ARTIFICIAL SYNAPSES

Abstract
Described herein are compositions and techniques related to generation and therapeutic application of artificial synapses. Artificial synapses are engineered extracellular vesicles, including exosomes, which incorporate sticky binders on their surface to anchor signaling domains against biological targets, such as receptors. These engineered additives can be organized in genetic vector constructs, expressed in mammalian cells, wherein the sticky binders attach to extracellular vesicles such as exosomes, thereby presenting their joined signaling domains which are rapidly taken up by recipient cells. Artificial synapses adopt the hallmark biophysical and biochemical features of extracellular vesicles, allowing for rapid deployment and scale-up. Importantly, this strategy can allow for kinetically favorable signal generation and signal propagation. This includes, for example, increasing density of agonist presentation to support receptor clustering—an onerous barrier for traditional receptor targeting strategies.
Description
REFERENCE TO SEQUENCE LISTING

This application contains a sequence listing submitted as an electronic xml file named, “085172-000001USD1_ST.26” created on Nov. 9, 2022 and having a size in bytes of 724,326 bytes. The information contained in this electronic file is hereby incorporated by reference in its entirety.


FIELD OF THE INVENTION

This invention relates to the generation of artificial synapses or extracellular vesicles, including features of extracellular vesicles engineered to deliver signaling, for therapeutic use, including treatment of immune diseases and cancer.


BACKGROUND

Extracellular vesicles (EVs) play a critical role in intercellular communication by transferring microRNAs, lipids, and proteins to neighboring cells. The delivery of encapsulated molecules within EVs is a highly promising strategy as a therapeutic platform in many contexts, exploiting the unique biophysical and biochemical characteristics of extracellular vesicles (EVs). However, there remains a great need in the art for a flexible and dynamic platform, where specific biological signals can be reliably targeted without off-target effects and that provide a robust cellular response to achieve a therapeutic effect, such as modulating inflammation.


SUMMARY

The compositions and methods provided herein are based, in part, on the discovery that extracellular vesicles can be used to express engineered fusion polypeptides that can modulate biological signal generation. These engineered vesicles, also termed artificial synapses, adopt the hallmark biophysical and biochemical features of extracellular vesicles, but are further engineered with vesicle targeting domains (e.g., sticky binders) and signaling domains, optionally joined by a linker with specific functions. The fusion polypeptides provided herein are designed and produced as nucleic acid constructs (e.g., vectors) and expressed in cells, such as mammalian cells. In particular, the vesicle targeting domain of each fusion polypeptide anchors the polypeptide to the extracellular vesicle lipid membrane, thereby presenting the signaling domain(s) of the polypeptide. The signaling domains on or within the vesicle membrane can make contact with recipient cells via target polypeptides (e.g., receptors on the extracellular surface of the recipient cell). Importantly, this strategy can allow for kinetically favorable signal generation and signal propagation. This includes, for example, increasing density of agonist presentation to support receptor clustering of a target receptor located on a target cell—an onerous barrier for traditional receptor targeting strategies.


This strategy was applied to alter immune checkpoint signaling, by engineering artificial synapses through genetic constructs with lipid binding glycosylphosphatidylinositol (GPI) sticky binders joined with programmed death-ligand 1 (PD-L1) signaling domain, e.g., human programmed death-ligand 1 (hPD-L1), expressed in cells and capable of attachment to exosomes. Isolation, purification, and analysis of artificial synapses revealed a high density of signaling domains of the hPD-L1-GPI fusion polypeptide. The hPD-L1 artificial synapse exosomes further demonstrated enhanced agonist signaling than soluble PD-L1 ligand alone, supporting receptor clustering on a target cell. When applied to a model of experimental autoimmune uveoretinitis (EAU), a statistically significant reduction in EAU symptoms was observed.


Thus, in one aspect, provided herein is an engineered extracellular vesicle or artificial vesicle comprising: at least one fusion polypeptide comprising: at least one protein of interest (POI) domain; and at least one vesicle targeting domain. In some embodiments of any of the aspects, the engineered extracellular vesicle is an exosome. In some embodiments, of any of the aspects, the fusion protein further comprises at least one linker. In some embodiments of any of the aspects, the POI domain can substantially bind to a target polypeptide.


In another aspect, provided herein is an engineered extracellular vesicle comprising: at least one fusion polypeptide comprising:

    • (i) at least one protein of interest (POI) domain or a fragment thereof; and
    • (ii) at least one vesicle targeting domain,
    • wherein the POI domain is in an extracellular position relative to a lipid membrane of the extracellular vesicle.


In another aspect, provided herein is an engineered extracellular vesicle comprising:

    • (a) a first fusion polypeptide comprising:
      • (i) at least one protein of interest (POI) domain or a fragment thereof; and
      • (ii) at least one vesicle targeting domain,
    • wherein the at least one POI domain is in an extracellular position relative to a lipid membrane of the extracellular vesicle,
    • (b) a second fusion polypeptide comprising:
      • (i) at least one protein of interest (POI) domain or a fragment thereof; and
      • (ii) at least one vesicle targeting domain,


        wherein the POI domain is in an extracellular position relative to a lipid membrane of the extracellular vesicle,


        and wherein the at least one vesicle targeting domain is within a lipid membrane of the extracellular vesicle.


In another aspect, provided herein is an extracellular vesicle composition comprising: a plurality of artificial synapses,


wherein each artificial synapse comprises (i) an extracellular vesicle; (ii) one or more sticky binders; and (iii) one or more signaling domains.


In another aspect, provided herein is a composition comprising a plurality of the engineered extracellular vesicles provided herein.


In another aspect, provided herein is a composition comprising two or more of the engineered extracellular vesicles provided herein.


In another aspect, provided herein is a composition comprising three or more of the engineered extracellular vesicles provided herein.


In another aspect, provided herein is a method of producing the engineered extracellular vesicle or the compositions provided herein, comprising:

    • (a) providing a population of cells expressing a vector construct encoding one or more sticky binder and one or more signaling domains; and
    • (b) isolating a plurality of artificial synapses from the population of cells.


In another aspect, provided herein is a method of producing the engineered extracellular vesicle or the compositions provided herein, comprising:

    • (a) providing a population of cells expressing a vector construct encoding one or more sticky binder and one or more signaling domains; and
    • (b) isolating a plurality of artificial synapses from the population of cells; and
    • (c) purifying the plurality of artificial synapses from the population of cells.


In another aspect, provided herein is a method of modulating inflammation in a subject, the method comprising:

    • administering a composition comprising a plurality of engineered extracellular vesicles to a subject in need thereof,
    • wherein the engineered extracellular vesicles comprise at least one fusion polypeptide comprising:
      • (i) at least one protein of interest (POI) domain or a fragment thereof; and
      • (ii) at least one vesicle targeting domain.


In another aspect, provided herein is a use of a composition or engineered extracellular vesicle provided herein for the treatment of an inflammatory disease or condition.


In another aspect, provided herein is a use of a composition or engineered extracellular vesicle provided herein for the treatment of an autoimmune disease or condition.


In another aspect, provided herein is a use of a composition or engineered extracellular vesicle provided herein for the treatment of cancer.


In one embodiment of any of the aspects, the engineered extracellular vesicle is an exosome.


In another embodiment of any of the aspects, the protein of interest (POI) domain or a fragment thereof is a N-terminal domain of the fusion polypeptide. In another embodiment of any of the aspects, the POI domain is selected from the group consisting of: Table 1. In another embodiment of any of the aspects, the POI domain is PD-L1 or a fragment thereof. In another embodiment of any of the aspects, the POI domain is PD-L2 or a fragment thereof. In another embodiment of any of the aspects, the POI domain is FGL1 or a fragment thereof. In another embodiment of any of the aspects, the POI domain is 4-1BBL or a fragment thereof. In another embodiment of any of the aspects, the POI domain is CTLA-4 or a fragment thereof. In another embodiment of any of the aspects, the protein of interest (POI) domain is HVEM or a fragment thereof.


In another embodiment of any of the aspects, the vesicle targeting domain is a C-terminal domain of the fusion polypeptide. In another embodiment of any of the aspects, the vesicle targeting domain is in a luminal position relative to the lipid membrane of the extracellular vesicle. In another embodiment of any of the aspects, the vesicle targeting domain in an exterior position relative to the lipid membrane of the extracellular vesicle. In another embodiment of any of the aspects, the vesicle targeting domain is selected from the group consisting of: Table 3. In another embodiment of any of the aspects, the vesicle targeting domain is selected from the group consisting of: a Glycosylphosphatidylinositol (GPI) anchor, a fatty acylation site, and a prenylation site. In another embodiment of any of the aspects, the vesicle targeting domain is C1C2. In another embodiment of any of the aspects, the vesicle targeting domain is a GPI anchor.


In another embodiment of any of the aspects, the fusion polypeptide comprises at least two POI domains and/or at least two exosome targeting domains.


In another embodiment of any of the aspects, the POI domain substantially binds to one or more of a target polypeptide. In another embodiment of any of the aspects, the target polypeptide is selected from the group consisting of: Table 2.


In another embodiment of any of the aspects, the fusion polypeptide further comprises a peptide linker. In another embodiment of any of the aspects, the fusion polypeptide further comprises a fragment crystallizable region (Fc) domain. In another embodiment of any of the aspects, the linker is in an exterior position relative to the lipid membrane of the extracellular vesicle. In another embodiment of any of the aspects, the linker is a transmembrane linker. In another embodiment of any of the aspects, the linker is in a luminal position relative to the lipid membrane of the extracellular vesicle.


In another embodiment of any of the aspects, the engineered extracellular vesicle does not comprise an endogenous POI polypeptide.


In another embodiment of any of the aspects, the composition further comprises a pharmaceutically acceptable carrier.


In another embodiment of any of the aspects, the one or more sticky binders or the vesicle targeting domain is selected from the group consisting of: a GPI anchor, a fatty acylation site, and a prenylation site.


In another embodiment of any of the aspects, the signaling domain or the protein of interest comprises one or more of: PD-L1, PD-L2, CTLA-4 (CD152), 4-1BBL (CD137L), HVEM (CD270), FGL1, OX-2 (CD200), Galectin-9, PVR (CD155), Nectin-2 (CD112) isoform alpha, Nectin-2 (CD112) isoform beta, Nectin-2 (CD112) isoform delta, IL-10, TSG-6, B7-H3 (CD276), B7-H4 (VTCN1), B7-H5 (VISTA), B7-H7 (HHLA2), BTNL1, VSIG8, VSIG3 (IGSF11), VSIG4, TIM-3 (HAVCR2), TIM-4 (TIMD4), CEACAM1, BTN3A1, BTN3A2, BTN2A1, BTNL8, BTN2A2, BTN1A1, TIGIT, CD27L (CD70), CD30L (CD153), GITRL, CD40L (CD154), LIGHT (CD258), TL1, CD80, CD86, LFA-3 (CD58), SLAM (CD150), CD40, CD28, CD28H, CD2, LFA-3 (CD58), CD48, CD226, DR3, DcR3, FasL, TIM-1 (CD365), PD-1, or active fragment thereof.


In another embodiment of any of the aspects, the isolating is via size exclusion chromatography. In another embodiment of any of the aspects, the purifying is via multimodal chromatography. In another embodiment of any of the aspects, the method further comprises performing an assay for POI binding to a target polypeptide.


In another embodiment of any of the aspects, the vector construct further encodes a promoter. In another embodiment of any of the aspects, the promoter is a tissue-specific promoter or an inducible promotor.


In one embodiment of any of the aspects, the method further comprises selecting a subject that has or is suspected of having an autoimmune disease or an inflammatory disease or condition. In another embodiment of any of the aspects, the inflammatory disease and/or condition is acute. In another embodiment of any of the aspects, the inflammatory related disease and/or condition is chronic.


In another embodiment of any of the aspects, administering the composition provided herein comprises injection, topical administration, or inhalation.





A BRIEF DESCRIPTION OF THE DRAWINGS


FIG. 1 shows construct representation of fusion polypeptides for labeling an exosome surface with Type I membrane proteins.



FIGS. 2A-2B. FIG. 2A shows nucleic acid (SEQ ID NO: 199) and translated protein (SEQ ID NO: 200) sequences of full-length Phosphatidylserine binding: Lactadherin (MFGE8) C1C2. Underlined nucleic acid sequence highlights the sequence translated to the C1C2 protein. Bold and underlined text highlights the C1C2 domain used to anchor signaling domains of interest (i.e. PD-L1 extracellular domain) onto the surface of the Inventors' artificial synapses. FIG. 2B shows nucleic acid (SEQ ID NO: 196) and translated protein (SEQ ID NO: 197) sequences of full length CD55 (DAF) Glycosylphosphatidylinositol (GPI) anchor. Bold and underlined text highlights the GPI anchor domain used to anchor signaling domains of interest (i.e. PD-L1 extracellular domain) onto the surface of the Inventors' artificial synapses engineered from exosomes.



FIG. 3 demonstrates the nucleic acid (SEQ ID NO: 219) and translated protein (SEQ ID NO: 220) sequence for the Fc linker used in genetically engineered constructs is shown in bold and underlined.



FIGS. 4A-4C. FIG. 4A demonstrates nucleic acid (SEQ ID NO: 1) and translated protein (SEQ ID NO: 2) sequence of human PD-L1 (CD274). Bold and underlined sequence highlights the PD-L1 extracellular domain used in the Inventors' artificial synapses engineered from exosomes. FIG. 4B demonstrates nucleic acid (SEQ ID NO: 5) and protein (SEQ ID NO: 6) sequence of human PD-L2. Bold and underlined sequence highlights the PD-L2 extracellular domain used in the Inventors' artificial synapses engineered from exosomes. FIG. 4C shows nucleic acid (SEQ ID NO: 9) and protein (SEQ ID NO: 10) sequence of human CTLA-4 (CD152). Bold and underlined sequence highlights the CTLA-4 extracellular domain used in the Inventors' artificial synapses.



FIGS. 5A-5WW. FIG. 5A shows an exemplary embodiment of pcDNA5-FRT cloning vector with a gene sequence coding for a fusion polypeptide inserted into a multiple cloning site. FIG. 5B shows an exemplary embodiment of the Gateway® destination vector pEF5-FRT-V5-DEST with a gene sequence coding for a fusion polypeptide inserted into a multiple cloning site. The vectors were used for constitutive high-level expression of fusion polypeptide described herein in mammalian cells. FIG. 5C shows the nucleic acid (SEQ ID NO: 223) and protein (SEQ ID NO: 224) sequence for the hCTLA4-Fc-GPI fusion polypeptide wherein the text for the signaling domain is bolded, Fc linker is underlined, and sticky binder is italicized. FIG. 5D shows the nucleic acid (SEQ ID NO: 283) and protein (SEQ ID NO: 284) sequence for the hPDL1-GPI-P2A-hHVEM-GPI fusion polypeptide wherein the text for the signaling domain hPDL1 and hHVEM are bolded, P2A sequence is underlined, and sticky binder GPI is italicized. With P2A included, a self-cleaving peptide sequence, artificial synapses with this feature will have both hPDL1-GPI and hHVEM-GPI loaded onto the surface. FIG. 5E shows the nucleic acid (SEQ ID NO: 239) and protein (SEQ ID NO: 240) sequence for the hPDL1-GPI-P2A-hFGL1-GPI fusion polypeptide wherein the text for the signaling domain hPDL1 and hFGL1 are bolded, P2A sequence is underlined, and sticky binder GPI is italicized. With P2A included, a self-cleaving peptide sequence, artificial synapses with this feature will have both hPDL1-GPI and FGL1-GPI loaded onto the surface. FIG. 5F shows the nucleic acid (SEQ ID NO: 225) and protein (SEQ ID NO: 226) sequence for the hPDL1-GPI fusion polypeptide wherein the text for the signaling domain hPDL1 is bolded and sticky binder GPI is italicized. FIG. 5G shows the nucleic acid (SEQ ID NO: 229) and protein (SEQ ID NO: 230) sequence for the hPDL1-Fc-GPI fusion polypeptide wherein the text for the signaling domain hPDL1 is bolded, Fc is underlined, and sticky binder GPI is italicized. FIG. 5H shows the nucleic acid (SEQ ID NO: 233) and protein (SEQ ID NO: 234) sequence for the hPDL2-Fc-GPI fusion polypeptide wherein the text for the signaling domain hPDL2 is bolded, Fc is underlined, and sticky binder GPI is italicized. FIG. 5I shows the nucleic acid (SEQ ID NO: 227) and protein (SEQ ID NO: 228) sequence for the hPDL1-C1C2 fusion polypeptide wherein the text for the signaling domain hPDL1 is bolded and sticky binder C1C2 is italicized. FIG. 5J shows the nucleic acid (SEQ ID NO: 231) and protein (SEQ ID NO: 232) sequence for the hPDL2-C1C2 fusion polypeptide wherein the text for the signaling domain hPDL2 is bolded and sticky binder C1C2 is italicized. FIG. 5K shows the nucleic acid (SEQ ID NO: 235) and protein (SEQ ID NO: 236) sequence for the 4F2-h41BBL fusion polypeptide wherein the text for the signaling domain h41BBL is bolded and sticky binder 4F2 is italicized. FIG. 5L shows the nucleic acid (SEQ ID NO: 237) and protein (SEQ ID NO: 238) sequence for the hPDL1-4Fc-GPI fusion polypeptide wherein the text for the signaling domain hPDL1 is bolded, 4Fc is underlined, and sticky binder GPI is italicized. FIG. 5M shows the nucleic acid (SEQ ID NO: 243) and protein (SEQ ID NO: 244) sequence for the Myr-NanoLuc Luciferase fusion polypeptide wherein the text for the signaling domain NanoLuc Luciferase is bolded, and sticky binder Myr is italicized. FIG. 5N shows the nucleic acid (SEQ ID NO: 241) and protein (SEQ ID NO: 242) sequence for the Myr-mScarlet fusion polypeptide wherein the text for the signaling domain mScarlet is bolded, and sticky binder Myr is italicized. FIG. 5O shows the nucleic acid (SEQ ID NO: 245) and protein (SEQ ID NO: 246) sequence for the secreted isoform of hPDL1 (SecPDL1) fusion polypeptide hSecPDL1-GPI wherein the text for the signaling domain hSecPDL1 is bolded and sticky binder GPI is italicized. FIG. 5P shows the nucleic acid (SEQ ID NO: 247) and protein (SEQ ID NO: 248) sequence for the Tfr2-h41BBL fusion polypeptide wherein the text for the signaling domain h41BBL is bolded and sticky binder Tfr2 is italicized. FIG. 5Q shows the nucleic acid (SEQ ID NO: 249) and protein (SEQ ID NO: 250) sequence for the CD9tm3-h41BBL fusion polypeptide wherein the text for the signaling domain h41BBL is bolded and sticky binder CD9tm3 is italicized. FIG. 5R shows the nucleic acid (SEQ ID NO: 251) and protein (SEQ ID NO: 252) sequence for the Myr/Palm-4F2-h41BBL fusion polypeptide wherein the text for the signaling domain h41BBL is bolded, sticky binder Myr/Palm is underlined, and sticky binder 4F2 is italicized. FIG. 5S shows the nucleic acid (SEQ ID NO: 253) and protein (SEQ ID NO: 254) sequence for the Myr/Palm-Link-h41BBL fusion polypeptide wherein the text for the signaling domain h41BBL is bolded, sticky binder Myr/Palm is italicized and underlined, and sticky binder Link (in this embodiment a GSSG linker) is in regular text (not underlined and not italicized). FIG. 5T shows the nucleic acid (SEQ ID NO: 255) and protein (SEQ ID NO: 256) sequence for the hPDL1-Link-GPI fusion polypeptide wherein the text for the signaling domain hPDL1 is bolded, Link is underlined (in this embodiment a GSSG linker), and sticky binder GPI is italicized. FIG. 5U shows the nucleic acid (SEQ ID NO: 257) and protein (SEQ ID NO: 258) sequence for the secreted isoform of hPDL1 (SecPDL1) fusion polypeptide hSecPDL1-CD9tm2 wherein the text for the signaling domain hSecPDL1 is bolded and sticky binder CD9tm2 is italicized. FIG. 5V shows the nucleic acid (SEQ ID NO: 259) and protein (SEQ ID NO: 260) sequence for the secreted isoform of hPDL1 (SecPDL1) fusion polypeptide hSecPDL1-CD9tm2-KRAS wherein the text for the signaling domain hSecPDL1 is bolded, sticky binder CD9tm2 is italicized, and sticky binder KRAS is italicized and underlined. FIG. 5W shows the nucleic acid (SEQ ID NO: 261) and protein (SEQ ID NO: 262) sequence for the secreted isoform of hPDL1 (SecPDL1) fusion polypeptide hSecPDL1-CD9tm4 wherein the text for the signaling domain hSecPDL1 is bolded and sticky binder CD9tm4 is italicized. FIG. 5X shows the nucleic acid (SEQ ID NO: 263) and protein (SEQ ID NO: 264) sequence for the secreted isoform of hPDL1 (SecPDL1) fusion polypeptide hSecPDL1-CD81 wherein the text for the signaling domain hSecPDL1 is bolded and sticky binder CD81 is italicized. FIG. 5Y shows the nucleic acid (SEQ ID NO: 265) and protein (SEQ ID NO: 266) sequence for the hCD200-Fc-GPI fusion polypeptide wherein the text for the signaling domain hCD200 is bolded, Fc is underlined, and sticky binder GPI is italicized, a spacer sequence domain (regular text, not underlined and not italicized) separates hCD200 sequence from the Fc domain, a spacer sequence domain (regular text, not underlined and not italicized) separates Fc sequence from the GPI. FIG. 5Z shows the nucleic acid (SEQ ID NO: 267) and protein (SEQ ID NO: 268) sequence for the hFGL1-GPI fusion polypeptide wherein the text for the signaling domain hFGL1 is bolded, and sticky binder GPI is italicized. FIG. 5AA shows the nucleic acid (SEQ ID NO: 269) and protein (SEQ ID NO: 270) sequence for the hGal9-Fc-GPI fusion polypeptide wherein the text for the signaling domain hGal9 is bolded, Fc is underlined, and sticky binder GPI is italicized. FIG. 5BB shows the nucleic acid (SEQ ID NO: 271) and protein (SEQ ID NO: 272) sequence for the hCD200-GPI fusion polypeptide wherein the text for the signaling domain hCD200 is bolded, and sticky binder GPI is italicized. FIG. 5CC shows the nucleic acid (SEQ ID NO: 273) and protein (SEQ ID NO: 274) sequence for the hGa19-GPI fusion polypeptide wherein the text for the signaling domain hGal9 is bolded, and sticky binder GPI is italicized. FIG. 5DD shows the nucleic acid (SEQ ID NO: 275) and protein (SEQ ID NO: 276) sequence for the hHVEM-GPI fusion polypeptide wherein the text for the signaling domain hHVEM is bolded, and sticky binder GPI is italicized. FIG. 5EE shows the nucleic acid (SEQ ID NO: 277) and protein (SEQ ID NO: 278) sequence for the hPDL2-GPI fusion polypeptide wherein the text for the signaling domain hPDL2 is bolded, and sticky binder GPI is italicized. FIG. 5FF shows the nucleic acid (SEQ ID NO: 279) and protein (SEQ ID NO: 280) sequence for the hTSG6-GPI fusion polypeptide wherein the text for the signaling domain hTSG6 is bolded, and sticky binder GPI is italicized. FIG. 5GG shows the nucleic acid (SEQ ID NO: 281) and protein (SEQ ID NO: 282) sequence for the hHVEM-Fc-GPI fusion polypeptide wherein the text for the signaling domain hHVEM is bolded, Fc is underlined, and sticky binder GPI is italicized. FIG. 5HH shows the nucleic acid (SEQ ID NO: 285) and protein (SEQ ID NO: 286) sequence for the mCTLA4-Fc-GPI fusion polypeptide wherein the text for the signaling domain mCTLA4 is bolded, Fc is underlined, and sticky binder GPI is italicized. FIG. 5II shows the nucleic acid (SEQ ID NO: 287) and protein (SEQ ID NO: 288) sequence for the mPDL1-C1C2 fusion polypeptide wherein the text for the signaling domain mPDL1 is bolded and sticky binder C1C2 is italicized. FIG. 5JJ shows the nucleic acid (SEQ ID NO: 289) and protein (SEQ ID NO: 290) sequence for the mPDL1-Fc-GPI fusion polypeptide wherein the text for the signaling domain mPDL1 is bolded, Fc is underlined, and sticky binder GPI is italicized. FIG. 5KK shows the nucleic acid (SEQ ID NO: 291) and protein (SEQ ID NO: 292) sequence for the mPDL1-GPI fusion polypeptide wherein the text for the signaling domain mPDL1 is bolded and sticky binder GPI is italicized. FIG. 5LL shows the nucleic acid (SEQ ID NO: 293) and protein (SEQ ID NO: 294) sequence for the mPDL2-C1C2 fusion polypeptide wherein the text for the signaling domain mPDL2 is bolded and sticky binder C1C2 is italicized. FIG. 5MM shows the nucleic acid (SEQ ID NO: 295) and protein (SEQ ID NO: 296) sequence for the mPDL2-Fc-GPI fusion polypeptide wherein the text for the signaling domain mPDL2 is bolded, Fc is underlined, and sticky binder GPI is italicized. FIG. 5NN shows the nucleic acid (SEQ ID NO: 297) and protein (SEQ ID NO: 298) sequence for the mPDL1-mFc-GPI fusion polypeptide wherein the text for the signaling domain mPDL2 is bolded, mFc is underlined, and sticky binder GPI is italicized. FIG. 5OO shows the nucleic acid (SEQ ID NO: 299) and protein (SEQ ID NO: 300) sequence for the mPDL2-GPI fusion polypeptide wherein the text for the signaling domain mPDL2 is bolded and sticky binder GPI is italicized. FIG. 5PP shows the nucleic acid (SEQ ID NO: 301) and protein (SEQ ID NO: 302) sequence for the mPDL1-GPI-P2A-mHVEM-GPI fusion polypeptide wherein the text for the signaling domain mPDL1 and mHVEM are bolded, P2A sequence is underlined, and sticky binder GPI is italicized. With P2A included, a self-cleaving peptide sequence, artificial synapses with this feature will have both mPDL1-GPI and mHVEM-GPI loaded onto the surface. FIG. 5QQ shows the nucleic acid (SEQ ID NO: 303) and protein (SEQ ID NO: 304) sequence for the hPDL1-ADAM10 fusion polypeptide wherein the text for the signaling domain mPDL1 is bolded and sticky binder ADAM10 is italicized. FIG. 5RR shows the nucleic acid (SEQ ID NO: 305) and protein (SEQ ID NO: 306) sequence for the hPDL1-4Fc-CD9tm2 fusion polypeptide wherein the text for the signaling domain hPDL1 is bolded, 4Fc is underlined, and sticky binder CD9tm2 is italicized. FIG. 5SS shows the nucleic acid (SEQ ID NO: 307) and protein (SEQ ID NO: 308) sequence for the fusion polypeptide hPDL1-4Fc-CD9tm2-KRAS wherein the text for the signaling domain hPDL1 is bolded, sticky binder 4Fc is underlined, sticky binder CD9tm2 is italicized, and sticky binder KRAS is italicized and underlined. FIG. 5TT shows the nucleic acid (SEQ ID NO: 309) and protein (SEQ ID NO: 310) sequence for the hPDL1-Fc-CD9tm2 fusion polypeptide wherein the text for the signaling domain hPDL1 is bolded, Fc is underlined, and sticky binder CD9tm2 is italicized. FIG. 5UU shows the nucleic acid (SEQ ID NO: 311) and protein (SEQ ID NO: 312) sequence for the fusion polypeptide hPDL1-Fc-CD9tm2-KRAS wherein the text for the signaling domain hPDL1 is bolded, sticky binder Fc is underlined, sticky binder CD9tm2 is italicized, and sticky binder KRAS is italicized and underlined. FIG. 5VV shows the nucleic acid (SEQ ID NO: 313) and protein (SEQ ID NO: 314) sequence for the mPDL1-mFc-CD9tm2 fusion polypeptide wherein the text for the signaling domain mouse PDL1 (mPDL1) is bolded, mouse mFc (mFc) is underlined, and sticky binder CD9tm2 is italicized. FIG. 5WW shows the nucleic acid (SEQ ID NO: 315) and protein (SEQ ID NO: 316) sequence for the fusion polypeptide mPDL1-mFc-CD9tm2-KRAS wherein the text for the signaling domain mPDL1 is bolded, sticky binder mFc is underlined, sticky binder CD9tm2 is italicized, and sticky binder KRAS is italicized and underlined. Wherein mPDL1 and mFc are mouse PDL1 and mouse Fc, respectively.



FIG. 6 shows hPD-L1-Fc-GPI artificial synapse purification via a multimodal resin marketed for exosome purification. Large MW artificial synapses elute in the first fraction as shown by the high hPD-L1 concentration and artificial synapse quantity (2.26E9 synapses/ml) in elution 1. Clean in place (CIP) fractions show bound and eliminated proteins from the Inventors' artificial synapse elution.



FIG. 7 shows hPDL1-Fc-GPI exosome purification via size exclusion chromatography using a resin marketed for exosome purification. Artificial synapses engineered from exosomes eluted from via a multimodal resin may be further purified via size exclusion chromatography using a resin marketed for exosome purification as shown here. Using a size exclusion chromatography, artificial synapses elute in fractions 7-9. Total protein (determined by qBit) and hPD-L1 ng/ml (determined by ELISA) of each fraction is shown in the graph. Bars show exosome number per ml (i.e., 1E10 exosomes/ml etc.). Fractions 7-9 contain >99% purified artificial synapses. Fractions 7-9 are pooled and may be concentrated using a filtration device, for example a 10K MWCO Amicon centrifugal filter. Final purified product may be filtered through a low protein binding filter, for example a 0.2 μm or 0.45 μm PES filter.



FIG. 8 shows hPD-L1 Expression on exosomes, quantity and hPD-L1 concentration was determined in size exclusion chromatography fractions 7-9. Knowing the molecular weight of engineered hPD-L1, the Inventors can determine the number of hPD-L1 molecules per exosome to be approximately between 12 and 40 hPD-L1/exosome. This value is consistent between different purification runs and constructs.



FIG. 9 shows the purification of hPD-L2-Fc-GPI artificial synapses engineered from exosomes via multimodal resin marketed for exosome purification. This graph shows Abs 280 of fractions and quantity of hPDL2 in indicated fractions. Exosomes eluted in Elution 1. Clean in place (CIP) fractions show bound and eliminated proteins from the Inventors' artificial synapse elution.



FIG. 10 shows purification of hPD-L2-Fc-GPI labeled exosomes via size exclusion column as shown here using size exclusion resin marketed for exosome purification. Fractions containing large molecular weight exosomes (Fractions 7-9) showed high hPD-L2 concentration indicating that the purified exosomes contain hPD-L2-Fc-GPI. Total protein (determined by qBit) and hPD-L1 ng/ml (determined by ELISA) of each fraction is shown in the graph. Lower molecular weight unbound hPD-L2-Fc-GPI eluted at later fractions.



FIG. 11 shows hCTLA4-Fc-GPI exosome purification via size exclusion column as shown here using size exclusion resin marketed for exosome purification. Using size exclusion chromatography, exosomes elute in fractions 7-9. Total protein (determined by qBit) and hCTLA4 ng/ml (determined by ELISA) of each fraction is shown in the graph. Fractions 7-9 are pooled and contain >99% purified exosomes. Pooled exosome fractions may then be concentrated using a filtration device, for example a 10K MWCO Amicon centrifugal filter. Final purified product may be filtered through a low protein binding filter, for example a 0.2 μm or 0.45 um PES filter. Knowing the molecular weight of engineered hCTLA-4, the Inventors can determine the number of hCTLA-4 molecules per exosome to be approximately 233 hCTLA-4/exosome.



FIGS. 12A-12B. FIG. 12A shows PD-1 Signaling Bioassay Method. The Inventors established a method to validate that PD-L1 and PD-L2 artificial synapses engineered from exosomes can bind to cells expressing PD-1 ligand. To perform this validation method, the Inventors modified the PathHunter PD-1 Signaling Bioassay from DiscoverX Briefly, the PathHunter PD-1 Signaling Bioassay relies on the well-established PathHunter Enzyme Fragment Complementation (EFC) technology to interrogate receptor activity. EFC consists of a split β-galactosidase (β-gal) enzyme: the Enzyme Donor (ED) and Enzyme Acceptor (EA) fragments which independently have no β-gal activity. However, when forced to complement they form an active β-gal enzyme that will hydrolyze substrate to produce a chemiluminescent signal. The PathHunter PD-1 Signaling Bioassay consists of human cells engineered to stably express an ED-tagged PD-1 receptor, while EA is fused to the phosphotyrosine-binding SH2 domain of the intracellular signaling protein, SHP1. Ligand or antibody-induced activation of the receptor results in phosphorylation of the receptor's cytosolic tail. Ligand engagement, through addition of ligand-presenting artificial synapses engineered from exosomes, results in phosphorylation of PD-1, leading to the recruitment of SHP1-EA. This forces complementation of the EFC components to create an active β-gal enzyme. This active enzyme hydrolyzes substrate to create chemiluminescence as a measure of receptor activity. Addition of an antagonist (e.g., antibody to PD-L1) blocks PD-1 signaling, and will prevent complementation, resulting in a loss of signal. FIG. 12B shows that the Inventors obtained approximately 10,000× higher increase in Relative Light Units (RLU) in Jurkat signaling cells treated with PD-L1 or PD-L2 labeled artificial synapses when compared to soluble PD-L1-Fc or PD-L2-Fc ligand, respectively. Meaning, it took 10,000× less ug/ml of PD-L1 or PD-L2 on artificial synapses than solubilized PD-L1-Fc or PD-L2 ligand to achieve the same RLU signaling. Shown is a dose-response curve for the PD-L1 and PD-L2 artificial synapses engineered from exosomes vs soluble PD-L1 and PD-L2 signaling bioassay.



FIG. 13A-13C. FIG. 13A shows experimental EAU outline Test Agent A—unmodified exosomes, Test Agent B—mPDL1-Fc-GPI artificial synapses engineered from exosomes 40 ug/ml, Test Agent C—mPDL1-Fc-GPI artificial synapses engineered from exosomes 400 ug/ml, IRBP—interphotoreceptor retinoid-binding protein (IRBP) peptide, BID—Bis in die (2× daily) p.o.—Per os (orally) FIG. 13B shows that EAU symptoms appear at day 6. 1st intravitreal injection and 2nd intravenous injections are performed on Day 6. There is a statistically significant initial reduction in EAU in mouse PD-L1 (mPD-L1) artificial synapses engineered from exosomes treated rats via either the intravitreal and intravenous delivery modes. 2nd intravitreal and 3rd intravenous injections are performed on Day 12. There appears to be a more rapid rate of resolution in the 1× intravitreal and intravenous groups. FIG. 13C shows that weights of rats were monitored throughout the study. 3rd intravitreal and 4th intravenous injections are performed on Day 16. There does not appear to be any significant change in EAU in any of the test groups. The aforementioned results provide proof of principle of successfully treating an autoimmune condition (i.e. EAU) with human cell derived artificial synapses with PD-L1.



FIG. 14 shows 2 types of ligands displayed on the exosome surface (Type I and Type II membrane proteins). Type I membrane proteins wherein the N-Terminus is on the luminal (interior) side of the exosome membrane and the C-Terminus is on the exterior of the exosome. Type II membrane proteins wherein the N-Terminus is on the exterior while the C-Terminus is on the interior.



