/v) Surfactant P20) was loaded onto an anti-hFC biosensor. After washing off excess antibody, the sensor tips were dipped into 10 μg/mL of His-tagged H1N1 (A/Wisconsin/588/2019)/(A/Victoria/2570/2019) hemagglutinin proteins (SinoBiological Cat. 40787-V08H) in kinetics buffer for a 300 s period of association and a 300 s period of dissociation. The association and dissociation graphs were generated using Octet Data Acquisition Software v9, and the robust binding to H1N1 hemagglutinin protein was confirmed. Binding of anti-HA1-IgG-12K (FIG. 5A and FIG. 6A) and anti-HA15-IgG-12K (FIGS. 5B and 6B) chimeric mucoadhesive proteins also showed strong binding to HA from the H3N2 (A/Aichi/2/1968) strain using His-tagged H3N2 HA (SinoBiological Cat. 11707-V08H) as the binding partner; binding was unaffected by the presence of polycationic moieties.

Example 24. Neutralization of Pseudoviral Infection by Anti-HA Mucoadhesive Chimeric Proteins In Vitro

This Example demonstrates that anti-HA IgG mucoadhesive chimeric antibodies are able to block H1N1 and H3N2 pseudovirus infection in HEK293F cells. Briefly, exemplary anti-HA antibodies HA1-IgG-12K and HA15-hIgG-12K, were serially diluted (400, 100, 25, 6.25, 1.5625, 0.0977, 0.0244, 0.0061, 0 nM) and were then incubated with HA-pseudotyped lentivirus. The pseudotyped virus contains the EF1-α-driven luciferase and GFP reporter genes separated by a P2A self-cleaving peptide. Following a 30 min incubation of the anti-HA hIgG antibody with H1N1 or H3N2 pseudotyped lentivirus (H1N1 at 1 μL/well, H3N2 at 0.5 μl/well), the incubated antibody and lentivirus solution was added to 1×10⁶ HEK293F cells. The cells were cultured in 5% CO₂ at 37° C. for 48 h. The degree of cellular infection with the pseudotyped virus was determined by detecting the luciferase level of the infected cells (Promega Luciferase Assay).

FIG. 7A and FIG. 7B demonstrate that a low quantity of anti-HA antibody HA1-IgG-12K (FIG. 7A) or HA15-IgG-12K (FIG. 7B) was a sufficient antibody concentration to completely block the infection of HEK293F cells, shown by the attenuation of the luciferase signal. The EC50 and EC90 values were calculated for each assay.

Example 25. Protective Effects of Anti-HA Mucoadhesive Chimeric Proteins in a Mouse Model of Infection

The protective effects of human anti-HA1-IgG or anti-HA15-IgG mucoadhesive chimeric protein in a mouse model of infection was clearly demonstrated for both of the mucoadhesive HA1 and HA15 antibodies. In the experiments described here, mice were challenged mice H3N2 influenza pseudovirus by directly dropping at least 2.0×10⁵ particles into the nostrils of the mice. Inhibition of viral infection was achieved by pre-administration of HA15-IgG-6K and HA15-IgG-12K, or HA15-IgG antibody with no mucoadhesive fragment. Enhancement of protection by HA15-IgG-6K and HA15-IgG-12K compared with HA15-IgG antibody illustrates the advantage of adding mucoadhesive fragment, as shown in FIG. 9.

To test if chimeric proteins comprising anti-HA1 antibodies fused to a 12K mucoadhesive polycationic peptide fragment could block infectious influenza viruses or pseudoviruses in vivo, the HA hIgG chimeric protein (sequence shown in Table 1; e.g., HA1-IgG-12K) was tested in an in vivo pseudovirus protection assay. 6-week-old young adult BALB/c mice (Jackson Labs) were pretreated with HA1-IgG-12K chimeric protein. Doses of 100 μg per each nostril were delivered to the mice through nasal administration. A control group received no pretreatment with any antibody (denoted “Vehicle”).

10 hours after nasal administration of the mucoadhesive proteins/antibodies, both groups of mice were dosed with H3N2 pseudotyped lentivirus. Animals were closely monitored after nasal administration of the pseudovirus; on day 5 and day 7 following pseudoviral application, bioluminescence and body weight were measured for each mouse. FIG. 8A shows bioluminescent imaging of the mice before pseudoviral dosing (Day-1) and on Days 5 and 7 after dosing. FIG. 8B is a graph representing the luminescence values for each group. Mice receiving pretreatment with HA-IgG-12K chimeric mucoadhesive proteins show a significant reduction of luminescence compared to unpretreated mice on Days 5 and 7 indicating a resistance to pseudoviral infection.

In another experiment, an HA15-hIgG mucoadhesive chimeric protein mixture (sequences shown in Table 1; e.g., HA15-hIgG-6K and HA15-hIgG-12K) were compared to the unmodified HA15-hIgG antibody lacking the C-terminal mucoadhesive peptide modification, in an in vivo pseudovirus protection assay. Seven groups of 4-week-old young adult BALB/c mice (Jackson Labs) were pretreated with HA15-hIgG-6K and HA15-hIgG-12K chimeric protein mix (50/50) or unmodified HA15-hIgG. Doses of 100 μg per nostril were delivered to 2 groups of mice through nasal administration. A control group received no pretreatment with any antibody (“Vehicle”). 10 hours after nasal administration of the mucoadhesive proteins or antibodies, all groups are dosed with H3N2 pseudotyped lentivirus as in the previous example. FIG. 9A shows the bioluminescence imaging for each mouse and FIG. 9B depicts the corresponding values as a graph. This Example demonstrates the protective effect of the mucoadhesive moiety in protecting mice from pseudoviral infection. Compared to “Vehicle” and HA15-IgG with no modification, the mice pretreated with HA15-IgG-12K show a significant resistance to pseudoviral infection. Enhancement of protection by HA15-IgG-6K and HA15-IgG-12K compared with unmodified HA15-IgG antibody shows the advantage of adding mucoadhesive fragment and the role the cationic moiety plays in resisting infection.

Example 26. HA or NA Mucoadhesive Chimeric Proteins Activate Complement Pathway to Induce Virolysis

Example 26A. ACE2 Mucoadhesive Chimeric Proteins Activate Complement Pathway

The complement pathway is an important aspect of innate immunity. Activation of the complement pathway induces vital host responses to protect against acute, chronic, and recurrent viral infections (Huber et al., 2006; Mellors et al, 2020). Virus opsonization can be induced by complement pathway activation, wherein the opsonization of the viral surface can lead to the aggregation of the viruses, as well as phagocytosis of these viruses (due to complement receptors on phagocytic cells) and virolysis (Mellors et al., 2020). Therefore, HA or NA mucoadhesive chimeric proteins are tested for their ability to activate the complement pathway, and subsequently kill Influenza pseudovirus. This Example demonstrates that HA or NA mucoadhesive chimeric proteins (HA1-hIgG-12K, HA2-hIgG-12K, HA15-hIgG-12K, NA1-hIgG-12K, NA2-hIgG-12K, or any mucoadhesive chimeric protein listed in Table 1) bind HA or NA and trigger the complement pathway.

Briefly, a complement pathway assay is performed (using a CH₅₀ Functional Test Kit; CTK-907, Creative Biolabs) with some modifications. Plasma with normal complement activity is used as a positive control, and plasma with low complement activity is used as a negative control. In this assay, complement in serum samples and control samples is first activated. HA1-hIgG-12K, HA2-hIgG-12K, HA15-IgG-12K, HA1-hIgG-12H, HA2-hIgG-12H, HA15-IgG-12H, NA1-IgG-12K, NA2-IgG-12K, NA1-IgG-12H and NA2-hIgG-12H (separately) are incubated with the HA or NA protein if the Influenza A strain and complement immunoassay reagents including antibody to TCC (terminal complement complexes) and purified human complement proteins (Cat. #A3724; Quidel). Following a 5 min incubation, erythrocytes are added to the HA- or NA-hIgG-12K proteins, complement, and HA or NA protein mixture, and were further incubated at 37° C. for 25 min, then centrifuged at 400×g for 5 min. The supernatant is analyzed at OD₄₁₅ to detect hemoglobin release.

HA-IgG-12K and NA-hIgG-12K chimeric proteins activate the complement pathway. The results demonstrate the ability of HA or NA mucoadhesive chimeric proteins to bind the Influenza virus HA protein in vitro and induce complement pathway activation.

Example 26B. HA Mucoadhesive Chimeric Protein can Kill Influenza Pseudovirus Via Complement Pathway Activation

This Example demonstrates that HA1-, HA2-, HA15-hIgG-12K or NA1-NA2-hIgG-12K (or any of the mucoadhesive chimeric peptides listed in Table1) chimeric proteins kills Influenza pseudovirus by activating the complement pathway. Plasma comprises complement molecules or white blood cells that can produce complement molecules.

HA1-hIgG-12K, HA2-hIgG-12K, HA15-hIgG-12K, NA1-hIgG-12K, NA2-hIgG-12K chimeric proteins are incubated with pseudotyped lentivirus expressing the HA, NA and M2 proteins of the Influenza A strain according to the method described in Example 21. The pseudotyped virus contains the EF1-α-driven luciferase reporter gene. The incubated HA- or NA-hIgG-12K/pseudovirus mixture is added to serially diluted human complement IgG/IgM (Cat. #340105, Pel Freez Biologicals). Following a 3 h incubation of the HA- or NA-hIgG-12K chimeric protein with pseudotyped lentivirus and complement, the incubated solution is added to HEK293T-HNM cells. Cells are cultured in 5% CO₂ at 37° C. for 48 h. The degree of cellular infection with the pseudotyped virus is determined by detecting the luciferase level of the infected cells (Promega Luciferase Assay). HA1-hIgG-12K, HA2-hIgG-12K, HA15-hIgG-12K, NA1-hIgG-12K, NA2-hIgG-12K chimeric proteins activate the complement pathway, thereby killing pseudovirus expressing the Influenza A HA or NA protein which leads to lower pseudoviral infection of HEK293T-HMN cells as determined by the fluctuation in luciferase luminescence.

Taken together, these results show that HA or NA mucoadhesive chimeric proteins activate the complement pathway and induce virolysis of Influenza A pseudovirus.

Example 26C. HA or NA Mucoadhesive Chimeric Peptides Kill Influenza Virus in Plasma

HA or NA mucoadhesive chimeric proteins are evaluated to assess whether they can bind and kill Influenza virus, using “capture and kill” assays in plasma. Plasma comprises complement molecules or white blood cells that can produce complement molecules.

Influenza pseudovirus viruses are incubated with plasma mixed with various HA mucoadhesive chimeric proteins (e.g., HA1-hIgG-12K, HA2-hIgG-12K, A HA15-hIgG-12K, NA1-hIgG-12K, NA2-hIgG-12K separately) or control plasma (e.g., plasma that was not mixed with HA or NA mucoadhesive chimeric proteins) for 72 h at 37° C. After 72 h, the cultures are analyzed for HA or NA protein concentration. Production of HA or NA protein in the absence of anti-HA-hIgG mucoadhesive peptides in the plasma is designated as 100%.

Plasma mixed with various HA- or NA-hIgG mucoadhesive chimeric proteins have decreased HA or NA protein concentration compared to the control plasma. The results demonstrate that HA- and NA-hIgG mucoadhesive chimeric peptides kill influenza pseudoviruses in plasma.

Example 27. ACE2 Mucoadhesive Chimeric Proteins with Various Positively Charged Mucoadhesive Peptide Fragments Bind Mucin In Vitro

The mucin-binding ability of mucoadhesive chimeric proteins with various positively charged mucoadhesive peptide fragments was tested.

For this Example, a set of chimeric proteins were designed and generated to target a different viral antigen, SARS-CoV-2 spike protein's Si subunit. These chimeric proteins, “ACE2-Fc1 mucoadhesive chimeric proteins”, are composed of a fragment of SARS-CoV-2 Si's receptor ACE2 (amino acids 19-740 of human ACE2, i.e., SEQ ID NO: 496) whose C-terminus was fused to the N-terminus of IgG's CH1+Fc fragment (CH1, SEQ ID NO: 393; CH₂—CH₃, SEQ ID NO: 391), which was in turn fused to the N-terminus of various mucoadhesive peptides to generate various ACE740-Fc1 mucoadhesive chimeric proteins. These chimeric proteins bear mucoadhesive peptides with a mixture of positively and non-positively charged amino acids of varying lengths. For example, mucoadhesive peptides as short as five amino acids (HHHHH, SEQ ID NO: 407) or six amino acids (HHHHHH, SEQ ID NO: 291) were tested, as well as peptides with positively charged amino acids other than lysine. In addition, mucoadhesive peptides with fewer than 5 consecutive positively charged amino acids were analyzed, such as peptides bearing two to three consecutive positively charged amino acids interspersed with a non-positively charged amino acid (KKKGKKK, SEQ ID NO: 408; KKAHHGKKAHHV, SEQ ID NO: 409; and KKARRGKKARRV, SEQ ID NO: 410).

The mucin-binding ability of various ACE740-Fc1 mucoadhesive chimeric proteins was analyzed using the method described in Example 9B. Briefly, mucin-coated plates were blocked overnight in BSA, washed, and 0.5 μg/well of ACE740-Fc1 mucoadhesive chimeric protein was added to the plate. The plates were stained with HRP-conjugated goat-anti-human IgG and tested for HRP activity. FIG. 10 shows significant mucin binding for all tested ACE740-Fc1 mucoadhesive chimeric proteins, greater than ACE2-Fc1 protein lacking a positively charged mucoadhesive peptide.

Although this Example shows mucin binding results of mucoadhesive chimeric proteins targeting a different viral antigen, the ability of the various positively charged mucoadhesive peptides to increase mucin-binding capability of chimeric proteins is expected to be a conserved property of the mucoadhesive chimeric proteins comprising anti-influenza antibody moieties as well.