FIG. 15 shows a schematic representation of several embodiments of Type I membrane protein constructs, which include but are not limited to: PD-L1, PD-L2, FGL1, OX40L.



FIG. 16 shows a schematic representation of several embodiments of the surface of an extracellular vesicle engineered with a Type I membrane protein of interest (POI) with a variable membrane anchor. Vesicle targeting sequences such as select sequences from 4F2 (CD98), ADAM10, CD298, TFR2, transmembrane portions of CD9, MARCKS, KRAS, and GPI from CD55. Proteins engineered to include a targeting sequence domain may include one or more linkers between the sticky binder and signaling domain (e.g., an Fc linker or a bond sequence wherein the bond sequence may be dimerization or multimerization sequence).



FIG. 17 shows a schematic representation of the surface of an exosome engineered with an extracellular portion of the Type II membrane protein of interest (POI) with transmembrane/exosome targeting domains.



FIG. 18 shows a schematic representation of an exosome engineered with an extracellular portion of the Type II membrane protein 4-1BB.



FIG. 19 demonstrates a construct design for labeling an exosome surface with Type II membrane proteins.



FIG. 20 shows a schematic representation of a construct design for labeling an exosome surface with multiple POI domains operably linked by a cleavable (e.g., P2A) linker.



FIG. 21 shows a flow chart of purification and analytical processes provided herein.



FIG. 22 shows a PD-L1 labeled exosome constructs.



FIG. 23 shows several embodiments of the surface of an exosome engineered with PD-L1. The PD-L1 can be the membrane-bound PD-L1 isotype or secreted PD-L1 (SecPD-L1).



FIG. 24 demonstrates size exclusion chromatography for purifying human PD-L1-GPI (no Fc) exosomes. Left panel: Protein, RNA and DNA measurements in SEC fractions are shown. Invitrogen Qubit fluorometric assays were used to measure biomolecules from unmodified concentrated cell media SEC fractions or hPD-L1-Exo-Tag concentrated cell media SEC fractions. PD-L1 was measured using an R&D systems PD-L1 ELISA kit. Right panel shows dot-blot immunoblot analysis of SEC fractions. A 96-well dot blot apparatus was used to immobilize 50 ul of each SEC fraction onto PVDF. Right bottom figures: Exosome size and concentration was measured in fraction 7 by tunable resistive pulse sensing (TRPS).



FIG. 25 demonstrates that GPI anchors hPD-L1 on exosomes.



FIG. 26 demonstrates that a multimodal resin marketed for exosome purification purifies and disaggregates exosomes.



FIG. 27 shows the exosome decoration with hPD-L1-Fc-GPI.



FIGS. 28A-28B. FIG. 28A shows the exosome decoration with hPD-L1-Fc-GPI. Fraction 7 contained the purified hPD-L1-Fc-GPI vesicles. FIG. 28B shows size exclusion chromatography (SEC) purification results of various embodiments of human PD-L1 displayed on the surface of extracellular vesicles.



FIG. 29 shows that mouse PD-L1-Fc-GPI exosomes have higher valency than mPD-L1-GPI.



FIG. 30A-30C demonstrates comparison proteomics of transprotein expression and shows that surface labeling on the engineered extracellular vesicles provided herein do not affect the relative expression of native and associated exosome proteins. FIG. 30A shows hPD-L1-Fc-GPI. FIG. 30B shows hPD-L2-FcGPI. FIG. 30C shows hCTLA4-Fc-GPI.



FIG. 31 shows production of mPD-L1-Fc-GPI in STR Bioreactor.



FIG. 32 shows purification of mPD-L1-Fc-GPI (STR) via SEC. Graph shows mPD-L1 ng/ml vs Total Protein ug/ml.



FIG. 33 shows purification mPDL1-Fc-GPI (STR bioreactor).



FIG. 34 shows a schematic representation of the 4-1BBL labeled exosomes. Top: Vector map showing the N-terminal cystolic domain, a transmembrane (TM) domain, and the POI domain at the C-terminus. Bottom: An embodiment of an engineered EV with a type-II membrane display of the fusion protein.



FIG. 35 shows embodiments of a 4-1BBL display exosome.



FIG. 36A-36B. FIG. 36A shows the protein engineering and purification of 4F2-4-1BBL labeled exosomes. FIG. 36B confirms that h4-1BBL is displayed on the engineered exosomes.



FIG. 37 shows internal fusion protein loading of exosomes.



FIG. 38 shows internal loading of exosomes with mScarlet (RFP).



FIGS. 39A-39B. FIG. 39A shows internal loading of exosomes with NanoLuc luciferase. FIG. 39B shows tetraspanin characterization of exosomes internally loaded with NanoLuc luciferase.



FIGS. 40A-40B. FIG. 40A shows the mechanism of PD-L1 engineered extracellular vesicles induce membrane clustering and receptor agonism on a target cell. An exemplary model of proposed mechanism of extracellular vesicles with a Type I membrane protein signaling domain (PD-L1) promoting receptor clustering on a target cell, wherein receptor clustering promotes increased potency of signal transduction of the target receptor. Antagonist antibodies function well at blocking receptors. Antibodies are poor agonist modalities due to their general inability to cluster receptors. Ligands on a membrane surface are potent agonists, however the cost and cold chain logistics of cell therapies makes commercialization difficult and expensive. Extracellular vesicles engineered with Type I membrane protein are able to induce receptor clustering of target receptors and initiate and propagate a potent signal response on a target cell. FIG. 40B shows the mechanism of 4-1BBL engineered extracellular vesicles induce membrane clustering and receptor agonism on a target cell. An exemplary model of proposed mechanism of extracellular vesicles with a Type II membrane protein signaling domain (4-1BBL) promoting receptor clustering on a target cell, wherein receptor clustering promotes increased potency of signal transduction of the target receptor. Soluble ligands are often poor agonist modalities due to their general inability to cluster receptors. Ligands displayed on a membrane surface are potent agonists, however the cost and cold chain logistics of cell therapies makes commercialization difficult and expensive. Extracellular vesicles engineered with Type II membrane protein are able to induce receptor clustering of target receptors and initiate and propagate a potent signal response on a target cell.





DETAILED DESCRIPTION

The compositions and methods provided herein are based, in part, on the discovery that engineered extracellular vesicles (e.g., exosomes) expressing an engineered fusion protein (e.g., PD-L1) reduces inflammation in an animal model of experimental autoimmune uveoretinitis (EAU), an autoimmune disorder. The compositions and methods provided herein are further based, in part, on the discovery that engineered extracellular vesicles produce enhanced signaling compared to an equal quantity of recombinant ligand. Since some cellular receptors, (e.g., PD-1) require clustering or super-clustering to promote a signaling response, it stands to reason that extracellular vesicles engineered to express ligands on their surface wherein the ligands may engage target receptors on target cells and promote clustering of said target receptors thereby promoting a signal response on said target cell.


In one aspect, provided herein is an engineered extracellular vesicle comprising: at least one fusion polypeptide comprising: at least one protein of interest (POI) domain; and at least one vesicle targeting domain. In some embodiments of any of the aspects, the engineered extracellular vesicle is an exosome. In some embodiments, of any of the aspects, the fusion protein further comprises at least one linker. In some embodiments of any of the aspects, the POI domain can substantially bind to a target polypeptide. In some embodiments of any of the aspects provided herein, the engineered extracellular vesicle is an artificial synapse.


Generally, the extracellular vesicles (e.g., exosomes) provided herein are produced by contacting a population of cells with a nucleic acid construct encoding the fusion proteins provided herein and isolating a plurality of extracellular vesicles. The extracellular vesicles can then be purified by methods provided herein and are formulated for therapeutic use, including but not limited to, for the treatment of autoimmune diseases, cancer, or modulating inflammation in a subject.


The compositions and methods provided herein are specifically designed to exploit the membrane trafficking mechanisms of extracellular vesicles and rely on the hallmark biophysical and biochemical properties of extracellular vesicles, such as exosomes. The vesicles/artificial synapses provided herein are specifically engineered to induce/agonize and propagate biological signaling via a target polypeptide (e.g., by activating a receptor or enzyme or agonizing said receptor or enzyme). Alternatively, the engineered extracellular vesicles provided herein can act as cellular decoys or to reduce or antagonize biological signaling, e.g., by blocking an endogenous ligand from binding to a target cellular receptor and preventing activation of the receptor.


Engineering of the extracellular vesicles provided herein extends these capabilities significantly by incorporating sticky binders attaching to extracellular vesicles such as exosomes, further coupled with signaling domains of choice. For example, attachment of sticky binders to exosomes, along with their linked signaling domains, allows for receptor clustering for biological signal induction/agonism and propagation not otherwise possible. In this aspect, the aforementioned design achieves the aim of an engineered extracellular vesicle by inducing the desired biological signaling in a target recipient cell.


Various aspects and embodiments of the compositions and methods are provided herein in detail below.


Engineered Extracellular Vesicle (EV) Compositions

The compositions provided herein comprises at least one extracellular vesicle (also termed artificial synapse or abbrv: EV), wherein the extracellular vesicle comprises at least one fusion polypeptide or a plurality of fusion polypeptides comprising: at least one vesicle targeting domain (e.g., sticky binders); and at least one protein of interest domain or a fragment thereof (also termed signaling domains).


Extracellular vesicles (EVs) are lipid particles that are released from various cell types that function to transfer “cargo” such as nucleic acids and proteins to other cells. EVs are not able to replicate but serve as cell messengers. EV-mediated signals can be transmitted by all the different biomolecule categories—protein, lipids, nucleic acids and sugars—and the unique package of this information provides both protection and the option of simultaneous delivery of multiple different messengers even to sites remote to the vesicular origin. See, e.g., Yáñez-Mó M, Siljander P R, Andreu Z, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015; 4:27066. Published 2015 May 14. doi:10.3402/jev.v4.27066, which is incorporated herein by reference in its entirety. Furthermore, there is an increasing amount of evidence that shows that EVs can modulate a milieu of cellular signaling processes. See, e.g., Yadid et al. Science Translation Medicine (2020); Cerqueira de Abreu et al. Nature Reviews Cardiology (2020); Zhang W. et al. Protein J. (2019); Zha Q B et al. Tumor Biology. February 2017; Tan et al. (2016) Recent advances of exosomes in immune modulation and autoimmune diseases, Autoimmunity, 49:6, 357-365; Kalluri R, LeBleu V S. et al. The biology, function, and biomedical applications of exosomes. Science. 2020 Feb. 7; 367(6478); which is incorporated herein by reference in its entirety.


There are various types of extracellular vesicles that are named for their site of origin in a cell, size, and structural and/or functional properties. In some embodiments of any of the aspects provided herein, the extracellular vesicle is an exosome, ectosome, macrovesicle, microparticle, apoptotic body, vesicular organelle, oncosome, exosphere, exomeres, or cell derived nanovesicle (CDN) ((e.g., by genesis via grating or shearing cells), liposomes or the like known by one of ordinary skill in the art. In various embodiments, the extracellular vesicle comprises a phospholipid bilayer with an exterior phospholipid layer and an interior phospholipid layer, wherein the exterior phospholipid layer has an external surface and an internal surface, wherein the interior phospholipid layer has an internal surface and an external surface, and the internal surface of the exterior phospholipid layer faces the internal surface of the interior phospholipid layer, and the phospholipid bilayer encloses an internal space, wherein the external surface of the interior phospholipid layer faces the internal space and wherein the external surface of the exterior phospholipid layer faces an extracellular environment, and the external surface of the inner phospholipid layer is the internal surface of the extracellular vesicle.


In various embodiments, the extracellular vesicles range in size from 30 nanometers (nm) to 300 nm. In various embodiments, the plurality of EVs range in size from about 30 nm to about 150 nm. In various embodiments, the plurality of EVs or artificial synapses includes one or more artificial synapses that are about 10 nm to about 250 nm in diameter, including those about 10 nm to about 15 nm, about 15 nm to about 20 nm, about 20 nm to about 25 nm, about 25 nm to about 30 nm, about 30 nm to about 35 nm, about 35 nm to about 40 nm, about 40 nm to about 50 nm, about 50 nm to about 60 nm3 about 60 nm to about 70 nm, about 70 nm to about 80 nm, about 80 nm to about 90 nm, about 90 nm to about 95 nm, about 95 nm to about 100 nm, about 100 nm to about 105 nm, about 105 nm to about 110 nm, about 110 nm to about 115 nm, about 115 nm to about 120 nm, about 120 nm to about 125 nm, about 125 nm to about 130 nm, about 130 nm to about 135 nm, about 135 nm to about 140 nm, about 140 nm to about 145 nm, about 145 nm to about 150 nm, about 150 to about 200 nm, about 200 nm to about 250 nm, about 250 nm or more.


In some embodiments of any of the aspects provided herein, the EV is an exosome. Exosomes are membrane-bound EVs that are produced in the endosomal compartment of most eukaryotic cells. As used herein, the term “exosome” refers to a species of extracellular vesicle between about 20 nm to about 400 μm in diameter, e.g, about 30 nm-200 nm in diameter by inward invagination of a portion of a membrane of an endosome (for example an early or late endosome), wherein the endosome is within a cell comprising a plasma membrane, and the exosome is released from the cell upon fusion of another portion of the endosome membrane with the plasma membrane. An exosome may refer to a species of extracellular vesicle between 20 nm-400 μM in diameter, more preferably 30 nm-200 nm in diameter, that originates by budding of a portion of a plasma membrane from a cell wherein the budded portion of the plasma membrane is released to the extracellular environment.


The EVs (e.g., exosomes or cell derived vesicles) provided herein may comprise cargo, for example, peptides, proteins, nucleic acids, lipids, metabolites, carbohydrates, biomolecules, small molecules, large molecules, vesicles, organelles, or fragments thereof. Exosome cargo may be located within the internal space of the exosome. EV cargo may be membrane bound spanning one or both layers of the exosome phospholipid bilayer (for example a transmembrane protein). EV cargo may be in contact with the exterior or interior surface of the exosome, for example through a covalent bond or a non-covalent bond. The phospholipid bilayer of the EV or exosome provided herein may comprise one or more transmembrane proteins, wherein a portion of the one or more transmembrane membrane proteins is located within the internal space of the exosome. The phospholipid bilayer of the EV or exosome provided herein may comprise one or more transmembrane proteins, wherein a portion of the one or more transmembrane membrane proteins traverses the EV phospholipid bilayer. The phospholipid bilayer of the EV may comprise one or more transmembrane proteins, wherein the one or more transmembrane membrane proteins comprises a domain on the exterior of the exosome.


In some embodiments of any of the aspects, the extracellular vesicles or exosomes provided herein endogenously express CD81+, CD82+, CD37+, CD63+, CD9+, CD151+, CD105+, or any combination thereof. In various embodiments, the plurality of artificial synapses includes one or more artificial synapses expressing a biomarker. In certain embodiments, the biomarkers are tetraspanins. In other embodiments, the tetraspanins are one or more selected from the group including CD63, CD81, CD82, CD53, CD151, and CD37. In other embodiments, the artificial synapses express one or more lipid raft associated proteins (e.g., glycosylphosphatidylinositol-anchored proteins and flotillin), cholesterol, sphingolipids such as sphingomyelin, and/or hexosylceramides.


In other embodiments, the biological protein is related to exosome formation and packaging of cytosolic proteins, e.g., Hsp70, Hsp90, 14-3-3 epsilon, PKM2, GW182 and AGO2. In certain embodiments, the artificial synapses express CD63, HSP70, CD105 or combinations thereof. In other embodiments, the artificial synapses do not express CD9 or CD81, or express neither. For example, plurality of artificial synapses can include one or more artificial synapses that are CD63+, HSP+, CD105+, CD9−, and CD81−.


The EVs provided herein are specifically engineered to express fusion polypeptides that elicit biological signaling via a target cell. In some embodiments, the fusion polypeptide is overexpressed to elicit a biological response on a target cell or target polypeptide. The engineered EV comprises at least one fusion polypeptide and can comprise a plurality of the same or different fusion polypeptides provided herein. The fusion polypeptides provided herein comprise a protein of interest domain, also termed the signaling domain.


The fusion polypeptides provided herein can comprise one or more of a protein of interest domain, such that expression of said fusion polypeptide is permitted and that the number of POI domains does not impede protein expression or folding. Furthermore, the EVs provided herein can express more than one fusion protein (e.g., encoded by multiple different nucleic acid constructs). One of skill in the art can appreciate that an engineered EV can include one or more combinations of different signaling domains and/or vesicle targeting domains, or that one can use a plurality of engineered EVs, each including one or more vesicle targeting domains and one or more signaling domains.


In some embodiments, the EVs provided herein comprise one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more fusion proteins. The fusion proteins can be encoded by the same vector or separate vectors. In some embodiments of any of the aspects, the engineered extracellular vesicle comprises at least two POI domains and/or at least two vesicle targeting domains.


In some embodiments, the fusion polypeptide comprises one or more, two or more, three or more, four or more, five or more, or six or more POI domains on the same polypeptide or nucleic acid construct encoding said polypeptide. For example, the fusion polypeptides provided herein can express a fusion polypeptide encoding one or more, two or more, three or more, four or more, five or more, or six or more signaling domains. In another example, the fusion polypeptides provided herein can express a fusion polypeptide encoding an immune checkpoint protein or a protein involved in immune or cell synapse or any combination or fragment thereof.


In some embodiments, the EV comprises one or more, two or more, three or more, four or more, five or more, or six or more fusion polypeptides on the same EV. For example, EVs comprising one or more, two or more, three or more, four or more, five or more, or six or more fusion polypeptides wherein the fusion polypeptides encode a signaling domain. In another example, EVs comprising one or more, two or more, three or more, four or more, five or more, or six or more fusion polypeptides wherein the fusion polypeptides encode for one or more immune checkpoint proteins or proteins involved in immune or cell synapse, or any combination or fragment thereof.


In various embodiments, the signaling domain is a protein or peptide of interest, or a fragment thereof. In various embodiments, the protein of interest (signaling domain) is an immune checkpoint protein. The terms “immune checkpoint protein” or “protein involved in immune or cell synapse” can include but are not limited to adenosine A2A receptor (A2AR), Galectin 9, fibrinogen-like protein 1 (FGL-1), platelet endothelial adhesion factor-1 (PECAM-1), tumor necrosis factor gene 6 protein (TSG-6), Stabilin-1 (STAB-1) also known as Clever-1, Neuropilin 1 (NRP1), Neuropilin 2 (NRP2), semaphorin-3A (SEMA3A), semaphorin-3F (SEMA3F), repulsive guidance molecule B (RGMB) also known as DRG11, T-cell immunoglobulin and mucin domain 3 (TIM-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), human leukocyte antigen (HLA) class I, HLA class II, high mobility group protein B1 (HMGB1), phosphatidylserine, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1), T-cell receptor (TCR), Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1), SHP-2, F-Box protein 38 (FBXO38), signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) also known as SH2D1A, B7RP1, indoleamine 2,3-dioxygenase (IDO), NADH oxidase 2 (NOX2), tumor necrosis factor receptor (TNFR) superfamily member 18 (TNFRSF18) (also known as activation inducible TNFR family receptor (AITR), glucocorticoid-induced TNFR related (GITR) protein, and CD357), B7-H4 also known as V-set domain containing T-cell activator inhibitor (VTCN1), B7-H5 (also known as V-domain Ig suppressor of T-cell activation (VISTA), platelet receptor Gi24, and stress induced secreted protein 1 (SISP1), B7-H6 (also known as NCR3LG1), B7-H7 (also known as human endogenous retrovirus-H (HERV-H) long terminal repeat-associating protein 2 (HHLA2), apelin receptor (APLNR), interferon gamma (IFN y) receptor, programmed cell death-1 (PD-1), Protein Wnt-5a (WNT5A), serine/threonine-protein kinase PAK4, interleukin 6 (IL-6), interleukin-10 (IL-10), NKG2 family of C-type lectin receptors (for example NKG2A, B, C, D, E, F and H), ligands of NKG2 family, killer cell immunoglobulin-like receptors, CD-2, cluster of differentiation 4 (CD4), CD8, CD27, CD27 ligand (CD27L, also known as CD70), CD28, CD28H (also known as transmembrane and immunoglobulin domain containing 2 (TMIGD2) and Ig containing and proline-rich receptor-1 (IGPR1)), CD39, CD40, CD44, integrin associated protein (CD47), carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1 also known as CD66a), CD73, B7-1 (also known as CD80), B7-2 (also known as CD86), CD94, CD96, immunoglobulin superfamily member 2 (IGSF2) also known as CD101, nectin cell adhesion molecule 2 (NECTIN2) (also known as herpesvirus entry mediator B (HVEB), poliovirus receptor related 2 (PRR2, PVRL2 and PVRR2) and CD112), poliovirus receptor related immunoglobulin domain containing protein (PVIRG) also known as CD112R, CD122 (also known as IL5RB and P70-75), OX40 (also known as tumor necrosis factor receptor superfamily member 4 (TNFRSF4) and CD134), OX40 ligand (OX40L), 4-1BB (also known as CD137), CD134 (also known as 4-1BB ligand (4-1BBL) and as tumor necrosis factor ligand superfamily member 9 (TNFSF9) and CD137L), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) also known as CD152, CD154 (also known as CD40L), poliovirus receptor (PVR) also known as CD155, killer-cell immunoglobulin-like receptors (KIRs) (for example but not limited to CD158 family, CD158a, CD158g, CD158h, KIR2DL1, KIR2DS1, KIRDS3, and KIR2DS5), CD160, signal-regulatory protein alpha (SIRPα) also known as CD172a, OX-2 also known as CD200, CD200R, lymphocyte-activation gene 3 (LAG-3) also known as CD223, CD226, OX40L also known as CD252, herpes virus entry mediator (HVEM) also known as tumor necrosis factor receptor superfamily member 14 (TNFRSF14) and CD270, B- and T-lymphocyte attenuator (BTLA) also known as CD272, programmed cell death ligand-2 (PD-L2) (also known as B7-DC, PDCD1LG2, and CD273), programmed cell death-ligand 1 (PD-L1) (also known as B7-H1 and CD274), B7-H2 (also known as inducible T-cell co-stimulator ligand (ICOSLG), B7RP1, and CD275), B7-H3 also known as CD276, inducible T-cell co-stimulator (ICOS) also known as CD278, programed cell death protein 1 (PD-1) also known as CD279, leukocyte-associated Ig-like receptor-1 (LAIR-1) also known as CD305, collagen family of proteins (for example but not limited to collagen I, collagen II, collagen III alpha 1, collagen IV, collagen XXIII alpha 1, collagen XXV alpha 1), sialic acid-binding immunoglobulin-type lectin 7 (SIGLEC7) also known as CD328, sialic acid-binding immunoglobulin-type lectin 7 (SIGLEC9) also known as CD329, natural cytotoxicity triggering receptor 3 (NKp30) also known as CD337, or any isoform, fragment, variation thereof, or a ligand to the aforementioned proteins thereof, or the like known by one of ordinary skill in the art. All variants are encompassed by the present invention.


In some embodiments of any of the aspects provided herein, the protein of interest domain (POI domain) comprises a polypeptide or a fragment thereof or a nucleic acid encoding said polypeptide or fragment thereof selected from the group consisting of: Table 1 (below). Non-limiting examples of nucleic acid sequences that encode the POI domains provided herein are also provided in Table 1.









TABLE 1







Type I Proteins of Interest Amino Acid Sequence








Protein of
Transcript Sequence (SEQ ID NO:)


Interest
Amino Acid Sequence (SEQ ID NO:)





Human
>NM_014143.4 Homo sapiens CD274 molecule (CD274),


Programmed
transcript variant 1, mRNA


death-ligand 1
AGTTCTGCGCAGCTTCCCGAGGCTCCGCACCAGCCGCGCTTCTGTCCGCCTGCAGGG


(PD-L1)
CATTCCAGAAAGATGAGGATATTTGCTGTCTTTATATTCATGACCTACTGGCATTTG



CTGAACGCATTTACTGTCACGGTTCCCAAGGACCTATATGTGGTAGAGTATGGTAGC



AATATGACAATTGAATGCAAATTCCCAGTAGAAAAACAATTAGACCTGGCTGCACTA



ATTGTCTATTGGGAAATGGAGGATAAGAACATTATTCAATTTGTGCATGGAGAGGAA



GACCTGAAGGTTCAGCATAGTAGCTACAGACAGAGGGCCCGGCTGTTGAAGGACCAG



CTCTCCCTGGGAAATGCTGCACTTCAGATCACAGATGTGAAATTGCAGGATGCAGGG



GTGTACCGCTGCATGATCAGCTATGGTGGTGCCGACTACAAGCGAATTACTGTGAAA



GTCAATGCCCCATACAACAAAATCAACCAAAGAATTTTGGTTGTGGATCCAGTCACC



TCTGAACATGAACTGACATGTCAGGCTGAGGGCTACCCCAAGGCCGAAGTCATCTGG



ACAAGCAGTGACCATCAAGTCCTGAGTGGTAAGACCACCACCACCAATTCCAAGAGA



GAGGAGAAGCTTTTCAATGTGACCAGCACACTGAGAATCAACACAACAACTAATGAG



ATTTTCTACTGCACTTTTAGGAGATTAGATCCTGAGGAAAACCATACAGCTGAATTG



GTCATCCCAGAACTACCTCTGGCACATCCTCCAAATGAAAGGACTCACTTGGTAATT



CTGGGAGCCATCTTATTATGCCTTGGTGTAGCACTGACATTCATCTTCCGTTTAAGA



AAAGGGAGAATGATGGATGTGAAAAAATGTGGCATCCAAGATACAAACTCAAAGAAG



CAAAGTGATACACATTTGGAGGAGACGTAATCCAGCATTGGAACTTCTGATCTTCAA



GCAGGGATTCTCAACCTGTGGTTTAGGGGTTCATCGGGGCTGAGCGTGACAAGAGGA



AGGAATGGGCCCGTGGGATGCAGGCAATGTGGGACTTAAAAGGCCCAAGCACTGAAA



ATGGAACCTGGCGAAAGCAGAGGAGGAGAATGAAGAAAGATGGAGTCAAACAGGGAG



CCTGGAGGGAGACCTTGATACTTTCAAATGCCTGAGGGGCTCATCGACGCCTGTGAC



AGGGAGAAAGGATACTTCTGAACAAGGAGCCTCCAAGCAAATCATCCATTGCTCATC



CTAGGAAGACGGGTTGAGAATCCCTAATTTGAGGGTCAGTTCCTGCAGAAGTGCCCT



TTGCCTCCACTCAATGCCTCAATTTGTTTTCTGCATGACTGAGAGTCTCAGTGTTGG



AACGGGACAGTATTTATGTATGAGTTTTTCCTATTTATTTTGAGTCTGTGAGGTCTT



CTTGTCATGTGAGTGTGGTTGTGAATGATTTCTTTTGAAGATATATTGTAGTAGATG



TTACAATTTTGTCGCCAAACTAAACTTGCTGCTTAATGATTTGCTCACATCTAGTAA



AACATGGAGTATTTGTAAGGTGCTTGGTCTCCTCTATAACTACAAGTATACATTGGA



AGCATAAAGATCAAACCGTTGGTTGCATAGGATGTCACCTTTATTTAACCCATTAAT



ACTCTGGTTGACCTAATCTTATTCTCAGACCTCAAGTGTCTGTGCAGTATCTGTTCC



ATTTAAATATCAGCTTTACAATTATGTGGTAGCCTACACACATAATCTCATTTCATC



GCTGTAACCACCCTGTTGTGATAACCACTATTATTTTACCCATCGTACAGCTGAGGA



AGCAAACAGATTAAGTAACTTGCCCAAACCAGTAAATAGCAGACCTCAGACTGCCAC



CCACTGTCCTTTTATAATACAATTTACAGCTATATTTTACTTTAAGCAATTCTTTTA



TTCAAAAACCATTTATTAAGTGCCCTTGCAATATCAATCGCTGTGCCAGGCATTGAA



TCTACAGATGTGAGCAAGACAAAGTACCTGTCCTCAAGGAGCTCATAGTATAATGAG



GAGATTAACAAGAAAATGTATTATTACAATTTAGTCCAGTGTCATAGCATAAGGATG



ATGCGAGGGGAAAACCCGAGCAGTGTTGCCAAGAGGAGGAAATAGGCCAATGTGGTC



TGGGACGGTTGGATATACTTAAACATCTTAATAATCAGAGTAATTTTCATTTACAAA



GAGAGGTCGGTACTTAAAATAACCCTGAAAAATAACACTGGAATTCCTTTTCTAGCA



TTATATTTATTCCTGATTTGCCTTTGCCATATAATCTAATGCTTGTTTATATAGTGT



CTGGTATTGTTTAACAGTTCTGTCTTTTCTATTTAAATGCCACTAAATTTTAAATTC



ATACCTTTCCATGATTCAAAATTCAAAAGATCCCATGGGAGATGGTTGGAAAATCTC



CACTTCATCCTCCAAGCCATTCAAGTTTCCTTTCCAGAAGCAACTGCTACTGCCTTT



CATTCATATGTTCTTCTAAAGATAGTCTACATTTGGAAATGTATGTTAAAAGCACGT



ATTTTTAAAATTTTTTTCCTAAATAGTAACACATTGTATGTCTGCTGTGTACTTTGC



TATTTTTATTTATTTTAGTGTTTCTTATATAGCAGATGGAATGAATTTGAAGTTCCC



AGGGCTGAGGATCCATGCCTTCTTTGTTTCTAAGTTATCTTTCCCATAGCTTTTCAT



TATCTTTCATATGATCCAGTATATGTTAAATATGTCCTACATATACATTTAGACAAC



CACCATTTGTTAAGTATTTGCTCTAGGACAGAGTTTGGATTTGTTTATGTTTGCTCA



AAAGGAGACCCATGGGCTCTCCAGGGTGCACTGAGTCAATCTAGTCCTAAAAAGCAA



TCTTATTATTAACTCTGTATGACAGAATCATGTCTGGAACTTTTGTTTTCTGCTTTC



TGTCAAGTATAAACTTCACTTTGATGCTGTACTTGCAAAATCACATTTTCTTTCTGG



AAATTCCGGCAGTGTACCTTGACTGCTAGCTACCCTGTGCCAGAAAAGCCTCATTCG



TTGTGCTTGAACCCTTGAATGCCACCAGCTGTCATCACTACACAGCCCTCCTAAGAG



GCTTCCTGGAGGTTTCGAGATTCAGATGCCCTGGGAGATCCCAGAGTTTCCTTTCCC



TCTTGGCCATATTCTGGTGTCAATGACAAGGAGTACCTTGGCTTTGCCACATGTCAA



GGCTGAAGAAACAGTGTCTCCAACAGAGCTCCTTGTGTTATCTGTTTGTACATGTGC



ATTTGTACAGTAATTGGTGTGACAGTGTTCTTTGTGTGAATTACAGGCAAGAATTGT



GGCTGAGCAAGGCACATAGTCTACTCAGTCTATTCCTAAGTCCTAACTCCTCCTTGT



GGTGTTGGATTTGTAAGGCACTTTATCCCTTTTGTCTCATGTTTCATCGTAAATGGC



ATAGGCAGAGATGATACCTAATTCTGCATTTGATTGTCACTTTTTGTACCTGCATTA



ATTTAATAAAATATTCTTATTTATTTTGTTACTTGGTACACCAGCATGTCCATTTTC



TTGTTTATTTTGTGTTTAATAAAATGTTCAGTTTAACATCCCA (SEQ ID NO:



1)






>NP_054862.1 programmed cell death 1 ligand 1 isoform a



precursor [Homo sapiens]



MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYW



EMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRC



MISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSD



HQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPE



LPLAHPPNERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDT



HLEET (SEQ ID NO: 2)





Mouse PD-L1
>NM_021893.3 Mus musculus CD274 antigen (Cd274), mRNA



GAAATCGTGGTCCCCAAGCCTCATGCCAGGCTGCACTTGCACGTCGCGGGCCAGTCT



CCTCGCCTGCAGATAGTTCCCAAAACATGAGGATATTTGCTGGCATTATATTCACAG



CCTGCTGTCACTTGCTACGGGCGTTTACTATCACGGCTCCAAAGGACTTGTACGTGG



TGGAGTATGGCAGCAACGTCACGATGGAGTGCAGATTCCCTGTAGAACGGGAGCTGG



ACCTGCTTGCGTTAGTGGTGTACTGGGAAAAGGAAGATGAGCAAGTGATTCAGTTTG



TGGCAGGAGAGGAGGACCTTAAGCCTCAGCACAGCAACTTCAGGGGGAGAGCCTCGC



TGCCAAAGGACCAGCTTTTGAAGGGAAATGCTGCCCTTCAGATCACAGACGTCAAGC



TGCAGGACGCAGGCGTTTACTGCTGCATAATCAGCTACGGTGGTGCGGACTACAAGC



GAATCACGCTGAAAGTCAATGCCCCATACCGCAAAATCAACCAGAGAATTTCCGTGG



ATCCAGCCACTTCTGAGCATGAACTAATATGTCAGGCCGAGGGTTATCCAGAAGCTG



AGGTAATCTGGACAAACAGTGACCACCAACCCGTGAGTGGGAAGAGAAGTGTCACCA



CTTCCCGGACAGAGGGGATGCTTCTCAATGTGACCAGCAGTCTGAGGGTCAACGCCA



CAGCGAATGATGTTTTCTACTGTACGTTTTGGAGATCACAGCCAGGGCAAAACCACA



CAGCGGAGCTGATCATCCCAGAACTGCCTGCAACACATCCTCCACAGAACAGGACTC



ACTGGGTGCTTCTGGGATCCATCCTGTTGTTCCTCATTGTAGTGTCCACGGTCCTCC



TCTTCTTGAGAAAACAAGTGAGAATGCTAGATGTGGAGAAATGTGGCGTTGAAGATA



CAAGCTCAAAAAACCGAAATGATACACAATTCGAGGAGACGTAAGCAGTGTTGAACC



CTCTGATCGTCGATTGGCAGCTTGTGGTCTGTGAAAGAAAGGGCCCATGGGACATGA



GTCCAAAGACTCAAGATGGAACCTGAGGGAGAGAACCAAGAAAGTGTTGGGAGAGGA



GCCTGGAACAACGGACATTTTTTCCAGGGAGACACTGCTAAGCAAGTTGCCCATCAG



TCGTCTTGGGAAATGGATTGAGGGTTCCTGGCTTAGCAGCTGGTCCTTGCACAGTGA



CCTTTTCCTCTGCTCAGTGCCGGGATGAGAGATGGAGTCATGAGTGTTGAAGAATAA



GTGCCTTCTATTTATTTTGAGTCTGTGTGTTCTCACTTTGGGCATGTAATTATGACT



GGTGAATTCTGACGACATGATAGATCTTAAGATGTAGTCACCAAACTCAACTGCTGC



TTAGCATCCTCCGTAACTACTGATACAAGCAGGGAACACAGAGGTCACCTGCTTGGT



TTGACAGGCTCTTGCTGTCTGACTCAAATAATCTTTATTTTTCAGTCCTCAAGGCTC



TTCGATAGCAGTTGTTCTGTATCAGCCTTATAGGTGTCAGGTATAGCACTCAACATC



TCATCTCATTACAATAGCAACCCTCATCACCATAGCAACAGCTAACCTCTGTTATCC



TCACTTCATAGCCAGGAAGCTGAGCGACTAAGTCACTTGCCCACAGAGTATCAGCTC



TCAGATTTCTGTTCTTCAGCCACTGTCCTTTCAGGATAGAATTTGTCGTTAAGAAAT



TAATTTAAAAACTGATTATTGAGTAGCATTGTATATCAATCACAACATGCCTTGTGC



ACTGTGCTGGCCTCTGAGCATAAAGATGTACGCCGGAGTACCGGTCGGACATGTTTA



TGTGTGTTAAATACTCAGAGAAATGTTCATTAACAAGGAGCTTGCATTTTAGAGACA



CTGGAAAGTAACTCCAGTTCATTGTCTAGCATTACATTTACCTCATTTGCTATCCTT



GCCATACAGTCTCTTGTTCTCCATGAAGTGTCATGAATCTTGTTGAATAGTTCTTTT



ATTTTTTAAATGTTTCTATTTAAATGATATTGACATCTGAGGCGATAGCTCAGTTGG



TAAAACCCTTTCCTCACAAGTGTGAAACCCTGAGTCTTATCCCTAGAACCCACATAA



AAAACAGTTGCGTATGTTTGTGCATGCTTTTGATCCCAGCACTAGGGAGGCAGAGGC



AGGCAGATCCTGAGCTCTCATTGACCACCCAGCCTAGCCTACATGGTTAGCTCCAGG



CCTACAGGAGCTGGCAGAGCCTGAAAAACGATGCCTAGACACACACACACACACACA



CACACACACACACACACACACACACCATGTACTCATAGACCTAAGTGCACCCTCCTA



CACATGCACACACATACAATTCAAACACAAATCAACAGGGAATTGTCTCAGAATGGT



CCCCAAGACAAAGAAGAAGAAAAACACCAAACCAGCTCTATTCCCTCAGCCTATCCT



CTCTACTCCTTCCTAGAAGCAACTACTATTGTTTTTGTATATAAATTTACCCAACGA



CAGTTAATATGTAGAATATATATTAAAGTGTCTGTCAATATATATTATCTCTTTCTT



TCTTTCTTCCTTTCTTTCTTTCTTTCTTTCTTTCTTTCTTTCTTTCTTTCTTTCTTT



CTTCCTTCCTTCCTTCCTTCCTTCCTTCCTTCCTTCCTTTCTTTCTTTCTTTCTTTT



TTTCTGTCTATCTGTACCTAAATGGTTGCTCACTATGCATTTTCTGTGCTCTTCGCC



CTTTTTATTTAATGTATGGATATTTATGCTGCTTCCAGAATGGATCTAAAGCTCTTT



GTTTCTAGGTTTTCTCCCCCATCCTTCTAGGCATCTCTCACACTGTCTAGGCCAGAC



ACCATGTCTGCTGCCTGAATCTGTAGACACCATTTATAAAGCACGTACTCACCGAGT



TTGTATTTGGCTTGTTCTGTGTCTGATTAAAGGGAGACCATGAGTCCCCAGGGTACA



CTGAGTTACCCCAGTACCAAGGGGGAGCCTTGTTTGTGTCTCCATGGCAGAAGCAGG



CCTGGAGCCATTTTGGTTTCTTCCTTGACTTCTCTCAAACACAGACGCCTCACTTGC



TCATTACAGGTTCTCCTTTGGGAATGTCAGCATTGCTCCTTGACTGCTGGCTGCCCT



GGAAGGAGCCCATTAGCTCTGTGTGAGCCCTTGACAGCTACTGCCTCTCCTTACCAC



AGGGGCCTCTAAGATACTGTTACCTAGAGGTCTTGAGGATCTGTGTTCTCTGGGGGG



AGGAAAGGAGGAGGAACCCAGAACTTTCTTACAGTTTTCCTTGTTCTGTCACATGTC



AAGACTGAAGGAACAGGCTGGGCTACGTAGTGAGATCCTGTCTCAAAGGAAAGACGA



GCATAGCCGAACCCCCGGTGGAACCCCCTCTGTTACCTGTTCACACAAGCTTATTGA



TGAGTCTCATGTTAATGTCTTGTTTGTATGAAGTTTAAGAAAATATCGGGTTGGGCA



ACACATTCTATTTATTCATTTTATTTGAAATCTTAATGCCATCTCATGGTGTTGGAT



TGGTGTGGCACTTTATTCTTTTGTGTTGTGTATAACCATAAATTTTATTTTGCATCA



GATTGTCAATGTATTGCATTAATTTAATAAATATTTTTATTTATTAAAAAAAAAAAA



AAAAA (SEQ ID NO: 3)






>NP_068693.l programmed cell death 1 ligand 1 precursor



[Mus musculus]



MRIFAGIIFTACCHLLRAFTITAPKDLYVVEYGSNVTMECRFPVERELDLLALVVYW



EKEDEQVIQFVAGEEDLKPQHSNFRGRASLPKDQLLKGNAALQITDVKLQDAGVYCC



IISYGGADYKRITLKVNAPYRKINQRISVDPATSEHELICQAEGYPEAEVIWTNSDH



QPVSGKRSVTTSRTEGMLLNVTSSLRVNATANDVFYCTFWRSQPGQNHTAELIIPEL



PATHPPQNRTHWVLLGSILLFLIVVSTVLLFLRKQVRMLDVEKCGVEDTSSKNRNDT



QFEET (SEQ ID NO: 4)





Human PD-L2
>NM_025239.4 Homo sapiens programmed cell death 1 ligand



2 (PCD1LG2), mRNA



ACTCTCATGTTACGGCAAACCTTAAGCTGAATGAACAACTTTTCTTCTCTTGAATAT



ATCTTAACGCCAAATTTTGAGTGCTTTTTTGTTACCCATCCTCATATGTCCCAGCTA



GAAAGAATCCTGGGTTGGAGCTACTGCATGTTGATTGTTTTGTTTTTCCTTTTGGCT



GTTCATTTTGGTGGCTACTATAAGGAAATCTAACACAAACAGCAACTGTTTTTTGTT



GTTTACTTTTGCATCTTTACTTGTGGAGCTGTGGCAAGTCCTCATATCAAATACAGA



ACATGATCTTCCTCCTGCTAATGTTGAGCCTGGAATTGCAGCTTCACCAGATAGCAG



CTTTATTCACAGTGACAGTCCCTAAGGAACTGTACATAATAGAGCATGGCAGCAATG



TGACCCTGGAATGCAACTTTGACACTGGAAGTCATGTGAACCTTGGAGCAATAACAG



CCAGTTTGCAAAAGGTGGAAAATGATACATCCCCACACCGTGAAAGAGCCACTTTGC



TGGAGGAGCAGCTGCCCCTAGGGAAGGCCTCGTTCCACATACCTCAAGTCCAAGTGA



GGGACGAAGGACAGTACCAATGCATAATCATCTATGGGGTCGCCTGGGACTACAAGT



ACCTGACTCTGAAAGTCAAAGCTTCCTACAGGAAAATAAACACTCACATCCTAAAGG



TTCCAGAAACAGATGAGGTAGAGCTCACCTGCCAGGCTACAGGTTATCCTCTGGCAG



AAGTATCCTGGCCAAACGTCAGCGTTCCTGCCAACACCAGCCACTCCAGGACCCCTG



AAGGCCTCTACCAGGTCACCAGTGTTCTGCGCCTAAAGCCACCCCCTGGCAGAAACT



TCAGCTGTGTGTTCTGGAATACTCACGTGAGGGAACTTACTTTGGCCAGCATTGACC



TTCAAAGTCAGATGGAACCCAGGACCCATCCAACTTGGCTGCTTCACATTTTCATCC



CCTTCTGCATCATTGCTTTCATTTTCATAGCCACAGTGATAGCCCTAAGAAAACAAC



TCTGTCAAAAGCTGTATTCTTCAAAAGACACAACAAAAAGACCTGTCACCACAACAA



AGAGGGAAGTGAACAGTGCTATCTGAACCTGTGGTCTTGGGAGCCAGGGTGACCTGA



TATGACATCTAAAGAAGCTTCTGGACTCTGAACAAGAATTCGGTGGCCTGCAGAGCT



TGCCATTTGCACTTTTCAAATGCCTTTGGATGACCCAGCACTTTAATCTGAAACCTG



CAACAAGACTAGCCAACACCTGGCCATGAAACTTGCCCCTTCACTGATCTGGACTCA



CCTCTGGAGCCTATGGCTTTAAGCAAGCACTACTGCACTTTACAGAATTACCCCACT



GGATCCTGGACCCACAGAATTCCTTCAGGATCCTTCTTGCTGCCAGACTGAAAGCAA



AAGGAATTATTTCCCCTCAAGTTTTCTAAGTGATTTCCAAAAGCAGAGGTGTGTGGA



AATTTCCAGTAACAGAAACAGATGGGTTGCCAATAGAGTTATTTTTTATCTATAGCT



TCCTCTGGGTACTAGAAGAGGCTATTGAGACTATGAGCTCACAGACAGGGCTTCGCA



CAAACTCAAATCATAATTGACATGTTTTATGGATTACTGGAATCTTGATAGCATAAT



GAAGTTGTTCTAATTAACAGAGAGCATTTAAATATACACTAAGTGCACAAATTGTGG



AGTAAAGTCATCAAGCTCTGTTTTTGAGGTCTAAGTCACAAAGCATTTGTTTTAACC



TGTAATGGCACCATGTTTAATGGTGGTTTTTTTTTTGAACTACATCTTTCCTTTAAA



AATTATTGGTTTCTTTTTATTTGTTTTTACCTTAGAAATCAATTATATACAGTCAAA



AATATTTGATATGCTCATACGTTGTATCTGCAGCAATTTCAGATAAGTAGCTAAAAT



GGCCAAAGCCCCAAACTAAGCCTCCTTTTCTGGCCCTCAATATGACTTTAAATTTGA



CTTTTCAGTGCCTCAGTTTGCACATCTGTAATACAGCAATGCTAAGTAGTCAAGGCC



TTTGATAATTGGCACTATGGAAATCCTGCAAGATCCCACTACATATGTGTGGAGCAG



AAGGGTAACTCGGCTACAGTAACAGCTTAATTTTGTTAAATTTGTTCTTTATACTGG



AGCCATGAAGCTCAGAGCATTAGCTGACCCTTGAACTATTCAAATGGGCACATTAGC



TAGTATAACAGACTTACATAGGTGGGCCTAAAGCAAGCTCCTTAACTGAGCAAAATT



TGGGGCTTATGAGAATGAAAGGGTGTGAAATTGACTAACAGACAAATCATACATCTC



AGTTTCTCAATTCTCATGTAAATCAGAGAATGCCTTTAAAGAATAAAACTCAATTGT



TATTCTTCAACGTTCTTTATATATTCTACTTTTGGGTA (SEQ ID NO: 5)






>NP_079515.2 programmed cell death 1 ligand 2 precursor



[Homo sapiens]



MIFLLLMLSLELQLHQIAALFTVTVPKELYIIEHGSNVTLECNFDTGSHVNLGAITA



SLQKVENDTSPHRERATLLEEQLPLGKASFHIPQVQVRDEGQYQCIIIYGVAWDYKY



LTLKVKASYRKINTHILKVPETDEVELTCQATGYPLAEVSWPNVSVPANTSHSRTPE



GLYQVTSVLRLKPPPGRNFSCVFWNTHVRELTLASIDLQSQMEPRTHPTWLLHIFIP



FCIIAFIFIATVIALRKQLCQKLYSSKDTTKRPVTTTKREVNSAI (SEQ ID NO:



6)





Mouse PD-L2
>NM_021396.2 Mus musculus programmed cell death 1 ligand



2 (Pdcd1lg2), mRNA



GACCACATCATTTTTGTTCCCTTTGTTGGATATATCCTAATGTCAAATGTGGCATAT



CTTTGTTGTCTCCTTCTGTCTCCCAACTAGAGAGAACACACTTACGGCTCCTGTCCC



GGGCAGGTTTGGTTGTCGGTGTGATTGGCTTCCAGGGAACCTGATACAAGGAGCAAC



TGTGTGCTGCCTTTTCTGTGTCTTTGCTTGAGGAGCTGTGCTGGGTGCTGATATTGA



CACAGACCATGCTGCTCCTGCTGCCGATACTGAACCTGAGCTTACAACTTCATCCTG



TAGCAGCTTTATTCACCGTGACAGCCCCTAAAGAAGTGTACACCGTAGACGTCGGCA



GCAGTGTGAGCCTGGAGTGCGATTTTGACCGCAGAGAATGCACTGAACTGGAAGGGA



TAAGAGCCAGTTTGCAGAAGGTAGAAAATGATACGTCTCTGCAAAGTGAAAGAGCCA



CCCTGCTGGAGGAGCAGCTGCCCCTGGGAAAGGCTTTGTTCCACATCCCTAGTGTCC



AAGTGAGAGATTCCGGGCAGTACCGTTGCCTGGTCATCTGCGGGGCCGCCTGGGACT



ACAAGTACCTGACGGTGAAAGTCAAAGCTTCTTACATGAGGATAGACACTAGGATCC



TGGAGGTTCCAGGTACAGGGGAGGTGCAGCTTACCTGCCAGGCTAGAGGTTATCCCC



TAGCAGAAGTGTCCTGGCAAAATGTCAGTGTTCCTGCCAACACCAGCCACATCAGGA



CCCCCGAAGGCCTCTACCAGGTCACCAGTGTTCTGCGCCTCAAGCCTCAGCCTAGCA



GAAACTTCAGCTGCATGTTCTGGAATGCTCACATGAAGGAGCTGACTTCAGCCATCA



TTGACCCTCTGAGTCGGATGGAACCCAAAGTCCCCAGAACGTGGCCACTTCATGTTT



TCATCCCGGCCTGCACCATCGCTTTGATCTTCCTGGCCATAGTGATAATCCAGAGAA



AGAGGATCTAGGGGAAGCTGTATTACGGAAGAAGATCTGGACCTGCGGTCTTGGGAG



TTGGAAGGATCTGATGGGAAACCCTCAAGAGACTTCTGGACTCAAAGTGAGAATCTT



GCAGGACCTGCCATTTGCACTTTTGAACCCTTTGGACGGTGACCCAGGGCTCCGAAG



AGGAGCTTGTAAGACTGACAATCTTCCCTCTGTCTCAAGACTCTCTGAACAGCAAGA



CCCCAATGGCACTTTAGACTTACCCCTGGGATCCTGGACCCCAGTGAGGGCCTAAGG



CTCCTAATGACTTTCAGGGTGAGAACAAAAGGAATTGCTCTCCGCCCCACCCCCACC



TCCTGCTTTCCGCAGGGAGACATGGAAATTCCCAGTTACTAAAATAGATTGTCAATA



GAGTTATTTATAGCCCTCATTTCCTCCGGGGACTTGGAAGCTTCAGACAGGGTTTTT



CATAAACAAAGTCATAACTGATGTGTTTTACAGCATCCTAGAATCCTGGCAGCCTCT



GAAGTTCTAATTAACTGGAAGCATTTAAGCAACACGTTAAGTACCCCCACTGTGGTA



TTTGTTTCTACTTTTCTGTTTTTAAAGTGTGAGTCACAAGGTAATTGTTGTAACCTG



TGATATCACTGTTTCTTGTGTCTCTTCTTTCAACTACATCTTTTAAAACAAAACGGT



GTGGGGTTTGGTTGTTTTGGTGGTAGTGGTAGTGTTTCTCAGTGGTATCTCCTTAAG



AAAAAAAATCATCATGCCAGTGAATTGTTTCTTCAGCCATTTCAGATGGGAAGCTGG



AATAGCCTGTCCCCCAAGCTAAGCCTTCTTCCCTAGCTTTCTGCGTGATTTTACATT



GAGCATTCCTGTTGCTTTGTTTCTATAACTGTAATGTGGTGATGTCATTGTTAGGGC



ACTTGAGGGTGGGCGTTCTGGAAGTCCTTTCAGGTTAGTGTTTGGGGGCAGGGTTGC



TCAGAATACATAAAGGTGCTAACTTAAACTGCAGCCATGGAGCTCAGTGAATTCACT



AACCTTCGGGCTGTCCAAATGTGCACATTAGCTACTGTGACCCCTGTAGGTTAGGGA



GCCTGAAGCCAGCTCTTTACCTGGTGTTTAGACTCAGCAGAATTTGGAGTCAATGGG



ACCAAATGGTTGTGAAATTAAGATTTGAAGTGTGCATCTTATTTTATCACCATCTGC



CCAACAAAACTTCAGAAAATGCCTTTGAAGCACAAAAATGTAATCGTTTATGTGAAA



TCTCTGAGTTGCATTTAGATGCCCATTGCAGCAAGGTGGCTCTCTCACAGATTCCAC



ACCTTAGCCTAAGATACCAGACAGCAGGACAGAGAGAAAAGTCCTTCCTGGTGTGCA



AACTTCCTTACACTGGACCTCGCCTCTCAGGTGTGTGATTGGTAGGCCAAATCCCGA



TAGCCAATCGGTGTTGGGTGCTTTGTCTGCTCTACTGGGAGTCCAGTGGTACAATGG



ATTCTGGCAAAATGCTGCCATCTTGGCCCTCGCTGGGCTGCTTTCTAGGATATTCAT



AGAGAAAGGGCCGTCCAGATCCAGTATCCTAAAATCCTGAGAGGAGAATATAAGTTA



GTGTGTCTCACTATAACTATCTCTATGATCGGTCACATTACTATCTAACAGTTACCA



AATACTATATGCCTAATACTGGTAAGCATTTTATACACACCATTGGATTGAATCCTC



TCAAAATCCTCAAAAAGGAAGTTATTAATACCTCCATAGGCAAGGAGCCCAGAACCC



AGAGAGGTCAGGCAGTCTAGTTATAGATGCCTGCTTTGTTTAGAAGTGAACAAGAGC



ATCAAATTATTAATGTGCCCTGGTTATTAATGCGCCCTGGTTACCTGCTGGATGGAA



CATCAAGGTGGACTTTTGGCAGTTGCATACACCCAGAGGTATTTTGGCTATTCACGG



ATTAATTTCACACGAAGTGTTTCAGAGACATGTGTAGGGGAAGTCCGGGTTCAGGGG



GCCTAAGATTCAAACTCTAGCTTAGCTACGTCTGACCTCCCTAAGCACTAACTTACT



ATCAAAAGAATGAGCAGTAAAAGAATGGTGTTTACTGCCTGCCTTTATCAGGCAGTG



AACGTGCAGCGGGCAACGAATGCTTGATAAGTGTGTGTCAGTGTGAAGTCCCATGTA



CCAGCCGCTGTCCCCACTGCAAAAGCAGCAGAGCGCTCAGACATCATCAGCTGATTT



ACCAGCAGCAGATTTCTTCTTCTAGTCCCATCCCTGAAGAAGCTTCCAGCCTAGGTA



CATTGCATGGGCTTTGTGCTCCAGGAGTTCCTACACAGCCCTCAACTTCAACACAGG



CAAAGTGCTTACTGATCCTCATGTATCTTACAGGGTCCCCTCTACCCACAATACCTC



ATTGCTGGAACTTCAAATCTTCCTGAATAAAAGCTTGCCCGTGGTTTAATTA (SEQ



ID NO: 7)






>NP_067371.1 programmed cell death 1 ligand 2 precursor



[Mus musculus]



MLLLLPILNLSLQLHPVAALFTVTAPKEVYTVDVGSSVSLECDFDRRECTELEGIRA



SLQKVENDTSLQSERATLLEEQLPLGKALFHIPSVQVRDSGQYRCLVICGAAWDYKY



LTVKVKASYMRIDTRILEVPGTGEVQLTCQARGYPLAEVSWQNVSVPANTSHIRTPE



GLYQVTSVLRLKPQPSRNFSCMFWNAHMKELTSAIIDPLSRMEPKVPRTWPLHVFIP



ACTIALIFLAIVIIQRKRI (SEQ ID NO: 8)





Human
>NM_005214.5 Homo sapiens cytotoxic T-lymphocyte


CTLA-4
associated protein 4 (CTLA4), transcript variant 1, mRNA


(CD152)
GCTTTCTATTCAAGTGCCTTCTGTGTGTGCACATGTGTAATACATATCTGGGATCAA



AGCTATCTATATAAAGTCCTTGATTCTGTGTGGGTTCAAACACATTTCAAAGCTTCA



GGATCCTGAAAGGTTTTGCTCTACTTCCTGAAGACCTGAACACCGCTCCCATAAAGC



CATGGCTTGCCTTGGATTTCAGCGGCACAAGGCTCAGCTGAACCTGGCTACCAGGAC



CTGGCCCTGCACTCTCCTGTTTTTTCTTCTCTTCATCCCTGTCTTCTGCAAAGCAAT



GCACGTGGCCCAGCCTGCTGTGGTACTGGCCAGCAGCCGAGGCATCGCCAGCTTTGT



GTGTGAGTATGCATCTCCAGGCAAAGCCACTGAGGTCCGGGTGACAGTGCTTCGGCA



GGCTGACAGCCAGGTGACTGAAGTCTGTGCGGCAACCTACATGATGGGGAATGAGTT



GACCTTCCTAGATGATTCCATCTGCACGGGCACCTCCAGTGGAAATCAAGTGAACCT



CACTATCCAAGGACTGAGGGCCATGGACACGGGACTCTACATCTGCAAGGTGGAGCT



CATGTACCCACCGCCATACTACCTGGGCATAGGCAACGGAACCCAGATTTATGTAAT



TGATCCAGAACCGTGCCCAGATTCTGACTTCCTCCTCTGGATCCTTGCAGCAGTTAG



TTCGGGGTTGTTTTTTTATAGCTTTCTCCTCACAGCTGTTTCTTTGAGCAAAATGCT



AAAGAAAAGAAGCCCTCTTACAACAGGGGTCTATGTGAAAATGCCCCCAACAGAGCC



AGAATGTGAAAAGCAATTTCAGCCTTATTTTATTCCCATCAATTGAGAAACCATTAT



GAAGAAGAGAGTCCATATTTCAATTTCCAAGAGCTGAGGCAATTCTAACTTTTTTGC



TATCCAGCTATTTTTATTTGTTTGTGCATTTGGGGGGAATTCATCTCTCTTTAATAT



AAAGTTGGATGCGGAACCCAAATTACGTGTACTACAATTTAAAGCAAAGGAGTAGAA



AGACAGAGCTGGGATGTTTCTGTCACATCAGCTCCACTTTCAGTGAAAGCATCACTT



GGGATTAATATGGGGATGCAGCATTATGATGTGGGTCAAGGAATTAAGTTAGGGAAT



GGCACAGCCCAAAGAAGGAAAAGGCAGGGAGCGAGGGAGAAGACTATATTGTACACA



CCTTATATTTACGTATGAGACGTTTATAGCCGAAATGATCTTTTCAAGTTAAATTTT



ATGCCTTTTATTTCTTAAACAAATGTATGATTACATCAAGGCTTCAAAAATACTCAC



ATGGCTATGTTTTAGCCAGTGATGCTAAAGGTTGTATTGCATATATACATATATATA



TATATATATATATATATATATATATATATATATATATATATATATATTTTAATTTGA



TAGTATTGTGCATAGAGCCACGTATGTTTTTGTGTATTTGTTAATGGTTTGAATATA



AACACTATATGGCAGTGTCTTTCCACCTTGGGTCCCAGGGAAGTTTTGTGGAGGAGC



TCAGGACACTAATACACCAGGTAGAACACAAGGTCATTTGCTAACTAGCTTGGAAAC



TGGATGAGGTCATAGCAGTGCTTGATTGCGTGGAATTGTGCTGAGTTGGTGTTGACA



TGTGCTTTGGGGCTTTTACACCAGTTCCTTTCAATGGTTTGCAAGGAAGCCACAGCT



GGTGGTATCTGAGTTGACTTGACAGAACACTGTCTTGAAGACAATGGCTTACTCCAG



GAGACCCACAGGTATGACCTTCTAGGAAGCTCCAGTTCGATGGGCCCAATTCTTACA



AACATGTGGTTAATGCCATGGACAGAAGAAGGCAGCAGGTGGCAGAATGGGGTGCAT



GAAGGTTTCTGAAAATTAACACTGCTTGTGTTTTTAACTCAATATTTTCCATGAAAA



TGCAACAACATGTATAATATTTTTAATTAAATAAAAATCTGTGGTGGTCGTTTTCCG



GA (SEQ ID NO: 9)






>NP_005205.2 cytotoxic T-lymphocyte protein 4 isoform



CTLA4-TM precursor [Homo sapiens]



MACLGFQRHKAQLNLATRTWPCTLLFFLLFIPVFCKAMHVAQPAVVLASSRGIASFV



CEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNL



TIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEPCPDSDFLLWILAAVS



SGLFFYSFLLTAVSLSKMLKKRSPLTTGVYVKMPPTEPECEKQFQPYFIPIN (SEQ



ID NO: 10)





Mouse CTLA-
>NM_009843.4 Mus musculus cytotoxic T-lymphocyte-


4 (CD152)
associated protein 4 (Ctla4), transcript variant 1, mRNA



CTACACATATGTAGCACGTACCTTGGATCAAAGCTGTCTATATAAAGTCCCCGAGTC



TGTGTGGGTTCAAACACATCTCAAGGCTTCTGGATCCTGTTGGGTTTTACTCTGCTC



CCTGAGGACCTCAGCACATTTGCCCCCCAGCCATGGCTTGTCTTGGACTCCGGAGGT



ACAAAGCTCAACTGCAGCTGCCTTCTAGGACTTGGCCTTTTGTAGCCCTGCTCACTC



TTCTTTTCATCCCAGTCTTCTCTGAAGCCATACAGGTGACCCAACCTTCAGTGGTGT



TGGCTAGCAGCCATGGTGTCGCCAGCTTTCCATGTGAATATTCACCATCACACAACA



CTGATGAGGTCCGGGTGACTGTGCTGCGGCAGACAAATGACCAAATGACTGAGGTCT



GTGCCACGACATTCACAGAGAAGAATACAGTGGGCTTCCTAGATTACCCCTTCTGCA



GTGGTACCTTTAATGAAAGCAGAGTGAACCTCACCATCCAAGGACTGAGAGCTGTTG



ACACGGGACTGTACCTCTGCAAGGTGGAACTCATGTACCCACCGCCATACTTTGTGG



GCATGGGCAACGGGACGCAGATTTATGTCATTGATCCAGAACCATGCCCGGATTCTG



ACTTCCTCCTTTGGATCCTTGTCGCAGTTAGCTTGGGGTTGTTTTTTTACAGTTTCC



TGGTCACTGCTGTTTCTTTGAGCAAGATGCTAAAGAAAAGAAGTCCTCTTACAACAG



GGGTCTATGTGAAAATGCCCCCAACAGAGCCAGAATGTGAAAAGCAATTTCAGCCTT



ATTTTATTCCCATCAACTGAAAGGCCGTTTATGAAGAAGAAGGAGCATACTTCAGTC



TCTAAAAGCTGAGGCAATTTCAACTTTCCTTTTCTCTCCAGCTATTTTTACCTGTTT



GTATATTTTAAGGAGAGTATGCCTCTCTTTAATAGAAAGCTGGATGCAAAATTCCAA



TTAAGCATACTACAATTTAAAGCTAAGGAGCATGAACAGAGAGCTGGGATATTTCTG



TTGTGTCAGAACCATTTTACTAAAAGCATCACTTGGAAGCAGCATAAGGATATAGCA



TTATGGTGTGGGGTCAAGGGAACATTAGGGAATGGCACAGCCCAAAGAAAGGAAGGG



GGTGAAGGAAGAGATTATATTGTACACATCTTGTATTTACCTGAGAGATGTTTATGA



CTTAAATAATTTTTAAATTTTTCATGCTGTTATTTTCTTTAACAATGTATAATTACA



CGAAGGTTTAAACATTTATTCACAGAGCTATGTGACATAGCCAGTGGTTCCAAAGGT



TGTAGTGTTCCAAGATGTATTTTTAAGTAATATTGTACATGGGTGTTTCATGTGCTG



TTGTGTATTTGCTGGTGGTTTGAATATAAACACTATGTATCAGTGTCGTCCCACAGT



GGGTCCTGGGGAGGTTTGGCTGGGGAGCTTAGGACACTAATCCATCAGGTTGGACTC



GAGGTCCTGCACCAACTGGCTTGGAAACTAGATGAGGCTGTCACAGGGCTCAGTTGC



ATAAACCGATGGTGATGGAGTGTAAACTGGGTCTTTACACTCATTTTATTTTTTGTT



TCTGCTTTTGTTTTCTTCAATGATTTGCAAGGAAACCAAAAGCTGGCAGTGTTTGTA



TGAACCTGACAGAACACTGTCTTCAAGGAAATGCCTCATTCCTGAGACCAGTAGGTT



TGTTTTTTTAGGAAGTTCCAATACTAGGACCCCCTACAAGTACTATGGCTCCTCGAA



AACACAAAGTTAATGCCACAGGAAGCAGCAGATGGTAGGATGGGATGCACAAGAGTT



CCTGAAAACTAACACTGTTAGTGTTTTTTTTTTAACTCAATATTTTCCATGAAAATG



CAACCACATGTATAATATTTTTAATTAAATAAAAGTTTCTTGTGATTGTTTT (SEQ



ID NO: 11)






>NP_033973.2 cytotoxic T-lymphocyte protein 4 isoform 1



precursor [Mus musculus]



MACLGLRRYKAQLQLPSRTWPFVALLTLLFIPVFSEAIQVTQPSVVLASSHGVASFP



CEYSPSHNTDEVRVTVLRQTNDQMTEVCATTFTEKNTVGFLDYPFCSGTFNESRVNL



TIQGLRAVDTGLYLCKVELMYPPPYFVGMGNGTQIYVIDPEPCPDSDFLLWILVAVS



LGLFFYSFLVTAVSLSKMLKKRSPLTTGVYVKMPPTEPECEKQFQPYFIPIN (SEQ



ID NO: 12)





Human 4-
>NM_003811.4 Homo sapiens TNF superfamily member 9


1BBL
(TNFSF9), mRNA


(CD137L)
AGTCTCTCGTCATGGAATACGCCTCTGACGCTTCACTGGACCCCGAAGCCCCGTGGC



CTCCCGCGCCCCGCGCTCGCGCCTGCCGCGTACTGCCTTGGGCCCTGGTCGCGGGGC



TGCTGCTGCTGCTGCTGCTCGCTGCCGCCTGCGCCGTCTTCCTCGCCTGCCCCTGGG



CCGTGTCCGGGGCTCGCGCCTCGCCCGGCTCCGCGGCCAGCCCGAGACTCCGCGAGG



GTCCCGAGCTTTCGCCCGACGATCCCGCCGGCCTCTTGGACCTGCGGCAGGGCATGT



TTGCGCAGCTGGTGGCCCAAAATGTTCTGCTGATCGATGGGCCCCTGAGCTGGTACA



GTGACCCAGGCCTGGCAGGCGTGTCCCTGACGGGGGGCCTGAGCTACAAAGAGGACA



CGAAGGAGCTGGTGGTGGCCAAGGCTGGAGTCTACTATGTCTTCTTTCAACTAGAGC



TGCGGCGCGTGGTGGCCGGCGAGGGCTCAGGCTCCGTTTCACTTGCGCTGCACCTGC



AGCCACTGCGCTCTGCTGCTGGGGCCGCCGCCCTGGCTTTGACCGTGGACCTGCCAC



CCGCCTCCTCCGAGGCTCGGAACTCGGCCTTCGGTTTCCAGGGCCGCTTGCTGCACC



TGAGTGCCGGCCAGCGCCTGGGCGTCCATCTTCACACTGAGGCCAGGGCACGCCATG



CCTGGCAGCTTACCCAGGGCGCCACAGTCTTGGGACTCTTCCGGGTGACCCCCGAAA



TCCCAGCCGGACTCCCTTCACCGAGGTCGGAATAACGTCCAGCCTGGGTGCAGCCCA



CCTGGACAGAGTCCGAATCCTACTCCATCCTTCATGGAGACCCCTGGTGCTGGGTCC



CTGCTGCTTTCTCTACCTCAAGGGGCTTGGCAGGGGTCCCTGCTGCTGACCTCCCCT



TGAGGACCCTCCTCACCCACTCCTTCCCCAAGTTGGACCTTGATATTTATTCTGAGC



CTGAGCTCAGATAATATATTATATATATTATATATATATATATATTTCTATTTAAAG



AGGATCCTGAGTTTGTGAATGGACTTTTTTAGAGGAGTTGTTTTGGGGGGGGGGGGG



TCTTCGACATTGCCGAGGCTGGTCTTGAACTCCTGGACTTAGACGATCCTCCTGCCT



CAGCCTCCCAAGCAACTGGGATTCATCCTTTCTATTAATTCATTGTACTTATTTGCT



TATTTGTGTGTATTGAGCATCTGTAATGTGCCAGCATTGTGCCCAGGCTAGGGGGCT



ATAGAAACATCTAGAAATAGACTGAAAGAAAATCTGAGTTATGGTAATACGTGAGGA



ATTTAAAGACTCATCCCCAGCCTCCACCTCCTGTGTGATACTTGGGGGCTAGCTTTT



TTCTTTCTTTCTTTTTTTTGAGATGGTCTTGTTCTGTCAACCAGGCTAGAATGCAGC



GGTGCAATCATGAGTCAATGCAGCCTCCAGCCTCGACCTCCCGAGGCTCAGGTGATC



CTCCCATCTCAGCCTCTCGAGTAGCTGGGACCACAGTTGTGTGCCACCACACTTGGC



TAACTTTTTAATTTTTTTGCGGAGACGGTATTGCTATGTTGCCAAGGTTGTTTACAT



GCCAGTACAATTTATAATAAACACTCATTTTTCCTCCC (SEQ ID NO: 13)






>NP_003802.1 tumor necrosis factor ligand superfamily



member 9 [Homo sapiens]



MEYASDASLDPEAPWPPAPRARACRVLPWALVAGLLLLLLLAAACAVFLACPWAVSG



ARASPGSAASPRLREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPG



LAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLR



SAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQL



TQGATVLGLFRVTPEIPAGLPSPRSE (SEQ ID NO: 14)





Mouse 4-1BBL 
>NM_009404.3 Mus musculus tumor necrosis factor (ligand)