SEQUENCE LISTING
SEQ
ID
NO	Sequence	Description
1	GFTFSTYA	HA1 HC-CDR1
2	ISYDANYK	HA1 HC-CDR2
3	AKDSQLRSLLYFEWLSQGYFDY	HA1 HC-CDR3
4	QSVTFNYKNY	HA1 LC-CDR1
5
6	QQHYRTPPT	HA1 LC-CDR3
7	KYAIN	HA2 HC-CDR1
8	GIIPFFGTTNYAQKFQG	HA2 HC-CDR2
9	PSITESHYCLDCAAKDYYYGLDV	HA2 HC-CDR3
10	GFTVSSNY	HA3 HC-CDR1
11	TYSGGNT	HA3 HC-CDR2
12	ATVPSFHGMDV	HA3 HC-CDR3
13	QSISSY	HA3 LC-CDR1
14
15	QQSYSTPPIT	HA3 LC-CDR3
16	GSTFGDFA	HA4 HC-CDR1
17	TSAGGDRT	HA4 HC-CDR2
18	ARLDSSGFHYGRPGRN	HA4 HC-CDR3
19	QDISYY	HA4 LC-CDR1
20
21	QQYKSLPYT	HA4 LC-CDR3
22	GFTFSGFS	HA5 HC-CDR1
23	ISTSGNYM	HA5 HC-CDR2
24	ARGGGYNWNLFDY	HA5 HC-CDR3
25	QSLNSNY	HA5 LC-CDR1
26
27	QQYGNSPLT	HA5 LC-CDR3
28	GVSVTSDIYY	HA6 HC-CDR1
29	IFYNGDT	HA6 HC-CDR2
30	ARGTEDLGYCSSGSCPNH	HA6 HC-CDR3
31	QNIRSF	HA6 LC-CDR1
32
33	QQSYNTPPT	HA6 LC-CDR3
34	GFTFSTYW	HA7 HC-CDR1
35	INQDGGEK	HA7 HC-CDR2
36	ARGFLERLLLGRQGAYYYGMDV	HA7 HC-CDR3
37	QIISSS	HA7 LC-CDR1
38
39	QQSYSTPPELT	HA7 LC-CDR3
40	RFTSSSYW	HA8 HC-CDR1
41	IKQDGSEK	HA8 HC-CDR2
42	ARGFLERLLLGRQGAYYYGMDV	HA8 HC-CDR3
43	QSISSS	HA8-LC-CDR1
44
45	QQSYTMPPELT	HA8 LC-CDR3
46	GGSINSSHSF	HA9 HC-CDR1
47	IYSTGNS	HA9 HC-CDR2
48	ARESLWNPDYYYYMDV	HA9 HC-CDR3
49	QSFSSH	HA9 LC-CDR1
50
51	QQSYSVPYT	HA9 LC-CDR3
52	GFTFSTYN	HA10 HC-CDR1
53	ISTSSNTI	HA10 HC-CDR2
54	ARDRGCSSTNCYVVGYYFYGMDV	HA10 HC-CDR3
55	QGISSY	HA10 LC-CDR1
56
57	QQADSFPLT	HA10 LC-CDR3
58	GVTFISHA	HA11 HC-CDR1
59	IIAIFGTT	HA11 HC-CDR2
60	ARGETYYEGNFDF	HA11 HC-CDR3
61	QSISSY	HA11 LC-CDR1
62
63	QQSYSTPPIT	HA11 LC-CDR3
64	SYAMH	HA12 HC-CDR1
65	VVSYDGNYKYYADSVQG	HA12 HC-CDR2
66	DSRLRSLLYFEWLSQGYFNP	HA12 HC-CDR3
67	WGSYLES	HA12 LC-CDR1
68	QQHYRTPPS	HA12 LC-CDR2
69	QSITFDYKNYLA	HA12 LC-CDR3
70	SYNAVWN	HA13 HC-CDR1
71	RTYYRSGWYNDYAESVKS	HA13 HC-CDR2
72	SGHITVFGVNVDAFDM	HA13 HC-CDR3
73	RTSQSLSSYTH	HA13 LC-CDR1
74	AASSRGS	HA13 LC-CDR2
75	QQSRT	HA13 LC-CDR3
76	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1 VH
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSS
77	DIVMTQSPDSLAVSLGERATINCKSSQSVTFNYKNYLAWYQQKPGQPPKLL	HA1 VL
	IYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHYRTPPTFG
	QGTKVEIK
78	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2 VH
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSS
79	QSVLTQPPSASGTPGQSVTISCSGSRSNIGGNTVNWYQHLPGMAPKLLIYSS	HA2 VL
	NQRSSGVPDRFSGSKSGTSASLAISGLQSEDDADYYCASWDDSLNGVVFG
	GGTKLTVLG
80	EVQLVESGGDLVQPGGSLRLSCAASGFTVSSNYMSWVRQVPGKGLDWVS	HA3 VH
	VTYSGGNTYYADSVKGRFTISRHNSKNTLYLQMNSLRIEDTAVYYCATVPS
	FHGMDVWGQGTTVTVSS
81	DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAAS	HA3 VL
	SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRL
	EIK
82	EVQLLESGGGLVQPGGSLRISCAASGSTFGDFAMSWVRQSPGRGLEWVSV	HA4 VH
	TSAGGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRGEDTAMYYCARL
	DSSGFHYGRPGRNWGQGTLVTVSS
83	DIQMTHSPPSLSASVGDRITITCQASQDISYYLIWYQQKPGKAPKPLIYDASN	HA4 VL
	LEAGVPSRFSASGSGTDFTLTISSLQPEDLATYYCQQYKSLPYTFGQGTKLEI
	K
84	EVQLVESGGGLVKPGGSLRLSCAASGFTFSGFSMNWVRQVPGKGLEWVSS	HA5 VH
	ISTSGNYMYYADSVKGRFTISRDNAKKSFSLQMNSLRAEDSAIYYCARGGG
	YNWNLFDYWGQGSLVTVSS
85	EIVLTQSPGTLSLSPGERATLSCRASQSLNSNYLAWYQQKPGQAPRLLIYGA	HA5 VL
	SSRATGIPDRFSGSGSGTDFTLTITRLESEDFAVYYCQQYGNSPLTFGGGTK
	VEIK
86	QVQLQESGPGLVKPSETLSLTCSVSGVSVTSDIYYWTWIRQPPGKGLEWIG	HA6 VH
	YIFYNGDTNYNPSLKSRVTMSIDTSKNEFSLRLTSVTAADTAVYFCARGTE
	DLGYCSSGSCPNHWGQGTLVTVSS
87	DIQMTQSPSSLSASIGDRVTITCRPSQNIRSFLNWFQHKPGKAPKLLIYAASN	HA6 VL
	LQSGVPSRFSGSGSGTEFTLTIRSLQPEDFATYYCQQSYNTPPTFGQGTKVEI
	K
88	EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYWMTWVRQAPGKGLEWVA	HA7 VH
	NINQDGGEKYFVDSVKGRFTISRDNAKNSLFLQMNTLRAEDTAVYYCARG
	FLERLLLGRQGAYYYGMDVWGQGTTVTVSS
89	DIQMTQSPSSLSASVGDRVSMTCRASQIISSSLNWYQQKPGKAPKLLIYAAS	HA7 VL
	NLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPELTFGGGTK
	VEIK
90	EVQLVQSGGGLVQPGGSLRLSCEASRFTSSSYWITWVRQAPGKGLEWVAN	HA8 VH
	IKQDGSEKYFVDSVKGRFTISRDNASNSLYLQMSSLRAEDTAVYYCARGFL
	ERLLLGRQGAYYYGMDVWGQGTTVTVSS
91	DIQMTQSPSSLSASVGDRVTMTCRASQSISSSLNWYQQKPGKAPKLLIYAA	HA8 VL
	SNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTMPPELTFGGG
	TKVQIK
92	QVQLVESGPGLVKPSQTLSLTCTVSGGSINSSHSFWSWIRQPAGKGLEWIG	HA9 VH
	RIYSTGNSNYNPSLKSRVTISLDTSKNQFSLKLSSVTAADTAVYYCARESLW
	NPDYYYYMDVWGKGTLVTVSS
93	DIVMTQSPSSLSASVGDRVTITCRASQSFSSHLNWYQQKPGRAPDLLIYAAS	HA9 VL
	SLHSGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQSYSVPYTFGQGTKL
	QIK
94	EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYNMNWVRQAPGKGLEWLS	HA10 VH
	YISTSSNTIYYADSVKGRFTISRDNAKNSLFLQMNSLRDEDTAVYYCARDR
	GCSSTNCYVVGYYFYGMDVWGQGTTVTVSS
95	DIQMTQSPSSVSASVGDRVTITCRASQGISSYLAWYQLKPGRAPKLLIYGAT	HA10 VL
	RLQSGVPSRFSGSGSGTDFTLTISGLQPEDFATYHCQQADSFPLTFGQGTRL
	EIK
96	QVHLVQSGPEVKKPGSSVKVSCKASGVTFISHAISWVRQAPGQGLEWVGG	HA11 VH
	IIAIFGTTNYAQKFQGRVTVTTDKSTNTVYMELSRLRSEDTAIYYCARGETY
	YEGNFDFWGQGTLVTVSS
97	DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAAS	HA11 VL
	SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRL
	EIK
98	QVQLLETGGGLVKPGQSLKLSCAASGFTFTSYAMHWVRQPPGKGLEWVA	HA12 VH
	VVSYDGNYKYYADSVQGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK
	DSRLRSLLYFEWLSQGYFNPWGQGTTLTVSS
99	DIQMTQSPSSLSASVGDRVTITCRSSQSITFDYKNYLAWYQQKPGKAPKLLI	HA12 VL
	YWGSYLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHYRTPPSFGQ
	GTKVEIK
100	QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSYNAVWNWIRQSPSRGLEWLG	HA13 VH
	RTYYRSGWYNDYAESVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARS
	GHITVFGVNVDAFDMWGQGTMVTVSS
101	DIQMTQSPSSLSASVGDRVTITCRTSQSLSSYTHWYQQKPGKAPKLLIYAAS	HA13 VL
	SRGSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSRTFGQGTKVEIK
102	PDSVIRTQQRQTTMESVLSWVFLVAILQGEVQLVESGGDLVKPGGSLRLSC	HA14 VH
	VASGFTFSDFDMSWVRQAPGKGLQWVAAIAYDGSSTYYTDAVKGRFTISR
	DNARNTVYLQMDNSLRAEDTAVYYCASPTTVPTIDWFYYWGQGTLVTVS
103	MLWIPGSTGEAVMTQTPLSLAVTPGELATISCRANQSLLRSDGKSYLWYLQ	HA14 VL
	KPGPQTPRPLIYEASKRFSGVSGRFSGSGTDFTKITRVEADEVGYYCQQGLH
	FPPFQGTKVEI
104	GDSIGGSY	NA1 HC-CDR1
105	IYYTGIT	NA1 HC-CDR2
106	ARGDYSGYDRDVQVELMDV	NA1 HC-CDR3
107	QTISIF	NA1 LC-CDR1
108
109	QQSYSAPWT	NA1 LC-CDR3
110	GYTFINHA	NA2 HC-CDR1
111	IIPIFGLA	NA2 HC-CDR2
112	ARDTVAVYEDFDWSSPYFFYMDV	NA2 HC-CDR3
113	QSAGSKS	NA2 LC-CDR1
114
115	QRYGTSLVT	NA2 LC-CDR3
116	GYTFTDYY	NA3 HC-CDR1
117	IHPGSTNT	NA3 HC-CDR2
118	AISLGDGYYVYAMVC	NA3 HC-CDR3
119	QNVVTN	NA3 LC-CDR1
120
121	QQYHSYPFT	NA3 LC-CDR3
122	DSEVFPIVY	NA4 HC-CDR1
123	ILPSFGRT	NA4 HC-CDR2
124	ARGDHGNWLAY	NA4 HC-CDR3
125	QDVSTN	NA4 LC-CDR1
126
127	QQHYSAPWT	NA4 LC-CDR3
128	GLTFSGYA	NA5 HC-CDR1
129	IIASGGST	NA5 HC-CDR2
130	AQHTKSHYYSGMGV	NA5 HC-CDR3
131	QDISNY	NA5 LC-CDR1
132
133	QQYDNLPLT	NA5 LC-CDR3
134	RYNIIELS	NA6 HC-CDR1
135	IDPDDSER	NA6 HC-CDR2
136	AAARRPIRGEYHYALDV	NA6 HC-CDR3
137	QSVSSSY	NA6 LC-CDR1
138
139	HHYAKV	NA6 LC-CDR3
140	GGSFGGYY	NA7 HC-CDR1
141	INHSGST	NA7 HC-CDR2
142	ARGRGGYATYYYYYYVDV	NA7 HC-CDR3
143	QSVSSY	NA7 LC-CDR1
144
145	QQRSNWLT	NA7 LC-CDR3
146	GFTFDDYGM	NA8 HC-CDR1
147	LNWNGDITA	NA8 HC-CDR2
148	TWGEYTTREEPINSWY	NA8 HC-CDR3
149	DISSFL	NA8 LC-CDR1
150
151	LNSYPLETF	NA8 LC-CDR3
152	GFTFDDYGM	NA9 HC-CDR1
153	LNWNGDITA	NA9 HC-CDR2
154	TWGDYTTGEEIINSWY	NA9 HC-CDR3
155	DISSYL	NA9 LC-CDR1
156
157	LKSYPLETF	NA9 LC-CDR3
158	GFKFDDYAM	NA10 HC-CDR1
159	LNWNGDITA	NA10 HC-CDR2
160	SWGDYTRGPEPKITWY	NA10 HC-CDR3
161	GIDGYL	NA10 LC-CDR1
162
163	LDSYPLETF	NA10 LC-CDR3
164	NAWMS	NA11 HC-CDR1
165	RIKTKTEGETVDYAAPVKG	NA11 HC-CDR2
166	TTGLTRSSLGGFVDY	NA11 HC-CDR3
167	RSSQTVLSSSNNENFLA	NA11 LC-CDR1
168	WASTRAS	NA11 LC-CDR2
169	LQYLTTPRT	NA11 LC-CDR3
170	DYYMS	NA12 HC-CDR1
171	YISSSSTYTDYADSVKG	NA12 HC-CDR2
172	ATVADTAYSRGRPQITHFDN	NA12 HC-CDR3
173	FGDKLGEKYAY	NA12 LC-CDR1
174	QDTKRPS	NA12 LC-CDR2
175	QTWDSTLVF	NA12 LC-CDR3
176	DLVIH	NA13 HC-CDR1
177	VMGYDGGNKDYAESVKG	NA13 HC-CDR2
178	ARASYFGELRDEYYSFAMDV	NA13 HC-CDR3
179	RASQSVSRSYLA	NA13 LC-CDR1
180	GASSRAT	NA13 LC-CDR2
181	QLYGTSPPYT	NA13 LC-CDR3
182	NAWMS	NA14 HC-CDR1
183	RIKKESEGGTIDYGAPVKG	NA14 HC-CDR2
184	TIPNPQIVVVTTTPHSH	NA14 HC-CDR3
185	GGNNIGSKNVH	NA14 LC-CDR1
186	YDSDRPS	NA14 LC-CDR2
187	QVWDSSSDHWV	NA14 LC-CDR3
188	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1 VH
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS
	GYDRDVQVELMDVWGKGTTVTVSS
189	DIQMTQSPSSLSASVRDKVTFVCRASQTISIFLNWYQHKPGEAPKLLIYAAS	NA1 VL
	RLQSGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQQSYSAPWTFGQGTK
	VEIK
190	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQGLEWVG	NA2 VH
	GIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLRSDDTAVYYCARDT
	VAVYEDFDWSSPYFFYMDVWGKGTTVTVSS
191	EIVLTQSPATLSLFPGERATLSCRASQSAGSKSLAWYQHKVGQPPRLLINGA	NA2 VL
	SSRATGIPDRFSGSGSGPDFNLTISRLEPEDFAVYYCQRYGTSLVTFGGGTK
	VEIK
192	QVHLQQSGPEVARPGASVKLSCKASGYTFTDYYLNWVKQRPRQGLEWIG	NA3 VH
	QIHPGSTNTYYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVYFCAISLG
	DGYYVYAMVCWGQGTAVTVSS
193	DIVMTQSQKFMSTSVGDRVSVTCKASQNVVTNVVWYQQKPGQSPKPLIYS	NA3 VL
	ASYRYSGVPDRFTGSGSGTDFTLTISNV
194	QVHLQQSGSELRSPGSSVKLSCKDFDSEVFPIVYMRWIRQKPGHGFEWIGDI	NA4 VH
	LPSFGRTIYGEKFEDKATLDADTVSNTAYLELNSLTSEDSAIYYCARGDHG
	NWLAYWGQGTLVTVSA
195	DIVMTQSHKFMSTSVGDRVTITCKASQDVSTNVAWYQQKPGQSPKLLIYW	NA4 VL
	ASTRHTGVPNRFTGIISGTDYTLTISSVQAEDRALYYCQQHYSAPWTFGGG
	TKLEIK
196	EVQLLQSGGGLVQPGGSLRLSCAASGLTFSGYAMSWVRQVPGKGPECVSG	NA5 VH
	IIASGGSTYFADSVKGRFTISRDNSKNTLDLEMNSLRAEDTAVYYCAQHTK
	SHYYSGMGVWGQGTTVTVSS
197	DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQRPGKAPKLLIYDA	NA5 VL
	ANLETGVPSRFSGSGSATQFTFTISGLQPEDFATYYCQQYDNLPLTFGGGTK
	VEIK
198	QVQLVQSGAEVRKPGASVKVSCKVSRYNIIELSMDWVRQAPGKGLEWMG	NA6 VH
	GIDPDDSERIYAQKLQGRVTMTEDTSTDTAYMELSGLRSEDTAIYYCAAAR
	RPIRGEYHYALDVWGQGTAVTVSS
199	EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLGWYQQKPGQAPRLLIYRA	NA6 VL
	SSRATGIPHRFSGSGSGTEFTLTITRLEPEDFAVYYCHHYAKVFGQGTKVEI
	K
200	QVQLQQWGAGLLKPSETLSLTCAVYGGSFGGYYWNWIRQPPGKGLEWIG	NA7 VH
	EINHSGSTNYNPSLKSRVTLSVDTSKNQVSLNVSSVTAADTAVYYCARGRG
	GYATYYYYYYVDVWGKGTTVTVSS
201	EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDAS	NA7 VL
	KRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWLTFGGGTKVE
	LE
202	EVQLVESGGRVVRPGGSLRLSCAASGFTFDDYGMSWVRQPPGKGLEFVSG	NA8 VH
	LNWNGDITAFTDSVKGRETISRDNVKSSLYLQMNSLRADDTAFYYCARVR
	TWGDYTTGEEIINSWYFDLWGRGTLVTVSS
203	DIQLTQSPSFLSASVGDRVTITCRASQDISSYLAWYQQKPGNAPKVLIYAAS	NA8 VL
	LLSGVPSRFSAFGSGTEFTLTISSLQPEDFATYYCQHLKSYPLETFGPGTKVD
	IK
204	EVQLVESGGRVVRPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEFVSG	NA9 VH
	LNWNGDITAFTDSVKGRETISRDNAKSSLYLQMNSLRADDTAFYYCARVR
	TWGEYTTREEPIHSWYFDLWGRGTLVTVSS
205	DIQLTQSPSFLSASVGDRVTITCRASQDISSYLAWYQQKPGNAPKLLIYAAS	NA9 VL
	LLSGVPSRFSAFGSGTEFTLTISSLQPEDFATYYCQHLKSYPLETFGPGTKVD
	IK
206	EVQLVESGGRALRPGGSLRLSCAASGFKFDDYAMSWVRQVPGKGLEFVSG	NA10 VH
	LNWNGDITAYTDSVKGRETVSRDNAKNSLYLHINSPKPEDTALYYCARTSS
	WGDYTRGPEPKITWYFDLWGRGTLVTVSS
207	DIQLTQSPSFLSASVGDRITITCRASQGIDGYLAWYQQRPGKAPNLLIYAAS	NA10 VL
	LLSGVPSRFSGSGYGTEFTLTISSLQPEDFATYYCQHLDSYPLETFGPGTKV
	DIK
208	EVQLVESGGGLVKPGQSLRLSCAASGFTFTNAWMSWVRQAPGKGLEWVG	NA11 VH
	RIKTKTEGETVDYAAPVKGRITISRDDSKNMVYLQLKSLKIEDAAVYYCTT
	GLTRSSLGGFVDYWGPGTLVTVSS
209	DIVMTQSPDSLTVSLGERATINCRSSQTVLSSSNNENFLAWYQQKSGQPPN	NA11 VL
	LLIYWASTRASGVPDRFSGSGSGTDFTLTISSLQTEDVAVYYCLQYLTTPRT
	FGQGTKVEIK
210	VQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWISYIS	NA12 VH
	SSSTYTDYADSVKGRFTVSRDNAKNSLYLQMNNLRAEDTAVYYCATVAD
	TAYSRGRPQITHFDNWGQGTLVTVSS
211	SYELTQPPSMSVSPGQTATITCFGDKLGEKYAYWYQQKPGQSPLLVIYQDT	NA12 VL
	KRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCQTWDSTLVFFGGGTK
	LTVL
212	VQLVESGGGVVQPGGSLRLSCAVSGLTINDLVIHWVRQPPDKGLEWVAV	NA13 VH
	MGYDGGNKDYAESVKGRFSISGDNPQNTLYLQINSLRVEDTAVYYCARAS
	YFGELRDEYYSFAMDVWGQGTTVTVSS
213	EIVLTQSPGTLSLSPGERGTLSCRASQSVSRSYLAWYQQKPGQAPRLLIYGA	NA13 VL
	SSRATGIPDRFSGSGSGTDFTLTISRLEPEDFALYYCQLYGTSPPYTFGQGTK
	VEIK
214	EVQLVESGGGLVKPGGSLRLSCAASGFTVSNAWMSWVRQAPGKGLEWVG	NA14 VH
	RIKKESEGGTIDYGAPVKGRFTISRDESKNILYLHMKSLITDDTAVYYCTIPN
	PQIVVVTTTPHSHWGQGTLVTVSS
215	SYELTQPPSVSVAPGKTARITCGGNNIGSKNVHWYQQKPGQAPVLVIYYDS	NA14 VL
	DRPSAIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSSDHWVFGGG
	TKLAVL
216	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-6H
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-hIgG heavy
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	chain (HC) fused
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	to 6H)
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHH
	HH
217	DIVMTQSPDSLAVSLGERATINCKSSQSVTFNYKNYLAWYQQKPGQPPKLL	HA1 light chain
	IYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHYRTPPTFG	(LC)
	QGTKVEIKGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWK
	ADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEG
	STVEKTVAPTECS
218	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-12H
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-hIgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to 12H)
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHH
	HHHHHHHH
219	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-30H
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to 30H)
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHH
	HHHHHHHHHHHHHHHHHHHHHHHHHH
220	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-6K
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to 6K)
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKKK
	KK
221	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-12K
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to 12K)
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGG
	SKKKKKKKKKKKK
222	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-30K
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to 30K)
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKKK
	KKKKKKKKKKKKKKKKKKKKKKKKKK
223	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-6R
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to 6R)
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKRRRR
	RR
224	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-12R
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to 12R)