(CD137L)
superfamily, member 9 (Tnfsf9), mRNA



ATAAAGCACGGGCACTGGCGGGAGACGTGCACTGACCGACCGTGGTAATGGACCAGC



ACACACTTGATGTGGAGGATACCGCGGATGCCAGACATCCAGCAGGTACTTCGTGCC



CCTCGGATGCGGCGCTCCTCAGAGATACCGGGCTCCTCGCGGACGCTGCGCTCCTCT



CAGATACTGTGCGCCCCACAAATGCCGCGCTCCCCACGGATGCTGCCTACCCTGCGG



TTAATGTTCGGGATCGCGAGGCCGCGTGGCCGCCTGCACTGAACTTCTGTTCCCGCC



ACCCAAAGCTCTATGGCCTAGTCGCTTTGGTTTTGCTGCTTCTGATCGCCGCCTGTG



TTCCTATCTTCACCCGCACCGAGCCTCGGCCAGCGCTCACAATCACCACCTCGCCCA



ACCTGGGTACCCGAGAGAATAATGCAGACCAGGTCACCCCTGTTTCCCACATTGGCT



GCCCCAACACTACACAACAGGGCTCTCCTGTGTTCGCCAAGCTACTGGCTAAAAACC



AAGCATCGTTGTGCAATACAACTCTGAACTGGCACAGCCAAGATGGAGCTGGGAGCT



CATACCTATCTCAAGGTCTGAGGTACGAAGAAGACAAAAAGGAGTTGGTGGTAGACA



GTCCCGGGCTCTACTACGTATTTTTGGAACTGAAGCTCAGTCCAACATTCACAAACA



CAGGCCACAAGGTGCAGGGCTGGGTCTCTCTTGTTTTGCAAGCAAAGCCTCAGGTAG



ATGACTTTGACAACTTGGCCCTGACAGTGGAACTGTTCCCTTGCTCCATGGAGAACA



AGTTAGTGGACCGTTCCTGGAGTCAACTGTTGCTCCTGAAGGCTGGCCACCGCCTCA



GTGTGGGTCTGAGGGCTTATCTGCATGGAGCCCAGGATGCATACAGAGACTGGGAGC



TGTCTTATCCCAACACCACCAGCTTTGGACTCTTTCTTGTGAAACCCGACAACCCAT



GGGAATGAGAACTATCCTTCTTGTGACTCCTAGTTGCTAAGTCCTCAAGCTGCTATG



TTTTATGGGGTCTGAGCAGGGGTCCCTTCCATGACTTTCTCTTGTCTTTAACTGGAC



TTGGTATTTATTCTGAGCATAGCTCAGACAAGACTTTATATAATTCACTAGATAGCA



TTAGTAAACTGCTGGGCAGCTGCTAGATAAAAAAAAATTTCTAAATCAAAGTTTATA



TTTATATTAATATATAAAAATAAATGTGTTTGT (SEQ ID NO: 15)






>NP_033430.1 tumor necrosis factor ligand superfamily



member 9 [Mus musculus]



MDQHTLDVEDTADARHPAGTSCPSDAALLRDTGLLADAALLSDTVRPTNAALPTDAA



YPAVNVRDREAAWPPALNFCSRHPKLYGLVALVLLLLIAACVPIFTRTEPRPALTIT



TSPNLGTRENNADQVTPVSHIGCPNTTQQGSPVFAKLLAKNQASLCNTTLNWHSQDG



AGSSYLSQGLRYEEDKKELVVDSPGLYYVFLELKLSPTFTNTGHKVQGWVSLVLQAK



PQVDDFDNLALTVELFPCSMENKLVDRSWSQLLLLKAGHRLSVGLRAYLHGAQDAYR



DWELSYPNTTSFGLFLVKPDNPWE (SEQ ID NO: 16)





Human
>NM_003820.4 Homo sapiens TNF receptor superfamily member


HVEM
14 (TNFRSF14), transcript variant 1, DNA


(CD270)
ATACCGGCCCTTCCCCTCGGCTTTGCCTGGACAGCTCCTGCCTCCCGCAGGGCCCAC



CTGTGTCCCCCAGCGCCGCTCCACCCAGCAGGCCTGAGCCCCTCTCTGCTGCCAGAC



ACCCCCTGCTGCCCACTCTCCTGCTGCTCGGGTTCTGAGGCACAGCTTGTCACACCG



AGGCGGATTCTCTTTCTCTTTCTCTTTCTCTTCTGGCCCACAGCCGCAGCAATGGCG



CTGAGTTCCTCTGCTGGAGTTCATCCTGCTAGCTGGGTTCCCGAGCTGCCGGTCTGA



GCCTGAGGCATGGAGCCTCCTGGAGACTGGGGGCCTCCTCCCTGGAGATCCACCCCC



AAAACCGACGTCTTGAGGCTGGTGCTGTATCTCACCTTCCTGGGAGCCCCCTGCTAC



GCCCCAGCTCTGCCGTCCTGCAAGGAGGACGAGTACCCAGTGGGCTCCGAGTGCTGC



CCCAAGTGCAGTCCAGGTTATCGTGTGAAGGAGGCCTGCGGGGAGCTGACGGGCACA



GTGTGTGAACCCTGCCCTCCAGGCACCTACATTGCCCACCTCAATGGCCTAAGCAAG



TGTCTGCAGTGCCAAATGTGTGACCCAGCCATGGGCCTGCGCGCGAGCCGGAACTGC



TCCAGGACAGAGAACGCCGTGTGTGGCTGCAGCCCAGGCCACTTCTGCATCGTCCAG



GACGGGGACCACTGCGCCGCGTGCCGCGCTTACGCCACCTCCAGCCCGGGCCAGAGG



GTGCAGAAGGGAGGCACCGAGAGTCAGGACACCCTGTGTCAGAACTGCCCCCCGGGG



ACCTTCTCTCCCAATGGGACCCTGGAGGAATGTCAGCACCAGACCAAGTGCAGCTGG



CTGGTGACGAAGGCCGGAGCTGGGACCAGCAGCTCCCACTGGGTATGGTGGTTTCTC



TCAGGGAGCCTCGTCATCGTCATTGTTTGCTCCACAGTTGGCCTAATCATATGTGTG



AAAAGAAGAAAGCCAAGGGGTGATGTAGTCAAGGTGATCGTCTCCGTCCAGCGGAAA



AGACAGGAGGCAGAAGGTGAGGCCACAGTCATTGAGGCCCTGCAGGCCCCTCCGGAC



GTCACCACGGTGGCCGTGGAGGAGACAATACCCTCATTCACGGGGAGGAGCCCAAAC



CACTGACCCACAGACTCTGCACCCCGACGCCAGAGATACCTGGAGCGACGGCTGCTG



AAAGAGGCTGTCCACCTGGCGGAACCACCGGAGCCCGGAGGCTTGGGGGCTCCGCCC



TGGGCTGGCTTCCGTCTCCTCCAGTGGAGGGAGAGGTGGGGCCCCTGCTGGGGTAGA



GCTGGGGACGCCACGTGCCATTCCCATGGGCCAGTGAGGGCCTGGGGCCTCTGTTCT



GCTGTGGCCTGAGCTCCCCAGAGTCCTGAGGAGGAGCGCCAGTTGCCCCTCGCTCAC



AGACCACACACCCAGCCCTCCTGGGCCAGCCCAGAGGGCCCTTCAGACCCCAGCTGT



CTGCGCGTCTGACTCTTGTGGCCTCAGCAGGACAGGCCCCGGGCACTGCCTCACAGC



CAAGGCTGGACTGGGTTGGCTGCAGTGTGGTGTTTAGTGGATACCACATCGGAAGTG



ATTTTCTAAATTGGATTTGAATTCGGCTCCTGTTTTCTATTTGTCATGAAACAGTGT



ATTTGGGGAGATGCTGTGGGAGGATGTAAATATCTTGTTTCTCCTCAAA (SEQ ID



NO: 17)






>NP_003811.2 tumor necrosis factor receptor superfamily



member 14 isoform 1 precursor [Homo sapiens]



MEPPGDWGPPPWRSTPKTDVLRLVLYLTFLGAPCYAPALPSCKEDEYPVGSECCPKC



SPGYRVKEACGELTGTVCEPCPPGTYIAHLNGLSKCLQCQMCDPAMGLRASRNCSRT



ENAVCGCSPGHFCIVQDGDHCAACRAYATSSPGQRVQKGGTESQDTLCQNCPPGTFS



PNGTLEECQHQTKCSWLVTKAGAGTSSSHWVWWFLSGSLVIVIVCSTVGLIICVKRR



KPRGDVVKVIVSVQRKRQEAEGEATVIEALQAPPDVTTVAVEETIPSFTGRSPNH



(SEQ ID NO: 18)





Mouse HVEM
>NM_178931.2 Mus musculus tumor necrosis factor receptor


(CD270)
superfamily, member 14 (herpesvirus entry mediator)



(Tnfrsf14), mRNA



GCTCTTGGCCTGAAGTTTCTTGATCAAGAAAATGGAACCTCTCCCAGGATGGGGGTC



GGCACCCTGGAGCCAGGCCCCTACAGACAACACCTTCAGGCTGGTGCCTTGTGTCTT



CCTTTTGAACTTGCTGCAGCGCATCTCTGCCCAGCCCTCATGCAGACAGGAGGAGTT



CCTTGTGGGAGACGAGTGCTGCCCCATGTGCAACCCAGGTTACCATGTGAAGCAGGT



CTGCAGTGAGCATACAGGCACAGTGTGTGCCCCCTGTCCCCCACAGACATATACCGC



CCATGCAAATGGCCTGAGCAAGTGTCTGCCCTGCGGAGTCTGTGATCCAGACATGGG



CCTGCTGACCTGGCAGGAGTGCTCCAGCTGGAAGGACACTGTGTGCAGATGCATCCC



AGGCTACTTCTGTGAGAACCAGGATGGGAGCCACTGTTCCACATGCTTGCAGCACAC



CACCTGCCCTCCAGGGCAGAGGGTAGAGAAGAGAGGGACTCACGACCAGGACACTGT



ATGTGCTGACTGCCTAACAGGGACCTTCTCACTTGGAGGGACTCAGGAGGAATGCCT



GCCCTGGACCAACTGCAGTGCATTTCAACAGGAAGTAAGACGTGGGACCAACAGCAC



AGACACCACCTGCTCCTCCCAGGTCGTCTACTACGTTGTGTCCATCCTTTTGCCACT



TGTGATAGTGGGAGCTGGGATAGCTGGATTCCTCATCTGCACGCGAAGACACCTGCA



CACCAGCTCAGTGGCCAAGGAGCTGGAGCCTTTCCAGGAACAACAGGAGAACACCAT



CAGGTTTCCAGTCACCGAGGTTGGGTTTGCTGAGACCGAGGAGGAGACAGCCTCCAA



CTGAACAAATTCTGGGTGACAAGACACCGAGGAGACGT (SEQ ID NO: 19)






>NP_849262.1 tumor necrosis factor receptor superfamily



member 14 precursor [Mus musculus]



MEPLPGWGSAPWSQAPTDNTFRLVPCVFLLNLLQRISAQPSCRQEEFLVGDECCPMC



NPGYHVKQVCSEHTGTVCAPCPPQTYTAHANGLSKCLPCGVCDPDMGLLTWQECSSW



KDTVCRCIPGYFCENQDGSHCSTCLQHTTCPPGQRVEKRGTHDQDTVCADCLTGTFS



LGGTQEECLPWTNCSAFQQEVRRGTNSTDTTCSSQVVYYVVSILLPLVIVGAGIAGF



LICTRRHLHTSSVAKELEPFQEQQENTIRFPVTEVGFAETEEETASN (SEQ ID



NO: 20)





Human FGL1
>NM_004467.4 Homo sapiens fibrinogen like 1 (FGL1),



transcript variant 1, mRNA



AATGCAGTTACAGGATCCTGGGAAGCAGAGTGTCTGGATGGAACCTGAGCTGGGTCT



CTGACTCACTTCTGACTTTAGTTTTTTCAAGGGGGAACATGGCAAAGGTGTTCAGTT



TCATCCTTGTTACCACCGCTCTGACAATGGGCAGGGAAATTTCGGCGCTCGAGGACT



GTGCCCAGGAGCAGATGCGGCTCAGAGCCCAGGTGCGCCTGCTTGAGACCCGGGTCA



AACAGCAACAGGTCAAGATCAAGCAGCTTTTGCAGGAGAATGAAGTCCAGTTCCTTG



ATAAAGGAGATGAGAATACTGTCATTGATCTTGGAAGCAAGAGGCAGTATGCAGATT



GTTCAGAGATTTTCAATGATGGGTATAAGCTCAGTGGATTTTACAAAATCAAACCTC



TCCAGAGCCCAGCAGAATTTTCTGTTTATTGTGACATGTCCGATGGAGGAGGATGGA



CTGTAATTCAGAGACGATCTGATGGCAGTGAAAACTTTAACAGAGGATGGAAAGACT



ATGAAAATGGCTTTGGAAATTTTGTCCAAAAACATGGTGAATATTGGCTGGGCAATA



AAAATCTTCACTTCTTGACCACTCAAGAAGACTACACTTTAAAAATCGACCTTGCAG



ATTTTGAAAAAAATAGCCGTTATGCACAATATAAGAATTTCAAAGTTGGAGATGAAA



AGAATTTCTACGAGTTGAATATTGGGGAATATTCTGGAACAGCTGGAGATTCCCTTG



CGGGGAATTTTCATCCTGAGGTGCAGTGGTGGGCTAGTCACCAAAGAATGAAATTCA



GCACGTGGGACAGAGATCATGACAACTATGAAGGGAACTGCGCAGAAGAAGATCAGT



CTGGCTGGTGGTTTAACAGGTGTCACTCTGCAAACCTGAATGGTGTATACTACAGCG



GCCCCTACACGGCTAAAACAGACAATGGGATTGTCTGGTACACCTGGCATGGGTGGT



GGTATTCTCTGAAATCTGTGGTTATGAAAATTAGGCCAAATGATTTTATTCCAAATG



TAATTTAATTGCTGCTGTTGGGCTTTCGTTTCTGCAATTCAGCTTTGTTTAAAGTGA



TTTGAAAAATACTCATTCTGAACATATCCATGCGCAATCATGATAACTGTTGTGAGT



AGTGCTTTTCATTCTTCTCACTTGCCTTTGTTACTTAATGTGCTTTCAGTACAGCAG



ATATGCAATATTCACCAAATAAATGTAGACTGTGTTAATA (SEQ ID NO: 21)






>NP_004458.3 fibrinogen-like protein 1 precursor [Homo




sapiens]




MAKVFSFILVTTALTMGREISALEDCAQEQMRLRAQVRLLETRVKQQQVKIKQLLQE



NEVQFLDKGDENTVIDLGSKRQYADCSEIFNDGYKLSGFYKIKPLQSPAEFSVYCDM



SDGGGWTVIQRRSDGSENFNRGWKDYENGFGNFVQKHGEYWLGNKNLHFLTTQEDYT



LKIDLADFEKNSRYAQYKNFKVGDEKNFYELNIGEYSGTAGDSLAGNFHPEVQWWAS



HQRMKFSTWDRDHDNYEGNCAEEDQSGWWFNRCHSANLNGVYYSGPYTAKTDNGIVW



YTWHGWWYSLKSVVMKIRPNDFIPNVI (SEQ ID NO: 22)





Mouse FGL1
>NM_145594.2 Mus musculus fibrinogen-like protein 1



(Fgl1), mRNA



GTTAGAAGTTCCTGGGAGGCTCTGTGTGGATGGACTGAGCCTAGCTAAGTCCTGATT



CATTTTGACTTGAGTTCTCTCAGTGGGAAGAATGGGAAAGATTTACAGCTTCGTCCT



GGTCGCCATTGCTCTGATGATGGGAAGGGAAGGTTGGGCCCTCGAGAGTGAGAACTG



CTTGCGGGAGCAGGTGAGGCTCAGGGCTCAGGTGCACCAGCTTGAGACCCGGGTCAA



ACAACAACAGACCATGATTGCACAGCTCTTGCATGAGAAGGAAGTCCAGTTTCTGGA



TAAAGGATCGGAGAACAGTTTCATTGACCTTGGAGGCAAGAAGCAGTATGCAGATTG



TTCAGAGATTTACAATGACGGATTTAAGCAGAGTGGATTTTACAAAATCAAACCTCT



TCAGAGCCTGGCAGAATTCTCTGTTTATTGTGACATGTCTGATGGAGGGGGATGGAC



TGTAATTCAGAGACGATCTGATGGCAGTGAGAACTTTAACAGGGGTTGGAATGACTA



TGAAAATGGCTTTGGAAACTTTGTCCAAAACAATGGCGAATACTGGCTGGGTAACAA



AAACATTAACTTGCTAACTATTCAAGGAGACTACACTTTAAAAATCGACCTGACAGA



TTTTGAGAAAAACAGCAGCTTCGCACAATACCAAAGTTTTAAAGTTGGTGATAAAAA



GTCTTTTTATGAACTAAATATTGGAGAATATTCTGGCACAGCTGGAGATTCCCTGTC



AGGAACTTTTCATCCTGAAGTACAGTGGTGGGCTAGTCACCAAAGGATGAAGTTCAG



CACGTGGGACAGAGATAACGACAATTACCAAGGAAACTGTGCTGAGGAAGAGCAGTC



TGGCTGGTGGTTTAACAGGTGTCACTCTGCAAACCTGAACGGTGTTTACTACCGTGG



TTCCTACAGGGCAGAAACGGATAATGGTGTTGTGTGGTACACCTGGCATGGGTGGTG



GTATTCCTTGAAATCTGTGGTTATGAAAATTAGGCCAAGTGATTTTATTCCAAATAT



TATTTAGTTGCCCTCATTGGGATCTCCTTTCTGTAATTCATCTTGGTTTACTTGAAA



ATAAATATTTGAAAAAGATATAATTCTGAATAACACA (SEQ ID NO: 23)






>NP_663569.2 fibrinogen-like protein 1 precursor [Mus




musculus]




MGKIYSFVLVAIALMMGREGWALESENCLREQVRLRAQVHQLETRVKQQQTMIAQLL



HEKEVQFLDKGSENSFIDLGGKKQYADCSEIYNDGFKQSGFYKIKPLQSLAEFSVYC



DMSDGGGWTVIQRRSDGSENFNRGWNDYENGFGNFVQNNGEYWLGNKNINLLTIQGD



YTLKIDLTDFEKNSSFAQYQSFKVGDKKSFYELNIGEYSGTAGDSLSGTFHPEVQWW



ASHQRMKFSTWDRDNDNYQGNCAEEEQSGWWFNRCHSANLNGVYYRGSYRAETDNGV



VWYTWHGWWYSLKSVVMKIRPSDFIPNII (SEQ ID NO: 24)





Human OX-2
>NM_005944.7 Homo sapiens CD200 molecule (CD200),


(CD200)
transcript variant 1, mRNA



AGAGCTCCAGGCGCACATCCGCAGTCAGCCACCTCGCGCGCGCCTCCAGGAGCAAGG



ATGGAGAGGCTGGTGATCAGGATGCCCTTCTCTCATCTGTCTACCTACAGCCTGGTT



TGGGTCATGGCAGCAGTGGTGCTGTGCACAGCACAAGTGCAAGTGGTGACCCAGGAT



GAAAGAGAGCAGCTGTACACACCTGCTTCCTTAAAATGCTCTCTGCAAAATGCCCAG



GAAGCCCTCATTGTGACATGGCAGAAAAAGAAAGCTGTAAGCCCAGAAAACATGGTC



ACCTTCAGCGAGAACCATGGGGTGGTGATCCAGCCTGCCTATAAGGACAAGATAAAC



ATTACCCAGCTGGGACTCCAAAACTCAACCATCACCTTCTGGAATATCACCCTGGAG



GATGAAGGGTGTTACATGTGTCTCTTCAATACCTTTGGTTTTGGGAAGATCTCAGGA



ACGGCCTGCCTCACCGTCTATGTACAGCCCATAGTATCCCTTCACTACAAATTCTCT



GAAGACCACCTAAATATCACTTGCTCTGCCACTGCCCGCCCAGCCCCCATGGTCTTC



TGGAAGGTCCCTCGGTCAGGGATTGAAAATAGTACAGTGACTCTGTCTCACCCAAAT



GGGACCACGTCTGTTACCAGCATCCTCCATATCAAAGACCCTAAGAATCAGGTGGGG



AAGGAGGTGATCTGCCAGGTGCTGCACCTGGGGACTGTGACCGACTTTAAGCAAACC



GTCAACAAAGGCTATTGGTTTTCAGTTCCGCTATTGCTAAGCATTGTTTCCCTGGTA



ATTCTTCTCGTCCTAATCTCAATCTTACTGTACTGGAAACGTCACCGGAATCAGGAC



CGAGAGCCCTAAATAAGTCACACAGCACCCTGAAAGTGATTCCCTGGTCTACTTGAA



TTTGACACAAGAGAAAAGCAGGAGGAAAAGGGGCCATTCTCCAAAGGACCTGAAAGA



GCAAAAGAGGTGGGAGCGAAAGCCTTAAGGATCCCACGACTTTTTACTGCCATCTGA



GCTACTCAGTGTTTGAATCCCAAGAGGAAGTCAGTTTACCTCTCAGGTCTGTTGTAG



GACTTGATTTTGTAAAGCAATGCCATGTTATGTGGTTGAAAGGGCACTGGACTTAGT



TAGTATCAGGAGCACTGAGCTCACAGACTGACTTGGGCTCCTACTGGTGGGGACCTC



TGTTAGTCACTTTACCTCATCCAAAGTATAAAGGAATTGGACCAAATAATTTACCAC



ATAGCTCTAAAACTTAATTTAAAATGTAATTCCAGAAAAAAAAAGGGAATAAGCAAA



GGGGGAAGAATTGAAAGAGAGAGAGAAGAAAGAATACAGAGAGCTTACCTTTTGCCT



TTCTGTTGATGTTACATCTCTTCTTCCTATGTTCTTAGGTCTATGAGTCTGTTTCCC



CATCATTTGGTATCTAGTCCAGTTCCTGCTTACTGCTTTGCTAATAGCTGGCCTTGC



TAGAATCCTTGGTTTCACTGCTGTTCTTCATGTGCTTCTATGAGATTTACTCCAACA



CAAATAGGACTGAATTTATTGTGAAGTAACATTGGCAATCTTAACTTATTCATTTAA



CTTATTTTTATAGCTAGATAAATATTGTTAGTCTTAGACAATAGCTCACATTTTTTG



AGAAGCATGCCCTCCCTGTCCATTTGTCTTATAACATGACCCAGCCCTATTTTACGT



CATTCTAAATTCAGCCTCATATAATGAAAATACATTATGAAAACAGATGTTTAGGAG



ATTTCCTGTATAGCAGTCAGCCAATTCATATGCTTTGTCTCTGCTGGCTTCTTTTTC



CATGCGTTAACTTTTCCCAATAGCAGAGGAGGCAAATATGAGCATACAATCCCTTTG



TTCTAAAGATATTGTTCCAGCTAGTGGAATGATGTTGAATCTTTAATAACCATAATT



AGTTGCTTTTTCAGTATCTTCTGCTTTGTCTGTGTCTATCCAGTGGCCTAGGAATTA



AAGTGTAAGTTGTTTTCGCTGTTAAATTGGATATTTATATATATATATAGCAAGATT



TTCATGTGTTATTTAATTCTGTATTGTTTCTTATATTTGTAGTAAAATATTGAACAA



TTAAAAGTGTTGACTCCAAA (SEQ ID NO: 25)






>NP_005935.4 OX-2 membrane glycoprotein isoform a



precursor [Homo sapiens]



MERLVIRMPFSHLSTYSLVWVMAAVVLCTAQVQVVTQDEREQLYTPASLKCSLQNAQ



EALIVTWQKKKAVSPENMVTFSENHGVVIQPAYKDKINITQLGLQNSTITFWNITLE



DEGCYMCLFNTFGFGKISGTACLTVYVQPIVSLHYKFSEDHLNITCSATARPAPMVF



WKVPRSGIENSTVTLSHPNGTTSVTSILHIKDPKNQVGKEVICQVLHLGTVTDFKQT



VNKGYWFSVPLLLSIVSLVILLVLISILLYWKRHRNQDREP (SEQ ID NO: 26)





Mouse OX-2
>NM_010818.3 Mus musculus CD200 antigen (Cd200),


(CD200)
transcript variant 1, mRNA



GGGCGTGGTTGGTTGGTCGTCTCTTCCTCCACACTAGAGGAGCTGTAGAGTCTGCCT



GTGCAGTGGAGGGGGCTCTCTCTACGGCGAATAGTAGTGTCCCTGCTCACAGGTGTT



GCGGAGATATCCTCCATCGTGGAAGAGCTCAGACCCCGAGAAGCTGGTGTCTAGCTG



CGGCCCAGAGCAAGGATGGGCAGTCTGGTATTCAGGAGACCTTTCTGCCATCTCTCC



ACCTACAGCCTGATTTGGGGCATGGCAGCAGTAGCGCTGAGCACAGCTCAAGTGGAA



GTGGTGACCCAGGATGAAAGAAAGGCGCTGCACACAACTGCATCCTTACGATGTTCT



CTAAAAACATCCCAGGAACCCTTGATTGTGACATGGCAGAAAAAGAAAGCCGTGAGC



CCAGAAAACATGGTCACCTACAGCAAAACCCATGGGGTTGTAATCCAGCCTGCCTAC



AAAGACAGGATAAATGTCACAGAGCTGGGACTCTGGAACTCAAGCATCACCTTCTGG



AACACAACATTGGAAGATGAGGGCTGCTACATGTGTCTCTTCAACACGTTTGGTTCT



CAGAAGGTCTCAGGAACAGCTTGCCTTACCCTCTATGTACAGCCCATAGTACACCTT



CACTACAACTATTTTGAAGACCACCTAAACATCACTTGCTCTGCGACTGCCCGTCCA



GCCCCTGCCATCTCCTGGAAGGGTACTGGGACAGGAATTGAGAATAGTACCGAGAGT



CACTTCCATTCAAATGGGACTACATCTGTCACCAGCATCCTCCGGGTCAAAGACCCC



AAAACTCAAGTTGGGAAGGAAGTGATCTGCCAGGTTTTATACCTGGGGAATGTGATT



GACTACAAGCAGAGTCTGGACAAAGGATTTTGGTTTTCAGTTCCACTGTTGCTAAGC



ATTGTTTCTCTGGTAATTCTTCTGATCTTGATCTCCATCTTACTATACTGGAAACGT



CACCGAAATCAGGAGCGGGGTGAATCATCACAGGGGATGCAAAGAATGAAATAAGAG



CTCTAAAGAAATTATACAGAACCCTGAACGTGTTTCCCTGGTCTACTTGAATCTGAT



GTGAAAGAAAAGCAGGAGGGAAAAGGCCATTCTCCATAGGACCTAAGGAGAGCAAAA



GACCAGACACGAGCCTGTGAGGGATTTGACTTTTTGCTGTTGTCCCAGGTCCTCGGT



GTTTGCATTCCAAGAGGAAGTCGAGTGCCTCGGGTCTGTTGTAGGACTTGATTTTTT



TTTTTTTTGTAGAGCAATGCAGTGCCATGCTGTTAGAAAGGCTCCAGACTTAGAACC



ACCAGTGCCAAGCCAGCTCTCAGACCGACTAGGGCTCCCATCGGAGGAACAAATCGT



AGTCAACTTACCTCACAGAGCTCTCTGGTCCTTACACAAAGTAGAAAGGAGTGGGAC



CAGAAAATTGGCCATGTCTGAAATCTGATGGAATTTTTAGGAAGAAAACTGAAGAAT



AAGCAAAAGAAGAAAGAACACAGAAGGGTCCAAAGAGCTTCTGAGAGTACCTTTTGC



CTTTCTGTTGGTGTCCCAGCTCTGGTTTTGTTCTTAGGTCCGCCAGTGTGTTTCCCT



GTTGTTTGAGTATCTAGTTGACTACCTGCTACTGTTCTGCTGATGGTTGGCCTTGCT



AGAATCCCTGACTCCCCTGCCGTTCTCTATGTGCTTCTATGAGGGTTACTATGATGA



AAATAGAGCAGAAGATAGTGTGAAGTAACATTGGCAACTGTAATGTGTCCATTTAAC



TTATTTTTATAGCACTTAGGCAATATTGTTAGTCTTAGTGAGTAGTTCACATCTTTA



CAAAAGCATGCTCTCCCTATCCATTGGGCCCACAATAACACTCTCTTTGAGGCCATT



CTGAATCCTGTCTCGTGTAATGATAATATATTATGAAAACAGATACTTTAAGAATTT



CCTGTACAGCAGTCAGTTGTTTATTCTCTCTCTCTCTCTCTCTCTCTCTCTCCCTCC



CCCACCCCAGCTTCTTTTTCTGTGACTTTGTTTTTCATAAAGAGAAGGCATCTCCTG



AATACAATCGCTTTGTTCTGAAGACATCGTGAACTATTAATTCTTAACCCTTTGACA



AAACTAGTGAAGTTGTTTTCTGTATCTTTTGCTTCATCTGTCTTTATAGAGTGACCT



AGGAATTCAAGTGTAAGTTGTTTCCATTGTTGAACTGGATATTTATATACTTGGTAT



GCTTTTCACGTGTTATTTAATTCTGTATAATTTCCTATATTTGTATTAAAATATTGA



GCAATTAAAAGTGTCAACTAAATATTTGATGTGGCATTCCCTTGAGAAATATAGAAA



TAAAGAATAAAAAAAAAAAAAAAAAA (SEQ ID NO: 27)






>NP_034948.3 OX-2 membrane glycoprotein isoform 1



precursor [Mus musculus]



MGSLVFRRPFCHLSTYSLIWGMAAVALSTAQVEVVTQDERKALHTTASLRCSLKTSQ



EPLIVTWQKKKAVSPENMVTYSKTHGVVIQPAYKDRINVTELGLWNSSITFWNTTLE



DEGCYMCLENTFGSQKVSGTACLTLYVQPIVHLHYNYFEDHLNITCSATARPAPAIS



WKGTGTGIENSTESHFHSNGTTSVTSILRVKDPKTQVGKEVICQVLYLGNVIDYKQS



LDKGFWFSVPLLLSIVSLVILLILISILLYWKRHRNQERGESSQGMQRMK (SEQ ID



NO: 28)





Human
>NM_009587.3 Homo sapiens galectin 9 (LGALS9), transcript


Galectin-9
variant 1, mRNA



CTTTGTTAAGTCGTTCCCTCTACAAAGGACTTCCTAGTGGGTGTGAAAGGCAGCGGT



GGCCACAGAGGCGGCGGAGAGATGGCCTTCAGCGGTTCCCAGGCTCCCTACCTGAGT



CCAGCTGTCCCCTTTTCTGGGACTATTCAAGGAGGTCTCCAGGACGGACTTCAGATC



ACTGTCAATGGGACCGTTCTCAGCTCCAGTGGAACCAGGTTTGCTGTGAACTTTCAG



ACTGGCTTCAGTGGAAATGACATTGCCTTCCACTTCAACCCTCGGTTTGAAGATGGA



GGGTACGTGGTGTGCAACACGAGGCAGAACGGAAGCTGGGGGCCCGAGGAGAGGAAG



ACACACATGCCTTTCCAGAAGGGGATGCCCTTTGACCTCTGCTTCCTGGTGCAGAGC



TCAGATTTCAAGGTGATGGTGAACGGGATCCTCTTCGTGCAGTACTTCCACCGCGTG



CCCTTCCACCGTGTGGACACCATCTCCGTCAATGGCTCTGTGCAGCTGTCCTACATC



AGCTTCCAGAACCCCCGCACAGTCCCTGTTCAGCCTGCCTTCTCCACGGTGCCGTTC



TCCCAGCCTGTCTGTTTCCCACCCAGGCCCAGGGGGCGCAGACAAAAACCTCCCGGC



GTGTGGCCTGCCAACCCGGCTCCCATTACCCAGACAGTCATCCACACAGTGCAGAGC



GCCCCTGGACAGATGTTCTCTACTCCCGCCATCCCACCTATGATGTACCCCCACCCC



GCCTATCCGATGCCTTTCATCACCACCATTCTGGGAGGGCTGTACCCATCCAAGTCC



ATCCTCCTGTCAGGCACTGTCCTGCCCAGTGCTCAGAGGTTCCACATCAACCTGTGC



TCTGGGAACCACATCGCCTTCCACCTGAACCCCCGTTTTGATGAGAATGCTGTGGTC



CGCAACACCCAGATCGACAACTCCTGGGGGTCTGAGGAGCGAAGTCTGCCCCGAAAA



ATGCCCTTCGTCCGTGGCCAGAGCTTCTCAGTGTGGATCTTGTGTGAAGCTCACTGC



CTCAAGGTGGCCGTGGATGGTCAGCACCTGTTTGAATACTACCATCGCCTGAGGAAC



CTGCCCACCATCAACAGACTGGAAGTGGGGGGCGACATCCAGCTGACCCATGTGCAG



ACATAGGCGGCTTCCTGGCCCTGGGGCCGGGGGCTGGGGTGTGGGGCAGTCTGGGTC



CTCTCATCATCCCCACTTCCCAGGCCCAGCCTTTCCAACCCTGCCTGGGATCTGGGC



TTTAATGCAGAGGCCATGTCCTTGTCTGGTCCTGCTTCTGGCTACAGCCACCCTGGA



ACGGAGAAGGCAGCTGACGGGGATTGCCTTCCTCAGCCGCAGCAGCACCTGGGGCTC



CAGCTGCTGGAATCCTACCATCCCAGGAGGCAGGCACAGCCAGGGAGAGGGGAGGAG



TGGGCAGTGAAGATGAAGCCCCATGCTCAGTCCCCTCCCATCCCCCACGCAGCTCCA



CCCCAGTCCCAAGCCACCAGCTGTCTGCTCCTGGTGGGAGGTGGCCTCCTCAGCCCC



TCCTCTCTGACCTTTAACCTCACTCTCACCTTGCACCGTGCACCAACCCTTCACCCC



TCCTGGAAAGCAGGCCTGATGGCTTCCCACTGGCCTCCACCACCTGACCAGAGTGTT



CTCTTCAGAGGACTGGCTCCTTTCCCAGTGTCCTTAAAATAAAGAAATGAAAATGCT



TGTTGGCACATTCA (SEQ ID NO: 29)






>NP_033665.1 galectin-9 isoform long [Homo sapiens]



MAFSGSQAPYLSPAVPFSGTIQGGLQDGLQITVNGTVLSSSGTRFAVNFQTGFSGND



IAFHFNPRFEDGGYVVCNTRQNGSWGPEERKTHMPFQKGMPFDLCFLVQSSDFKVMV



NGILFVQYFHRVPFHRVDTISVNGSVQLSYISFQNPRTVPVQPAFSTVPFSQPVCFP



PRPRGRRQKPPGVWPANPAPITQTVIHTVQSAPGQMFSTPAIPPMMYPHPAYPMPFI



TTILGGLYPSKSILLSGTVLPSAQRFHINLCSGNHIAFHLNPRFDENAVVRNTQIDN



SWGSEERSLPRKMPFVRGQSFSVWILCEAHCLKVAVDGQHLFEYYHRLRNLPTINRL



EVGGDIQLTHVQT (SEQ ID NO: 30)