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKRRRR
	RRRRRRRR
225	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-30R
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to 30R)
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKRRRR
	RRRRRRRRRRRRRRRRRRRRRRRRRR
226	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-6O
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to 6O)
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKOOOO
	OO
227	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-12O
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to 12O)
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKOOOO
	OOOOOOOO
228	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-30O
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to 30O)
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKOOOO
	OOOOOOOOOOOOOOOOOOOOOOOOOO
229	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-6X-1
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	HHKKQQ)
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHKK
	OO
230	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-6X-2
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	HQRKHR)
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHORK
	HR
231	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-6X-3
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	HKRSQH)
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHKRS
	OH
232	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-6X-4
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	RRHTHR)
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKRRHT
	HR
233	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-12X-1
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	HHHKKKRRRO
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL	OO)
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHK
	KKRRROOO
234	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-30X-1
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	HKROHKROHK
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL	ROHKROHKRO
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY	HKROHKROHK)
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHKRO
	HKROHKROHKROHKROHKROHKROHK
235	SGSRSNIGGNTVN	HA2 LC-CDR1
236	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-12X-2
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	HHOAKKRCOO
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL	QH)
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHQA
	KKRCQQQH
237	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-30X-2
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	KOHRSOKRHTO
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL	RHKAHORKCK
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY	ROKQRKHOS)
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKOHR
	SOKRHTORHKAHORKCKROKORKHOS
238	SSNQRSS	HA2 LC-CDR2
239	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-12X-3
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	HRKOORKHHR
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL	KK)
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHRKO
	ORKHHRKK
240	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-30X-3
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	KKROSRRHOTO
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL	OHHAROKHCK
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY	HROQRHKKS
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKRO
	SRRHOTOOHHAROKHCKHROQRHKKS
241	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-12X-4
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	KRAHOKCORKS
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL	H)
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKRAH
	OKCORKSH
242	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-30X-4
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSSVFPLAPSSKSTSGGTAALGC	fused to
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	HRKQOHRSOO
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL	KTRRRAHROCH
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY	HHSRHOTHR)
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHRKQ
	OHRSOOKTRRRAHROCHHHSRHOTHR
243	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG-6H
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(HA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 6H)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHH
	HH
244	QSVLTQPPSASGTPGQSVTISCSGSRSNIGGNTVNWYQHLPGMAPKLLIYSS	HA2 LC
	NQRSSGVPDRFSGSKSGTSASLAISGLQSEDDADYYCASWDDSLNGVVFG
	GGTKLTVLGGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAW
	KADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHE
	GSTVEKTVAPTECS
245	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG-12H
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(HA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 12H)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHH
	HHHHHHHH
246	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG-30H
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(HA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 30H)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHH
	HHHHHHHHHHHHHHHHHHHHHHHHHH
247	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG-6K
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(HA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 6K)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKKK
	KK
248	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG-12K
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(HA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 12K)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGG
	SKKKKKKKKKKKK
249	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG-30K
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(HA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 30K)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKKK
	KKKKKKKKKKKKKKKKKKKKKKKKKK
250	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG-6R
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(HA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 6R)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKRRRR
	RR
251	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG-12R
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(HA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 12R)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKRRRR
	RRRRRRRR
252	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG-30R
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(HA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 30R)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKRRRR
	RRRRRRRRRRRRRRRRRRRRRRRRRR
253	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG-6O
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(HA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 6O)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKCOOO
	OOO
254	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG-12O
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(HA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 12O)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKCOOO
	OOOOOOOOO
255	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG-30O
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(HA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 30O)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKOOOO
	OOOOOOOOOOOOOOOOOOOOOOOOOO
256	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG-6X-7
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(HA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	KKOORR)
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKOO
	RR
257	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG-12X-5
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(HA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	HHHRRR)
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKRR
	OOHHHRRR
258	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG-30X-1
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(HA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	HKROHKROHK
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL	ROHKROHKRO
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY	HKROHKROHK)
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHKRO
	HKROHKROHKROHKROHKROHKROHK
259	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG-6H
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	(NA1-IgG HC
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD	fused to 6H)
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC
	NVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
	PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV
	LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
	ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
	SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHHHH
260	DIQMTQSPSSLSASVRDKVTFVCRASQTISIFLNWYQHKPGEAPKLLIYAAS	NA1 LC
	RLQSGVPSRFSGSGSGTDFTLTISGLQPEDFATYYCQQSYSAPWTFGQGTK
	VEIKGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGS
	PVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
	KTVAPTECS
261	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG-12H
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	(NA1-IgG HC
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD	fused to 12H)
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC
	NVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
	PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV
	LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
	ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
	SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHHHHHHH
	HHH
262	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG-30H
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	(NA1-IgG HC
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD	fused to 30H)
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC
	NVNHKPSNTKVDKKVEPKSCRSLVPRGSSGHHHHHHHHHHHHHHHHHHH
	HHHHHHHHHHH
263	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG-6K
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	(NA1-IgG HC
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD	fused to 6K)
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC
	NVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
	PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV
	LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
	ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
	SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKKKKK
264	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG-12K
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	(NA1-IgG HC
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD	fused to 12K)
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC
	NVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
	PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV
	LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
	ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
	SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSKKKK
	KKKKKKKK
265	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG-30K
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	(NA1-IgG HC
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD	fused to 30K)
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC
	NVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
	PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV
	LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
	ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
	SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKKKKKKKK
	KKKKKKKKKKKKKKKKKKKKK
266	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG-6R
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	(NA1-IgG HC
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD	fused to 6R)
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC
	NVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
	PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV
	LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
	ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
	SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKRRRRRR
267	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG-12R
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	(NA1-IgG HC
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD	fused to 12R)
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC
	NVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
	PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV
	LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
	ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
	SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKRRRRRRRRRR
	RR
268	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG-30R
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	(NA1-IgG HC
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD	fused to 30R)
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC
	NVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
	PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV
	LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
	ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
	SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKRRRRRRRRRR
	RRRRRRRRRRRRRRRRRRRR
269	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG-6O
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	(NA1-IgG HC
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD	fused to 6O)
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC
	NVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
	PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV
	LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
	ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
	SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKOOOOOO
270	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG-12O
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	(NA1-IgG HC
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD	fused to 12O)
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC
	NVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
	PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV
	LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
	ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
	SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKOOOOOOOOO
	OOO
271	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG-30O
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	(NA1-IgG HC
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD	fused to 30O)
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC
	NVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
	PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV
	LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
	ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
	SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKQQOOOOOOO
	OOOOOOOOOOOOOOOOOOOOO
272	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG-6X-5
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	(NA1-IgG HC
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD	fused to
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC	KKHHRR)
	NVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
	PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV
	LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
	ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
	SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKHHRR
273	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG-12X-5
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	(NA1-IgG HC
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD	fused to
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC	KKRROOHHHR
	NVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT	RR)
	PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV
	LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
	ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
	SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKRROOHHH
	RRR
274	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG-30X-1
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	(NA1-IgG HC
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD	fused to
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC	HKROHKROHK
	NVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT	ROHKROHKRO
	PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV	HKROHKROHK)
	LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
	ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
	SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHKROHKROH
	KROHKROHKROHKROHKROHK
275	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQGLEWVG	NA2-hIgG-6H
	GIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLRSDDTAVYYCARDT	(NA2-IgG HC
	VAVYEDFDWSSPYFFYMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 6H)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHH
	HH
276	EIVLTQSPATLSLFPGERATLSCRASQSAGSKSLAWYQHKVGQPPRLLINGA	NA2 LC
	SSRATGIPDRFSGSGSGPDFNLTISRLEPEDFAVYYCQRYGTSLVTFGGGTK
	VEIKGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGS
	PVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
	KTVAPTECS
277	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQGLEWVG	NA2-hIgG-12H
	GIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLRSDDTAVYYCARDT	(NA2-IgG HC
	VAVYEDFDWSSPYFFYMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 12H)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHH
	HHHHHHHH
278	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQGLEWVG	NA2-hIgG-30H
	GIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLRSDDTAVYYCARDT	(NA2-IgG HC
	VAVYEDFDWSSPYFFYMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 30H)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHH
	HHHHHHHHHHHHHHHHHHHHHHHHHH
279	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQGLEWVG	NA2-hIgG-6K
	GIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLRSDDTAVYYCARDT	(NA2-IgG HC
	VAVYEDFDWSSPYFFYMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 6K)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKKK
	KK
280	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQGLEWVG	NA2-hIgG-12K
	GIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLRSDDTAVYYCARDT	(NA2-IgG HC
	VAVYEDFDWSSPYFFYMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 12K)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGG
	SKKKKKKKKKKKK
281	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQGLEWVG	NA2-hIgG-30K
	GIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLRSDDTAVYYCARDT	(NA2-IgG HC
	VAVYEDFDWSSPYFFYMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 30K)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKKK
	KKKKKKKKKKKKKKKKKKKKKKKKKK
282	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQGLEWVG	NA2-hIgG-6R
	GIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLRSDDTAVYYCARDT	(NA2-IgG HC
	VAVYEDFDWSSPYFFYMDVWGKGTTVTVSSASVFPLAPSSKSTSGGTAAL	fused to 6R)
	GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL
	GTQTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKD
	TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
	YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY
	TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS
	DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKRRR
	RRR
283	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQGLEWVG	NA2-hIgG-12R
	GIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLRSDDTAVYYCARDT	(NA2-IgG HC
	VAVYEDFDWSSPYFFYMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 12R)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKRRRR
	RRRRRRRR
284	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQGLEWVG	NA2-hIgG-30R
	GIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLRSDDTAVYYCARDT	(NA2-IgG HC
	VAVYEDFDWSSPYFFYMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 30R)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKRRRR
	RRRRRRRRRRRRRRRRRRRRRRRRRR
285	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQGLEWVG	NA2-hIgG-6O
	GIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLRSDDTAVYYCARDT	(NA2-IgG HC
	VAVYEDFDWSSPYFFYMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 6O)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKOOOO
	OO
286	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQGLEWVG	NA2-hlgG-12O
	GIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLRSDDTAVYYCARDT	(NA2-IgG HC
	VAVYEDFDWSSPYFFYMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 12O)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKOOOO
	OOOOOOOO
287	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQGLEWVG	NA2-hIgG-30O
	GIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLRSDDTAVYYCARDT	(NA2-IgG HC
	VAVYEDFDWSSPYFFYMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 30O)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKOOOO
	OOOOOOOOOOOOOOOOOOOOOOOOOO
288	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQGLEWVG	NA2-hIgG-6X-6
	GIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLRSDDTAVYYCARDT	(NA2-IgG HC
	VAVYEDFDWSSPYFFYMDVWGKGTTVTVSSVFPLAPSSKSTSGGTAALGC	fused to
	LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	OORRHH)
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKOORR
	HH
289	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQGLEWVG	NA2-hIgG-12X-6
	GIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLRSDDTAVYYCARDT	(NA2-IgG HC
	VAVYEDFDWSSPYFFYMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	OOORRRKKKH
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL	HH)
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKOOOR
	RRKKKHHH
290	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQGLEWVG	NA2-hIgG-30X-1
	GIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLRSDDTAVYYCARDT	(NA2-IgG HC
	VAVYEDFDWSSPYFFYMDVWGKGTTVTVSSASVFPLAPSSKSTSGGTAAL	fused to
	GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL	HKROHKROHK
	GTQTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKD	ROHKROHKRO
	TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST	HKROHKROHK)
	YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY
	TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS
	DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHKR
	OHKROHKROHKROHKROHKROHKROHK
291	HHHHHH	6H
292	HHHHHHHHHHHH	12H
293	HHHHHHHHHHHHHHHHHHHHHHHHHHHHHH	30H
294	KKKKKK	6K
295	KKKKKKKKKKKK	12K
296	KKKKKKKKKKKKKKKKKKKKKKKKKKKKKK	30K
297	RRRRRR	6R
298	RRRRRRRRRRRR	12R
299	RRRRRRRRRRRRRRRRRRRRRRRRRRRRRR	30R
300	OOOOOO	6O
301	OOOOOOOOOOOO	12O
302	OOOOOOOOOOOOOOOOOOOOOOOOOOOOOO	30O
303	HHKKOO	6X-1
304	HORKHR	6X-2
305	HKRSOH	6X-3
306	RRHTHR	6X-4
307	KKOORR	6X-7
308	KKHHRR	6X-5
309	OORRHH	6X-6
310	HHHKKKRRROOO	12X-1
311	HHOAKKRCOOOH	12X-2
312	HRKQQRKHHRKK	12X-3
313	KRAHOKCORKSH	12X-4
314	KKRROOHHHRRR	12X-5
315	OOORRRKKKHHH	12X-6
316	HKROHKROHKROHKROHKROHKROHKROHK	30X-1
317	KOHRSOKRHTORHKAHORKCKROKORKHOS	30X-2
318	KKROSRRHOTOOHHAROKHCKHROTRHKKS	30X-3
319	HRKOOHRSOOKTRRRAHROCHHHSRHOTHR	30X-4
320	GRHKAKNHIRRPKSRWKKWHKYRKVHRHKVHKGRR	35X-1
321	WRKVHHYKKQHKNRAHGKLKLRAKIHQRSRMHGKQKHYHR	40X-2
322	AHHKCRRGHKQKILHRRPHKFHRWKRVHKGRHGKKHRRHKHR	42X-1
323	QHRGKAKYHRTHHVKKQRHGRKNHKVHRHARKFHKIRRLKCHKKH	45X-1
324	HNKRFKKGRHVRHSRHKSHRRTHKYHHWRHYRKVHRCKKAHKSHHRVH	50X-1
	HK
325	AHGRPHQFKRQCKAHQVKHILKRTQSHQYKQVHQRNKQAQKMRKIRGG	50X-2
	HK
326	MKTIIALSCILCLVFAQKIPGNDNSTATLCLGHHAVPNGTIVKTITDDRIEVT	>QHA30968A/
	NATELVQNSSIGEICDSPHQILDGENCTLIDALLGDPQCDGFQNKKWDLFVE	Yokosuka/NHRC_
	RNKAYSNCYPYDVPDYASLRSLVASSGTLEFNNESFNWAGVTQNGTSSSCI	QID_FDX70722/
	RGSKSSFFSRLNWLTHLNSKYPALNVTMPNNEQFDKLYIWGVHHPGTDKD	2019 2019 Apr. 17
	QISLYAQSSGRITVSTKRSQQAVIPNIGSRPRIRDIPSRISIYWTIVKPGDILLIN
	STGNLIAPRGYFKIRSGKSSIMRSDAPIGKCKSECITPNGSIPNDKPFQNVNRI
	TYGACPRYVKQSTLKLATGMRNVPERQTRGIFGAIAGFIENGWEGLVDGW
	YGFRHQNSEGRGQAADLKSTQAAIDQINGKLNRLIGKTNEKFHQIEKEFSE
	VEGRIQDLEKYVEDTKIDLWSYNAELLVALENQHTIDLTDSEMNKLFEKTK
	KQLRENAEDMGNGCFKIYHKCDNACMGSIRNGTYDHNVYRDEALNNRFQ
	IKGVELKSGYKDWILWISFAISCFLLCVVLLGFIMWACQKGNIRCNICI
327	MNPNQKIITIGSICMTIGMANLILQIGNIISIWVSHSIQIGNQSQIETCNKSVIT	>QHA30980A/
	YENNTWVNQTYVNISNTNSAARQSVASVKLAGNSSLCPVSGWAIYSKDNS	Yokosuka/NHRC_
	VRIGSKGDVFVIREPFISCSPLECRTFFLTQGALLNDKHSNGTIKDRSPYRTL	QID_FDX70778/
	MSCPIGEVPSPYNSRFESVAWSASACHDGTNWLTIGVSGPDSGAVAVLKY	2019 2019 May 30
	NGIITDTIKSWRNNILRTQESECACVNGSCFTIMTDGPSDGQASYKIFRIEKG
	KIIKSVEMKAPNYHYEECSCYPDSSEITCVCRDNWHGSNRPWVSFNQNLEY
	QMGYICSGVFGDNPRPNDKTGSCGPVSSNGANGVKGFAFKYGNGVWIGR
	TKSISSRKGFEMIWDPNGWTGTDNKFSKKQDIVGINEWSGYSGSFVQHPEL
	TGLNCIRPCFWVELIRGRPEENTIWTSGSSISFCGVDSDIVGWSWPDGAELP
	FTIDK
328	VFAQKIPGNDNSTATLCLGHHAVPNGTIVKTITNDRIEVTNATELVQNSSIG	>QFG38740A/
	EICDSPHLILDGKNCTLIDALLGDPQCDGFQNKKWDLFVERSKAYSNCYPY	Thailand/TM-
	DVPDYASLRSLVASSGTLEFNNESFNWTGVKQNGTSSACIRKSSSSFFSRLN	5434_51/2019
	WLTHLNYTYPALNVTMPNNEQFDKLYIWGVHHPGTDKDQIFLYAQSSGRI	2019 Apr. 01
	TVSTKRSQQTVIPNIGSRPRIRDIPSRISIYWTIVKPGDILLINSTGNLIAPRGYF
	KIQSGKSSIMRSDAPIGKCKSECITPNGSIPNDKPFQNVNRITYGTCPRYVKH
	STLKLATGMRNVPEKQTRGIFGAIAGFIENGWEGMVDGWYGFRHQNSEGR
	GQAADLKSTQAAIDQINGKLNRLIGKTNEKFHQIEKEFSEVEGRIQDLEKYV
	EDTKIDLWSYNAELLVALENQHTIDLTDSEMNKLFEKTKKQLRENAEDMG
	NGCFKIYHKCDNACIGSIRNGTYDHNVYRDEALNNRFQIKGVELKSGYKD
	WILWISFAISCFLLCVALLGFIMWACQKGN
329	SLTISTICFFMQIAILITTVTLHFKQYEFNSPPNNQVMLCEPTIIERNITEIVYLT	>QFP41505A/
	NTTIEKEICLKPAEYRNWSKPQCGITGFAPFSKDNSIRLSAGGDIWVTREPY	Thailand/TM-
	VSCDPDKCYQFALGQGTTLNNVHSNNTVRDRTPYRTLLMNELGVPFHLGT	5434_51/2019
	KQVCMAWSSSSCHDGKAWLHVCITGDDKNATASFIYNGRLVDSVVSWSK	2019 Apr. 01
	DILRTQESECVCINGTCTVVMTDGNATGKADTKILFIEEGKIVHTSKLSGSA
	QHVEECSCYPRYPGVRCVCRDNWKGSNRPIVDINIKDHSIVSSYVCSGLVG
	DTPRKSDSSSSSHCLNPNNEEGGHGVKGWAFDDGNDVWMGRTINETSRLG
	YETFKVVEGWSNSKSKLQINRQVIVDRGDRSGYSGIFSVEGKSCINRCFYVE
	LIRGRKEETEVLWTSNSIVVFCGTSGTYGT
330	MKTIIALSCILCLVFAQKIPGNDNSTATLCLGHHAVPNGTIVKTITNDRIEVT	>QDC19555A/
	NATELVQNSSIGEICDSPHQILDGENCTLIDALLGDPQCDGFQNKKWDLFVE	Germany/9496/
	RNKAYSNCYPYDVPDYASLRSLVASSGTLEFNNESFNWAGVTQNGTSSSCI	2019 2019 Apr. 03
	RGSKSSFFSRLNWLTHLNSKYPALNVTMPNNEQFDKLYIWGVHHPGTDKD
	QTSLYAQSSGRITVSTKRSQQAVIPNIGSRPRIRDIPSRISIYWTIVKPGDILLI
	NSTGNLIAPRGYFKIRSGKSSIMKSDAPIGKCKSECITPNGSIPNDKPFQNVN
	RITYGACPRYVKQSTLKLATGMRNVPEKQTRGIFGAIAGFIENGWEGLVDG
	WYGFRHQNSEGRGQAADLKSTQAAIDQINGKLNRLIGKTNEKFHQIEKEFS
	EVEGRIQDLEKYVEDTKIDLWSYNAELLVALENQHTIDLTDSEMNKLFEKT
	KKQLRENAEDMGNGCFKIYHKCDNACMGSIRNGTYDHNVYRDEALNNRF
	QIKGVELKSGYKDWILWISFAISCFLLCVVLLGFIMWACQKGNIRCNICI
331	MNPNQKIITISSVSLTISTICFFMQIAILITTVTLHFKQYEFNPPPNNQVMLCEP	>QDC19627A/
	TIIERNITEIVYLTNTTIEREICPKPAEYRNWSKPQCGITGFAPFSKDNSIRLSA	Germany/9496/
	GGDIWVTREPYVSCDPDKCYQFALGQGTTINNVHSNNTARDRTPHRTLLM	2019 2019 Apr. 03
	SELGVPFHLGTKQVCIAWSSSSCHDGKAWLHVCITGDDKNATASFIYNGRL
	VDSVVSWSKDILRTQESECVCINGTCTVVMTDGNATGKADTKILFIEEGKI
	VHTSKLSGSAQHVEECSCYPRYPGVRCVCRDNWKGSNRPIVDINIKDHSIV
	SSYVCSGLVGDTPRKTDSSSSSHCLNPNNEKGGHGVKGWAFDDGNDVWM
	GRTINETSRLGYETFKVVEGWSNSKSKLQINRQVIVDRGDRSGYSGIFSVEG
	KSCINRCFYVELIRGRKEETEVLWTSNSIVVFCGTSGTYGTGSWPDGADLN
	LMHI
332	MNPNQKIITIGSICMTIGTANLILQIGNIISIWVSHSIQIGNQSQIETCNKSVITY	>QIA57890A/
	ENNTWVNQTFVNISNTNSAARQSVASVKLAGNSSLCPVSGWAIYSKDNSV	Delaware/55/2019
	RIGSKGDVFVIREPFISCSPLECRTFFLTQGALLNDKHSNGTIKDRSPYRTLM	2019 Dec. 11
	SCPIGEVPSPYNSRFESVAWSASACHDGTNWLTIGISGPDSGAVAVLKYNGI
	ITDTIKSWRNKILRTQESECACVNGSCFTIMTDGPSDGQASYKIFRIEKGKII
	KSVEMKAPNYHYEECSCYPDSSEITCVCRDNWHGSNRPWVSFNQNLEYQ
	MGYICSGVFGDNPRPNDKTGSCGPVSSNGANGVKGFSFKYGNGVWIGRTK
	SISSRKGFEMIWDPNGWTGTDNKFSKKQDIVGINEWSGYSGSFVQHPELTG
	LNCIRPCFWVELIRGRPEENTIWTSGSSISFCGVDSDIVGWSWPDGAELPFTI
	DK
333	MNPNQKIITIGSICMTIGMANLILQIGNIISIWVSHSIQTGNQSQIETCNKNVIT	>QIA57903A/