Mouse
>NM_010708.2 Mus musculus lectin, galactose binding,


Galectin-9
soluble 9 (Lgals9), transcript variant 1, mRNA



GCCAAATAGCTGTGGTTTCTGTTTCCTAGCTCAGCCCTGCCCTGCGCAGAGTTCTGT



CGTCCACCATCGAGTGAGGAAGAGAGCATTGGTTCCCCTGAGATAGAAGAGATGGCT



CTCTTCAGTGCCCAGTCTCCATACATTAACCCGATCATCCCCTTTACTGGACCAATC



CAAGGAGGGCTGCAGGAGGGACTTCAGGTGACCCTCCAGGGGACTACCAAGAGTTTT



GCACAAAGGTTTGTGGTGAACTTTCAGAACAGCTTCAATGGAAATGACATTGCCTTC



CACTTCAACCCCCGGTTTGAGGAAGGAGGGTATGTGGTTTGCAACACGAAGCAGAAC



GGACAGTGGGGTCCTGAGGAGAGAAAGATGCAGATGCCCTTCCAGAAGGGGATGCCC



TTTGAGCTTTGCTTCCTGGTGCAGAGGTCAGAGTTCAAGGTGATGGTGAACAAGAAA



TTCTTTGTGCAGTACCAACACCGCGTACCCTACCACCTCGTGGACACCATCGCTGTC



TCCGGCTGCTTGAAGCTGTCCTTTATCACCTTCCAGAACTCTGCAGCCCCTGTCCAG



CATGTCTTCTCCACAGTGCAGTTCTCTCAGCCAGTCCAGTTCCCACGGACCCCTAAG



GGGCGCAAACAGAAAACTCAGAACTTTCGTCCTGCCCACCAGGCACCCATGGCTCAA



ACTACCATCCATATGGTTCACAGCACCCCTGGACAGATGTTCTCTACTCCTGGAATC



CCTCCTGTGGTGTACCCCACCCCAGCCTATACCATACCTTTCTACACCCCCATTCCA



AATGGGCTTTACCCGTCCAAGTCCATCATGATATCAGGCAATGTCTTGCCAGATGCT



ACGAGGTTCCATATCAACCTTCGCTGTGGAGGTGACATTGCTTTCCACCTGAACCCC



CGTTTCAATGAGAATGCTGTTGTCCGAAACACTCAGATCAACAACTCCTGGGGGCAG



GAAGAGCGAAGTCTGCTTGGGAGGATGCCCTTCAGTCGAGGCCAGAGCTTCTCGGTG



TGGATCATATGTGAAGGTCACTGCTTCAAGGTAGCTGTGAATGGTCAACACATGTGT



GAATATTACCACCGCCTGAAGAACTTGCAGGATATCAACACTCTAGAAGTGGCGGGT



GATATCCAGCTGACCCACGTGCAGACATAGGCAAGGTCTCTGGCCTAGGGATAAGGG



CTGGAGCACTCTGCCTGTGTCTTATCTTTCCCCTGTCTCAGCCCTGGCACCATCAGA



AGAGATCATCACTTATAGGAATTCCAGGAAGGTGAAATTCCCAATTGACTCCCTCCA



CAAAGGGGGTTTTCTAGGCTGTGTGGCACATGGCTGTCAGCCCATAGTCTGAGCCAT



TGCCCCCAAGCTAGCTATATACTGAGGGAAGTGACCCTCCTGGGTTTGCTCAGATCT



CTGATCGTTCCCCCCTCTGTGGCCCTTTTCTTTCACCCCTCCAGGAGAGCCACCCTG



ATATCATCCCACTGGCCTCCAACTGACCCACAATGTCCACAGTAACTTTCCCCCATT



CTCACCCAGTATCCATAAAATAAAGAAATAATATTGCTTGTCTACAC (SEQ ID



NO: 31)






>NP_034838.2 ga1ectin-9 isoform 1 [Mus musculus]



MALFSAQSPYINPIIPFTGPIQGGLQEGLQVTLQGTTKSFAQRFVVNFQNSFNGNDI



AFHFNPRFEEGGYVVCNTKQNGQWGPEERKMQMPFQKGMPFELCFLVQRSEFKVMVN



KKFFVQYQHRVPYHLVDTIAVSGCLKLSFITFQNSAAPVQHVFSTVQFSQPVQFPRT



PKGRKQKTQNFRPAHQAPMAQTTIHMVHSTPGQMFSTPGIPPVVYPTPAYTIPFYTP



IPNGLYPSKSIMISGNVLPDATRFHINLRCGGDIAFHLNPRFNENAVVRNTQINNSW



GQEERSLLGRMPFSRGQSFSVWIICEGHCFKVAVNGQHMCEYYHRLKNLQDINTLEV



AGDIQLTHVQT (SEQ ID NO: 32)





Human PVR
>NM_006505.5 Homo sapiens PVR cell adhesion molecule


(CD155)
(PVR), transcript variant 1, mRNA



AGTCACTTGTCTGGAGCTTGAAGAAGTGGGTATTCCCCTTCCCACCCCAGGCACTGG



AGGAGCGGCCCCCCGGGGATTCCAGGACCTGAGCTCCGGGAGCTGGACTCGCAGCGA



CCGCGGCAGAGCGAGCGGGCGCCGGGAAGCGAGGAGACGCCCGCGGGAGGCCCAGCT



GCTCGGAGCAACTGGCATGGCCCGAGCCATGGCCGCCGCGTGGCCGCTGCTGCTGGT



GGCGCTACTGGTGCTGTCCTGGCCACCCCCAGGAACCGGGGACGTCGTCGTGCAGGC



GCCCACCCAGGTGCCCGGCTTCTTGGGCGACTCCGTGACGCTGCCCTGCTACCTACA



GGTGCCCAACATGGAGGTGACGCATGTGTCACAGCTGACTTGGGCGCGGCATGGTGA



ATCTGGCAGCATGGCCGTCTTCCACCAAACGCAGGGCCCCAGCTATTCGGAGTCCAA



ACGGCTGGAATTCGTGGCAGCCAGACTGGGCGCGGAGCTGCGGAATGCCTCGCTGAG



GATGTTCGGGTTGCGCGTAGAGGATGAAGGCAACTACACCTGCCTGTTCGTCACGTT



CCCGCAGGGCAGCAGGAGCGTGGATATCTGGCTCCGAGTGCTTGCCAAGCCCCAGAA



CACAGCTGAGGTTCAGAAGGTCCAGCTCACTGGAGAGCCAGTGCCCATGGCCCGCTG



CGTCTCCACAGGGGGTCGCCCGCCAGCCCAAATCACCTGGCACTCAGACCTGGGCGG



GATGCCCAATACGAGCCAGGTGCCAGGGTTCCTGTCTGGCACAGTCACTGTCACCAG



CCTCTGGATATTGGTGCCCTCAAGCCAGGTGGACGGCAAGAATGTGACCTGCAAGGT



GGAGCACGAGAGCTTTGAGAAGCCTCAGCTGCTGACTGTGAACCTCACCGTGTACTA



CCCCCCAGAGGTATCCATCTCTGGCTATGATAACAACTGGTACCTTGGCCAGAATGA



GGCCACCCTGACCTGCGATGCTCGCAGCAACCCAGAGCCCACAGGCTATAATTGGAG



CACGACCATGGGTCCCCTGCCACCCTTTGCTGTGGCCCAGGGCGCCCAGCTCCTGAT



CCGTCCTGTGGACAAACCAATCAACACAACTTTAATCTGCAACGTCACCAATGCCCT



AGGAGCTCGCCAGGCAGAACTGACCGTCCAGGTCAAAGAGGGACCTCCCAGTGAGCA



CTCAGGCATGTCCCGTAACGCCATCATCTTCCTGGTTCTGGGAATCCTGGTTTTTCT



GATCCTGCTGGGGATCGGGATTTATTTCTATTGGTCCAAATGTTCCCGTGAGGTCCT



TTGGCACTGTCATCTGTGTCCCTCGAGTACAGAGCATGCCAGCGCCTCAGCTAATGG



GCATGTCTCCTATTCAGCTGTGAGCAGAGAGAACAGCTCTTCCCAGGATCCACAGAC



AGAGGGCACAAGGTGACAGCGTCGGGACTGAGAGGGGAGAGAGACTGGAGCTGGCAA



GGACGTGGGCCTCCAGAGTTGGACCCGACCCCAATGGATGAAGACCCCCTCCAAAGA



GACCAGCCTCCCTCCCTGTGCCAGACCTCAAAACGACGGGGGCAGGTGCAAGTTCAT



AGGTCTCCAAGACCACCCTCCTTTCATTTGCTAGAAGGACTCACTAGACTCAGGAAA



GCTGTTAGGCTCACAGTTACAGTTTATTACAGTAAAAGGACAGAGATTAAGATCAGC



AAAGGGAGGAGGTGCACAGCACACGTTCCACGACAGATGAGGCGACGGCTTCCATCT



GCCCTCTCCCAGTGGAGCCATATAGGCAGCACCTGATTCTCACAGCAACATGTGACA



ACATGCAAGAAGTACTGCCAATACTGCCAACCAGAGCAGCTCACTCGAGATCTTTGT



GTCCAGAGTTTTTTGTTTGTCTTGAGACAGGGTCTGGCTCTGTTGGCAGACTAGAGT



ACAGTGGTGAGATCACAGTTCATTGCAGCCTTGACTTCTCAACGCCAAGTCATCCTC



CCACCTCAGCCTCCTGAGTAGCTATGACTACAGGTATGTGCCACCACGTCTGGCTAA



TCTTTTTATTATTTGTAAAGTCGAGGTTTCCCTGTGTTGCCCAGGCTGGTCTTGAAC



TCTTGGCTCCAAGTGATACTTCTGCCTTGGCCTCCCAAAGTGCTGAATTAAGCAGCT



CACCATCCACACGGCTGACCTCATACATCAAGCCAATACCGTGTGGCCCAAGACCCC



CACCATAAATCACATCATTAGCATGAACCACCCAGAGTGGCCCAAGACTCCAAGATC



AGCTACCAGGCAGGATATTCCAAGGGCTTAGAGATGAATGCCCAGGAGCTGAGGATA



AAGGGCCCGATCTTTCTTTGGGCAAGGTTAAGCCTTTACTGCATAGCAGACCACACA



GAAGGGTGTGGGCCACCAGAGAATTTTGGTAAAAATTTGGCCTCTGGCCTTGAGCTT



CTAAATCTCTGTATCCGTCAGATCTCTGTGGTTACAAGAAACAGCCACTGACCCTGG



TCACCAGAGGCTGCAATTCAGGCCGCAAGCAGCTGCCTGGGGGGTGTCCAAGGAGCA



GAGAAAACTACTAGATGTGAACTTGAAGAAGGTTGTCAGCTGCAGCCACTTTCTGCC



AGCATCTGCAGCCACTTTCTGCCAGCATCTGCAGCCAGCAAGCTGGGACTGGCAGGA



AATAACCCACAAAAGAAGCAAATGCAATTTCCAACACAAGGGGGAAGGGATGCAGGG



GGAGGCAGCGCTGCAGTTGCTCAGGACACGCTCCTATAGGACCAAGATGGATGCGAC



CCAAGACCCAGGAGGCCCAGCTGCTCAGTGCAACTGACAAGTTAAAAAGGTCTATGA



TCTTGAGGGCAGACAGCAGAATTCCTCTTATAAAGAAAACTGTTTGGGAAAATACGT



TGAGGGAGAGAAGACCTTGGGCCAAGATGCTAAATGGGAATGCAAAGCTTGAGCTGC



TCTGCAAGAGAAAATAAGCAGGACAGAGGATTTGCTCTGGACAGAGATGGAAGAGCC



GGGAACAGAGAAGTGTGGGGAAGAGATAGGAACCAGCAGGATGGCAGGGGCAAAGGG



CTCAAGGGTGAGGAGGCCAGTGGGACCCCACAGAGTTGGGGAGATAAAGGAACATTG



GTTGCTTTGGTGGCACGTAAGCTCCTTGTCTGTCTCCAGCACCCAGAATCTCATTAA



AGCTTATTTATTGTACCTCCAGCGGCTGTGTGCAATGGGGTCTTTTGTGGAAATCAA



GGAGCAGACAGGTTTCATGTGTACTGTCACCACGTGGGATGGAACCAGAGGCATGGA



AGCAAGACGCTAAATGAAGAGGGCCATAAGGGCTGGGATTCCCAGGCACCTTAGGAA



CAGCTTGTCTTTTTTTTTTTCCTCTCCAAAAAAAATGTTTAAGGGACGGTGTCTCCT



GTCACCCAGGCTGGAGTGCAATGGCACGATCATAGCTCATTGCAGCCTCTAACTCCG



GGGCTCAAGCAATCCTCCCACCTCAGCCTACCAAGTAGCTGTGACCACAGCTGCCCC



TCACCATGCTAAGCTAATTTTTTTAATTAGATAGTACATAAACGTCCCAAAATTAGA



AGATAAAAAGACATGAGGGATCCATTCTAATTTGTGTTTGGAGTGTAATGGTCCAGC



TCCATTCTTCTGCACATGGATATCCAGTTTTACACAACACTGTGAATGTAATGAATG



CCACTGAATCATACACTCAAAAATAGCTAAAATGGCAAATTGTCTGTTATCTCTTTT



TAACCACCATTTTTGAAAATTAATTATACCAAAAAACCATTGAATAGTGCACTTTAT



TTATTTATTTATTTGTTTATTTATTTATTTATTTTAGAAATAAGAGTCTCACTTTGT



TGCCCAGGCTGGAGTGCAGTGGCGTGATCATGGCTCATTGCAGCCTCGACCTGCTGG



GCTCGGGCTATCCTTCCATCTCAGCCTCCCGAGTAGCTGGGACTATAGGTGGGCGCC



ACCCCACCTGGCTAAATCTCTTTTTAACTTTTGTAGAGATAGGCATCTCGCTATGTT



GCCTAGGCTGGGCTGGAACTCCTGGGCTCAAGTGCTCCTCCTGCCTTGGCCTCCCAA



AGCGCTAGGATTACAGATGTGAGCCACCGCGCCCACCCTGAACCTTACTTTTTTTGC



TCAGTTTCTGGTAATTCAGAGAATGCCTCCTGAGTTGTTCTACACCCACCTCATATT



CCATGGGAGGGCTGTACAGGGCTTTTTTAACGAGGCCTCTAAGGACAGGCATTTGTA



TCCTTTCCAGCCTTTCACTATTACAATGTTGTAGTGAATAACTTTACACACTGTCAT



TTATTTTACTTTTTTTTTTTTTTATTTTAGAGAAAGGAATCTTGCCATCTTGCCCAG



GCTGGTCTCAAATTCCTGGGCCCAAACAATCCTCCCGCCTTGGCCTCCTAAAGTACT



GGGATTTATAGGCATAAGCCACCGTGCCTGGCCAATGCACACTGTCATTTAGCTCAT



GTTAACACCTGAGTGTAGGACACACTCCTGGAGGTGGAATTGCTGGGCCAAAGAGTA



TGTTTCTTGTCATTGTGATAGATATTGACAAATGAACCCTCACAGAAGTTGTGCTGA



GTTCTGTTCCCACCAGCGACGTAGGCGATGACCTTTTTCTGGAGGGAGGGGGCATCC



TTGGAGTCCACAGAGCCAGGAATGGAGAGTGGGCCCAGAATTTTGGTATAGGTGTTG



TATAAACTTATAGTAAGGTTAAGAAAACCGCAACTATCCTTATCAGAGACTTGGCGG



GGGGCAGGGTATGATGGAGATCATAAGGAGGCTAAAACACTCCACACCCTCCCTCTG



CATTGCTCCTGCACGGGAGTCGGGAATCTTTTCAGGTTGATACGATCTCACCTTGAG



GAGCTGTGAGGTCCCAGAAGCCTCTGGGTTGCAGATTGCTTGGGGTGAAAATGTCTG



TGCTACTGAAATCTAACTTTTTACAAAAAATTACGGGCTGGGCGCAGTGGCTCACGC



CTGTAATCCCAGCACTTTGGGAGGCTGCAGCGGGTGGATCACTTGAGGTAAGGAGTT



CAAGACCAGACCATAGTGAAACCGTGTCTCTACAAAAAAAATTAGCCAGGTGTGGTG



GTGCATGCTTGTAATCCCAGCTACTCAGAAGGCTGAGGTGGGAGAATCCCTTGAACC



CGGGAAGTGGAGGCTGGAGTAAACCATGATCGAGTTACTGCACTCCAGCCTGGGTGA



CAAGAGTGAGACTCTGTCTCCAAAAAAAAAAAAAAAAAAAAAAAAACTGGATTGCCT



GGCTCTACTCCGGGCACAGCATGCAGGCCCAGTTCTGCTGCTCTGCTGTTTGTTCTG



CTTTCCTCCACATATTGGCATCACCCTCTGGTGCCAAGATGGCTGCTGCATTCCAGG



CATCACATCCAGACTCAGACCCAGAGAAGCTGCCCATCCCTACCTGGGTGAGCCTTT



GTAGGAACGAGAAACCGCATCCAGCAGCAGAAACCTCACCCAGCAGCGTCTTTTCCG



GTCTCATTCACCAGCGCCGCCCACCGCTCAACCAATCCCTGGCCAAAAGAATGGGAC



CGCCTGGAAGGCTGGACCAAACAGGACCTGCCCTCTGGGGCTGGGGAGAGGCCCAGA



TGAAGGCTGCAGGACAGGATGGACTCCTAGACCTCTGTTACCAGCAGTGACTACCTC



TGTCTGGGTGGTTGGAACATGTTTGAATTTTATTCTAAGTACTGTCTACAAGTTCTG



CAATAAACCTTGACTCTTCTTTTAATAATGCAAAA (SEQ ID NO: 33)






>NP_006496.4 poliovirus receptor isoform alpha precursor



[Homo sapiens]



MARAMAAAWPLLLVALLVLSWPPPGTGDVVVQAPTQVPGFLGDSVTLPCYLQVPNME



VTHVSQLTWARHGESGSMAVFHQTQGPSYSESKRLEFVAARLGAELRNASLRMFGLR



VEDEGNYTCLFVTFPQGSRSVDIWLRVLAKPQNTAEVQKVQLTGEPVPMARCVSTGG



RPPAQITWHSDLGGMPNTSQVPGFLSGTVTVTSLWILVPSSQVDGKNVTCKVEHESF



EKPQLLTVNLTVYYPPEVSISGYDNNWYLGQNEATLTCDARSNPEPTGYNWSTTMGP



LPPFAVAQGAQLLIRPVDKPINTTLICNVTNALGARQAELTVQVKEGPPSEHSGMSR



NAIIFLVLGILVFLILLGIGIYFYWSKCSREVLWHCHLCPSSTEHASASANGHVSYS



AVSRENSSSQDPQTEGTR (SEQ ID NO: 34)





Mouse PVR
>NM_027514.2 Mus musculus poliovirus receptor (Pvr), mRNA


(CD155)
AGGCGGCACCCGCTTAGCTGAGATTCCAGCACTTGACTTCAGGGTTTCGGAGAGATA



AGGCGCTTGGCCGTTACTAACTGGACTACAAAGAGCTGGATCGGACCGGAACCACAT



GGCTCAACTCGCCCGAGCCACCCGCTCCCCGCTGTCATGGCTGCTGCTGCTGTTCTG



CTATGCACTCCGGAAAGCGGGTGGGGATATACGTGTGCTGGTGCCCTACAATTCGAC



AGGCGTCTTGGGAGGGTCGACCACCTTGCACTGTAGTCTGACTTCTAATGAGAATGT



GACTATCACTCAAATAACCTGGATGAAGAAGGATTCAGGTGGATCCCACGCTCTTGT



GGCTGTCTTCCACCCCAAGAAGGGGCCCAACATCAAAGAGCCAGAGAGGGTGAAATT



CTTGGCTGCCCAACAGGATCTGAGGAACGCATCTCTGGCCATCTCGAACTTAAGTGT



AGAAGACGAAGGCATCTATGAATGTCAGATTGCCACATTCCCCAGAGGCAGTAGAAG



CACCAATGCCTGGCTGAAGGTGCAAGCCCGACCTAAGAACACTGCAGAGGCCCTGGA



GCCCTCTCCCACCTTGATACTGCAGGATGTGGCTAAATGCATCTCTGCCAATGGTCA



CCCTCCTGGACGAATCTCTTGGCCCTCGAATGTGAATGGAAGTCACCGTGAAATGAA



GGAACCAGGGTCCCAGCCGGGCACCACCACAGTTACCAGCTACCTCTCCATGGTACC



TTCTCGCCAGGCAGACGGCAAGAACATCACCTGCACGGTGGAGCATGAAAGCTTACA



GGAGCTGGACCAGCTGCTGGTGACCCTTTCCCAACCCTATCCACCTGAAAACGTGTC



CATCTCTGGCTATGACGGCAACTGGTATGTTGGCCTCACTAACTTGACCCTGACCTG



TGAAGCTCACAGCAAACCAGCGCCTGACATGGCTGGATATAACTGGAGCACGAACAC



GGGTGACTTTCCCAACTCTGTTAAGCGCCAGGGCAATATGCTTCTAATCTCCACCGT



AGAGGATGGTCTCAATAACACGGTCATTGTGTGCGAAGTCACCAATGCCCTAGGGTC



TGGGCAGGGCCAAGTGCACATCATTGTTAAAGAGAAACCTGAGAATATGCAGCAAAA



TACAAGATTACACCTAGGCTACATCTTTCTTATCGTCTTTGTCCTCGCTGTAGTCAT



CATCATCGCAGCACTATACACTATACGAAGATGCAGGCATGGTCGTGCTCTGCAGTC



CAATCCCTCAGAGAGGGAGAACGTCCAGTATTCATCTGTGAACGGCGACTGTAGACT



GAACATGGAGCCAAACAGCACAAGGTGACGGTGCTGGGTAGACAGAACTAAGGAACT



TGAAGGCATAGCAACTGGAACCCTACTCTCATAAATGAAGAAGCCTCCAGAGAGACT



GGCTGCTCAGTGTGATGAGCATAGCAAGTTTGGGGGGTCTCCCAGGATGCTGCCGAA



TTCCACGTTGTCAAAAGGACCCATGGAGGCCAGTGTGTTGGCTCACTCTTGACATCT



CAGCAAGCTGGGGGGGGGGGGGGGAGCATAAAGCAAGGTTGAGTCTAGCTTGGGCTA



TAGAGCAAAGCCCTGTCCATACACAAACAAGCTAAGGGGCTTTGAGACGGTCAGAAA



CTGAAGTCTTGCTTTGGGTAAGGTAAATCCTCTACCGCATGTATGTGCTAGACTTGA



AAGACTTCCACACAGACCTCTTTATAAGTTGACTCCATTGGGGCTATCCCCTCCTCT



CTGGACAAGGTCTCTGTATGTAGCCAAGGCTAGGCTCAAACTCACAGAGATATGTCT



GCTTCTACCTCCCCAGTGCTAGAGTTGAAAGTATTTGTGCCACTGCACTTTTCTAGG



TCTTCTTTTAATGAAGTAAAGTATATATTTATAAAAAGCTATTTAGTTATATATATA



TATATTTTTGAGACTATTTCATAGAGCCCAAGCTAACCTCAAACTTACTATGTAGCC



AAGAGTGATGGTAAACTAATTTATTTTAATTTATTTGTCTTCAATTTTAACCATCAC



CCAACCCCTGCTCCCTTCCATATCTTCTTTCAATCCATTTCATTGTCTTTTTCTTCC



CAGACACTATTCTGACTTACGTCTCCATTACAAACATTTTATTGAACTACATAAAAA



TGTGTGAACCACAAAAAAAAAATGTATTTGTCAAAATTGTAGTTGTCTTTCTGAGGC



TGACCTGAGTTCTCTGATACCATTCTCTCCAGTTGTATCCAGTTTCCTGTAAACAAT



GTGACTTTGTTTTTCTCAGTAGCTAAAACATCCCAATTATGTGAGTGTACACTTTCT



TTACTCATTCCTCTGTGGGCCACCAGCTGGGTTGGTTCCATATCTGAGCTATTGTGC



ATGGAATTGTCTCTGTGGTGGGTTTAGTAAACTCCCAGGAATGCCTGTACATGTTTG



TAGAGGCCAGAAGAAGGCACAAAATCTTGAGCCAGGCTTACATGCACTTGTGAGTAG



CCCCACATAGGTGCTAAGAACCCAGTTCAGGTCCTCTGCTGTGGGATGGTGGGCTGT



GCACAGAAAGCCTGGTCCCGGTCTAGCAAAGGTCTGGAACTCCGGAGCCGGTGGGCT



GTGATTTACACCAGCATGGGATGGAAGGAGTTGGACCTCGCCTCCTGGGCACCTGGC



TCCTGTCACATAGCTACAGCCTCCCACAGCCCCCCTATAGGGAGGTATGCAGCATCA



ATCACATAGTAGCTGCACTAAGCCCTCCCACATGCAAATAAGGTTTCCCCAAACTCT



CAGTCCAAGCCAATGAAAAGTACCTGCTGTCAAACCCTAAATCATCCCCAAAACTCT



GTAAGTCCTATCAGGGAATAAAATGTGTGTGAAAACTAAAAAAAAAAAAAAA (SEQ



ID NO: 35)






>NP_081790.1 poliovirus receptor precursor [Mus musculus]



MAQLARATRSPLSWLLLLFCYALRKAGGDIRVLVPYNSTGVLGGSTTLHCSLTSNEN



VTITQITWMKKDSGGSHALVAVFHPKKGPNIKEPERVKFLAAQQDLRNASLAISNLS



VEDEGIYECQIATFPRGSRSTNAWLKVQARPKNTAEALEPSPTLILQDVAKCISANG



HPPGRISWPSNVNGSHREMKEPGSQPGTTTVTSYLSMVPSRQADGKNITCTVEHESL



QELDQLLVTLSQPYPPENVSISGYDGNWYVGLTNLTLTCEAHSKPAPDMAGYNWSTN



TGDFPNSVKRQGNMLLISTVEDGLNNTVIVCEVTNALGSGQGQVHIIVKEKPENMQQ



NTRLHLGYIFLIVFVLAVVIIIAALYTIRRCRHGRALQSNPSERENVQYSSVNGDCR



LNMEPNSTR (SEQ ID NO: 36)





Human
>NM_002856.3 Homo sapiens nectin cell adhesion molecule 2


Nectin-2
(NECTIN2), transcript variant alpha, mRNA


(CD112)
GTGACGTCAGCGGGTTCGAACCGCCGGAGCTGAGCGAGAGGCCGGGGGTGCCGAGCC


isoform alpha
GGGCGGGGAGAGCTGGGCCGGGAGAGCAGAACAGGGAGGCTAGAGCGCAGCGGGAAC



CGGCCCGGAGCCGGAGCCGGAGCCCCACAGGCACCTACTAAACCGCCCAGCCGATCG



GCCCCCACAGAGTGGCCCGCGGGCCTCCGGCCGGGCCCAGTCCCCTCCCGGGCCCTC



CATGGCCCGGGCCGCTGCCCTCCTGCCGTCGAGATCGCCGCCGACGCCGCTGCTGTG



GCCGCTGCTGCTGCTGCTGCTCCTGGAAACCGGAGCCCAGGATGTGCGAGTTCAAGT



GCTACCCGAGGTGCGAGGCCAGCTCGGGGGCACCGTGGAGCTGCCGTGCCACCTGCT



GCCACCTGTTCCTGGACTGTACATCTCCCTGGTGACCTGGCAGCGCCCAGATGCACC



TGCGAACCACCAGAATGTGGCCGCCTTCCACCCTAAGATGGGTCCCAGCTTCCCCAG



CCCGAAGCCTGGCAGCGAGCGGCTGTCCTTCGTCTCTGCCAAGCAGAGCACTGGGCA



AGACACAGAGGCAGAGCTCCAGGACGCCACGCTGGCCCTCCACGGGCTCACGGTGGA



GGACGAGGGCAACTACACTTGCGAGTTTGCCACCTTCCCCAAGGGGTCCGTCCGAGG



GATGACCTGGCTCAGAGTCATAGCCAAGCCCAAGAACCAAGCTGAGGCCCAGAAGGT



CACGTTCAGCCAGGACCCTACGACAGTGGCCCTCTGCATCTCCAAAGAGGGCCGCCC



ACCTGCCCGGATCTCCTGGCTCTCATCCCTGGACTGGGAAGCCAAAGAGACTCAGGT



GTCAGGGACCCTGGCCGGAACTGTCACTGTCACCAGCCGCTTCACCTTGGTGCCCTC



GGGCCGAGCAGATGGTGTCACGGTCACCTGCAAAGTGGAGCATGAGAGCTTCGAGGA



ACCAGCCCTGATACCTGTGACCCTCTCTGTACGCTACCCTCCTGAAGTGTCCATCTC



CGGCTATGATGACAACTGGTACCTCGGCCGTACTGATGCCACCCTGAGCTGTGACGT



CCGCAGCAACCCAGAGCCCACGGGCTATGACTGGAGCACGACCTCAGGCACCTTCCC



GACCTCCGCAGTGGCCCAGGGCTCCCAGCTGGTCATCCACGCAGTGGACAGTCTGTT



CAATACCACCTTCGTCTGCACAGTCACCAATGCCGTGGGCATGGGCCGCGCTGAGCA



GGTCATCTTTGTCCGAGAAACCCCCAGGGCCTCGCCCCGAGATGTGGGCCCGCTGGT



GTGGGGGGCCGTGGGGGGGACACTGCTGGTGCTGCTGCTTCTGGCTGGGGGGTCCTT



GGCCTTCATCCTGCTGAGGGTGAGGAGGAGGAGGAAGAGCCCTGGAGGAGCAGGAGG



AGGAGCCAGTGGCGACGGGGGATTCTACGATCCGAAAGCTCAGGTGTTGGGAAATGG



GGACCCCGTCTTCTGGACACCAGTAGTCCCTGGTCCCATGGAACCAGATGGCAAGGA



TGAGGAGGAGGAGGAGGAGGAAGAGAAGGCAGAGAAAGGCCTCATGTTGCCTCCACC



CCCAGCACTCGAGGATGACATGGAGTCCCAGCTGGACGGCTCCCTCATCTCACGGCG



GGCAGTTTATGTGTGACCTGGACACAGACAGAGACAGAGCCAGGCCCGGCCCTCCCG



CCCCCGACCTGACCACGCCGGCCTAGGGTTCCAGACTGGTTGGACTTGTTCGTCTGG



ACGACACTGGAGTGGAACACTGCCTCCCACTTTCTTGGGACTTGGAGGGAGGTGGAA



CAGCACACTGGACTTCTCCCGTCTCTAGGGCTGCATGGGGAGCCCGGGGAGCTGAGT



AGTGGGGATCCAGAGAGGACCCCCGCCCCCAGAGACTTGGTTTTGGCTCCAGCCTTC



CCCTGGCCCCGTGACACTCAGGAGTTAATAAATGCCTTGGAGGAAAACA (SEQ ID



NO: 37)






>NP_002847.1 nectin-2 isoform alpha precursor [Homo




sapiens]




MARAAALLPSRSPPTPLLWPLLLLLLLETGAQDVRVQVLPEVRGQLGGTVELPCHLL



PPVPGLYISLVTWQRPDAPANHQNVAAFHPKMGPSFPSPKPGSERLSFVSAKQSTGQ



DTEAELQDATLALHGLTVEDEGNYTCEFATFPKGSVRGMTWLRVIAKPKNQAEAQKV



TFSQDPTTVALCISKEGRPPARISWLSSLDWEAKETQVSGTLAGTVTVTSRFTLVPS



GRADGVTVTCKVEHESFEEPALIPVTLSVRYPPEVSISGYDDNWYLGRTDATLSCDV



RSNPEPTGYDWSTTSGTFPTSAVAQGSQLVIHAVDSLFNTTFVCTVTNAVGMGRAEQ



VIFVRETPRASPRDVGPLVWGAVGGTLLVLLLLAGGSLAFILLRVRRRRKSPGGAGG



GASGDGGFYDPKAQVLGNGDPVFWTPVVPGPMEPDGKDEEEEEEEEKAEKGLMLPPP



PALEDDMESQLDGSLISRRAVYV (SEQ ID NO: 38)





Mouse Nectin-
>NM_001159724.1 Mus musculus nectin cell adhesion


2 (CD112)
molecule 2 (Nectin2), transcript variant 2, mRNA


isoform alpha
GAGCCCTAGGATCGGCTTGGCGAAGAGGGGCGGGGCCTGTGACGTCATGAGTCCGGC



CCGCTGGAGCTAAGCGAGGGGCCGGGGGGCGCGGATCCTGAGAGCCAGGCGAGGGAA



AGCTGGGCCGAACGAACTGATCCGGGGAGCCGTGAGCGGCGGAAGCCGGCCTGGAGC



CGGACACTTCAGACCCCTGACTGCCCTCCCAGCCGATCGGTACACGAAGAGTGGTCC



CTAGGCACCCCCTGCCCGGGCCCAGTCCCTCCCCGGGCCCCCCATGGCCCGGGCCGC



AGTCCTCCCGCCGTCCAGATTGTCACCGACGCTGCCGTTGTTGCCGCTGCTACTGCT



CCTGCTTCAGGAAACAGGAGCCCAAGATGTGCGGGTACGAGTGCTTCCCGAGGTCCG



GGGCCGCTTGGGAGGCACCGTGGAGTTACCGTGCCACCTGCTCCCACCCACGACGGA



GCGCGTCTCTCAGGTGACCTGGCAGCGCCTGGATGGCACAGTTGTGGCTGCTTTCCA



CCCATCCTTCGGAGTGGATTTCCCCAACTCTCAGTTCAGCAAGGACCGTCTGTCCTT



TGTCAGAGCGAGACCAGAAACAAACGCAGACCTGCGGGATGCCACACTGGCCTTCCG



GGGACTGAGGGTAGAGGACGAGGGCAATTACACCTGCGAGTTTGCCACGTTTCCCAA



CGGTACCCGCAGGGGGGTGACCTGGCTCAGAGTCATAGCCCAGCCTGAGAACCACGC



TGAAGCCCAGGAGGTCACAATTGGCCCCCAGTCGGTGGCTGTAGCCCGCTGTGTCTC



CACTGGGGGCCGCCCCCCTGCCCGAATCACCTGGATCTCATCTCTGGGTGGAGAGGC



CAAAGATACTCAGGAGCCAGGGATACAGGCTGGCACCGTCACTATCATCAGCCGATA



CTCCTTGGTGCCCGTGGGCCGAGCGGATGGCGTCAAGGTCACGTGTAGAGTGGAACA



CGAGAGCTTCGAAGAGCCGATCCTGCTGCCAGTGACCCTCTCTGTGCGCTACCCTCC



AGAAGTATCCATCTCCGGCTATGATGACAACTGGTACCTTGGCCGCAGTGAGGCCAT



ACTGACCTGTGATGTACGAAGCAACCCAGAGCCCACAGACTATGACTGGAGCACGAC



CTCGGGCGTCTTCCCAGCCTCTGCAGTGGCCCAGGGCTCTCAGCTGCTTGTCCACTC



TGTGGATCGAATGGTCAACACTACCTTCATCTGTACAGCCACCAACGCTGTGGGGAC



AGGCCGTGCTGAGCAGGTCATCCTGGTGCGAGACACCCCCCAGGCCTCCCGAGATGT



GGGTCCGCTGGTGTGGGGGGCCGTGGGGGGAACATTGCTGGTGCTACTCCTGGCTGG



GGGGTTCCTGGCCTTGATCCTGCTGAGGGGGAGGAGGAGGCGGAAGAGCCCTGGAGG



AGGAGGAAATGATGGCGACAGAGGATCCTACGATCCAAAGACTCAGGTGTTTGGGAA



CGGGGGTCCTGTCTTCTGGAGGTCAGCATCCCCTGAGCCCATGAGGCCAGATGGCAG



GGAGGAAGATGAGGAGGAGGAGGAAGAAATGAAGGCAGAGGAAGGTCTCATGCTACC



TCCACACGAGTCACCTAAGGACGACATGGAGTCCCATCTGGATGGCTCCCTCATCTC



TCGGCGGGCAGTTTACGTGTGACCCTACGATATAGACACTGGACACATGGAAACACC



AAGTTCCACCCTCACTGCCAACCACACCAATGCCAGCCAGCAACGATGGCTAGGGAC



CGGTTGGACTGGTTCTTCTGGGGCACACTGGAGTTGGAAGGGCACCGCCCCTGCTTT



CAGGATAGAGGACAAGTGGAACCACACAGACTCCTATCTTTAGGGCCTCATGGAGTA



GGGGACCCCAGGAGCGCCATGGTGCACACTCAGGACTCCTCAGAGCTTGCTTTCGGC



CCCAGCCTAGCCCTGGCCCCGAAACACTCAGGAGCTAATAAATGCCTTGTCGGAAAA



AAAAAAAAAAAAAA (SEQ ID NO: 39)