	YENNTWVNQTYVNISNTNSAARQSVASVKLAGNSSLCPVSGWAIYSKDNS	Delaware/56/2019
	VRIGSKGDVFVIREPFISCSPLECRTFFLTQGALLNDKHSNGTIKDRSPYRTL	2019 Dec. 12
	MSCPIGEVPSPYNSRFESVAWSASACHDGTNWLTIGISGPDSGAVAVLKYN
	GIITDTIKSWRNNILRTQESECACVNGSCFTMMTDGPSDGQASYKIFRIEKG
	KIIKSVEMKAPNYHYEECSCYPDSSEITCVCRDNWHGSNRPWVSFNQNLEY
	QMGYICSGVFGDNPRPNDKTGSCGPVSSNGANGVKGFSFKYGNGVWIGRT
	KSISSRKGFEMIWDPNGWTGTDNKFSKKQDIVGINEWSGYSGSFVQHPELT
	GLNCIRPCFWVELIRGRPEENTIWTSGSSISFCGVDSDIVGWSWPDGAELPF
	TIDK
334	MKAIIVLLMVVTSNADRICTGITSSNSPHVVKTATQGEVNVTGVIPLTTTPT	>QJA11920B/
	KSHFANLKGTETRGKLCPKCLNCTDLDVALGRPKCTGKIPSARVSILHEVR	Alabama/07/2020
	PVTSGCFPIMHDRTKIRQLPNLLRGYEHVRLSTHNVINAEGAPGGPYKIGTS	2020 Feb. 21
	GSCPNITNGNGFFATMAWAVPDKNKTATNPLTIEVPYVCTEGEDQITVWG
	FHSDNETQMAKLYGDSKPQKFTSSANGVTTHYVSQIGGFPNQTEDGGLPQ
	SGRIVVDYMVQKSGKTGTITYQRGILLPQKVWCAXGRSKVIKGSLPLIGEA
	DCLHEKYGGLNKSKPYYTGEHAKAIGNCPIWVKTPLKLANGTKYRPPAKL
	LKERGFFGAIAGFLEGGWEGMIAGWHGYTSHGAHGVAVAADLKSTQEAI
	NKITKNLNSLSELEVKNLQRLSGAMDELHNEILELDEKVDDLRADTISSQIE
	LAVLLSNEGIINSEDEHLLALERKLKKMLGPSAVEIGNGCFETKHKCNQTC
	LDKIAAGTFDAGEFSLPTFDSLNITAASLNDDGLDNHTILLYYSTAASSLAV
	TLMIAIFVVYMVSRDNVSCSICL
335	MLPSTIQTLTLFLTSGGVLLSLYVSASLSYLLYSDILLKFSPTEITAPTMPLDC	>QJA11911B/
	ANASNVQAVNRSATKGVILLLPEPEWTYPRLSCPGSTFQKALLISPHRFGET	Alabama/07/2020
	KGNSAPLIIREPFVACGPNECKHEALTHYAAQPGGYYNGTRGDRNKLRHLI	2020 Feb. 21
	SVKLGKIPTVENSIFHMAAWSGSACHDGKEWTYIGVDGPDNNALLKIKYG
	EAYTDTYHSYANNILRTQESACNCIGGNCYLMITDGSXSGVSECRFLKIREG
	RIIKEIFPTGRVKHTEECTCGFASNKTIECACRDNRYTAKRPFVKLNVETDT
	AEIRLMCTDTYLDTPRPNDGSITGPCESDGDKGSGGIKGGFVHQRMKSKIG
	RWYSRTMSQTERMGMGLYVKYGGDPWADSDALAFSGVMVSMKEPGWY
	SFGFEIKDKKCDVPCIGIEMVHDGGKETWHSAATAIYCLMGSGQLLWDTV
	TGVDMAL
336	MKAIIVLLMVVTSNADRICTGITSSNSPHVVKTATQGEVNVTGVIPLTTTPT	>QGT76054B/
	KSHFANLKGTETRGKLCPKCLNCTDLDVALGRPKCTGKIPSARVSILHEVR	China/b45/2019
	PVTSGCFPIMHDRTKIRQLPNLLRGYEHVRLSTHNVINAEDAPGGPYKIGTS	2019 Jan. 08
	GSCPNITNGNGFFATMAWAVPKNDKNKTATNPLTIEVPYICTEGEDQITVW
	GFHSDNETQMAKLYGDSKPQKFTSSANGVTTHYVSQIGGFPNQTEDGGLP
	QSGRIVVDYMVQKSGKTGTITYQRGILLPQKVWCASGRSKVIKGSLPLIGE
	ADCLHEKYGGLNKSKPYYTGEHAKAIGNCPIWVKTPLKLANGTKYRPPAK
	LLKERGFFGAIAGFLEGGWEGMIAGWHGYTSHGAHGIAVAADLKSTQEAI
	NKITKNLNSLSELEVKNLQRLSGAMDELHNEILELDEKVDDLRADTISSQIE
	LAVLLSNEGIINSEDEHLLALERKLKKMLGPSAVEIGNGCFETKHKCNQTC
	LDRIAAGTFDAGEFSLPTFDSLNITAASLNDDGLDNHTILLYYSTAASSLAV
	TLMIAIFVVYMVSRDNVSCSICL
337	MLPSTIQTLTLFLTSGGVLLSLYVSASLSYLLYSDILLKFSPTEITAPTMPLDC	>QGT76183B/
	ANASNVQAVNRSATKGATLLLPEPEWTYPRLSCPGSTFQKALLISPHRFGE	China/b45/2019
	TKGNSAPLIIREPFVACGPNECKHEALTHYAAQPGGYYNGTRGDRNKLRHL	2019 Jan. 08
	ISVKLGKIPTVENSIFHMAAWSGSACHDGKEWTYIGVDGPDNNALLKVKY
	GEAYTDTYHSYANNILRTQESACNCIGGNCYLMITDGSASGVSECRFLKIRE
	GRIIKEIFPTGRVKHTEECTCGFASNKTIECACRDNRYTAKRPFVKLNVETD
	TAEIRLMCTDTYLDTPRPNDGSITGPCESDGDEGSGGIKGGFVHQRMKSKI
	GRWYSRTMSKTERMGMGLYVKYGGDPWADSDALVFSGVMISMKEPGW
	YSFGFEIKDKKCDVPCIGIEMVHDGGKETWHSAATAIYCLMGSGQLLWDT
	VTGVDMAL
338	MKAIIVLLMVVTSNADRICTGITSSNSPHVVKTATQGEVNVTGVIPLTTTPT	>QDX11011B/
	KSHFANLKGTETRGKLCPKCLNCTDLDVALGRPKCTGKIPSARVSILHEVR	Japan/9830/2019
	PVTSGCFPIMHDRTKIRQLPNILRGYEHVRLSTHNVINAEDAPGRPYEIGTSG	2019 May 22
	SCPNITNGNGFFATMAWAVPKNKTATNPLTIEVPYICTEGEDQITVWGFHS
	DNETQMAKLYGDSKPQKFTSSANGVTTHYVSQIGGFPNQTEDGGLPQSGRI
	VVDYMVQKSGKTGTITYQRGILLPQKVWCASGRSKVIKGSLPLIGEADCLH
	EKYGGLNKSKPYYTGEHAKAIGNCPIWVKTPLKLANGTKYRPPAKLLKER
	GFFGAIAGFLEGGWEGMIAGWHGYTSHGAHGVAVAADLKSTQEAINKITK
	NLNSLSELEVKNLQRLSGAMDELHNEILELDEKVDDLRADTISSQIELAVLL
	SNEGIINSEDEHLLALERKLKKMLGPSAVEIGNGCFETKHKCNQTCLDRIAA
	GTFDAGEFSLPTFDSLNITAASLNDDGLDNHTILLYYSTAASSLAVTLMIAIF
	VVYMVSRDNVSCSICL
339	MLPSTIQTLTLFLTSGGVLLSLYVSASLSYLLYSDILLKFSPTEITAPTMPLDC	>QDX11015B/
	ANASNVQAVNRSATKGVTLLLPEPEWTYPRLSCPGSTFQKALLISPHRFGE	Japan/9830/2019
	TKGNSAPLIIREPFVACGPNECKHEALTHYAAQPGGYYNGTRGDRNKLRHL	2019 May 22
	ISVKLGKIPTVENSIFHMAAWSGSACHDGKEWTYIGVDGPDNNALLKVKY
	GEAYTDTYHSYANNILRTQESACNCIGGNCYLMITDGSASGVSECRFLKIRE
	GRIIKEIFPTGRVKHTEECTCGFASNKTIECACRDNKYTAKRPFVKLNVETD
	TAEIRLMCTDTYLDTPRPNDGSITGPCESDGDKGSGGIKGGFVHQRMKSKI
	GRWYSRTMSKTERMGMGLYVKYGGDPWADSDALTFSGVMVSMKEPGW
	YSFGFEIKDKKCDVPCIGIEMVHDGGKETWHSAATAIYCLMGSGQLLWDT
	VTGVDMAL
340	MKAIIVLLMVVTSNADRICTGITSSNSPHVVKTATQGEVNVTGVIPLTTTPT	>QDA45896B/
	KSHFANLKGTETRGKLCPKCLNCTDLDVALGRPKCTGKIPSARVSILHEVK	Moscow/2/2019
	PVTSGCFPIMHDRTKIRQLPNLLRGYEHVRLSTHNVINAEGAPGGPYKIGTS	2019 Feb. 22
	GSCPNITNGNGFFATMAWAVPDKNKTATNPLTIEVPYICTEGEDQITVWGF
	HSDNETQMAKLYGDSKPQKFTSSANGVTTHYVSQIGGFPNQTEDGGLPQS
	GRIVVDYMVQKSGKTGTITYQRGILLPQKVWCASGRSKVIKGSLPLIGEAD
	CLHEKYGGLNKSKPYYTGEHAKAIGNCPIWVKTPLKLANGTKYRPPAKLL
	KERGFFGAIAGFLEGGWEGMIAGWHGYTSHGAHGVAVAADLKSTQEAIN
	KITKNLNSLSELEVKNLQRLSGAMDELHNEILELDEKVDDLRADTISSQIEL
	AVLLSNEGIINSEDEHLLALERKLKKMLGPSAVEIGNGCFETKHKCNQTCL
	DKIAAGTFDAGEFSLPTFDSLNITAASLNDDGLDNHTILLYYSTAASSLAVT
	LMIAIFVVYMVSRDNVSCSICL
341	MLPSTIQTLTLFLTSGGVLLSLYVSASLSYLLYSDILLKFSPTEITAPTMPLDC	>QDA45899B/
	ANASNVQAVNRSATKGVTLLLPEPEWTYPRLSCPGSTFQKALLISPHRFGE	Moscow/2/2019
	TKGNSAPLIIREPFVACGPNECKHEALTHYAAQPGGYYNGTRGDRNKLRHL	2019 Feb. 22
	ISVKLGKIPTVENSIFHMAAWSGSACHDGKEWTYIGVDGPDNNALLKVKY
	GEAYTDTYHSYANNILRTQESACNCIGGNCYLMITDGSASGVSECRFLKIRE
	GRIIKEIFPTGRVKHTEECTCGFASNKTIECACRDNRYTAKRPFVKLNVETD
	TAEIRLMCTDTYLDTPRPNDGSITGPCESDGDKGSGGIKGGFVHQRMKSKI
	GRWYSRTMSKTERMGMGLYVKYGGDPWADSNALAFSGVMISMKEPGW
	YSFGFEIKDKKCDVPCIGIEMVHDGGKETWHSAATAIYCLMGSGQLLWDT
	VTGVDMAL
342	DYKDDDDKHHHHHH	Flag-His(6)
		purification tag
343	SRGGGGSGGGGSGGGGSLEMA	Linker A
344	GGGGS	Linker 1
345	GS(GS)n, where n ≥ 0	Linker 2
346	(GSGGS)n, where n ≥ 1	Linker 3
347	(GGGGS)n, where n ≥ 1	Linker 4
348	(GGGS)n, where n ≥ 1	Linker 5
349	MKTIIVLSYLFCLALSQDYSENNNSTATLCLGHHAVPNGTVVKTITDDQIEV	QDX47284.1
	TNATELVQSSSTGKICNNPHRILDGRDCTLIDALLGDPHCDVFQDETWDLY
	VERSSAFSNCYPYDVPDYASLRSLVASSGTLEFITEGFTWTGVTQNGGSSA
	CKRGPASGFFSRLNWLTKSGSAYPVLNVTMPNNDNFDKLYVWGVHHPST
	NQEQTNLYVQASGRVTVSTRKSQQTIIPNIGSRPWVRGQSGRISIYWTIVKP
	GDVLVINSNGNLIAPRGYFKMRTGKSSIMRSDAPIDTCISECITPNGSIPNDK
	PFQNVNKITYGACPKYVKQSTLKLATGMRNVPEKQTRGLFGAIAGFIENG
	WEGMIDGWYGFRHQNSEGTGQAADLKSTQAAIDQINGKLNRVIEKTNEKF
	HQIEKEFSEVEGRIQDLEKYVEDTKIDLWSYNAELLVALENQHTIDLTDSE
	MNKLFEKTRRQLRENAEDMGNGCFKIYHKCDNACIESIRNGTYDHDIYRD
	EALNNRFQIKGVELKSGYKDWILWISFAISCFLLCVVLLGFIMWACQRGNI
	RCNICI
350	MNPNQKIITIGSICMAIGIMSLVLQIGNIISIWVSHSIQTESKSHPETCNQSVIT	QDX47725.1
	YENNTWVNQTYLNISNTNLIVEQIVAPVTLAGNSSLCPISGWAIYSKDNGIR
	IGSKGDVFVIREPFISCSHLECRTFFLTQGALLNDKHSNGTVKDRSPYRTLM
	SCPVGEAPSPYNSRFESVAWSASACHDGISWLTIGISGPDNGAVAVLKYNGI
	ITDTVKSWRNNILRTQESECACINGSCFTIMTDGPSNGQASYKIFKIEKGKV
	VKSVELNAPNYHYEECSCYPDASEVMCVCRDNWHGSNRPWVSFNQDLEY
	QIGYICSGVFGDNPRPNDGTGSCGPVSSNGAYGVKGFSFRYGNGVWIGRTK
	STSSRSGFEMIWDPNGWTETDNSFSVKQDIVAITDWSGYSGSFVQHPELTG
	LDCVRPCFWVELIRGRPKENTIWTSGSSISFCGVNSDTVGWSWPDGAELPF
	TIDK
351	MRTVIALSYIFCLAFGQNLKGNENNAATLCLGHHAVPNGTMVKTITSDQIE	AFI61906.1
	VTNATEQVQNSSTGKICNNPHKILDGRDCTLIDALLGDPHCDVFQNETWDL
	FVERSNAFSNCYPYDVQDYASLRSIVASSGTLEFITEGFTWAGVTQNGGSG
	ACKRGPANGFFSRLNWLTKSGNTYQVLNVTMPNNNNFDKLYIWGVHHPS
	TNQEQTSLYIQASGRVTVSTRRSKQTIILNIESRPLVRCQSGRISVYWTIVKP
	GVILVINSNGNLIAPRGYFKMHIGKSTIMRSDAPVDTCISECITPNGSIPNEKP
	FQNVNKITYGACPKYVKQNTLKLSTGMRNVPERQTRGLFGAIAGFIENGW
	EGMVDGWYGFRHQNSEGTGQAADLKSTQAAIDQINGKLNRVIEKTNEKFH
	QIEKEFSEVEGRIQDLERYVEDTKVDLWSYNAELLVALENQNTIDLTDSEM
	NKLFEKTRRQLRENAEDMGNGCFKIYHKCDNACIESIRNGTYDHNIYRDEA
	VNNRFQIKGVELKSGYKDLILWISFAISCFLLCVVLLGFIMWACQRGNIRCN
	ICI
352	MNPNQKIIAIGSVSLIIATVCFLLQIAILATNVTLYFKQNECNIPSNSQVVPCK	ANW47171.1
	PIIIERNITEVVYLNNTTIEKEIYSVVLEYRNWSKPQCQITGFAPFSKDNSIRL
	SAGGDIWVTREPYVSCDPSKCYQFALGQGTTLNNKHSNGTIHDRISHRTLL
	MNELGVPFHLGTKQVCIAWSSSSCHDGKAWLHVCVTGDDKNATASFVYN
	GMLVDSIGSWSRNILRTQESECVCINGTCTVVMTDGSASGRADTRILFIREG
	KIVHISPLSGSAQHIEECSCYPRYPNVRCVCRDNWKGSNRPVIDINMADYSI
	DSSYVCSGLVGDTPRNDDSFSSSNCRDPNNERGNPGVKGWAFDNENDVW
	MGRTISKDLRSGYETFKVIGCRTTANSKSQVNRQVIVDNNNWSGYSGIFSV
	EGKSCVNRCFYVELIRGGPQETRVWWTSNSIVVFCGTSGTYGAGSWPDGA
	NINFMPI
353	MKTVIALSYIFCLAFGQNLLGNENNAATLCLGHHAVPNGTMVKTITDDQIE	QBQ33923.2
	VTNATELVQNSSTGKICNNPHKILDGRDCTLIDALLGDPHCDVFQNETWDL
	FVERSNAFSNCYPYDVPDYASLRSIVASSGTLEFITEGFTWAGVTQNGGSG
	ACKRGPANSFFSRLNWLTKSGNTYPVLNVTMPNNNNFDKLYIWGVHHPST
	DQEQTSLYIQASGRVTVSTRKSQQTIIPNIGSRPLVRGQSGRISVYWTIVEPG
	DILVINSNGNLIAPRGYFKMHIGKSSIMRSDAPIDTCISECITPNGSIPTEKPFQ
	NVNKITYGACPKYVKQNTLKLATGMRNVPERQTRGLFGAXAGFIENGWE
	GMVDGWYGFRHQNSEGTGQAADLKSTQAAIDQINGKLNRVIEKTNEKFH
	QIEKEFSEVEGRIQDLERYVEDTKIDLWSYNAELLVALENQNTIDLTDSEM
	NKLFEKTRRQLRENAEDMGNGCFKIYHKCDNACIESIRNGTYDHNIYRDEA
	VNNRFQIKGVELKSGYKDWILWISFAISCFLLCVVLLGFIMWACQRGNIRC
	NICI
354	MNPNQKIIAIGSVSLAIATVCFLLQIATLATTVTLYFKQNECNIPSNSQIVPCK	QBQ33992.2
	PIIIERNITEVVHLNNTTIEKEIYSVVLEYRNWSKPQCQITGFAPFSKDNSIRL
	SAGGDIWVTREPYVSCDPSKCYQFALGQGTTLNNKHSNSTIHDRTSYRTLL
	MNELGVPXHLGTKQVCIAWSSSSCHDGKAWLHVCVTGDDRNATASFVYN
	GMLVDSIGSWSRNILRTQESECVCINGTCTVVMTDGSASGKADTRILFIKEG
	KIIHISPLSGSAQHIEECSCYPQYPNVRCVCRDNWKGSNRPVIDINMADYNI
	NSSYVCSGLVGDTPRNDDSSSSSNCKDPNNERGNPGVKGWAFDNDNDVW
	MGRTISKDLRSGYETFKVIGGWTTANSKSQVNRQVIVDNNNWSGYSGIFSV
	EGKSCVNRCFYVELIRGGPQETRVWWTSNSIVVFCGTSGTYGTGSWPDGA
	NINFMPI
355	MNPNQKIITIGTASLGILIINVILHVVSIIVTVLVLNNNETGLNCKGTIIREYNE	AIZ95447.1
	TVRVEKITQWHNTSAIKYIERPPNEYYMNNTEPLCEAQGFAPFSKDNGIRIG
	SRGHVFVIREPFVSCSPSECRTFFLTQGSLLNDKHSNGTVKDRSPYRTLMSV
	KIGQSPNVYQARFESVAWSATACHDGKKWMTIGVTGPDNQAIAVVNYGG
	IPVDIINSWEGDILRTQESSCTCIKGNCYWVMTDGPANRQAKYRIFKAKDG
	RVIGQTDISFNGGHIEECSCYPNEGKVECICRDNWTGTNRPILVISSDLSYTV
	GYLCAGIPTDTPRGEDSQFTGSCTSPLGNKGYGVKGFGFRQGTDVWAGRTI
	SRTSRSRFEIIKIRNGWTQNSKDQIRRQVIIDDPNWSGYSGSFTLPVELTKKG
	CLVPCFWVEMIRGKPEETTIWTSSSSIVMCGVDHKIASWSWHDGAILPFDID
	KM
356	MKTTTIFIFILLTHWAYSQNPISNNNTATLCLGHHAVANGTLVKTISDDQIE	AXQ87682.1
	VTNATELVQSISMGKICNNSYRILDGRNCTLIDAMLGDPHCDVFQYENWD
	LFIERSSAFSNCYPYDIPDYASLRSIVASSGTLEFTAEGFTWTGVTQNGRSGA
	CKRGSTDSFFSRLNWLTKSGNSYPTLNVTMPNNKNEDKLYIWGIHHPSSNQ
	EQTKLYIQGSGRVTVSTKRSQQTIIPNIGSRPWVRGQSGRISIYWTIVKPGDI
	LMINSNGNLVAPRGYFKLKTGKSSVMRSDVPIDICVSECITPNGSISNDKPF
	QNVNKVTYGKCPKYIRQNTLKLATGMRNVPEKQIRGIFGAIAGFIENGWEG
	MVDGWYGFRYQNSEGTGQAADLKSTQTAIDQINEKLNRVIERTNEKFHQI
	EKEFSEVEGRIQDLEKYVEDTKIDLWSYNAELLVALENQHTIDLTDAEMNK
	LFEKTRRQLRENAEDMGGGCFKIYHKCDNACIGSIRNGTYDHYIYRDEALN
	NRFQIKGVELKSGYKDWILWISFAISCFLICVVLLGFIMWACQKGN
	IRCNICI
357	MKAILLVLLYTFVPTNADTLCIGYHANNSTDTVDTILERNVTVTHSVNLLE	AEA29582.1
	DKHNGRLCKLGGIAPLHLGKCNIAGWLLGNPECESLFTVSSWSYIVETSNS
	YNGTCYPGDFINYEELREQLSSVSSFERFEIFPKASSWPNHETNKGVTAACS
	HAGTKSFYRNLIWLVKKGNSYPNISKSYFNNKGNEVLVLWGIHHPSTNND
	QQTLYQNADTYVFVGTSKYNKKFKPEIAIRPKVRDQEGRMNYYWTLVEPG
	DKITFEATGNLVVPRYAFAMERNAGSGIIISDTPVHDCNTTCQTPKGAINTS
	LPFQNIHPTTIGKCPKYVKSTKLRLATGLRNVPSIQSRGLFGAIAGFIEGGWT
	GMVDGWYGYHHQNEQGSGYAADQKSTQNAIDGITNKVNSVIEKMNTQFT
	AVGKEFNHLEKRIENLNKKVDDGFLDVWTYNAELLILLENERTLDFHDSN
	VKNLYEKARRQLKNNAKEIGNGCFEFYHKCDNACMESVKNGTYDYPKYS
	EESRLNREEISGVKLDSTRIYQILAIYSTVASSSVLLVSLGAISFWMCSNGSL
	QCRICI
358	MNTNQRIITIGTVCLTVGIISLLLQIGNIVSLWISHSIQTGGKNHTEMCNKNVI	AHB21162.1
	TYVNNTWVNRTYVNISNTKIVNVQDVVSVILTGNSSLCPISGWAIYSKDNSI
	RIGSKGDIFVIREPFISCSHLECRTFFLTQGALLNDKHSNGTVKDRSPYRTLM
	SCPIGEAPSPYNSRFESVAWSASACHDGMGWLTIGISGPDNGAVAVLKYNG
	IITDTIKSWRNKILRTQESECVCMNGSCFTVLTDGPSNGQASYKIFKMEKGK
	IIKSIELDAPNYHYEECSCYPDAGKVMCVCRDNWHASNRPWVSFDQNLDY
	QIGYICSGVFGDNPRSNDGKGNCGPVHSNGANGVKGFSYRYGNGVWIGRT
	KSINSRSGFEMIWDPNGWTGTDSSFSMKQDIIALTDWSGYSGSFVQHPELT
	GMNCIRPCFWVELIRGQPKENTIWASGSSISFCGVNGETASWSWPDGADLP
	FTIDK
359	SGFSFSSSY	G126 HC-CDR1
360	LEWIACIYAGSSGSAYF	G126 HC-CDR2
361	APSYTYGYAGYAYAYSYYFN	G126 HC-CDR3
362	QSINN	G126 LC-CDR1
363	PKLLYDASDLA	G126 LC-CDR2
364	DYSTNN	G126 LC-CDR3
365	SNNAVWN	FY-UCA-VH HC-
		CDR1
366	RTYYRSKWYNDYAESVKS	FY-UCA-VH HC-
		CDR2
367	SGHITVFGVNVDAFDM	FY-UCA-VH HC-
		CDR3
368	TRSQSLSSYLH	FY-UCA-VH LC-
		CDR1
369	AASSLQS	FY-UCA-VH LC-
		CDR2
370	QQSRT	FY-UCA-VH LC-
		CDR3
371	LIYTGGTTYYADSVKG	AT10_004 HC-
		CDR1
372	VSALRFLQWPNYAMDV	AT10_004 HC-
		CDR2
373	SGTRSDVGGHNYVS	AT10_004 HC-
		CDR3
374	EVSHRPS	AT10_004 LC-
		CDR1
375	SSYTGEGPLGV	AT10_004 LC-
		CDR2
376	SYWMS	AT10_004 LC-
		CDR3
377	RHGIS	CR8001 HC-
		CDR1
378	WISAYTGDTDYAQKFQG	CR8001 HC-
		CDR2
379	GWGAVTSPFDF	CR8001 HC-
		CDR3
380	GWGAVTSPFDF	CR8001 LC-
		CDR1
381	DASNRAT	CR8001 LC-
		CDR2
382	QQRSNWLK	CR8001 LC-
		CDR3
383	QSLEESGGDLVKPGASLTLTCTASGFSFSSSYWICWVRQAPGKGLEWIACI	G126 VH
	YAGSSGSAYFASWAKGRFTISETSSTTVTLQMTSLTAADTATYFCARAPSY
	TYGYAGYAYAYSYYFNLWGPGTLVTVSS
384	VMTQTPASVEVTMGGTVTINCQASQSINNELCWYQQKPGQRPKLLIYDAS	G126 VL
	DLASGVPSRFKGSGSGTEFTLTISDLECADAATYYCQQDYSTNNVDNLFGG
	GTEVVVK
385	QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNNAVWNWIRQSPSRGLEWLG	FY-UCA-VH VH
	RTYYRSKWYNDYAESVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARS
	GHITVFGVNVDAFDMWGQGTMVTVSS
386	DIQMTQSPSSLSASVGDRVTITCRTSQSLSSYTHWYQQKPGKAPKLLIYAAS	FY-UCA-VH VL
	SRGSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSRTFGQGTKVEIK
387	EVQLVESGGGLIQPGGSLRLSCAASGFTVSSNYVSWVRQAPGKGLEWLSLI	AT10_004 VH
	YTGGTTYYADSVKGRFTISRDNSKNTVFLQMNSLRAEDAAMYYCARVSA
	LRFLQWPNYAMDV
388	QSALTQPASVSGSPGRSITISCSGTRSDVGGHNYVSWYQQHPGKAPKLMIY	AT10_004 VL
	EVSHRPSGVSNRFSGSKSGSTASLTISGLQSEDEADYYCSSYTGEGPLGV
389	QVQLVQSGAEVRKPGASVKVSCKASGYTFTRHGISWVRQAPGQGLEWMG	CR8001 VH
	WISAYTGDTDYAQKFQGRVTMTTDTSTNTAYMELRSLRSDDAAVYYCAR
	LRLQGEVVVPPSQSNWFDPWGQGTLVTVSS
390	EIVLTQSPATLSLYPGERATLSCRASQSVSRYLAWYQQKPGQAPRLLIYDAS	CR8001 VL
	NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCCDRQQRSNWLKITFGQ
	GTRLEIKGTV
391	TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN	Immunoglobulin
	WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS	Fc
	NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD	(CH2CH3)
	IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS
	VMHEALHNHYTQKSLSLSPGK
392	GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKA	Immunoglobulin
	GVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVA	CL
	PTECS
393	ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH	Immunoglobulin
	TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC	CH1
394	TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN	Immunoglobulin
	WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS	CH2
	NKALPAPIEKTISKAKGQPRE