>NP_001153196.1 nectin-2 isoform 2 precursor [Mus




musculus]




MARAAVLPPSRLSPTLPLLPLLLLLLQETGAQDVRVRVLPEVRGRLGGTVELPCHLL



PPTTERVSQVTWQRLDGTVVAAFHPSFGVDFPNSQFSKDRLSFVRARPETNADLRDA



TLAFRGLRVEDEGNYTCEFATFPNGTRRGVTWLRVIAQPENHAEAQEVTIGPQSVAV



ARCVSTGGRPPARITWISSLGGEAKDTQEPGIQAGTVTIISRYSLVPVGRADGVKVT



CRVEHESFEEPILLPVTLSVRYPPEVSISGYDDNWYLGRSEAILTCDVRSNPEPTDY



DWSTTSGVFPASAVAQGSQLLVHSVDRMVNTTFICTATNAVGTGRAEQVILVRDTPQ



ASRDVGPLVWGAVGGTLLVLLLAGGFLALILLRGRRRRKSPGGGGNDGDRGSYDPKT



QVFGNGGPVFWRSASPEPMRPDGREEDEEEEEEMKAEEGLMLPPHESPKDDMESHLD



GSLISRRAVYV (SEQ ID NO: 40)





Human
>NM_001042724.2 Homo sapiens nectin cell adhesion


Nectin-2
molecule 2 (NECTIN2), transcript variant delta, mRNA


(CD112)
GTGACGTCAGCGGGTTCGAACCGCCGGAGCTGAGCGAGAGGCCGGGGGTGCCGAGCC


isoform delta
GGGCGGGGAGAGCTGGGCCGGGAGAGCAGAACAGGGAGGCTAGAGCGCAGCGGGAAC



CGGCCCGGAGCCGGAGCCGGAGCCCCACAGGCACCTACTAAACCGCCCAGCCGATCG



GCCCCCACAGAGTGGCCCGCGGGCCTCCGGCCGGGCCCAGTCCCCTCCCGGGCCCTC



CATGGCCCGGGCCGCTGCCCTCCTGCCGTCGAGATCGCCGCCGACGCCGCTGCTGTG



GCCGCTGCTGCTGCTGCTGCTCCTGGAAACCGGAGCCCAGGATGTGCGAGTTCAAGT



GCTACCCGAGGTGCGAGGCCAGCTCGGGGGCACCGTGGAGCTGCCGTGCCACCTGCT



GCCACCTGTTCCTGGACTGTACATCTCCCTGGTGACCTGGCAGCGCCCAGATGCACC



TGCGAACCACCAGAATGTGGCCGCCTTCCACCCTAAGATGGGTCCCAGCTTCCCCAG



CCCGAAGCCTGGCAGCGAGCGGCTGTCCTTCGTCTCTGCCAAGCAGAGCACTGGGCA



AGACACAGAGGCAGAGCTCCAGGACGCCACGCTGGCCCTCCACGGGCTCACGGTGGA



GGACGAGGGCAACTACACTTGCGAGTTTGCCACCTTCCCCAAGGGGTCCGTCCGAGG



GATGACCTGGCTCAGAGTCATAGCCAAGCCCAAGAACCAAGCTGAGGCCCAGAAGGT



CACGTTCAGCCAGGACCCTACGACAGTGGCCCTCTGCATCTCCAAAGAGGGCCGCCC



ACCTGCCCGGATCTCCTGGCTCTCATCCCTGGACTGGGAAGCCAAAGAGACTCAGGT



GTCAGGGACCCTGGCCGGAACTGTCACTGTCACCAGCCGCTTCACCTTGGTGCCCTC



GGGCCGAGCAGATGGTGTCACGGTCACCTGCAAAGTGGAGCATGAGAGCTTCGAGGA



ACCAGCCCTGATACCTGTGACCCTCTCTGTACGCTACCCTCCTGAAGTGTCCATCTC



CGGCTATGATGACAACTGGTACCTCGGCCGTACTGATGCCACCCTGAGCTGTGACGT



CCGCAGCAACCCAGAGCCCACGGGCTATGACTGGAGCACGACCTCAGGCACCTTCCC



GACCTCCGCAGTGGCCCAGGGCTCCCAGCTGGTCATCCACGCAGTGGACAGTCTGTT



CAATACCACCTTCGTCTGCACAGTCACCAATGCCGTGGGCATGGGCCGCGCTGAGCA



GGTCATCTTTGTCCGAGAGACCCCCAACACAGCAGGCGCAGGGGCCACAGGCGGCAT



CATCGGGGGCATCATCGCCGCCATCATTGCTACTGCTGTGGCTGCCACGGGCATCCT



TATCTGCCGGCAGCAGCGGAAGGAGCAGACGCTGCAGGGGGCAGAGGAGGACGAAGA



CCTGGAGGGACCTCCCTCCTACAAGCCACCGACCCCAAAAGCGAAGCTGGAGGCACA



GGAGATGCCCTCCCAGCTCTTCACTCTGGGGGCCTCGGAGCACAGCCCACTCAAGAC



CCCCTACTTTGATGCTGGCGCCTCATGCACTGAGCAGGAAATGCCTCGATACCATGA



GCTGCCCACCTTGGAAGAACGGTCAGGACCCTTGCACCCTGGAGCCACAAGCCTGGG



GTCCCCCATCCCGGTGCCTCCAGGGCCACCTGCTGTGGAAGACGTTTCCCTGGATCT



AGAGGATGAGGAGGGGGAGGAGGAGGAAGAGTATCTGGACAAGATCAACCCCATCTA



TGATGCTCTGTCCTATAGCAGCCCCTCTGATTCCTACCAGGGCAAAGGCTTTGTCAT



GTCCCGGGCCATGTATGTGTGAGCTGCCATGCGCCTGGCGTCTCACATCTCACCTGT



TGATCCCTTAGCTTTCTTGCCAAGGATCTAGTGCCCCCTGACCTCTGGCCAGGCCAC



TGTCAGTTAACACATATGCATTCCATTTGTGATGTCTACCTTGGTGGCTCCACTATG



ACCCCTAACCCATGAGCCCAGAGAAATTCACCGTGATAATGGAATCCTGGCAACCTT



ATCTCATGAGGCAGGAGGTGGGGAAGGTGCTTCTGCACAACCTCTGATCCCAAGGAC



TCCTCTCCCAGACTGTGACCTTAGACCATACCTCTCACCCCCCAATGCCTCGACTCC



CCCAAAATCACAAAGAAGACCCTAGACCTATAATTTGTCTTCAGGTAGTAAATTCCC



AATAGGTCTGCTGGAGTGGGCGCTGAGGGCTCCCTGCTGCTCAGACCTGAGCCCTCC



AGGCAGCAGGGTCCCACTTACCCCCTCCCCACCCTGTTCCCCAAAGGTGGGAAAGAG



GGGATTCCCCAGCCCAAGGCAGGGTTTTCCCAGCACCCTCCTGTAAGCAGAAGTCTC



AGGGTCCAGACCCTTCCCTGAGCCCCCACCCCCACCCCAATTCCTGCCTACCAAGCA



AGCAGCCCCAGCCTAGGGTCAGACAGGGTGAGCCTCATACAGACTGTGCCTTGATGG



CCCCAGCCTTGGGAGAAGAATTTACTGTTAACCTGGAAGACTACTGAATCATTTTAC



CCTTGCCCAGTGGAATAGGACCTAAACATCCCCCTTCCGGGGAAAGTGGGTCATCTG



AATTGGGGGTAGCAATTGATACTGTTTTGTAAACTACATTTCCTACAAAATATGAAT



TTATACTTTGA (SEQ ID NO: 41)






>NP_001036189.1 nectin-2 isoform delta precursor [Homo




sapiens]




MARAAALLPSRSPPTPLLWPLLLLLLLETGAQDVRVQVLPEVRGQLGGTVELPCHLL



PPVPGLYISLVTWQRPDAPANHQNVAAFHPKMGPSFPSPKPGSERLSFVSAKQSTGQ



DTEAELQDATLALHGLTVEDEGNYTCEFATFPKGSVRGMTWLRVIAKPKNQAEAQKV



TFSQDPTTVALCISKEGRPPARISWLSSLDWEAKETQVSGTLAGTVTVTSRFTLVPS



GRADGVTVTCKVEHESFEEPALIPVTLSVRYPPEVSISGYDDNWYLGRTDATLSCDV



RSNPEPTGYDWSTTSGTFPTSAVAQGSQLVIHAVDSLFNTTFVCTVTNAVGMGRAEQ



VIFVRETPNTAGAGATGGIIGGIIAAIIATAVAATGILICRQQRKEQTLQGAEEDED



LEGPPSYKPPTPKAKLEAQEMPSQLFTLGASEHSPLKTPYFDAGASCTEQEMPRYHE



LPTLEERSGPLHPGATSLGSPIPVPPGPPAVEDVSLDLEDEEGEEEEEYLDKINPIY



DALSYSSPSDSYQGKGFVMSRAMYV (SEQ ID NO: 42)





Mouse Nectin-
>NM_008990.3 Mus musculus nectin cell adhesion molecule 2


2 (CD112)
(Nectin2), transcript variant 1, mRNA


isoform beta
GAGCCCTAGGATCGGCTTGGCGAAGAGGGGCGGGGCCTGTGACGTCATGAGTCCGGC



CCGCTGGAGCTAAGCGAGGGGCCGGGGGGCGCGGATCCTGAGAGCCAGGCGAGGGAA



AGCTGGGCCGAACGAACTGATCCGGGGAGCCGTGAGCGGCGGAAGCCGGCCTGGAGC



CGGACACTTCAGACCCCTGACTGCCCTCCCAGCCGATCGGTACACGAAGAGTGGTCC



CTAGGCACCCCCTGCCCGGGCCCAGTCCCTCCCCGGGCCCCCCATGGCCCGGGCCGC



AGTCCTCCCGCCGTCCAGATTGTCACCGACGCTGCCGTTGTTGCCGCTGCTACTGCT



CCTGCTTCAGGAAACAGGAGCCCAAGATGTGCGGGTACGAGTGCTTCCCGAGGTCCG



GGGCCGCTTGGGAGGCACCGTGGAGTTACCGTGCCACCTGCTCCCACCCACGACGGA



GCGCGTCTCTCAGGTGACCTGGCAGCGCCTGGATGGCACAGTTGTGGCTGCTTTCCA



CCCATCCTTCGGAGTGGATTTCCCCAACTCTCAGTTCAGCAAGGACCGTCTGTCCTT



TGTCAGAGCGAGACCAGAAACAAACGCAGACCTGCGGGATGCCACACTGGCCTTCCG



GGGACTGAGGGTAGAGGACGAGGGCAATTACACCTGCGAGTTTGCCACGTTTCCCAA



CGGTACCCGCAGGGGGGTGACCTGGCTCAGAGTCATAGCCCAGCCTGAGAACCACGC



TGAAGCCCAGGAGGTCACAATTGGCCCCCAGTCGGTGGCTGTAGCCCGCTGTGTCTC



CACTGGGGGCCGCCCCCCTGCCCGAATCACCTGGATCTCATCTCTGGGTGGAGAGGC



CAAAGATACTCAGGAGCCAGGGATACAGGCTGGCACCGTCACTATCATCAGCCGATA



CTCCTTGGTGCCCGTGGGCCGAGCGGATGGCGTCAAGGTCACGTGTAGAGTGGAACA



CGAGAGCTTCGAAGAGCCGATCCTGCTGCCAGTGACCCTCTCTGTGCGCTACCCTCC



AGAAGTATCCATCTCCGGCTATGATGACAACTGGTACCTTGGCCGCAGTGAGGCCAT



ACTGACCTGTGATGTACGAAGCAACCCAGAGCCCACAGACTATGACTGGAGCACGAC



CTCGGGCGTCTTCCCAGCCTCTGCAGTGGCCCAGGGCTCTCAGCTGCTTGTCCACTC



TGTGGATCGAATGGTCAACACTACCTTCATCTGTACAGCCACCAACGCTGTGGGGAC



AGGCCGTGCTGAGCAGGTCATCCTGGTGCGAGAGTCACCCAGCACAGCAGGAGCAGG



GGCCACTGGTGGCATCATTGGAGGTATTATCGCTGCCATCATCGCCACCGCAGTGGC



TGGCACAGGCATCCTCATCTGCCGACAACAGCGGAAGGAGCAGAGGCTTCAAGCTGC



GGATGAGGAAGAAGAACTGGAAGGACCTCCCTCCTATAAACCACCCACCCCGAAGGC



CAAGCTGGAGGAACCAGAGATGCCCTCTCAACTCTTCACCTTGGGGGCCTCAGAGCA



CAGCCCAGTGAAGACGCCATACTTTGATGCTGGTGTCTCTTGTGCTGATCAGGAGAT



GCCTCGGTATCACGAGCTGCCCACTCTGGAAGAGCGGTCAGGGCCCCTGCTGTTGGG



GGCTACAGGCCTGGGACCTTCTCTTCTGGTGCCTCCAGGACCCAATGTTGTGGAGGG



GGTTTCCCTGAGTCTCGAAGATGAGGAGGAAGATGATGAGGAGGAAGACTTCCTGGA



TAAAATCAACCCTATTTATGATGCCCTGTCCTACCCCAGCCCCTCTGACTCCTACCA



GAGCAAAGACTTTTTTGTGTCACGGGCCATGTATGTGTGAGGGAGGCACAGGGGCTC



TGACGTCTCACCTTTCACCCTTGACCCATGAGCTTTCCACCAGTAATCTAGGACACT



CTGACTTCCAGGCAGACCAGGGACAACTATCACCCATTGCAATCCACCTGTGACTTC



TTAGTGACTCCACCATGACGTCCAATCTATGATGTCTGAGGCAGGCAAACCTGCACA



ACTGGAAACCTGGAGATTTTTATCTCCCTTGGCAGGGAGCTCACCATATCCTTCTGC



ACCACCTGTGACCCCCCCCCCCCCCCCAAGGACTCCTAAGACTACGACCCTTTGACC



ATGCCACTCAGTATCTCAAGAACCCTTAAAGTCCCAAAGGAATCGGACCTTGCACTT



GTCCTCAGGCAATAGAGTCCAACAGATATGCAAGAACGGGATCAGGGGCTCCCTGTT



GCTCAGACCTGAGCCCTCCAGGCAGCAGAAGCTCACCTGATCCCTCCCCACCCTGCT



CCCCAAAGGTGAAAAGGAGAGGATTCCCCAATGTAAGGTAGGACCTCCCCATCTCCA



CCTACTCCTGCAGGCAGGAATCTCAGGTTTCTCACACCCTCTCCTCAGCACCCAGGT



TCCTGTCTCCAGAGCATGAATTCCAGGTCCAATGCTAGAGGGGAGAACCTAATGCAA



GTGTGCCTTGCCACCCCAAGTTTGGGAGACTCTGCTCTTATCCTGAGGACTACTGAA



TTCTTTTAACCCCTACCCAGTGAGATGAGAACTACATATCCCTCTTTAGGGGATGGT



GTGTGTATGTGTGTGTGATGGAGAATCTGGGCATCTGGGTTGGGAATTTTATTTTGT



AAGCATTTCCTACATAATATGAGTTTCTACTTTGATAAAGTCTTGTGTTTTCTGTG



(SEQ ID NO: 43)






>NP_033016.3 nectin-2 isoform 1 precursor [Mus musculus]



MARAAVLPPSRLSPTLPLLPLLLLLLQETGAQDVRVRVLPEVRGRLGGTVELPCHLL



PPTTERVSQVTWQRLDGTVVAAFHPSFGVDFPNSQFSKDRLSFVRARPETNADLRDA



TLAFRGLRVEDEGNYTCEFATFPNGTRRGVTWLRVIAQPENHAEAQEVTIGPQSVAV



ARCVSTGGRPPARITWISSLGGEAKDTQEPGIQAGTVTIISRYSLVPVGRADGVKVT



CRVEHESFEEPILLPVTLSVRYPPEVSISGYDDNWYLGRSEAILTCDVRSNPEPTDY



DWSTTSGVFPASAVAQGSQLLVHSVDRMVNTTFICTATNAVGTGRAEQVILVRESPS



TAGAGATGGIIGGIIAAIIATAVAGTGILICRQQRKEQRLQAADEEEELEGPPSYKP



PTPKAKLEEPEMPSQLFTLGASEHSPVKTPYFDAGVSCADQEMPRYHELPTLEERSG



PLLLGATGLGPSLLVPPGPNVVEGVSLSLEDEEEDDEEEDFLDKINPIYDALSYPSP



SDSYQSKDFFVSRAMYV (SEQ ID NO: 44)





Human IL-10
>NM_000572.3 Homo sapiens interleukin 10 (IL10),



transcript variant 1, mRNA



ACACATCAGGGGCTTGCTCTTGCAAAACCAAACCACAAGACAGACTTGCAAAAGAAG



GCATGCACAGCTCAGCACTGCTCTGTTGCCTGGTCCTCCTGACTGGGGTGAGGGCCA



GCCCAGGCCAGGGCACCCAGTCTGAGAACAGCTGCACCCACTTCCCAGGCAACCTGC



CTAACATGCTTCGAGATCTCCGAGATGCCTTCAGCAGAGTGAAGACTTTCTTTCAAA



TGAAGGATCAGCTGGACAACTTGTTGTTAAAGGAGTCCTTGCTGGAGGACTTTAAGG



GTTACCTGGGTTGCCAAGCCTTGTCTGAGATGATCCAGTTTTACCTGGAGGAGGTGA



TGCCCCAAGCTGAGAACCAAGACCCAGACATCAAGGCGCATGTGAACTCCCTGGGGG



AGAACCTGAAGACCCTCAGGCTGAGGCTACGGCGCTGTCATCGATTTCTTCCCTGTG



AAAACAAGAGCAAGGCCGTGGAGCAGGTGAAGAATGCCTTTAATAAGCTCCAAGAGA



AAGGCATCTACAAAGCCATGAGTGAGTTTGACATCTTCATCAACTACATAGAAGCCT



ACATGACAATGAAGATACGAAACTGAGACATCAGGGTGGCGACTCTATAGACTCTAG



GACATAAATTAGAGGTCTCCAAAATCGGATCTGGGGCTCTGGGATAGCTGACCCAGC



CCCTTGAGAAACCTTATTGTACCTCTCTTATAGAATATTTATTACCTCTGATACCTC



AACCCCCATTTCTATTTATTTACTGAGCTTCTCTGTGAACGATTTAGAAAGAAGCCC



AATATTATAATTTTTTTCAATATTTATTATTTTCACCTGTTTTTAAGCTGTTTCCAT



AGGGTGACACACTATGGTATTTGAGTGTTTTAAGATAAATTATAAGTTACATAAGGG



AGGAAAAAAAATGTTCTTTGGGGAGCCAACAGAAGCTTCCATTCCAAGCCTGACCAC



GCTTTCTAGCTGTTGAGCTGTTTTCCCTGACCTCCCTCTAATTTATCTTGTCTCTGG



GCTTGGGGCTTCCTAACTGCTACAAATACTCTTAGGAAGAGAAACCAGGGAGCCCCT



TTGATGATTAATTCACCTTCCAGTGTCTCGGAGGGATTCCCCTAACCTCATTCCCCA



ACCACTTCATTCTTGAAAGCTGTGGCCAGCTTGTTATTTATAACAACCTAAATTTGG



TTCTAGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCTGAGG



CGGGTGGATCACTTGAGGTCAGGAGTTCCTAACCAGCCTGGTCAACATGGTGAAACC



CCGTCTCTACTAAAAATACAAAAATTAGCCGGGCATGGTGGCGCGCACCTGTAATCC



CAGCTACTTGGGAGGCTGAGGCAAGAGAATTGCTTGAACCCAGGAGATGGAAGTTGC



AGTGAGCTGATATCATGCCCCTGTACTCCAGCCTGGGTGACAGAGCAAGACTCTGTC



TCAAAAAATAAAAATAAAAATAAATTTGGTTCTAATAGAACTCAGTTTTAACTAGAA



TTTATTCAATTCCTCTGGGAATGTTACATTGTTTGTCTGTCTTCATAGCAGATTTTA



ATTTTGAATAAATAAATGTATCTTATTCACATCA (SEQ ID NO: 45)






>NP_000563.1 inter1eukin-10 isoform 1 precursor [Homo




sapiens]




MHSSALLCCLVLLTGVRASPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQM



KDQLDNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGE



NLKTLRLRLRRCHRFLPCENKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAY



MTMKIRN (SEQ ID NO: 46)





Mouse IL-10
>NM_010548.2 Mus musculus interleukin 10 (Il10), mRNA



ACATTTAGAGACTTGCTCTTGCACTACCAAAGCCACAAGGCAGCCTTGCAGAAAAGA



GAGCTCCATCATGCCTGGCTCAGCACTGCTATGCTGCCTGCTCTTACTGACTGGCAT



GAGGATCAGCAGGGGCCAGTACAGCCGGGAAGACAATAACTGCACCCACTTCCCAGT



CGGCCAGAGCCACATGCTCCTAGAGCTGCGGACTGCCTTCAGCCAGGTGAAGACTTT



CTTTCAAACAAAGGACCAGCTGGACAACATACTGCTAACCGACTCCTTAATGCAGGA



CTTTAAGGGTTACTTGGGTTGCCAAGCCTTATCGGAAATGATCCAGTTTTACCTGGT



AGAAGTGATGCCCCAGGCAGAGAAGCATGGCCCAGAAATCAAGGAGCATTTGAATTC



CCTGGGTGAGAAGCTGAAGACCCTCAGGATGCGGCTGAGGCGCTGTCATCGATTTCT



CCCCTGTGAAAATAAGAGCAAGGCAGTGGAGCAGGTGAAGAGTGATTTTAATAAGCT



CCAAGACCAAGGTGTCTACAAGGCCATGAATGAATTTGACATCTTCATCAACTGCAT



AGAAGCATACATGATGATCAAAATGAAAAGCTAAAACACCTGCAGTGTGTATTGAGT



CTGCTGGACTCCAGGACCTAGACAGAGCTCTCTAAATCTGATCCAGGGATCTTAGCT



AACGGAAACAACTCCTTGGAAAACCTCGTTTGTACCTCTCTCCGAAATATTTATTAC



CTCTGATACCTCAGTTCCCATTCTATTTATTCACTGAGCTTCTCTGTGAACTATTTA



GAAAGAAGCCCAATATTATAATTTTACAGTATTTATTATTTTTAACCTGTGTTTAAG



CTGTTTCCATTGGGGACACTTTATAGTATTTAAAGGGAGATTATATTATATGATGGG



AGGGGTTCTTCCTTGGGAAGCAATTGAAGCTTCTATTCTAAGGCTGGCCACACTTGA



GAGCTGCAGGGCCCTTTGCTATGGTGTCCTTTCAATTGCTCTCATCCCTGAGTTCAG



AGCTCCTAAGAGAGTTGTGAAGAAACTCATGGGTCTTGGGAAGAGAAACCAGGGAGA



TCCTTTGATGATCATTCCTGCAGCAGCTCAGAGGGTTCCCCTACTGTCATCCCCCAG



CCGCTTCATCCCTGAAAACTGTGGCCAGTTTGTTATTTATAACCACCTAAAATTAGT



TCTAATAGAACTCATTTTTAACTAGAAGTAATGCAATTCCTCTGGGAATGGTGTATT



GTTTGTCTGCCTTTGTAGCAGACTCTAATTTTGAATAAATGGATCTTATTCG (SEQ



ID NO: 47)






>NP_034678.1 inter1eukin-10 precursor [Mus musculus]



MPGSALLCCLLLLTGMRISRGQYSREDNNCTHFPVGQSHMLLELRTAFSQVKTFFQT



KDQLDNILLTDSLMQDFKGYLGCQALSEMIQFYLVEVMPQAEKHGPEIKEHLNSLGE



KLKTLRMRLRRCHRFLPCENKSKAVEQVKSDFNKLQDQGVYKAMNEFDIFINCIEAY



MMIKMKS (SEQ ID NO: 48)





Human TSG-6
>NM_007115.3 Homo sapiens TNF alpha induced protein 6



(TNFAIP6), mRNA



AGTCACATTTCAGCCACTGCTCTGAGAATTTGTGAGCAGCCCCTAACAGGCTGTTAC



TTCACTACAACTGACGATATGATCATCTTAATTTACTTATTTCTCTTGCTATGGGAA



GACACTCAAGGATGGGGATTCAAGGATGGAATTTTTCATAACTCCATATGGCTTGAA



CGAGCAGCCGGTGTGTACCACAGAGAAGCACGGTCTGGCAAATACAAGCTCACCTAC



GCAGAAGCTAAGGCGGTGTGTGAATTTGAAGGCGGCCATCTCGCAACTTACAAGCAG



CTAGAGGCAGCCAGAAAAATTGGATTTCATGTCTGTGCTGCTGGATGGATGGCTAAG



GGCAGAGTTGGATACCCCATTGTGAAGCCAGGGCCCAACTGTGGATTTGGAAAAACT



GGCATTATTGATTATGGAATCCGTCTCAATAGGAGTGAAAGATGGGATGCCTATTGC



TACAACCCACACGCAAAGGAGTGTGGTGGCGTCTTTACAGATCCAAAGCAAATTTTT



AAATCTCCAGGCTTCCCAAATGAGTACGAAGATAACCAAATCTGCTACTGGCACATT



AGACTCAAGTATGGTCAGCGTATTCACCTGAGTTTTTTAGATTTTGACCTTGAAGAT



GACCCAGGTTGCTTGGCTGATTATGTTGAAATATATGACAGTTACGATGATGTCCAT



GGCTTTGTGGGAAGATACTGTGGAGATGAGCTTCCAGATGACATCATCAGTACAGGA



AATGTCATGACCTTGAAGTTTCTAAGTGATGCTTCAGTGACAGCTGGAGGTTTCCAA



ATCAAATATGTTGCAATGGATCCTGTATCCAAATCCAGTCAAGGAAAAAATACAAGT



ACTACTTCTACTGGAAATAAAAACTTTTTAGCTGGAAGATTTAGCCACTTATAAAAA



AAAAAAAAAGGATGATCAAAACACACAGTGTTTATGTTGGAATCTTTTGGAACTCCT



TTGATCTCACTGTTATTATTAACATTTATTTATTATTTTTCTAAATGTGAAAGCAAT



ACATAATTTAGGGAAAATTGGAAAATATAGGAAACTTTAAACGAGAAAATGAAACCT



CTCATAATCCCACTGCATAGAAATAACAAGCGTTAACATTTTCATATTTTTTTCTTT



CAGTCATTTTTCTATTTGTGGTATATGTATATATGTACCTATATGTATTTGCATTTG



AAATTTTGGAATCCTGCTCTATGTACAGTTTTGTATTATACTTTTTAAATCTTGAAC



TTTATAAACATTTTCTGAAATCATTGATTATTCTACAAAAACATGATTTTAAACAGC



TGTAAAATATTCTATGATATGAATGTTTTATGCATTATTTAAGCCTGTCTCTATTGT



TGGAATTTCAGGTCATTTTCATAAATATTGTTGCAATAAATATCCTTGAACACACAA



AAAAAAAAAAAAAA (SEQ ID NO: 49)






>NP_009046.2 tumor necrosis factor-inducible gene 6



protein precursor [Homo sapiens]



MIILIYLFLLLWEDTQGWGFKDGIFHNSIWLERAAGVYHREARSGKYKLTYAEAKAV



CEFEGGHLATYKQLEAARKIGFHVCAAGWMAKGRVGYPIVKPGPNCGFGKTGIIDYG



IRLNRSERWDAYCYNPHAKECGGVFTDPKQIFKSPGFPNEYEDNQICYWHIRLKYGQ



RIHLSFLDFDLEDDPGCLADYVEIYDSYDDVHGFVGRYCGDELPDDIISTGNVMTLK



FLSDASVTAGGFQIKYVAMDPVSKSSQGKNTSTTSTGNKNFLAGRFSHL (SEQ ID



NO: 50)





Mouse TSG-6
>NM_009398.2 Mus musculus tumor necrosis factor alpha



induced protein 6 (Tnfaip6), mRNA



CCGCTGCTCTGAGAATTTCGTGTGGGCAGCCCCGACATTGTAACCGGCTCTGCAACC



GAAGAGATGGTCGTCCTCCTTTGCTTATGCGTCTTGCTGTGGGAAGAGGCTCACGGA



TGGGGATTCAAGAACGGGATCTTTCATAACTCCATATGGCTTGAACAAGCAGCGGGC



GTATACCACAGAGAAGCTCGGGCTGGCAGATACAAGCTCACCTACGCCGAAGCCAAG



GCCGTATGTGAATTTGAAGGTGGTCGTCTCGCAACCTACAAGCAGCTAGAGGCAGCC



AGAAAAATTGGATTCCATGTCTGTGCTGCTGGATGGATGGCCAAGGGTAGAGTCGGA



TACCCCATTGTGAAACCTGGGCCCAACTGTGGATTTGGGAAAACGGGTATCATCGAT



TATGGAATCCGGCTCAACAGGAGTGAGCGATGGGATGCCTATTGCTACAACCCACAT



GCAAAGGAGTGTGGTGGTGTCTTCACAGATCCGAAGCGAATTTTTAAATCCCCGGGC



TTCCCAAATGAGTACGATGACAACCAGGTCTGCTACTGGCACATTCGGCTCAAGTAC



GGTCAGCGAATTCACCTGAGCTTTTTGGACTTTGACCTTGAACATGATCCAGGCTGC



TTGGCTGACTATGTAGAAATCTATGACAGTTATGATGACGTCCACGGCTTTGTAGGA



AGATACTGTGGTGATGAACTTCCAGAAGACATCATTAGCACAGGAAATGTCATGACC



TTGAAGTTTCTGAGTGATGCATCCGTCACGGCTGGAGGCTTCCAGATTAAATACGTC



ACAGTGGATCCTGCATCTAAATCCAGTCAAGCCAAAAATACAAGTACTACTGGAAAT



AAGAAGTTCTTACCTGGAAGGTTTAGCCATCTATAAAAAATTTTTTTTAAAAATGTT



CAAAACATCCAGTACAATATTTATATTTGTTTTTGTTGTTGTTGTTGGTTTTTTTTT



TTTTATTTTGTTTTGTTTTGTTTTTTTGAGACGGGGTTTCTCTGTATAGCCTTGGCT



GTCCTGGAACTCACTTTGAAGACCAGGCTGGCCTCGAACTCAGAAATCCACCTGCCT



CCGCCTACCAAGTGCTGGGATTAAAGGCGTCCACCACCACCGCCCGGCTTCAATATT



TATATTTGTAGCTCTTGGACCTCGTTTGTTCTCTTTTGTATTTTTATTATTAACATG



TATTTATTATTTTTCCAAATGTGAAAGCCATATGTAATTATGTGGAAAATTGACAAA



TAAATACAGAGAACTTCAAATGAGTTTTTTTTTTAAATCTCATAATTGTACTACACA



GAAATAACTAATGTTAAAGTTTTTAAATGTTTGTCTTTCATTCATTTTTCTACTTGT



AGTATATGTACATATGTAACTCTATGATTTGCGTTTGAATTTTGGCATTCTGCCTTT



TGTAACCTGATATTTTTAACCTTGACATTGTATAGCTCAAGCACTTCCCAAGATCTC



TGAGTTTTCTACAAAATGGGACTTTGTAAATATGATTGTTCCCTGCTTTATTTAAGC



TGAATTTATATTAGGATTTAAGGTTGTTTTCATAAATATTGCTGTAATAAATACTTT



TGGAT (SEQ ID NO: 51)






>NP_033424.1 tumor necrosis factor-inducible gene 6



protein precursor [Mus musculus]



MVVLLCLCVLLWEEAHGWGFKNGIFHNSIWLEQAAGVYHREARAGRYKLTYAEAKAV



CEFEGGRLATYKQLEAARKIGFHVCAAGWMAKGRVGYPIVKPGPNCGFGKTGIIDYG



IRLNRSERWDAYCYNPHAKECGGVFTDPKRIFKSPGFPNEYDDNQVCYWHIRLKYGQ



RIHLSFLDFDLEHDPGCLADYVEIYDSYDDVHGFVGRYCGDELPEDIISTGNVMTLK



FLSDASVTAGGFQIKYVTVDPASKSSQAKNTSTTGNKKFLPGRFSHL (SEQ ID



NO: 52)