395	PQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP	Immunoglobulin
	VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG	CH3
	K
396	PDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVT	Immunoglobulin
	SAPMPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVD	CH4
	KSTGK
397	MWWRLWWLLLLLLLLWGSSASAAIIPVEEENPDFWNREAAEALGAAKKL	Alkaline
	QPAQTAAKNLIIFLGDGMGVSTVTAARILKGQKKDKLGPEIPLAMDRFPYV	phosphatase
	ALSKTYNVDKHVPDSGATATAYLCGVKGNFQTIGLSAAARFNQCNTTRGN
	EVISVMNRAKKAGKSVGVVTTTRVQHASPAGTYAHTVNRNWYSDADVPA
	SARQEGCQDIATQLISNMDIDVILGGGRKYMFRMGTPDPEYPDDYSQGGTR
	LDGKNLVQEWLAKRQGARYVWNRTELMQASLDPSVTHLMGLFEPGDMK
	YEIHRDSTLDPSLMEMTEAALRLLSRNPRGFFLFVEGGRIDHGHHESRAYR
	ALTETIMEDDAIERAGQLTSEEDTLSLVTADHSHVFSFGGYPLRGSSIFGLAP
	GKARDRKAYTVLLYGNGPGYVLKDGARPDVTESESGSPEYRQQSAVPLDE
	ETHAGEDVAVFARGPQAHLVHGVQEQTFIAHVMAFAACLEPYTACDLAPP
	AGTTDAAHPGYSRVGAAGRFEQT
398	MKLVGSYTSPFVRKLSILLLEKGITFEFINELPYNADNGVAQFNPLGKVPVL	Glutathione-s-
	VTEEGECWFDSPIIAEYIELMNVAPAMLPRDPLESLRVRKIEALADGIMDAG	transferase
	LVSVREQARPAAQQSEDELLRQREKINRSLDVLEGYLVDGTLKTDTVNLA
	TIAIACAVGYLNFRRVAPGWCVDRPHLVKLVENLFSRESFARTEPPKA
399	LENHSRRLEMTNKQLWLRIQEL	bHLH-leucine
		zipper
400	LSIIAICLGSLGLILIILLSVVVWKLL	Leucine/isoleucine
		zipper
401	GPP(GPP)n, where n ≥ 0	Collagen-like
		peptide
402	EYFTLQIRGRERFEMFRELNEALELKDAQAG	p53
		tetramerization
		domain
403	MAEAGITGTWYNQLGSTFIVTAGADGALTGTYESAVGNAEGDYVLTGRY	Streptavidin (SA)
	DSAPATDGSGTALGWTVAWKNNYRNAHSATTWSGQYVGGAEARINTQW
	LLTSGTTEANAWKSTLVGHDTFTKVKPSAAS
404	GYIPEAPRDGQAYVRKDGEWVLLSTFL	T4 fibritin
405	GPQMLRELGETNAALQDVRELLRQQVREITFLKNTVMECDAC	COMP (cartilage
		oligomeric matrix
		protein)
406	PPKVSVFVPPRDGFFGNPRKSKLICQATGFSPRQIQVSWLREGKQVGSGVTT	Immunoglobulin
	DQVQAEAKESGPTTYKVTSTLTIKESDWLSQSMFTCRVDHRGLTFQQNASS	Fc
	MCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSVTISWTRQNGE	(CH2CH3CH4)
	AVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQT
	ISRPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQR
	GQPLSPEKYVTSAPMPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEA
	LPNRVTERTVDKSTGKPTLYNVSLVMSDTAGTCY
407	HHHHH	5H
408	KKKGKKK	7X-1
409	KKAHHGKKAHHV	12X-7
410	KKARRGKKARRV	12X-8
411	KLIHKKARVRGK	12x-9
412	ILRRKAHHGKIKKVR	15X-1
413	GHRVKKAVRHIKRL	15X-2
414	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG heavy
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	chain (HC)
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSTCPPCPAPELLGGPSVFLFPPK
	PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
	NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP
	QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
	LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
415	ASWDDSLNG	HA2 LC-CDR3
416	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-5H
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSTCPPCPAPELLGGPSVFLFPPK	fused to 5H)
	PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
	NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP
	QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
	LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
	HHHHH
417	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-7X-1
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSTCPPCPAPELLGGPSVFLFPPK	fused to
	PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY	KKKGKKK)
	NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP
	QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
	LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
	KKKGKKK
418	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-12X-7
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSTCPPCPAPELLGGPSVFLFPPK	fused to
	PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY	KKAHHGKKAH
	NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP	HV)
	QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
	LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
	KKAHHGKKAHHV
419	QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYAMHWVRQAPGKGLEWVA	HA1-hIgG-12X-8
	VISYDANYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD	(HA1-IgG HC
	SQLRSLLYFEWLSQGYFDYWGQGTLVTVSSTCPPCPAPELLGGPSVFLFPPK	fused to
	PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY	KKARRGKKAR
	NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP	RV)
	QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
	LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
	KKARRGKKARRV
420	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG heavy
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	chain (HC)
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
421	AGSGIIISDTPVHDCNTTCQTPKGAINTSLPFQNIHPITIGKCPKYVKSTKLRL	H1 (H1N1
	ATGLRNVPSIQSRGLFGAIAGFIEGGWTGMVDGWYGYHHQNEQGSGYAA	A/Tottori/YK041/
	DLKSTQNAIDKITNKVNSVIEKMNTQFTAVGKEFNHLEKRIENLNKKVDDG	2011)
	FLDIWTYNAELLVLLENERTLDYHDSNVKNLYEKVRNQLKNNAKEIGNGC	AB745403.1
	FEFYHKCDNTCMESVKNGTYDYPKYSEEAKLNREEIDGVKLESTRIYQIL
422	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG-5H
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(HA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 5H)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHH
	H
423	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG-7X-1
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(HA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	KKKGKKK)
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKKG
	KKK
424	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG-12X-7
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(HA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	KKAHHGKKAH
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL	HV)
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKAH
	HGKKAHHV
425	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	HA2-hIgG-12X-8
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(HA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	KKARRGKKAR
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL	RV)
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKAR
	RGKKARRV
426	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG heavy
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	chain (HC)
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC
	NVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
	PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV
	LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
	ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
	SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
427	RTGKSSIMRSDAPIGTCSSECITPNGSIPNDKPFQNVNKITYGACPKYVKQNT	H3N2A/
	LKLATGMRNVPEKQTRGIFGAIAGFIENGWEGMIDGWYGFRHQNSEGTGQ	Victoria/3/1975
	AADLKSTQAAIDQINGKLNRVIEKTNEKFHQIEKEFSEVEGRIQDLEKYVED	4O58
	TKIDLWSYNAELLVALENQHTIDLTDSEMNKLFEKTRRQLRENAEDMGNG
	CFKIYHKCDNACIGSIRNGTYDHDVYRDEALNNRFQIKGVELKSGYKDWI
428	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG-5H
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	(NA1-IgG HC
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD	fused to 5H)
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC
	NVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
	PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV
	LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
	ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
	SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHHH
429	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG-7X-1
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	(NA1-IgG HC
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD	fused to
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC	KKKGKKK)
	NVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
	PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV
	LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
	ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
	SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKKGKKK
430	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG-12X-7
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	(NA1-IgG HC
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD	fused to
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC	KKAHHGKKAH
	NVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT	HV)
	PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV
	LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
	ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
	SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKAHHGKKA
	HHV
431	QVQLQESGPGLVRPSETLSLTCTVSGDSIGGSYWNWIRQPPGKGLQWIGYI	NA1-hIgG-12X-8
	YYTGITNYNPSLKSRVTMSLDTSKNQISLKMDSVTAADTALYFCARGDYS	(NA1-IgG HC
	GYDRDVQVELMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKD	fused to
	YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC	KKARRGKKAR
	NVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT	RV)
	PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV
	LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD
	ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
	SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKARRGKKA
	RRV
432	EVQLVQSGAEVKKPGSSVKVSCKASGYTFINHALSWVRQAPGQGLEWVG	NA2-hIgG heavy
	GIIPIFGLAKYGQKFQDRVTITADESTKTAYMDLRSLRSDDTAVYYCARDT	chain (HC)
	VAVYEDFDWSSPYFFYMDVWGKGTTVTVSSSVFPLAPSSKSTSGGTAALG
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
433	RTGKSSIMRSDAPIGTCSSECITPNGSIPNDKPFQNVNKITYGACPKYVKQNT	H3 (H3N2A/
	LKLATGMRNVPEKQTRGIFGAIAGFIENGWEGMIDGWYGFRHQNSEGTGQ	Victoria/3/1975)
	AADLKSTQAAIDQINGKLNRVIEKTNEKFHQIEKEFSEVEGRIQDLEKYVED	4O58_A
	TKIDLWSYNAELLVALENQHTIDLTDSEMNKLFEKTRRQLRENAEDMGNG
	CFKIYHKCDNACIGSIRNGTYDHDVYRDEALNNRFQIKGVELKSGYKDWI
434	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	NA2-hIgG-5H
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(NA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to 5H)
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHH
	H
435	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	NA2-hIgG-7X-1
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(NA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	KKKGKKK)
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKKG
	KKK
436	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	NA2-hIgG-12X-7
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(NA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	KKAHHGKKAH
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL	HV)
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKAH
	HGKKAHHV
437	EVQLVESGAEVKKPGSSVKVSCRASGTFYKYAINWVRQAPGQGLEWMGG	NA2-hIgG-12X-8
	IIPFFGTTNYAQKFQGRLTITADGSTNTAYMQLDSLRSEDTAVYYCAGPSIT	(NA2-IgG HC
	ESHYCLDCAAKDYYYGLDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALG	fused to
	CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT	KKARRGKKAR
	QTYICNVNHKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTL	RV)
	MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
	RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
	LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
	GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKAR
	RGKKARRV
438	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15 VH
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN
	YYYYSGMDVWGQGTTVTVSS
439	GGTSNNYA	HA15 HC-CDR1
440	ISPIFGST	HA15 HC-CDR2
441	ARHGNYYYYSGMDV	HA15 HC-CDR3
442	QSALTQPPAVSGTPGQRVTISCSGSDSNIGRRSVNWYQQFPGTAPKLLIYSN	HA15 VL
	DQRPSVVPDRFSGSKSGTSASLAISGLQSEDEAEYYCAAWDDSLKGAVFGG
	GTQLTVL
443	DSNIGRRS	HA15 LC-CDR1
444	STIMKSELEYGNCNTKCQTPMGAINSSMPFHNIHPLTIGECPKYVKSNRLVL	H5 (H5N1A/
	ATGLRNTPQRERRRKKRGLFGAIAGFIEGGWQGMVDGWYGYHHSNEQGS	Hong
	GYAADKESTQKAIDGVTNKVNSIINKMNTQFEAVGREFNNLERRIENLNKK	Kong/156/97)
	MEDGFLDVWTYNAELLVLMENERTLDFHDSNVKNLYDKVRLQLRDNAK	Q56140
	ELGNGCFEFYHKCDNECMESVKNGTYDYPQYSEEARLNREEISGVKLESM
	GTYQIL
445	AAWDDSLKGAV	HA15 LC-CDR3
446	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	heavy chain (HC)
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
447	QSALTQPPAVSGTPGQRVTISCSGSDSNIGRRSVNWYQQFPGTAPKLLIYSN	HA15-hIgG
	DQRPSVVPDRFSGSKSGTSASLAISGLQSEDEAEYYCAAWDDSLKGAVFGG	light chain (LC)
	GTQLTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKA
	DGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGS
	TVEKTVAPTECS
448	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-5H
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to 5H)
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHHH
449	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-6H
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to 6H)
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHHHH
450	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-12H
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to 12H)
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHHHHHHHHHH
451	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-30H
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to 30H)
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHHHHHHHHHHH
	HHHHHHHHHHHHHHHHH
452	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-6K
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to 6K)
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKKKKK
453	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-12K
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to 12K)
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSKKKKKKKKKK
	KKK
454	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-30K
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to 30K)
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKKKKKKKKKKKK
	KKKKKKKKKKKKKKKKK
455	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-6R
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to 6R)
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKRRRRRR
456	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-12R
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to 12R)
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKRRRRRRRRRRRR
457	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-30R
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to 30R)
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKRRRRRRRRRRRRRR
	RRRRRRRRRRRRRRRR
458	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-6O
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to 6O)
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKOOOOOO
459	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-12O
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to 12O)
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKOOOOOOOOOOOO
460	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-30O
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to 30O)
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKOOOOOOOOOOOOO
	OOOOOOOOOOOOOOOOO
461	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-6X-1
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	HHKKOO)
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHKKOO
462	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-6X-2
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	HORKHR)
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHQRKHR
463	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-6X-3
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	HKRSOH)
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHKRSOH
464	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-6X-4
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	RRHTHR)
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKRRHTHR
465	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-6X-5
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	KKHHRR)
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKHHRR
466	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-6X-6
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	OORRHH)
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKOORRHH
467	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-6X-7
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	KKOORR)
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKOORR
468	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-7X-1
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	(HA15-IgG HC
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	fused to
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	KKKGKKK)
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKKGKKK
469	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-12X-
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	1
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	(HA15-IgG HC
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	fused to
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC	HHHKKKRRRO
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH	OO)
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHHKKKRRROOO
470	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hlgG-12X-
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	2
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	(HA15-IgG HC
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	fused to
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC	HHQAKKRCOO
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH	QH)
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHHQAKKRCOOQH
471	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-12X-
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	3
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	(HA15-IgG HC
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	fused to
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC	HRKOORKHHR
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH	KK)
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHRKQQRKHHRKK
472	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-12X-
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	4
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	(HA15-IgG HC
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	fused to
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC	KRAHOKCORKS
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH	H)
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKRAHOKOQRKSH
473	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-12X-
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	5
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	(HA15-IgG HC
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	fused to
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC	KKRROOHHHR
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH	RR)
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKRROOHHHRRR
474	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-12X-
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	6
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	(HA15-IgG HC
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	fused to
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC	OOORRRKKKH
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH	HH)
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKOOORRRKKKHHH
475	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-12X-
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	7
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	HA15 IgG HC
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	fused to
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC	KKAHHGKKAH
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH	HV
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKAHHGKKAHHV
476	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hlgG-12X-
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	8
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	(HA15-IgG HC
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	fused to
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC	KKARRGKKAR
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH	RV)
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKARRGKKARRV
477	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-30X-
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	1
	YYYYSGMDVWGQGTTVTVSSASVFPLAPSSKSTSGGTAALGCLVKDYFPE	(HA15-IgG HC
	PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN	fused to
	HKPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV	HKROHKROHK
	TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV	ROHKROHKRO
	LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT	HKROHKROHK)
	KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL
	TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKHKROHKROHKR
	OHKROHKROHKROHKROHK
478	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-30X-
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	2
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	(HA15-IgG HC
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	fused to
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC	KOHRSOKRHTO
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH	RHKAHORKCK
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN	ROKORKHOS)
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKOHRSOKRHTORHK
	AHORKCKROKORKHOS
479	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-30X-
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	3
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	(HA15-IgG HC
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	fused to
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC	KKROSRRHOTO
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH	OHHAROKHCK
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN	HROTRHKKS)
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKKKROSRRHOTOOHH
	AROKHCKHROTRHKKS
480	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-30X-
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	4
	YYYYSGMDVWGQGTTVTVSSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV	(HA15-IgG HC
	TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK	fused to
	PSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV	HRKQOHRSOO
	VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ	KTRRRAHROCH
	DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ	HHSRHOTHR)
	VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD
	KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHRKQOHRSOOKTRRR
	AHROCHHHSRHOTHR
481	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-35X-
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	1
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	(HA15-IgG HC
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	fused to
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC	GRHKAKNHIRR
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH	PKSRWKKWHK
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN	YRKVHRHKVH
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV	KGRR)
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGRHKAKNHIRRPKSR
	WKKWHKYRKVHRHKVHKGRR
482	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-40X-
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	2
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	(HA15-IgG HC
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	fused to
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC	WRKVHHYKKQ
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH	HKNRAHGKLK
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN	LRAKIHQRSRM
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV	HGKQKHYHR)
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKWRKVHHYKKQHKN
	RAHGKLKLRAKIHQRSRMHGKQKHYHR
483	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-42X-
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	1
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	(HA15-IgG HC
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	fused to
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC	AHHKCRRGHK
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH	QKILHRRPHKF
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN	HRWKRVHKGR
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV	HGKKHRRHKH
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKAHHKCRRGHKQKIL	R)
	HRRPHKFHRWKRVHKGRHGKKHRRHKHR
484	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-45X-
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	1
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	(HA15-IgG HC
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	fused to
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC	QHRGKAKYHR
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH	THHVKKQRHG
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN	RKNHKVHRHA
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV	RKFHKIRRLKC
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKQHRGKAKYHRTHHV	HKKH)
	KKQRHGRKNHKVHRHARKFHKIRRLKCHKKH
485	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-50X-
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	1
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	HA15-IgG HC
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	fused to
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC	HNKRFKKGRH
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH	VRHSRHKSHRR
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN	THKYHHWRHY
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV	RKVHRCKKAH
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHNKRFKKGRHVRHS	KSHHRVHHK)
	RHKSHRRTHKYHHWRHYRKVHRCKKAHKSHHRVHHK
486	QVQLVQSGAEVKKPGSSVKVSCKSSGGTSNNYAISWVRQAPGQGLDWMG	HA15-hIgG-50X-
	GISPIFGSTAYAQKFQGRVTISADIFSNTAYMELNSLTSEDTAVYFCARHGN	2
	YYYYSGMDVWGQGTTVTVSSSVFPLAPSSKSTSGGTAALGCLVKDYFPEP	(HA15-IgG HC
	VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNH	fused to
	KPSNTKVDKRVEPKSCTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC	AHGRPHOFKRO
	VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH	CKAHOVKHILK
	QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN	RTOSHOYKOVH
	QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV	QRNKOAOKMR
	DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKAHGRPHOFKROCKA	KIRGGHK)
	HOVKHILKRTOSHOYKOVHORNKOAOKMRKIRGGHK
487	QVQLLETGGGLVKPGQSLKLSCAASGFTFTSYAMHWVRQPPGKGLEWVA	HA16-IgG VH
	VVSYDGNYKYYADSVQGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK
	DSRLRSLLYFEWLSQGYFNPWGQGTTLTVSS
488	SYAMH	HA16-IgG HC-
		CDR1
489	VVSYDGNYKYYADSVQG	HA16-IgG HC-
		CDR2
490	DSRLRSLLYFEWLSQGYFNP	HA16-IgG HC-
		CDR3
491	DIQMTQSPSSLSASVGDRVTITCRSSQSITFDYKNYLAWYQQKPGKAPKLLI	HA16-IgG VL
	YWGSYLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHYRTPPSFGQ
	GTKVEIK
492	WGSYLES	HA16-IgG LC-
		CDR1
493	QQHYRTPPS	HA16-IgG LC-
		CDR2
494	QSITFDYKNYLA	HA16-IgG LC-
		CDR3
495	LSGESHGRILKTDLNSGNCVVQCQTEKGGLNSTLPFHNISKYAFGDCPKYIG	H7 (H9N2A/
	VKSLKLAIGLRNVPARSSRGLFGAIAGFIEGGWPGLVAGWYGFQHSNDQG	Egypt/ZU65/
	VGMAADRDSTQKAVDKITSKVNNIVDKMNKQYEIIDHEFSEVETRLNMIN	2016)
	NKIDDQIQDVWAYNAELLVLLENQKTLDEHDANVNNLYNKVKRALGSNA	ARM59253
	MEDGKGCFELYHKCDDQCMETIRNGTYNRRKYMEESRLGRQKIEGVKLES
	EGTYKIL
496	STIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITEENVQNMNNAGDK	ACE740
	WSAFLKEQSTLAQMYPLQEIQNLTVKLQLQALQQNGSSVLSEDKSKRLNTI	aa 19-740 of full-
	LNTMSTIYSTGKVCNPDNPQECLLLEPGLNEIMANSLDYNERLWAWESWR	length human
	SEVGKQLRPLYEEYVVLKNEMARANHYEDYGDYWRGDYEVNGVDGYDY	ACE2 protein
	SRGQLIEDVEHTFEEIKPLYEHLHAYVRAKLMNAYPSYISPIGCLPAHLLGD
	MWGRFWTNLYSLTVPFGQKPNIDVTDAMVDQAWDAQRIFKEAEKFFVSV
	GLPNMTQGFWENSMLTDPGNVQKAVCHPTAWDLGKGDFRILMCTKVTM
	DDFLTAHHEMGHIQYDMAYAAQPFLLRNGANEGFHEAVGEIMSLSAATPK
	HLKSIGLLSPDFQEDNETEINFLLKQALTIVGTLPFTYMLEKWRWMVFKGEI
	PKDQWMKKWWEMKREIVGVVEPVPHDETYCDPASLFHVSNDYSFIRYYT
	RTLYQFQFQEALCQAAKHEGPLHKCDISNSTEAGQKLFNMLRLGKSEPWT
	LALENVVGAKNMNVRPLLNYFEPLFTWLKDQNKNSFVGWSTDWSPYADQ
	SIKVRISLKSALGDKAYEWNDNEMYLFRSSVAYAMRQYFLKVKNQMILFG
	EEDVRVANLKPRISFNFFVTAPKNVSDIIPRTEVEKAIRMSRSRINDAFRLND
	NSLEFLGIQPTLGPPNQPPVS