Human B7-H3 
>NM_001024736.2 Homo sapiens CD276 molecule (CD276),


(CD276)
transcript variant 1, mRNA



ATTCGGGCCGGGCCTCGCTGCGGCGGCGACTGAGCCAGGCTGGGCCGCGTCCCTGAG



TCCCAGAGTCGGCGCGGCGCGGCAGGGGCAGCCTTCCACCACGGGGAGCCCAGCTGT



CAGCCGCCTCACAGGAAGATGCTGCGTCGGCGGGGCAGCCCTGGCATGGGTGTGCAT



GTGGGTGCAGCCCTGGGAGCACTGTGGTTCTGCCTCACAGGAGCCCTGGAGGTCCAG



GTCCCTGAAGACCCAGTGGTGGCACTGGTGGGCACCGATGCCACCCTGTGCTGCTCC



TTCTCCCCTGAGCCTGGCTTCAGCCTGGCACAGCTCAACCTCATCTGGCAGCTGACA



GATACCAAACAGCTGGTGCACAGCTTTGCTGAGGGCCAGGACCAGGGCAGCGCCTAT



GCCAACCGCACGGCCCTCTTCCCGGACCTGCTGGCACAGGGCAACGCATCCCTGAGG



CTGCAGCGCGTGCGTGTGGCGGACGAGGGCAGCTTCACCTGCTTCGTGAGCATCCGG



GATTTCGGCAGCGCTGCCGTCAGCCTGCAGGTGGCCGCTCCCTACTCGAAGCCCAGC



ATGACCCTGGAGCCCAACAAGGACCTGCGGCCAGGGGACACGGTGACCATCACGTGC



TCCAGCTACCAGGGCTACCCTGAGGCTGAGGTGTTCTGGCAGGATGGGCAGGGTGTG



CCCCTGACTGGCAACGTGACCACGTCGCAGATGGCCAACGAGCAGGGCTTGTTTGAT



GTGCACAGCATCCTGCGGGTGGTGCTGGGTGCAAATGGCACCTACAGCTGCCTGGTG



CGCAACCCCGTGCTGCAGCAGGATGCGCACAGCTCTGTCACCATCACACCCCAGAGA



AGCCCCACAGGAGCCGTGGAGGTCCAGGTCCCTGAGGACCCGGTGGTGGCCCTAGTG



GGCACCGATGCCACCCTGCGCTGCTCCTTCTCCCCCGAGCCTGGCTTCAGCCTGGCA



CAGCTCAACCTCATCTGGCAGCTGACAGACACCAAACAGCTGGTGCACAGTTTCACC



GAAGGCCGGGACCAGGGCAGCGCCTATGCCAACCGCACGGCCCTCTTCCCGGACCTG



CTGGCACAAGGCAATGCATCCCTGAGGCTGCAGCGCGTGCGTGTGGCGGACGAGGGC



AGCTTCACCTGCTTCGTGAGCATCCGGGATTTCGGCAGCGCTGCCGTCAGCCTGCAG



GTGGCCGCTCCCTACTCGAAGCCCAGCATGACCCTGGAGCCCAACAAGGACCTGCGG



CCAGGGGACACGGTGACCATCACGTGCTCCAGCTACCGGGGCTACCCTGAGGCTGAG



GTGTTCTGGCAGGATGGGCAGGGTGTGCCCCTGACTGGCAACGTGACCACGTCGCAG



ATGGCCAACGAGCAGGGCTTGTTTGATGTGCACAGCGTCCTGCGGGTGGTGCTGGGT



GCGAATGGCACCTACAGCTGCCTGGTGCGCAACCCCGTGCTGCAGCAGGATGCGCAC



GGCTCTGTCACCATCACAGGGCAGCCTATGACATTCCCCCCAGAGGCCCTGTGGGTG



ACCGTGGGGCTGTCTGTCTGTCTCATTGCACTGCTGGTGGCCCTGGCTTTCGTGTGC



TGGAGAAAGATCAAACAGAGCTGTGAGGAGGAGAATGCAGGAGCTGAGGACCAGGAT



GGGGAGGGAGAAGGCTCCAAGACAGCCCTGCAGCCTCTGAAACACTCTGACAGCAAA



GAAGATGATGGACAAGAAATAGCCTGACCATGAGGACCAGGGAGCTGCTACCCCTCC



CTACAGCTCCTACCCTCTGGCTGCAATGGGGCTGCACTGTGAGCCCTGCCCCCAACA



GATGCATCCTGCTCTGACAGGTGGGCTCCTTCTCCAAAGGATGCGATACACAGACCA



CTGTGCAGCCTTATTTCTCCAATGGACATGATTCCCAAGTCATCCTGCTGCCTTTTT



TCTTATAGACACAATGAACAGACCACCCACAACCTTAGTTCTCTAAGTCATCCTGCC



TGCTGCCTTATTTCACAGTACATACATTTCTTAGGGACACAGTACACTGACCACATC



ACCACCCTCTTCTTCCAGTGCTGCGTGGACCATCTGGCTGCCTTTTTTCTCCAAAAG



ATGCAATATTCAGACTGACTGACCCCCTGCCTTATTTCACCAAAGACACGATGCATA



GTCACCCCGGCCTTGTTTCTCCAATGGCCGTGATACACTAGTGATCATGTTCAGCCC



TGCTTCCACCTGCATAGAATCTTTTCTTCTCAGACAGGGACAGTGCGGCCTCAACAT



CTCCTGGAGTCTAGAAGCTGTTTCCTTTCCCCTCCTTCCTCCTCTTGCTCTAGCCTT



AATACTGGCCTTTTCCCTCCCTGCCCCAAGTGAAGACAGGGCACTCTGCGCCCACCA



CATGCACAGCTGTGCATGGAGACCTGCAGGTGCACGTGCTGGAACACGTGTGGTTCC



CCCCTGGCCCAGCCTCCTCTGCAGTGCCCCTCTCCCCTGCCCATCCTCCCCACGGAA



GCATGTGCTGGTCACACTGGTTCTCCAGGGGTCTGTGATGGGGCCCCTGGGGGTCAG



CTTCTGTCCCTCTGCCTTCTCACCTCTTTGTTCCTTTCTTTTCATGTATCCATTCAG



TTGATGTTTATTGAGCAACTACAGATGTCAGCACTGTGTTAGGTGCTGGGGGCCCTG



CGTGGGAAGATAAAGTTCCTCCCTCAAGGACTCCCCATCCAGCTGGGAGACAGACAA



CTAACTACACTGCACCCTGCGGTTTGCAGGGGGCTCCTGCCTGGCTCCCTGCTCCAC



ACCTCCTCTGTGGCTCAAGGCTTCCTGGATACCTCACCCCCATCCCACCCATAATTC



TTACCCAGAGCATGGGGTTGGGGCGGAAACCTGGAGAGAGGGACATAGCCCCTCGCC



ACGGCTAGAGAATCTGGTGGTGTCCAAAATGTCTGTCCAGGTGTGGGCAGGTGGGCA



GGCACCAAGGCCCTCTGGACCTTTCATAGCAGCAGAAAAGGCAGAGCCTGGGGCAGG



GCAGGGCCAGGAATGCTTTGGGGACACCGAGGGGACTGCCCCCCACCCCCACCATGG



TGCTATTCTGGGGCTGGGGCAGTCTTTTCCTGGCTTGCCTCTGGCCAGCTCCTGGCC



TCTGGTAGAGTGAGACTTCAGACGTTCTGATGCCTTCCGGATGTCATCTCTCCCTGC



CCCAGGAATGGAAGATGTGAGGACTTCTAATTTAAATGTGGGACTCGGAGGGATTTT



GTAAACTGGGGGTATATTTTGGGGAAAATAAATGTCTTTGTAAAAA (SEQ ID



NO: 53)






>NP_001019907.1 CD276 antigen isoform a precursor [Homo




sapiens]




MLRRRGSPGMGVHVGAALGALWFCLTGALEVQVPEDPVVALVGTDATLCCSFSPEPG



FSLAQLNLIWQLTDTKQLVHSFAEGQDQGSAYANRTALFPDLLAQGNASLRLQRVRV



ADEGSFTCFVSIRDFGSAAVSLQVAAPYSKPSMTLEPNKDLRPGDTVTITCSSYQGY



PEAEVFWQDGQGVPLTGNVTTSQMANEQGLFDVHSILRVVLGANGTYSCLVRNPVLQ



QDAHSSVTITPQRSPTGAVEVQVPEDPVVALVGTDATLRCSFSPEPGFSLAQLNLIW



QLTDTKQLVHSFTEGRDQGSAYANRTALFPDLLAQGNASLRLQRVRVADEGSFTCFV



SIRDFGSAAVSLQVAAPYSKPSMTLEPNKDLRPGDTVTITCSSYRGYPEAEVFWQDG



QGVPLTGNVTTSQMANEQGLFDVHSVLRVVLGANGTYSCLVRNPVLQQDAHGSVTIT



GQPMTFPPEALWVTVGLSVCLIALLVALAFVCWRKIKQSCEEENAGAEDQDGEGEGS



KTALQPLKHSDSKEDDGQEIA (SEQ ID NO: 54)





Mouse B7-H3
>NM_133983.4 Mus musculus CD276 antigen (Cd276), mRNA


(CD276)
CGGCGCGGCGCGCCAAAGTGACCTGGTACAGCCTGGACCCCAAGCTCATCGGCTTTG



TCTGGCTGGCCGCCTGGCCTCTTCCCACTTGGATTTGGATGATCCTGAGGCCTTTGG



AGGAACTTCGAGACAAAGGCCCCTCTTCCTCTTCCACGGGCAGGAGCAGCCATTCGC



CACGGAGAGCCCAGCTGTCAGCTGTCTCACAGGAAGATGCTTCGAGGATGGGGTGGC



CCCAGTGTGGGTGTGTGTGTGCGCACAGCACTGGGGGTGCTGTGCCTCTGCCTCACA



GGAGCTGTGGAAGTCCAGGTCTCTGAAGACCCCGTGGTGGCCCTGGTGGACACGGAT



GCCACCCTACGCTGCTCCTTTTCCCCAGAGCCTGGCTTCAGTCTGGCACAGCTCAAC



CTCATCTGGCAGCTGACAGACACCAAACAGCTGGTGCACAGCTTCACGGAGGGCCGG



GACCAAGGCAGTGCCTACTCCAACCGCACAGCGCTCTTCCCTGACCTGTTGGTGCAA



GGCAATGCGTCCTTGAGGCTGCAGCGCGTCCGAGTAACCGACGAGGGCAGCTACACC



TGCTTTGTGAGCATCCAGGACTTTGACAGCGCTGCTGTTAGCCTGCAGGTGGCCGCC



CCCTACTCGAAGCCCAGCATGACCCTGGAGCCCAACAAGGACCTACGTCCAGGGAAC



ATGGTGACCATCACGTGCTCTAGCTACCAGGGCTATCCGGAGGCCGAGGTGTTCTGG



AAGGATGGACAGGGAGTGCCCTTGACTGGCAATGTGACCACATCCCAGATGGCCAAC



GAGCGGGGCTTGTTCGATGTTCACAGCGTGCTGAGGGTGGTGCTGGGTGCTAACGGC



ACCTACAGCTGCCTGGTACGCAACCCGGTGTTGCAGCAAGATGCTCACGGCTCAGTC



ACCATCACAGGGCAGCCCCTGACATTCCCCCCTGAGGCTCTGTGGGTAACCGTGGGG



CTCTCTGTCTGTCTTGTGGTACTACTGGTGGCCCTGGCTTTCGTGTGCTGGAGAAAG



ATCAAGCAGAGCTGCGAGGAGGAGAATGCAGGTGCCGAGGACCAGGATGGAGATGGA



GAAGGATCCAAGACAGCTCTACGGCCTCTGAAACCCTCTGAAAACAAAGAAGATGAC



GGACAAGAAATTGCTTGATTGGGAGCTGCTGCCCTTCCCAGGTGGGGGGCCCACCCT



CTGGCAGTGTTGAGCTTCAATGCGAGCCCTTCCCCCAACGAATGGGTTTGTCCCACA



GATCTACCCGTTCGTCAAAGGACGTGGTCCATAGACCACCCACAGCCTTACTTTTCC



AATGGACTTAATTCCCATCATCCTGCAGCCTCATTTCTCCAGTGACACGATACACGA



ACCATCCTGCGGCCTTATTTCCCACGGACACGACACAAAGATGTCCCTCCTCGGTGT



TCCTCCAGAGTCGTCTGGTGGCCTTGTGATACGGCGTGAACCTTCTTCCTTCTGCCT



TACGTCTAATGGACACACACGCACCACCCCCACACCCTTGCTCCTCCAAAGCCATGC



AGACTGTGTAACTGCTATTATTCTCCAAGGGGCATCCTGTGCAGATGAAACCCTGCT



TTATTTCCCTGAAGACAGCTGCACAGTGACCTCTTAGTTCTTGCTCCCATGGCCCTG



ATGTATCCTAGTTACCAGCCCTCAACCTCAGTTCTGAGGGTGGGATCCCATCGCTCA



GCAAGGCTTCATCCTGACCTCCCTGCCCTGATCTGATCTGGCCCTGGCTTTTGTTGT



CTCGCTCCCTGACTAAGTGAGATGGGGCACTCTCCCGCCCCCGCCCCCCCCAGGTCA



CAGATACCTACCTGCAGCTGTGCGTGCTGGATCACGCACATACTTGCCTTGCATGGT



CTCCTGGCTGCCCTGGGCTGTGCCTGTTCTTCCATAGGAAGCAAGTTCTTGTCTCCC



TGGTTCTCAGGGCCCCTCAGGGGCTCAGCCTTCAGCCCTGTGCTTCCCCATGTTGGG



AATCTTTGTTACCTTTTTCTTCTTTGTAAATTAACATCTGATAACAACCACAGGGTC



CAATGGGACTTTCACAGACCTGCCAGCTAGATAAATAATGACAACAGAAGTTTATTA



ATATTTTAAGACTTAGGCCTTTTGCTGGGCAGCCTCCCAACTATTCTATCCTGACTA



ATCCTGGCACTATGTCCCACCACATGGCCAGGTCTACCTCTCTGCTCCACTCTCCAT



CCACCTCCATGTCTGCCAGCAAATCTCCCGTGATTCAGTTCTTCTCCCAGAGTCCCT



ATCTCTGCCCAGAAGTACCATCTTCGACTTCCTGCCCAACTATTGGCCGTCAGCTCT



TCATTAAAGCCGATCAGATGTAATTCTAGATTGCCTTAGGCAGGTGAGGAAGAAACA



AGTATTTGTAAAATATGAGACCAGCAATGGGCCATAGAAATAACAGCACCAGATCCT



GCCAGCATTTAGCCCTCTGTTGGTACAAAATTAACAATTGAATATACAGAGACCTAC



TTCCAGAGTGTACCCCAACAACAGGCGTGAGCATGGTGCTGGGTACTAGGGTCCTGC



TGGAAAATCAGAGACCTTACCTACAGCTGGGACATGACCTTGCTTCCGACTTACCCA



CCACTTCTGGATACCTCACCCTCAGCCCACACTATCCCTGGCCTAGGGCCCAGGGTA



GAGCCAGAAACATGGAGAAAGCATGGCCCCTTGCCGTACCTGGAGAACTGGGTATTT



TCCAGAGTCTTTATAGATGTGGACTGGAAGGCAGGTGGCCACAGCCGTGCAGACCTG



GGTCAGGTCAGAAACCTATGCCATGCTGGGACCTACTCAACAGCAGAAGCATGAAGA



GGGCCTGAGGACAAGAAAGGCCTTCTTACCATGGTGCTATTCTGGAGCTGGGATATA



TACCTGGCTTGTCTCTGACTGCCCTGGCTTCTGGCAGAACTTCTGATGTCCTCCTGA



AGGCCTCTCTCCCACCCCAGTACCTGAGAACCTGAGGATAATTTAAACATGGGACTC



TGGCCAGCACCTGGGAGAGACAGGTAGATCTCTGATTTTTGACTCAGCCTGGTCTAT



CGAGTGAGTTCCAGGACATCTGGGGCTACACAGAGAAACCATCTTAAAGACTAAAAA



TAATAAACATGAGACTGTAAACTGGGTGTATTTTGGGAGAAATAAATGTCTTTTTCT



TTCAA (SEQ ID NO: 55)






>NP_598744.1 CD276 antigen precursor [Mus musculus]



MLRGWGGPSVGVCVRTALGVLCLCLTGAVEVQVSEDPVVALVDTDATLRCSFSPEPG



FSLAQLNLIWQLTDTKQLVHSFTEGRDQGSAYSNRTALFPDLLVQGNASLRLQRVRV



TDEGSYTCFVSIQDFDSAAVSLQVAAPYSKPSMTLEPNKDLRPGNMVTITCSSYQGY



PEAEVFWKDGQGVPLTGNVTTSQMANERGLFDVHSVLRVVLGANGTYSCLVRNPVLQ



QDAHGSVTITGQPLTFPPEALWVTVGLSVCLVVLLVALAFVCWRKIKQSCEEENAGA



EDQDGDGEGSKTALRPLKPSENKEDDGQEIA (SEQ ID NO: 56)





Human B7-H4
>NM_024626.4 Homo sapiens V-set domain containing T cell


(VTCN1)
activation inhibitor 1 (VTCN1), transcript variant 1,



mRNA



GTGAGTCACCAAGGAAGGCAGCGGCAGCTCCACTCAGCCAGTACCCAGATACGCTGG



GAACCTTCCCCAGCCATGGCTTCCCTGGGGCAGATCCTCTTCTGGAGCATAATTAGC



ATCATCATTATTCTGGCTGGAGCAATTGCACTCATCATTGGCTTTGGTATTTCAGGG



AGACACTCCATCACAGTCACTACTGTCGCCTCAGCTGGGAACATTGGGGAGGATGGA



ATCCTGAGCTGCACTTTTGAACCTGACATCAAACTTTCTGATATCGTGATACAATGG



CTGAAGGAAGGTGTTTTAGGCTTGGTCCATGAGTTCAAAGAAGGCAAAGATGAGCTG



TCGGAGCAGGATGAAATGTTCAGAGGCCGGACAGCAGTGTTTGCTGATCAAGTGATA



GTTGGCAATGCCTCTTTGCGGCTGAAAAACGTGCAACTCACAGATGCTGGCACCTAC



AAATGTTATATCATCACTTCTAAAGGCAAGGGGAATGCTAACCTTGAGTATAAAACT



GGAGCCTTCAGCATGCCGGAAGTGAATGTGGACTATAATGCCAGCTCAGAGACCTTG



CGGTGTGAGGCTCCCCGATGGTTCCCCCAGCCCACAGTGGTCTGGGCATCCCAAGTT



GACCAGGGAGCCAACTTCTCGGAAGTCTCCAATACCAGCTTTGAGCTGAACTCTGAG



AATGTGACCATGAAGGTTGTGTCTGTGCTCTACAATGTTACGATCAACAACACATAC



TCCTGTATGATTGAAAATGACATTGCCAAAGCAACAGGGGATATCAAAGTGACAGAA



TCGGAGATCAAAAGGCGGAGTCACCTACAGCTGCTAAACTCAAAGGCTTCTCTGTGT



GTCTCTTCTTTCTTTGCCATCAGCTGGGCACTTCTGCCTCTCAGCCCTTACCTGATG



CTAAAATAATGTGCCTCGGCCACAAAAAAGCATGCAAAGTCATTGTTACAACAGGGA



TCTACAGAACTATTTCACCACCAGATATGACCTAGTTTTATATTTCTGGGAGGAAAT



GAATTCATATCTAGAAGTCTGGAGTGAGCAAACAAGAGCAAGAAACAAAAAGAAGCC



AAAAGCAGAAGGCTCCAATATGAACAAGATAAATCTATCTTCAAAGACATATTAGAA



GTTGGGAAAATAATTCATGTGAACTAGACAAGTGTGTTAAGAGTGATAAGTAAAATG



CACGTGGAGACAAGTGCATCCCCAGATCTCAGGGACCTCCCCCTGCCTGTCACCTGG



GGAGTGAGAGGACAGGATAGTGCATGTTCTTTGTCTCTGAATTTTTAGTTATATGTG



CTGTAATGTTGCTCTGAGGAAGCCCCTGGAAAGTCTATCCCAACATATCCACATCTT



ATATTCCACAAATTAAGCTGTAGTATGTACCCTAAGACGCTGCTAATTGACTGCCAC



TTCGCAACTCAGGGGCGGCTGCATTTTAGTAATGGGTCAAATGATTCACTTTTTATG



ATGCTTCCAAAGGTGCCTTGGCTTCTCTTCCCAACTGACAAATGCCAAAGTTGAGAA



AAATGATCATAATTTTAGCATAAACAGAGCAGTCGGCGACACCGATTTTATAAATAA



ACTGAGCACCTTCTTTTTAAACAAACAAATGCGGGTTTATTTCTCAGATGATGTTCA



TCCGTGAATGGTCCAGGGAAGGACCTTTCACCTTGTCTATATGGCATTATGTCATCA



CAAGCTCTGAGGCTTCTCCTTTCCATCCTGCGTGGACAGCTAAGACCTCAGTTTTCA



ATAGCATCTAGAGCAGTGGGACTCAGCTGGGGTGATTTCGCCCCCCATCTCCGGGGG



AATGTCTGAAGACAATTTTGGTTACCTCAATGAGGGAGTGGAGGAGGATACAGTGCT



ACTACCAACTAGTGGATAGAGGCCAGGGATGCTGCTCAACCTCCTACCATGTACAGG



ACGTCTCCCCATTACAACTACCCAATCCGAAGTGTCAACTGTGTCAGGGCTAAGAAA



CCCTGGTTTTGAGTAGAAAAGGGCCTGGAAAGAGGGGAGCCAACAAATCTGTCTGCT



TCCTCACATTAGTCATTGGCAAATAAGCATTCTGTCTCTTTGGCTGCTGCCTCAGCA



CAGAGAGCCAGAACTCTATCGGGCACCAGGATAACATCTCTCAGTGAACAGAGTTGA



CAAGGCCTATGGGAAATGCCTGATGGGATTATCTTCAGCTTGTTGAGCTTCTAAGTT



TCTTTCCCTTCATTCTACCCTGCAAGCCAAGTTCTGTAAGAGAAATGCCTGAGTTCT



AGCTCAGGTTTTCTTACTCTGAATTTAGATCTCCAGACCCTGCCTGGCCACAATTCA



AATTAAGGCAACAAACATATACCTTCCATGAAGCACACACAGACTTTTGAAAGCAAG



GACAATGACTGCTTGAATTGAGGCCTTGAGGAATGAAGCTTTGAAGGAAAAGAATAC



TTTGTTTCCAGCCCCCTTCCCACACTCTTCATGTGTTAACCACTGCCTTCCTGGACC



TTGGAGCCACGGTGACTGTATTACATGTTGTTATAGAAAACTGATTTTAGAGTTCTG



ATCGTTCAAGAGAATGATTAAATATACATTTCCTACACCA (SEQ ID NO: 57)






>NP_078902.2 V-set domain-containing T-cell activation



inhibitor 1 isoform 1 precursor [Homo sapiens]



MASLGQILFWSIISIIIILAGAIALIIGFGISGRHSITVTTVASAGNIGEDGILSCT



FEPDIKLSDIVIQWLKEGVLGLVHEFKEGKDELSEQDEMFRGRTAVFADQVIVGNAS



LRLKNVQLTDAGTYKCYIITSKGKGNANLEYKTGAFSMPEVNVDYNASSETLRCEAP



RWFPQPTVVWASQVDQGANFSEVSNTSFELNSENVTMKVVSVLYNVTINNTYSCMIE



NDIAKATGDIKVTESEIKRRSHLQLLNSKASLCVSSFFAISWALLPLSPYLMLK



(SEQ ID NO: 58)





Mouse B7-H4
>NM_178594.3 Mus musculus V-set domain containing T cell


(VTCN1)
activation inhibitor 1 (Vtcn1), mRNA



GTGAGTCACAACACCCAGGAGGGCAGCAGCAGGCAGGCAGCTCCACTCACCAAAATC



TGGCCCCACACACAGCAGGACTGTGGGAAGGAACTCCCTCTCCATGGCTTCCTTGGG



GCAGATCATCTTTTGGAGTATTATTAACATCATCATCATCCTGGCTGGGGCCATCGC



ACTCATCATTGGCTTTGGCATTTCAGGCAAGCACTTCATCACGGTCACGACCTTCAC



CTCAGCTGGAAACATTGGAGAGGACGGGACCCTGAGCTGCACTTTTGAACCTGACAT



CAAACTCAACGGCATCGTCATCCAGTGGCTGAAAGAAGGCATCAAAGGTTTGGTCCA



CGAGTTCAAAGAAGGCAAAGACGACCTCTCACAGCAGCATGAGATGTTCAGAGGCCG



CACAGCAGTGTTTGCTGATCAGGTGGTAGTTGGCAATGCTTCCCTGAGACTGAAAAA



CGTGCAGCTCACGGATGCTGGCACCTACACATGTTACATCCGCACCTCAAAAGGCAA



AGGGAATGCAAACCTTGAGTATAAGACCGGAGCCTTCAGTATGCCAGAGATAAATGT



GGACTATAATGCCAGTTCAGAGAGTTTACGCTGCGAGGCTCCTCGGTGGTTCCCCCA



GCCCACAGTGGCCTGGGCATCTCAAGTCGACCAAGGAGCCAATTTCTCAGAAGTCTC



CAACACCAGCTTTGAGTTGAACTCTGAGAATGTGACCATGAAGGTCGTATCTGTGCT



CTACAATGTCACAATCAACAACACATACTCCTGTATGATTGAAAACGACATTGCCAA



AGCCACCGGGGACATCAAAGTGACAGATTCAGAGGTCAAAAGGCGAAGTCAGCTGCA



GTTGCTGAACTCTGGGCCTTCCCCGTGTGTTTTTTCTTCTGCCTTTGTGGCTGGCTG



GGCACTCCTATCTCTCTCCTGTTGCCTGATGCTAAGATGAGGGGCCCTGGCTACACA



AAAGCATGCAACGTTGCTGGTCCAACAGAATCCCGGAGAACTACAGAAATATTTTCC



TCAAGACATGACCTAGTTTTATATTTCTAGAAGAAGATGAAATCATGTCTAGAAGTC



TGGAGAGAGCAGACAGGAACAAGATGTGGAAGGAAAACAAAAGTAACCCACAGACAC



CCCCGATCGGAACAAGATGGACCTAGAAAATAATTCAACCAAACTAGAGTATACTAA



GTGTGCTGTTACAATGTGTGTAGGGTAGGTGTCCTCCCACATCTCAGGGGCCTCCCC



TGGTCCACCAGCTCCTGAGTTAGGATGGGCTGTTATGATGTCACTCTGAAGGTTCCT



GGATGGTTCCTACTGCCATATACTCATTTTATATTCAGCACATTAAACCATAGTGAA



TGCTATGAAAAGCTGCTAATCAGCTGCCACTCCGAGATTCGGAGGTGGCAACGTCTG



AGTGACAGGTCCAGTGATTCGCTTCTCCTTAGGATGCTTTTACAAGCTCTTTGGCGT



CTCCTCCCACCTGGCAAATGCCAAATGCATAGGGGAGGGTGATCATCATTCTAGGGC



AAACAAAATAGTTGAGGGATGCTGATTTCCCAAATCATCCGAATCACTTCTCCCTTG



AGCAAACAAGCGCCCTGTTATTTCTCAAATGCTGCTTTGTGAATCAGTCCAGGGCAA



GGCGCTCTCCTCATCCCGCTATGTGGCCTTAAGTCATCGTAAGGTTTGAAGTTTCTA



CTTTCGATCCTGCATGGAGAGCTATAATCTCAGCTCCCCCGCCCCCCCCACACACAC



CTCTGCACACACACCCCCCCCCAACACTGGGAGTAAACCAGGATGATGTCCGTCTTC



TCATTCCCCATGTGACCGTTGGCAGTGTAGAGAGACTGATTGTCACAGCTAAAGGAA



GAGGGACAACAGGGTCACTGGTGTCTACAGAGATTATATTCTACGTGTCTCACTGAA



TTTACACAACTCCAAGTGCCAACCACATCAAGGTCAGGAAATCCTGAACTGGAATAA



GAAAGACCCAGAAGATGAATGTGAACAGATCCATTTGCTTCCCGACAGTGGGCACAG



ACTTCAGTCTCTGGCTACTGTTCCAAGACCCAGGGCTCTGCAATTGTGTGACATCCT



TCAGTGAACCCACATGGGAAATTCTCCATGGAATTATCTTCAGCCCACTGTACTTCT



GAATCCCTCTTCCTTCCTTCTGTGCCACACAGCAAGTCTGGCTTAAATGCTGCCTGA



TCTCCATTTCAAGTTTTCTGCCTCTGGATTTTTAGATCTCAAGACCATGGACGAAAC



ATCAGTTACAGCAACAAAAGTGAATTTTCCGTGCAGAGACTTCTAGGGGTTCTGTTT



GTTTTCAGGGTGCTAGAGATCACACTCAGATGCTCATATATGTTAGGTAAATGTTCT



CCCACTGAGTTACAGCCCAGCTCACACAGAGACTTCTAAAAGAAAATACGGCCATGC



TCTTTGAAATGGAGCATTGAGGGATGAAGTTTGGATGGCGAAGAAAACTTCTCACCA



GCTCTCTCCCCACATTCGTGCCAAGCACTGCCTCCCTAGACTTCGGGTCACCATATC



TGTACTACGTTTTGATACAGAAGGCTCGAGACCATTCAAGAGAATTATTTAGTACAC



(SEQ ID NO: 59)






>NP_848709.2 V-set domain containing T-cell activation



inhibitor 1 precursor [Mus musculus]



MASLGQIIFWSIINIIIILAGAIALIIGFGISGKHFITVTTFTSAGNIGEDGTLSCT



FEPDIKLNGIVIQWLKEGIKGLVHEFKEGKDDLSQQHEMFRGRTAVFADQVVVGNAS



LRLKNVQLTDAGTYTCYIRTSKGKGNANLEYKTGAFSMPEINVDYNASSESLRCEAP



RWFPQPTVAWASQVDQGANFSEVSNTSFELNSENVTMKVVSVLYNVTINNTYSCMIE



NDIAKATGDIKVTDSEVKRRSQLQLLNSGPSPCVFSSAFVAGWALLSLSCCLMLR



(SEQ ID NO: 60)





Human B7-H5
>NM_022153.2 Homo sapiens V-set immunoregulatory receptor


(VISTA)
(VSIR), mRNA



AGTCGCGGGAGGCTTCCCCGCGCCGGCCGCGTCCCGCCCGCTCCCCGGCACCAGAAG



TTCCTCTGCGCGTCCGACGGCGACATGGGCGTCCCCACGGCCCTGGAGGCCGGCAGC



TGGCGCTGGGGATCCCTGCTCTTCGCTCTCTTCCTGGCTGCGTCCCTAGGTCCGGTG



GCAGCCTTCAAGGTCGCCACGCCGTATTCCCTGTATGTCTGTCCCGAGGGGCAGAAC



GTCACCCTCACCTGCAGGCTCTTGGGCCCTGTGGACAAAGGGCACGATGTGACCTTC



TACAAGACGTGGTACCGCAGCTCGAGGGGCGAGGTGCAGACCTGCTCAGAGCGCCGG



CCCATCCGCAACCTCACGTTCCAGGACCTTCACCTGCACCATGGAGGCCACCAGGCT



GCCAACACCAGCCACGACCTGGCTCAGCGCCACGGGCTGGAGTCGGCCTCCGACCAC



CATGGCAACTTCTCCATCACCATGCGCAACCTGACCCTGCTGGATAGCGGCCTCTAC



TGCTGCCTGGTGGTGGAGATCAGGCACCACCACTCGGAGCACAGGGTCCATGGTGCC



ATGGAGCTGCAGGTGCAGACAGGCAAAGATGCACCATCCAACTGTGTGGTGTACCCA



TCCTCCTCCCAGGATAGTGAAAACATCACGGCTGCAGCCCTGGCTACGGGTGCCTGC



ATCGTAGGAATCCTCTGCCTCCCCCTCATCCTGCTCCTGGTCTACAAGCAAAGGCAG



GCAGCCTCCAACCGCCGTGCCCAGGAGCTGGTGCGGATGGACAGCAACATTCAAGGG



ATTGAAAACCCCGGCTTTGAAGCCTCACCACCTGCCCAGGGGATACCCGAGGCCAAA



GTCAGGCACCCCCTGTCCTATGTGGCCCAGCGGCAGCCTTCTGAGTCTGGGCGGCAT



CTGCTTTCGGAGCCCAGCACCCCCCTGTCTCCTCCAGGCCCCGGAGACGTCTTCTTC



CCATCCCTGGACCCTGTCCCTGACTCTCCAAACTTTGAGGTCATCTAGCCCAGCTGG



GGGACAGTGGGCTGTTGTGGCTGGGTCTGGGGCAGGTGCATTTGAGCCAGGGCTGGC



TCTGTGAGTGGCCTCCTTGGCCTCGGCCCTGGTTCCCTCCCTCCTGCTCTGGGCTCA



GATACTGTGACATCCCAGAAGCCCAGCCCCTCAACCCCTCTGGATGCTACATGGGGA



TGCTGGACGGCTCAGCCCCTGTTCCAAGGATTTTGGGGTGCTGAGATTCTCCCCTAG



AGACCTGAAATTCACCAGCTACAGATGCCAAATGACTTACATCTTAAGAAGTCTCAG



AACGTCCAGCCCTTCAGCAGCTCTCGTTCTGAGACATGAGCCTTGGGATGTGGCAGC



ATCAGTGGGACAAGATGGACACTGGGCCACCCTCCCAGGCACCAGACACAGGGCACG



GTGGAGAGACTTCTCCCCCGTGGCCGCCTTGGCTCCCCCGTTTTGCCCGAGGCTGCT



CTTCTGTCAGACTTCCTCTTTGTACCACAGTGGCTCTGGGGCCAGGCCTGCCTGCCC



ACTGGCCATCGCCACCTTCCCCAGCTGCCTCCTACCAGCAGTTTCTCTGAAGATCTG



TCAACAGGTTAAGTCAATCTGGGGCTTCCACTGCCTGCATTCCAGTCCCCAGAGCTT



GGTGGTCCCGAAACGGGAAGTACATATTGGGGCATGGTGGCCTCCGTGAGCAAATGG



TGTCTTGGGCAATCTGAGGCCAGGACAGATGTTGCCCCACCCACTGGAGATGGTGCT



GAGGGAGGTGGGTGGGGCCTTCTGGGAAGGTGAGTGGAGAGGGGCACCTGCCCCCCG



CCCTCCCCATCCCCTACTCCCACTGCTCAGCGCGGGCCATTGCAAGGGTGCCACACA



ATGTCTTGTCCACCCTGGGACACTTCTGAGTATGAAGCGGGATGCTATTAAAAACTA



CATGGGGAAACAGGTGCAAACCCTGGAGATGGATTGTAAGAGCCAGTTTAAATCTGC



ACTCTGCTGCTCCTCCCCCACCCCCACCTTCCACTCCATACAATCTGGGCCTGGTGG



AGTCTTCGCTTCAGAGCCATTCGGCCAGGTGCGGGTGATGTTCCCATCTCCTGCTTG



TGGGCATGCCCTGGCTTTGTTTTTATACACATAGGCAAGGTGAGTCCTCTGTGGAAT



TGTGATTGAAGGATTTTAAAGCAGGGGAGGAGAGTAGGGGGCATCTCTGTACACTCT



GGGGGTAAAACAGGGAAGGCAGTGCCTGAGCATGGGGACAGGTGAGGTGGGGCTGGG



CAGACCCCCTGTAGCGTTTAGCAGGATGGGGGCCCCAGGTACTGTGGAGAGCATAGT



CCAGCCTGGGCATTTGTCTCCTAGCAGCCTACACTGGCTCTGCTGAGCTGGGCCTGG



GTGCTGAAAGCCAGGATTTGGGGCTAGGCGGGAAGATGTTCGCCCAATTGCTTGGGG



GGTTGGGGGGATGGAAAAGGGGAGCACCTCTAGGCTGCCTGGCAGCAGTGAGCCCTG



GGCCTGTGGCTACAGCCAGGGAACCCCACCTGGACACATGGCCCTGCTTCTAAGCCC



CCCAGTTAGGCCCAAAGGAATGGTCCACTGAGGGCCTCCTGCTCTGCCTGGGCTGGG



CCAGGGGCTTTGAGGAGAGGGTAAACATAGGCCCGGAGATGGGGCTGACACCTCGAG



TGGCCAGAATATGCCCAAACCCCGGCTTCTCCCTTGTCCCTAGGCAGAGGGGGGTCC



CTTCTTTTGTTCCCTCTGGTCACCACAATGCTTGATGCCAGCTGCCATAGGAAGAGG



GTGCTGGCTGGCCATGGTGGCACACACCTGTCCTCCCAGCACTTTGCAGGGCTGAGG



TGGAAGGACCGCTTAAGCCCAGGTGTTCAAGGCTGCTGTGAGCTGTGTTCGAGCCAC



TACACTCCAGCCTGGGGACGGAGCAAAACTTTGCCTCAAAACAAATTTTAAAAAGAA



AGAAAGAAGGAAAGAGGGTATGTTTTTCACAATTCATGGGGGCCTGCATGGCAGGAG



TGGGGACAGGACACCTGCTGTTCCTGGAGTCGAAGGACAAGCCCACAGCCCAGATTC



CGGTTCTCCCAACTCAGGAAGAGCATGCCCTGCCCTCTGGGGAGGCTGGCCTGGCCC



CAGCCCTCAGCTGCTGACCTTGAGGCAGAGACAACTTCTAAGAATTTGGCTGCCAGA



CCCCAGGCCTGGCTGCTGCTGTGTGGAGAGGGAGGCGGCCCGCAGCAGAACAGCCAC



CGCACTTCCTCCTCAGCTTCCTCTGGTGCGGCCCTGCCCTCTCTTCTCTGGACCCTT



TTACAACTGAACGCATCTGGGCTTCGTGGTTTCCTGTTTTCAGCGAAATTTACTCTG



AGCTCCCAGTTCCATCTTCATCCATGGCCACAGGCCCTGCCTACAACGCACTAGGGA



CGTCCCTCCCTGCTGCTGCTGGGGAGGGGCAGGCTGCTGGAGCCGCCCTCTGAGTTG



CCCGGGATGGTAGTGCCTCTGATGCCAGCCCTGGTGGCTGTGGGCTGGGGTGCATGG



GAGAGCTGGGTGCGAGAACATGGCGCCTCCAGGGGGCGGGAGGAGCACTAGGGGCTG



GGGCAGGAGGCTCCTGGAGCGCTGGATTCGTGGCACAGTCTGAGGCCCTGAGAGGGA



AATCCATGCTTTTAAGAACTAATTCATTGTTAGGAGATCAATCAGGAATTAGGGGCC



ATCTTACCTATCTCCTGACATTCACAGTTTAATAGAGACTTCCTGCCTTTATTCCCT



CCCAGGGAGAGGCTGAAGGAATGGAATTGAAAGCACCATTTGGAGGGTTTTGCTGAC



ACAGCGGGGACTGCTCAGCACTCCCTAAAAACACACCATGGAGGCCACTGGTGACTG



CTGGTGGGCAGGCTGGCCCTGCCTGGGGGAGTCCGTGGCGATGGGCGCTGGGGTGGA



GGTGCAGGAGCCCCAGGACCTGCTTTTCAAAAGACTTCTGCCTGACCAGAGCTCCCA



CTACATGCAGTGGCCCAGGGCAGAGGGGCTGATACATGGCCTTTTTCAGGGGGTGCT



CCTCGCGGGGTGGACTTGGGAGTGTGCAGTGGGACAGGGGGCTGCAGGGGTCCTGCC



ACCACCGAGCACCAACTTGGCCCCTGGGGTCCTGCCTCATGAATGAGGCCTTCCCCA



GGGCTGGCCTGACTGTGCTGGGGGCTGGGTTAACGTTTTCTCAGGGAACCACAATGC



ACGAAAGAGGAACTGGGGTTGCTAACCAGGATGCTGGGAACAAAGGCCTCTTGAAGC



CCAGCCACAGCCCAGCTGAGCATGAGGCCCAGCCCATAGACGGCACAGGCCACCTGG



CCCATTCCCTGGGCATTCCCTGCTTTGCATTGCTGCTTCTCTTCACCCCATGGAGGC



TATGTCACCCTAACTATCCTGGAATGTGTTGAGAGGGATTCTGAATGATCAATATAG



CTTGGTGAGACAGTGCCGAGATAGATAGCCATGTCTGCCTTGGGCACGGGAGAGGGA



AGTGGCAGCATGCATGCTGTTTCTTGGCCTTTTCTGTTAGAATACTTGGTGCTTTCC



AACACACTTTCACATGTGTTGTAACTTGTTTGATCCACCCCCTTCCCTGAAAATCCT



GGGAGGTTTTATTGCTGCCATTTAACACAGAGGGCAATAGAGGTTCTGAAAGGTCTG



TGTCTTGTCAAAACAAGTAAACGGTGGAACTACGACTAAA (SEQ ID NO: 61)