Claims

1. A chimeric protein comprising: (a) an antibody moiety that specifically binds to a component of an influenza virus or a variant thereof; and(b) a mucoadhesive peptide fragment comprising at least about 5 positively charged amino acid residues, wherein the mucoadhesive peptide fragment facilitates attachment of the chimeric protein to a mucosa.

2. The chimeric protein of claim 1, comprising: (i) a single polypeptide chain; or(ii) two or more polypeptide, wherein the chimeric protein comprises two or more mucoadhesive peptide fragments, optionally wherein each of the two or more mucoadhesive peptide fragments comprises at least about 5 positively charged amino acid residues.

3. The chimeric protein of claim 1 or 2, wherein the mucoadhesive peptide fragment comprises at least about 6 positively charged amino acid residues.

4. The chimeric protein of any one of claims 1-3, wherein the positively charged amino acid residues are selected from the group consisting of lysine, arginine, histidine, ornithine, and combinations thereof.

5. The chimeric protein of claim 4, wherein the positively charged amino acid residues comprise lysines or histidines.

6. The chimeric protein of claim 5, wherein the mucoadhesive peptide fragment comprises about 5, about 6, about 12, or about 30 lysines or histidines.

7. The chimeric protein of any one of claims 1-6, wherein the mucoadheive peptide fragment comprises at least 5 contiguous positively charged amino acids.

8. The chimeric protein of any one of claims 1-7, wherein the positively charged amino acid residues are interspersed with one or more non-positively charged amino acid residues, optionally wherein at least about 50% of the amino acid residues in the mucoadhesive peptide fragment are positively charged amino acid residues.

9. The chimeric protein of any one of claims 1-8, wherein the mucoadhesive peptide fragment is no more than about 15 kD.

10. The chimeric protein of any one of claims 1-9, wherein the mucoadhesive peptide fragment has an isoelectric point (pI) higher than the pH of the mucosa.

11. The chimeric protein of any one of claims 1-10, wherein: (i) the mucoadhesive peptide fragment does not facilitate penetration of the chimeric protein into a cell of the mucosa;(ii) does not disrupt folding of the chimeric protein within a host cell expressing the chimeric protein;(ii) does not block secretion of the chimeric protein from a host cell expressing the chimeric protein; and/or(iv) does not interfere with the binding between the antibody moiety and the component of the influenza virus or variant thereof.

12. The chimeric protein of any one of claims 1-11, wherein the mucoadhesive peptide fragment comprises an amino acid sequence of any one of SEQ ID NOs: 291-325 and 407-413, or variants thereof comprising up to about 3 amino acid substitutions.

13. The chimeric protein of any one of claims 1-12, wherein the mucoadhesive peptide fragment is fused to the antibody moiety via a peptide linker.

14. The chimeric protein of claim 13, wherein the peptide linker comprises: (i) one or more oligomerization and/or multimerization domains;(ii) the constant region of a heavy chain of a full-length antibody or a fragment thereof, or the constant region of a light chain of a full-length antibody or a fragment thereof;(iii) an Fc region or a fragment thereof;(iv) a CH1, CH2, CH3, CH4, and/or CL domain or a fragment thereof;(v) an antibody hinge domain or a fragment thereof;(vi) a detectable enzymatic tag, optionally wherein the enzymatic tag is an alkaline phosphatase and/or a glutathione-s-transferase;(vii) a basic helix-loop-helix leucine zipper (bZIP) domain, bZIP isoleucine zipper domain, and/or bZIP-leucine/isoleucine zipper domain;(viii) a collagen-like peptide;(ix) a p53 tetramerization domain;(x) a streptavidin (SA) protein, optionally wherein the peptide linker further comprises a dextran scaffold or one or more maleimide polymers (DMGS);(xi) a bacteriophage T7 fibritin protein or a portion thereof; and/or(xii) a cartilage oligomeric matrix protein (COMP) protein.

15. The chimeric protein of any one of claims 1-14, wherein the antibody moiety: (i) is a full-length antibody, optionally wherein the antibody moiety is selected from the group consisting of an IgG, an IgA, an IgM, and an IgD;(ii) is an antigen-binding fragment selected from the group consisting of a Fab, a Fab′, a (Fab′)2, an Fv, a single chain Fv (scFv), an scFv-Fc, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, an scFv dimer, a domain antibody, a camelized single domain antibody, a bivalent domain antibody, a minibody, and a VHH; and/or(iii) is animal, human, humanized, camelid, or chimeric.

16. The chimeric protein of any one of claims 1-15, wherein the antibody moiety is a full-length antibody, and wherein: (i) the mucoadhesive peptide fragment is fused to the C-terminus of a heavy chain of the full-length antibody via a first optional peptide linker; and/or(ii) the mucoadhesive peptide fragment is fused to the C-terminus of a light chain of the full-length antibody via a second optional peptide linker.

17. The chimeric protein of claim 16, wherein the chimeric protein comprises: (i) a first and a second polypeptide chain each comprising from the N-terminus to the C-terminus: the heavy chain of the full-length antibody, the first optional peptide linker, and the mucoadhesive peptide fragment; and(ii) a third and a fourth polypeptide chain each comprising the light chain of the full-length antibody.

18. The chimeric protein of any one of claims 1-17, wherein the influenza virus is a Type A influenza virus (IAV), a Type B influenza virus (IBV), a Type C influenza virus (ICV), a Type D influenza virus (IDV), or a variant, subtype, or reassortant thereof.

19. The chimeric protein of any one of claims 1-18, wherein the influenza virus comprises an hemagglutinin (HA) antigen selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof.

20. The chimeric protein of any one of claims 1-19, wherein the influenza virus comprises an neuraminidase (NA) antigen selected from the group consisting of N1, N2, N3, N7, N8, and N9, or a variant or reassortant thereof.

21. The chimeric protein of any one of claims 1-20, wherein the influenza virus is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof.

22. The chimeric protein of any one of claims 1-21, wherein the component of the influenza virus or variant thereof is a viral surface protein or fragment thereof.

23. The chimeric protein of claim 22, wherein the viral surface protein is HA.

24. The chimeric protein of claim 23, wherein the chimeric protein comprises: (i) a heavy chain complementarity determining region (HC-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region (LC-CDR) 1 comprising the amino acid sequence of SEQ ID NO: 4, an LC-CDR2 comprising the amino acid sequence of WAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 6;(ii) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 235, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 238, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 415;(iii) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 439, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 440, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 441, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 443, an LC-CDR2 comprising the amino acid sequence of SND, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 445;(iv) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 76, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 76, and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 77, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 77;(v) a VH comprising the amino acid sequence of SEQ ID NO: 78, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 78, and a VL comprising the amino acid sequence of SEQ ID NO: 79, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 79;(vi) a VH comprising the amino acid sequence of SEQ ID NO: 438, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 438, and a VL comprising the amino acid sequence of SEQ ID NO: 442, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 443;(vii) a heavy chain (HC) polypeptide comprising the amino acid sequence of SEQ ID NO: 414, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 414, and a light chain (LC) polypeptide comprising the amino acid sequence of SEQ ID NO: 217, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 217;(viii) an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 420, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 420, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 244, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 244;(ix) an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 446, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 446, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 447, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 447;(x) a first and a second polypeptide chain each independently comprising the amino acid sequence of any one of SEQ ID NOs: 216, 218-234, 236, 237, 239-242, and 416-149, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 216, 218-234, 236, 237, 239-242, and 416-149, and a third and a fourth polypeptide chain each independently comprising the amino acid sequence of SEQ ID NO: 217, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 217;(xi) a first and a second polypeptide chain each independently comprising the amino acid sequence of any one of SEQ ID NOs: 243, 245-258, and 422-425, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 243, 245-258, and 422-425, and a third and a fourth polypeptide chain each independently comprising the amino acid sequence of SEQ ID NO: 244, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 244; or(xii) a first and a second polypeptide chain each independently comprising the amino acid sequence of any one of SEQ ID NOs: 448-468, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 448-468, and a third and a fourth polypeptide chain each independently comprising the amino acid sequence of SEQ ID NO: 447, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 447.

25. The chimeric protein of claim 24, wherein the component of the viral surface protein is NA.

26. The chimeric protein of claim 25, wherein the chimeric protein comprises: (i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 104, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 105, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 106, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 107, an LC-CDR2 comprising the amino acid sequence of AAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 109;(ii) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 110, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 111, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 112, an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 113, an LC-CDR2 comprising the amino acid sequence of GAS, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 115;(iii) a VH comprising the amino acid sequence of SEQ ID NO: 188, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 188, and a VL comprising the amino acid sequence of SEQ ID NO: 189, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 189;(iv) a VH comprising the amino acid sequence of SEQ ID NO: 190, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 190, and a VL comprising the amino acid sequence of SEQ ID NO: 191, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 191;(v) an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 426, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 426, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 260, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 260;(vi) an HC polypeptide comprising the amino acid sequence of SEQ ID NO: 432, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 432, and an LC polypeptide comprising the amino acid sequence of SEQ ID NO: 276, or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 276;(vii) a first and a second polypeptide chain each independently comprising the amino acid sequence of any one of SEQ ID NOs: 259, 261-274, and 428-431, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 259, 261-274, and 428-431, and a third and a fourth polypeptide chains each independently comprising the amino acid sequence of SEQ ID NO: 260, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 260; or(viii) a first and a second polypeptide chain each independently comprising the amino acid sequence of any one of SEQ ID NOs: 275, 277-290, and 435-437, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 275, 277-290, and 434-437, and a third and a fourth polypeptide chains each independently comprising the amino acid sequence of SEQ ID NO: 276, or a variant thereof comprising at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 276.

27. A pharmaceutical composition comprising the chimeric protein of any one of claims 1-26, and a pharmaceutically acceptable carrier.

28. The pharmaceutical composition of claim 27, wherein the pharmaceutical composition comprises a plurality of the chimeric proteins, and wherein at least two of the plurality of the chimeric proteins are different from each other.

29. The pharmaceutical composition of claim 27 or 28, wherein the pharmaceutical composition is formulated for intranasal administration, intraocular administration, and/or intrabronchial administration.

30. An isolated nucleic acid or a set of isolated nucleic acids encoding the chimeric protein of any one of claims 1-26.

31. A vector or a set of vectors comprising the nucleic acid or the set of nucleic acids of claim 30.

32. A host cell comprising the chimeric protein of any one of claims 1-26, the nucleic acid or set of nucleic acids of claim 30, the vector or set of vectors of claim 31.

33. A method of preparing a chimeric protein, comprising: (a) culturing a host cell of claim 32 under a condition effective to express the chimeric protein; and(b) obtaining the expressed chimeric protein from the host cell.

34. A method of preventing or treating an infection caused by an influenza virus or a variant thereof in an individual, comprising administering to the individual an effective amount of the chimeric protein of any one of claims 1-26, or the pharmaceutical composition of any one of claims 27-29.

35. A method of killing or neutralizing a virus in an individual, comprising administering to the individual an effective amount of the chimeric protein of any one of claims 1-26, or the pharmaceutical composition of any one of claims 27-29.

36. A method of activating the complement pathway in an individual, comprising administering to the individual an effective amount of the chimeric protein of any one of claims 1-26, or the pharmaceutical composition of any one of claims 27-29.

37. The method of claim 35 or 36, wherein at least one virus is killed or neutralized on the mucosa.

38. A method of preventing, treating, or reducing infection caused by a virus in an individual, comprising administering to the individual an effective amount of the chimeric protein of any one of claims 1-26, or the pharmaceutical composition of any one of claims 27-29, wherein at least one virus is killed or neutralized on the mucosa.

39. The method of any one of claims 35-38, wherein: (i) the chimeric protein activates the complement pathway in the individual; and/or(ii) the killing or neutralization is via activation of the complement pathway.

40. The method of any one of claims 35-39, wherein the virus is an influenza virus, optionally wherein the influenza virus is selected from the group consisting of a Type A influenza virus (IAV), a Type B influenza virus (IBV), a Type C influenza virus (ICV), a Type D influenza virus (IDV), or a variant, subtype, or reassortant thereof.

41. The method of claim 40, wherein the influenza virus: (i) comprises an HA antigen selected from the group consisting of H1, H2, H3, H5, H6, H7, H9, and H10, or a variant or reassortant thereof;(ii) comprises an NA antigen selected from the group consisting of N1, N2, N3, N7, N8, and N9, or a variant or reassortant thereof; and/or(iii) is selected from the group consisting of H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N9, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, or a variant or reassortant thereof.