>NP_071436.1 V-type immunoglobulin domain-containing



suppressor of T-cell activation precursor [Homo sapiens]



MGVPTALEAGSWRWGSLLFALFLAASLGPVAAFKVATPYSLYVCPEGQNVTLTCRLL



GPVDKGHDVTFYKTWYRSSRGEVQTCSERRPIRNLTFQDLHLHHGGHQAANTSHDLA



QRHGLESASDHHGNFSITMRNLTLLDSGLYCCLVVEIRHHHSEHRVHGAMELQVQTG



KDAPSNCVVYPSSSQDSENITAAALATGACIVGILCLPLILLLVYKQRQAASNRRAQ



ELVRMDSNIQGIENPGFEASPPAQGIPEAKVRHPLSYVAQRQPSESGRHLLSEPSTP



LSPPGPGDVFFPSLDPVPDSPNFEVI (SEQ ID NO: 62)





Mouse B7-H5
>NM_028732.4 Mus musculus V-set immunoregulatory receptor


(VISTA)
(Vsir), transcript variant 1, mRNA



GGGGGCGCTGCTGGGCGGGGAGCTTGCTCGGCCGCCTGCCTCGCCTTGGGCTCAGCA



TTCACTCTAGCGAGCGAGCGGCGTGTACAGCCGGCTCCCTGGGCTCCTGGAGTCCCG



CTTGCTCCAAGCGCACTCCAGCAGTCTCTTTCTGCTCTTGCCCGGCTCGACGGCGAC



ATGGGTGTCCCCGCGGTCCCAGAGGCCAGCAGCCCGCGCTGGGGAACCCTGCTCCTT



GCTATTTTCCTGGCTGCATCCAGAGGTCTGGTAGCAGCCTTCAAGGTCACCACTCCA



TATTCTCTCTATGTGTGTCCCGAGGGACAGAATGCCACCCTCACCTGCAGGATTCTG



GGCCCCGTGTCCAAAGGGCACGATGTGACCATCTACAAGACGTGGTACCTCAGCTCA



CGAGGCGAGGTCCAGATGTGCAAAGAACACCGGCCCATACGCAACTTCACATTGCAG



CACCTTCAGCACCACGGAAGCCACCTGAAAGCCAACGCCAGCCATGACCAGCCCCAG



AAGCATGGGCTAGAGCTAGCTTCTGACCACCACGGTAACTTCTCTATCACCCTGCGC



AATGTGACCCCAAGGGACAGCGGCCTCTACTGCTGTCTAGTGATAGAATTAAAAAAC



CACCACCCAGAACAACGGTTCTACGGGTCCATGGAGCTACAGGTACAGGCAGGCAAA



GGCTCGGGGTCCACATGCATGGCGTCTAATGAGCAGGACAGTGACAGCATCACGGCT



GCGGCCCTGGCCACCGGCGCCTGCATCGTGGGAATCCTCTGCCTCCCCCTTATCCTG



CTGCTGGTCTATAAGCAGAGACAGGTGGCCTCTCACCGCCGTGCCCAGGAGTTGGTG



AGGATGGACAGCAGCAACACCCAAGGAATCGAAAACCCAGGCTTCGAGACCACTCCA



CCCTTCCAGGGGATGCCTGAGGCCAAGACCAGGCCGCCACTGTCCTATGTGGCCCAG



CGGCAACCTTCGGAGTCAGGACGGTACCTGCTCTCTGACCCCAGCACACCTCTGTCG



CCTCCAGGCCCTGGGGACGTCTTTTTCCCATCCCTAGATCCAGTCCCTGACTCCCCT



AACTCTGAAGCCATCTAAACCAGCTGGGGAACCATGAACCATGGTACCTGGGTCAGG



GATATGTGCACTTGATCTATGGCTGGCCCTTGGACAGTCTTTTAGGCACTGACTCCA



GCTTCCTTGCTCCTGCTCTGAGCCTAGACTCTGCTTTTACAAGATGCACAGACCCTC



CCCTATCTCTTTCAGACGCTACTTGGGGGGCAGGGAGAAGATGTTGGATTGCTCATT



GCTGTTCTCAAGATCTTGGGATGCTGAGTTCTCCCTAGAGACTTGACTTCGACAGCC



ACAGATGTCAGATGACCTGCATCCTATGAACGTCCGGCTTGGCAAGAGCCTTTCTTC



ATGGAAACCAGTAGCCCGGAGGGGATGAGGTAGGCACCTTGCCACCCTCCCGGGAGA



GAGACACAAGATGTGAGAGACTCCTGCTCACTGTGGGGGTGTGGCTGGCCTGCTTGT



TTGCCTGAGGATGCTCCTCTGTTGGACTGACTCTATCCCCCTGGATTCTGGAGCTTG



GCTGGCCTATGTCCCACCAGAGGAGCATCTCAGCAGCCTTCCACCAGCAACCTGAGG



GCCTGCCAGCTTCGTGGCTCTGGGCTCTCATTACCTGTATGGCCGTCCACAGAGCTC



AGTGGCCAGAGGCTTTGAAACAGGAAGTACATGTCAGGTTCAGGAACCACTGTGAGC



TCATTAGTGTCTTGAGCAATGTGAGGCCTGGACCAGTGGACACGGAGGGAGGGTGGC



GAGAGGATGATGGGGATGATGAGGGGAACACGCTCCCTTCCTGTCCTTGTCATCCAC



CACTACCACTATTCAGTGTGGAGCAGTGGCAAAGGTGACCGACCTCCACAATGTCCT



AGTGATGCTGGACCATTTCTAAGTGTGAAAGAGATGCTATTAAAAACAGTATGTGGC



AATGGCTGCCAACAGCTGAGTGGACTGGAGGCACTGGCTTTAAGGCCCTGGAGGTGC



AGGGCCCGGTATGGGGATAGGGATGGGAGTTTCAGTGAGGGCCTAGGGATCACTCCG



CTTCTGACCACTCTTCTTCTGAGCCTCACCTCAGGGTGACCTTCAGGCACACAGAAG



AGCTTGCCCCTGGTCCGATACTACTCTTGGCTCTCATCTCCAGGGTTTGGCATGACC



TGGGCACACAGGGGGAGTCTTCAGAAAGGATTTTAAAGCATGAAAAGAAAGGGTAGT



TCTTGTGAGGTAGGGATGGGCAGCTGATGTTTGAGAGTGAGGAGGGATACGGCTGGG



CAGATCACTCTCCAGTCTCTAGAGGGAAAGTAGCTCTAAGTCTGGGAGAGCAGCAGC



CCAGTGGTACCATATGTCTTCTTGCAGCTTCCACTGGCTGGGCTGAACTGGGCATGG



GTAGGAAAGCTCCTGTTOTGGGCCTGCAGCCAGGGAGAACCCCATTCATTCCCTGAG



GACAGATGGGTGGGGAGAGAAGAGAGAGTTTCAGGCCGGGAAGCAGCAATAAGCTAT



CTGCTGGGGACCCAGACAAGTTGTCTGATGAGGTCCAAGATGTGGGATGCCAGTTAT



ACCTGGGGCTTGGGGATCCTTAGAGGCTTTGTATCATCATCATAGGAGTGTCGGGGT



GGCCAGGGCATCAAAGCCATGACCCCTGTTTTATCCTCAGGGTCCACTCTTCTGCAC



CATCCATTGCTCTAGATCTATGCAGTTACTATAGACAGAATGTGTTGTTCTGTTTGG



CTTTGGGGATAATGGCCTGGCGAACTGCCAGCTGTTCAGTGGCAGGGCTGTGAGGCC



AGTCAAAGACTAGAACCCACAGACCAGCTGAACGATGAGTATAGCCTGTCCCCTGGG



GGAGCCTGACCTGTCTCCAGCCCTAAGCTTCAGACCTCACCACTCAGATGACTTCTA



AGAATTTGCCTGTGGGGACCCCTGCATGGCTGCAGCTCCGTGGAAAGGAGAGGAGGC



CCCCAGCAGAAGAACCACTCGCTTCCTGCCCAGCTTCCTCCTGTAGGGCTCTAAGTC



TCTTCTTCTTGGGACCCTGCAAGCAAAGGCATGTCAGCTTGGTGGTTTCCTGTTTTG



GGTGAAGTTTTGTGTGGTCCGGGTTCTGTCTACATCCATGAACTTGGGTGCTACCAC



CTTGCTGCTGCTGTAGAGACAGCTGCAGGATCTTAGGGTGGAAAATGGAGGTGCCCT



GAGGTGCTAGCCCTTGGGGCAAAAGATGGGGTGGCAATGAGACACAGTGGGGAACTG



AGTTCCCCAAGAGGAGGGAGGAGCCCTGTAGCCTCAAGGGCCATATTGGGTTCCTGG



TACCAGCAAAAGCCTAGAGAGCGAAGTCTGTATTTTGAGGAGGTAATTGATCCTTAC



GGAATCCATCAGAAATTTGGAGCGGGTGCTTTATCTATCTCTGGAGGGTCTCTACCT



ATCTCCGATGAAGCTCTCCCTGGGCCTGGGATGGGAGAAACCAGGAGGAAAGGTGTC



TGATAAAGCAGGGGCTTCTTGACAAGCCAAAGGGCCACTGGTAGCTGTTGTGGACCG



AGCTGACCCTGCTGAAGTATTGTAGTGTGCCTTGGACCAACTTCTCAAAAGAGCAAC



CCCGGGGCTACCCTACTTCTGCCAGGAAGAGGCGGAGAAGGGGCTGAGAGGCCTGGA



AGGGGCTAGCTCCTTCTTTGAGAACTGCTCCCCGGAGGACTTGGAGGAGGCGGCTAG



GCTACGGGCTGCTGAGGGCCCTTTGTCTTTCCTAACCTGGGCACTGTTAGGATGCTC



CCTCCTGGAAAAGGCTTTCCTGGGTGTGAGCTAGAGCAGTGTCCATGCCAGCGCTGA



ACCTGCCATGGTGGGAGCTGAACTAAAAATTTCTCAGGGAACTAAAATAGGCAAAAG



AGGAACTGGGGGAGGAGGGTGCCAGGCAGGATGGGGGGAAGGGAGGGCAGTGCAAAA



GTCTCTTGAAACACAGACAGCCCAGCTGAGTGCCAGTCCCAGATCACAGAGAATACG



GCTCATCTGGCTCATGTTCTGCATGCTTGCTGCTTTACCCTGGCACTTTCCTTCTCC



ACCATGAGTGCGAGTCCTGGGAGTCCTGGGAGGGTGAGGATTAATGCCAGCCTGGGG



AGCAGATAGCTGACAGAGTCCTTGGGTAACTGGCTTGAACCAGGACCTCAGGATTCC



ACTCTGGGGATCTAGCTTTGTCTGGGCCAGTGAAGATCTCTATAATGGCATTATTGC



CAGGGGATAAACATTTCACTGGGTTCTGATCTGTTGGGTGTGGCTTCCTGGAAAATA



TGGTGAGAGGAATTCTGCTAAGGATACAGTTGATAAGAAAGTTCTGAGATTGATTAG



TAATGCCTGCCTTGGACTCAGGAAGGGAAGTGGCAGTATGAATGCCATGTCTTAATC



ATTTTGGTTAAAATATGCTTCCCAAAAGATTTCCACGTGTGTTCTTGTTTATTTGAC



ATCTGTCTCCATATCAGTCTTGAAAGCCTTTCTGTGTGTATATATATGATGTTTGCG



TGTATATATGTTTTTGTGTGTGCATATGGAAGTCAGAAATCACTGGGTGTCTTCCTC



CATTCCTTTGCAATGTATGTTTTTTTTTTTTTTACGATTTATTTACTATATGAATGT



TTTGCCTGAATACATGCATAGGTGTCACGTACATGCCTGCTGGAACGCTTGGAACTG



GAGTTACAGGTGGCTATGAGCTACAGTGTGAGCACTGGGAATCAAACCTGGGTCTTC



TGCAAGAGCAACAAATTAAAAGTCAGCTCTTAACTACTTGAGCTATTTTTCCAACTC



C (SEQ ID NO: 63)






>NP_083008.1 V-type immunoglobulin domain-containing



suppressor of T-cell activation isoform 1 precursor [Mus




musculus]




MGVPAVPEASSPRWGTLLLAIFLAASRGLVAAFKVTTPYSLYVCPEGQNATLTCRIL



GPVSKGHDVTIYKTWYLSSRGEVQMCKEHRPIRNFTLQHLQHHGSHLKANASHDQPQ



KHGLELASDHHGNFSITLRNVTPRDSGLYCCLVIELKNHHPEQRFYGSMELQVQAGK



GSGSTCMASNEQDSDSITAAALATGACIVGILCLPLILLLVYKQRQVASHRRAQELV



RMDSSNTQGIENPGFETTPPFQGMPEAKTRPPLSYVAQRQPSESGRYLLSDPSTPLS



PPGPGDVFFPSLDPVPDSPNSEAI (SEQ ID NO: 64)





Human B7-H7
>NM_007072.4 Homosapiens HERV-H LTR-associating 2


(HHLA2)
(HHLA2), transcript variant 1, mRNA



AGTTCTCTTCAAGTCATGTAATCGACTTTTTTGAATTAGTTTTCAGTTTCATTTTGT



TTTCCCTAATTCAAGTTGGGAACACTTCATTTTCCCCAATTCAAGTTGGGAACACTT



CCTTGGTATTTCCTTGCTACATGGACTTTAGCAAATGCTACTTTACTCTCCTTCCAG



CTACTCAGGAGGCTGAGGCAGGAGAATCGCTTGAACCCGGGAGGCGGAGGTTACAGT



GAGCCTTTTCCTAGTTTTACTGTTGGAAGCCTAACTCACAGGAGAGATTATGCAATA



CAGTCCTGAAGTCAAGGGAGGAGAGCATGTAGGAGAATACTAACCCTGCACAGATTG



TGATGGTGATGTGGAATATACTAAAGCCTAGAACGCACCTCCTCTGCATGACTAATA



TGTTCTGCACAAGACATGAAGGCACAGACAGCACTGTCTTTCTTCCTCATTCTCATA



ACATCTCTGAGTGGATCTCAAGGCATATTCCCTTTGGCTTTCTTCATTTATGTTCCT



ATGAATGAACAAATCGTCATTGGAAGACTTGATGAAGATATAATTCTCCCTTCTTCA



TTTGAGAGGGGATCCGAAGTCGTAATACACTGGAAGTATCAAGATAGCTATAAGGTT



CACAGTTACTACAAAGGCAGTGACCATTTGGAAAGCCAAGATCCCAGATATGCAAAC



AGGACATCCCTTTTCTATAATGAGATTCAAAATGGGAATGCGTCGCTATTTTTCAGA



AGAGTAAGCCTTCTGGACGAAGGAATTTACACCTGCTATGTAGGAACAGCAATTCAA



GTGATTACAAACAAAGTGGTGCTAAAGGTGGGAGTTTTTCTCACACCCGTGATGAAG



TATGAAAAGAGGAACACAAACAGCTTCTTAATATGCAGCGTGTTAAGTGTTTATCCT



CGTCCAATTATCACGTGGAAAATGGACAACACACCTATCTCTGAAAACAACATGGAA



GAAACAGGGTCTTTGGATTCTTTTTCTATTAACAGCCCACTGAATATTACAGGATCA



AATTCATCTTATGAATGTACAATTGAAAATTCACTGCTGAAGCAAACATGGACAGGG



CGCTGGACGATGAAAGATGGCCTTCATAAAATGCAAAGTGAACACGTTTCACTCTCA



TGTCAACCTGTAAATGATTATTTTTCACCAAACCAAGACTTCAAAGTTACTTGGTCC



AGAATGAAAAGTGGGACTTTCTCTGTCCTGGCTTACTATCTGAGCTCCTCACAAAAT



ACAATTATCAATGAATCCCGATTCTCATGGAACAAAGAGCTGATAAACCAGAGTGAC



TTCTCTATGAATTTGATGGATCTTAATCTTTCAGACAGTGGGGAATATTTATGCAAT



ATTTCTTCGGATGAATATACTTTACTTACCATCCACACAGTGCATGTAGAACCGAGC



CAAGAAACAGCTTCCCATAACAAAGGCTTATGGATTTTGGTGCCCTCTGCGATTTTG



GCAGCTTTTCTGCTGATTTGGAGCGTAAAATGTTGCAGAGCCCAGCTAGAAGCCAGG



AGGAGCAGACACCCTGCTGATGGAGCCCAACAAGAAAGATGTTGTGTCCCTCCTGGT



GAGCGCTGTCCCAGTGCACCCGATAATGGCGAAGAAAATGTGCCTCTTTCAGGAAAA



GTATAGGAAATGAGAGAAGACTGTGACAACTCATGACCTGCATCCTTAATATCCAGT



GACTTCATCTCCCCTTTCTTCACCACAATTCCAGGCAATGGCCTGTCGGAGCAGACA



ATTCTACCACTGCAAAGAGTTGTAACCATTTTCTGGTATCACATTTATTTTTCAAGA



CATACTTTTCAAGACATCATTCACTGACCCACTACCTGCATTGAGTATAAATGCCTG



GATGTTAAGGATTCCAATTTAACTTTGAAAAGAACTGTCTCATTCATTTACATTTCT



GTTACAGTCAGCCCAGGAGGTTACAGTGAGCTCTCCACTAAGAATCTGGAAGAAATG



CATCACTAGGGGTTGATTCCCAATCTGATCAACTGATAATGGGTGAGAGAGCAGGTA



AGAGCCAAAGTCACCTTAGTGGAAAGGTTAAAAACCAGAGCCTGGAAACCAAGATGA



TTGATTTGACAAGGTATTTTAGTCTAGTTTTATATGAACGGTTGTATCAGGGTAACC



AACTCGATTTGGGATGAATCTTAGGGCACCAAAGACTAAGACAGTATCTTTAAGATT



GCTAGGGAAAAGGGCCCTATGTGTCAGGCCTCTGAGCCCAAGCCAAGCATCGCATCC



CCTGTGATTTGCACGTATACATCCAGATGGCCTAAAGTAACTGAAGATCCACAAAAG



AAGTAAAAATAGCCTTAACTGATGACATTCCACCATTGTGATTTGTTCCTGCCCCAC



CCTAACTGATCAATGTACTTTGTAATCTCCCCCACCCTTAAGAAGGTACTTTGTAAT



CTTCCCCACCCTTAAGAAGGTTCTTTGTAATTCTCCCCACCCTTGAGAATGTACTTT



GTGAGATCCACCCTGCCCACAAAACATTGCTCTTAACTTCACCGCCTAACCCAAAAC



CTATAAGAACTAATGATAATCCATCACCCTTCGCTGACTCTCTTTTCGGACTCAGCC



CACCTGCACCCAGGTGAAATAAACAGCTTTATTGCTCACACAAA (SEQ ID NO:



65)






>NP_009003.1 HERV-H LTR-associating protein 2 isoform a



precursor [Homosapiens]



MKAQTALSFFLILITSLSGSQGIFPLAFFIYVPMNEQIVIGRLDEDIILPSSFERGS



EVVIHWKYQDSYKVHSYYKGSDHLESQDPRYANRTSLFYNEIQNGNASLFFRRVSLL



DEGIYTCYVGTAIQVITNKVVLKVGVFLTPVMKYEKRNTNSFLICSVLSVYPRPIIT



WKMDNTPISENNMEETGSLDSFSINSPLNITGSNSSYECTIENSLLKQTWTGRWTMK



DGLHKMQSEHVSLSCQPVNDYFSPNQDFKVTWSRMKSGTFSVLAYYLSSSQNTIINE



SRFSWNKELINQSDFSMNLMDLNLSDSGEYLCNISSDEYTLLTIHTVHVEPSQETAS



HNKGLWILVPSAILAAFLLIWSVKCCRAQLEARRSRHPADGAQQERCCVPPGERCPS



APDNGEENVPLSGKV (SEQ ID NO: 66





Mouse BTNL1
>NM_001111094.1 Mus musculus butyrophilin-like 1 (Btnl1),



mRNA



ACCCTTAAATAAGAGCTGAAGATGGCTGCAGCTTTCTCCTAGACTCCTCCAGGAGAA



ACTCTAAAGCCAGAGCCTGGGGGCAGCATTGTGTGTCCACCTTGCCACTGAGAACAT



CTACGGAAATTGGACACTCTGGCCCCAGCATCCACACGCTTGACTGTTGGCCACAGT



AACACAGGTGTGGATGGTCCCCAGAGCCAGGGTCCAGGAGTGCACTGAGGATCCCTG



GGGCTTCAAGGAACCCACAGCTCTGTCCAGACGGGAATTTTTTTCCTGAGAACTTTC



ACCTGTTGCCCTCCTATGGTGAACCTGGACTTGACCTTCCACTCTGATGATGAAGGG



CTCCCCCTCCGTCCCTCCAGCTGGTTGTCTCCTCCCTCTGCTCCTCCTGCTGTTTAC



CGGAGTCTCTGGAGAAGTGTCTTGGTTTTCTGTGAAGGGACCAGCTGAGCCCATCAC



TGTCCTGCTGGGGACTGAAGCCACCCTGCCCTGCCAGCTGTCTCCTGAACAGAGTGC



AGCTCGCATGCACATCCGATGGTACCGTGCCCAGCCCACCCCTGCTGTGCTGGTGTT



CCACAACGGACAGGAGCAGGGAGAGGTGCAGATGCCGGAATACAGGGGCAGGACCCA



GATGGTGAGACAAGCCATTGACATGGGAAGTGTGGCTCTGCAGATACAGCAGGTCCA



GGCCTCTGATGATGGCCTGTACCACTGTCAGTTTACAGATGGCTTCACCTCCCAAGA



GGTCTCCATGGAGCTTCGAGTCATAGGTTTAGGCTCTGCCCCTCTTGTTCACATGAC



AGGACCTGAGAATGATGGGATCCGAGTGTTGTGCTCCTCAAGTGGCTGGTTCCCAAA



ACCCAAAGTGCAATGGAGAGACACCTCCGGGAACATGCTACTGTCCTCCTCTGAGTT



GCAGACCCAAGACAGAGAAGGGCTCTTCCAGGTGGAAGTGTCTCTTTTGGTCACAGA



TAGAGCTATTGGCAATGTGATCTGCTCCATCCAAAATCCCATGTATGACCAGGAGAA



ATCGAAGGCCATCCTCCTCCCAGAGCCCTTCTTCCCCAAGACGTGTCCATGGAAAGT



AGCCCTGGTTTGTTCTGTCCTCATACTATTGGTCCTGCTCGGTGGGATCAGCCTTGG



AATCTGGAAAGAACATCAAGTCAAAAGGAGAGAAATTAAAAAATGGTCAAAGGAACA



TGAAGAAATGCTTCTGTTGAAGAAGGGGACAAAATCTGTACTGAAGATCAGAGATGA



CCTCCAGGCCGACCTAGATCGGAGGAAGGCGCTGTACAAAGAAGACTGGAAGAAGGC



CTTGCTGTACCCTGACTGGAGGAAGGAGCTGTTCCAGGAGGCTCCTGTGAGGATAAA



TTATGAAATGCCTGACCAGGACAAGACAGACTCAAGGACAGAAGAGAACAGAGGTGA



GGAGACTGTCAGCAGCTCACAAGTAGACCACAACCTCATCACACTCTCCCAGGAAGG



CTTCATGTTGGGAAGATACTACTGGGAGGTGGATGTCAAGGACACAGAGGAGTGGAC



ACTAGGAGTTTATGAGCTGTGCACTCAGGATGCATCACTTACAGACCCCTTGAGGAA



ATTCAGAGTCCTGGAAAAGAATGGAGATGGATACAGGGCTCTTGACTTCTGTTCCCA



AAACATTAATTCGGAAGAACCTCTGCAACTGAAGACACGTCCGCTGAAGATCGCCAT



CTTCTTGGATCAGGAAGACAATGACCTCTCTTTCTACAACATGACCGATGAGACACA



CATCTTTTCCTTTGCCCAGGTCCCTTTCTTGGGATCACCCTATCCTTACTTCACACG



TAATTCCATGGGGCTCTCTGCAACAGCACAGCCCTAAGTGATGTGCACAGGGAATTC



AATGGGTGGGTGCTGCAGCGTGCTACCCGTAAGGCCCTCTTAGGCAGGCACAGGGGG



CCTCTGACCAAGAGGCCTCTTAACCTGAGACTCCATGAGCCTCGGGGATCAGATCCT



GGACAAGATTCTCGGACCATCTGTGTCGTGCATGGTGTTATAGTTATTAATAGCCTT



CCTTCTTTTGACAAAAATGTGTTTAATCATTCCTAAGATAAATGAATCCATGGCTTT



CTGA (SEQ ID NO: 67)






>NP_001104564.1 butyrophilin-like protein 1 precursor



[Mus musculus]



MMKGSPSVPPAGCLLPLLLLLFTGVSGEVSWFSVKGPAEPITVLLGTEATLPCQLSP



EQSAARMHIRWYRAQPTPAVLVFHNGQEQGEVQMPEYRGRTQMVRQAIDMGSVALQI



QQVQASDDGLYHCQFTDGFTSQEVSMELRVIGLGSAPLVHMTGPENDGIRVLCSSSG



WFPKPKVQWRDTSGNMLLSSSELQTQDREGLFQVEVSLLVTDRAIGNVICSIQNPMY



DQEKSKAILLPEPFFPKTCPWKVALVCSVLILLVLLGGISLGIWKEHQVKRREIKKW



SKEHEEMLLLKKGTKSVLKIRDDLQADLDRRKALYKEDWKKALLYPDWRKELFQEAP



VRINYEMPDQDKTDSRTEENRGEETVSSSQVDHNLITLSQEGFMLGRYYWEVDVKDT



EEWTLGVYELCTQDASLTDPLRKFRVLEKNGDGYRALDFCSQNINSEEPLQLKTRPL



KIAIFLDQEDNDLSFYNMTDETHIFSFAQVPFLGSPYPYFTRNSMGLSATAQP



(SEQ ID NO: 68)





Human VSIG8
>NM_001013661.1 Homosapiens V-set and immunoglobulin



domain containing 8 (VSIG8), mRNA



ACTCATTGCACCTTCCTGCCACCCCAGGCAGTGTCTGGGCCCTCAGCTCCCCCTCCC



TCCACCTACCCCCTCACACCCACCACTACGACCCCACGGGATACCCAGCCCAGACGG



AGGAAACACCGAGCCTAGAGACATGAGAGTTGGAGGAGCATTCCACCTTCTACTCGT



GTGCCTGAGCCCAGCACTGCTGTCTGCTGTGCGGATCAACGGGGATGGACAGGAGGT



CCTGTACCTGGCAGAAGGTGATAATGTGAGGCTGGGCTGCCCCTACGTCCTGGACCC



TGAGGACTATGGTCCCAATGGGCTGGACATCGAGTGGATGCAGGTCAACTCAGACCC



CGCCCACCACCGAGAGAACGTGTTCCTTAGTTACCAGGACAAGAGGATCAACCATGG



CAGCCTTCCCCATCTGCAGCAGAGGGTCCGCTTTGCAGCCTCAGACCCAAGCCAGTA



CGATGCCTCCATCAACCTCATGAACCTGCAGGTATCTGATACAGCCACTTATGAGTG



CCGGGTGAAGAAGACCACCATGGCCACCCGGAAGGTCATTGTCACTGTCCAAGCACG



ACCTGCAGTGCCCATGTGCTGGACAGAGGGCCACATGACATATGGCAACGATGTGGT



GCTGAAGTGCTATGCCAGTGGGGGCTCCCAGCCCCTCTCCTACAAGTGGGCCAAGAT



CAGTGGGCACCATTACCCCTATCGAGCTGGGTCTTACACCTCCCAGCACAGCTACCA



CTCAGAGCTGTCCTACCAGGAGTCCTTCCACAGCTCCATAAACCAAGGCCTGAACAA



TGGGGACCTGGTGTTGAAGGATATCTCCAGAGCAGATGATGGGCTGTATCAGTGCAC



AGTGGCCAACAACGTGGGCTACAGTGTTTGTGTGGTGGAGGTGAAGGTCTCAGACTC



CCGGCGTATAGGCGTGATCATCGGCATCGTCCTGGGCTCTCTGCTCGCGCTGGGCTG



CCTGGCCGTAGGCATCTGGGGGCTCGTCTGCTGCTGCTGCGGGGGCTCCGGGGCTGG



CGGCGCCCGCGGTGCCTTCGGCTACGGCAACGGCGGCGGGGTCGGCGGAGGGGCCTG



CGGCGACTTGGCTAGTGAGATCAGAGAGGACGCCGTGGCGCCCGGGTGCAAGGCCAG



CGGGCGCGGCAGCCGCGTCACCCACCTCCTGGGGTACCCGACGCAGAACGTCAGCCG



CTCCCTGCGCCGCAAGTACGCGCCTCCCCCCTGCGGCGGCCCCGAGGACGTGGCCCT



GGCGCCCTGCACCGCCGCCGCCGCCTGCGAAGCGGGCCCCTCCCCGGTCTACGTCAA



GGTCAAGAGCGCGGAGCCGGCTGACTGCGCCGAGGGGCCGGTGCAGTGCAAGAACGG



CCTCTTGGTGTGAGCGCGCGCGCCGGGCCGGGCTGCGCCCCAGCCAGGAGGAGGGCG



CGGGGCTCTCTGTCTGCAGCTGGGGACACGTCGGGGCTGGGGACGACCTCGCTCGCC



CCAGGCTGCCAGGCGGCTGGGGGTGAAGGCATTTCCCTAAGGAAATGCGTAGGGAGG



CAGAGCCTCCTCCCCAAAAGTGGGAAGGGGCGGGCGAGGGCGGAGGAAGGCGATCCT



GAGCCTTCTCCGCACCCCCGGGACCGAAGGCTTGGGGGAGAGGGAGGGAGGAGGAGG



CTGAGTGTCCTAGAGCGGCTGAGGCCGGAGGCCTGGTGTCCCCAGCCTAAGCAGAGG



GCCCCGGGGGCCGGGTGGGTGGGGGTCTGTCTGGACGAATTGTTCTGTGTGTGAGGT



CTGAGCTCTGAGGCAGCAGTGTTAGCACAATAAAGAAACATTGAGACGTGA (SEQ



ID NO: 69)






>NP_001013683.1 V-set and immunoglobulin domain-



containing protein 8 precursor [Homo sapiens]



MRVGGAFHLLLVCLSPALLSAVRINGDGQEVLYLAEGDNVRLGCPYVLDPEDYGPNG



LDIEWMQVNSDPAHHRENVFLSYQDKRINHGSLPHLQQRVRFAASDPSQYDASINLM



NLQVSDTATYECRVKKTTMATRKVIVTVQARPAVPMCWTEGHMTYGNDVVLKCYASG



GSQPLSYKWAKISGHHYPYRAGSYTSQHSYHSELSYQESFHSSINQGLNNGDLVLKD



ISRADDGLYQCTVANNVGYSVCVVEVKVSDSRRIGVIIGIVLGSLLALGCLAVGIWG



LVCCCCGGSGAGGARGAFGYGNGGGVGGGACGDLASEIREDAVAPGCKASGRGSRVT



HLLGYPTQNVSRSLRRKYAPPPCGGPEDVALAPCTAAAACEAGPSPVYVKVKSAEPA



DCAEGPVQCKNGLLV (SEQ ID NO: 70)





Mouse VSIG8
>NM_177723.4 Mus musculus V-set and immunoglobulin domain



containing 8 (Vsig8), transcript variant 1, mRNA



ACTCATTGCATCTTCCTGCCACCCCGGGCAGTGTCTGGGCCCTCCGCTCCCCCTCCC



TCCACCTGCCCCTTCCACCCACCACCACCAGCCCACTGGAGCCCAGCTCAGGCGGAG



GAAAGACCAAGCCTAGAGACATGGGAGTTCGAGGAGCACTCCATCTTCTACTTGTGT



GCCTGAGCCCAGCACTGTTGTCTGCTGTAAGGATCAACGGGGATGGCCAGGAGGTCA



TGTACCTGGCAGAAGGTGACAATGTGAGGCTAGGCTGTCCCTACCTCCTGGATCCTG



AGGATTTGGGTACCAACAGTCTGGACATTGAGTGGATGCAAGTCAACTCAGAGCCCT



CACACAGGGAGAATGTTTTTCTTACTTATCAAGACAAGAGGATAGGTCATGGCAACC



TCCCCCATCTGCAGCAGAGGGTCCGCTTTGCAGCCTCAGACCCCAGCCAGTACGATG



CCTCCATCAACCTCATGAACCTGCAGGTATCTGACACAGCAACCTATGAGTGCCGGG



TGAAGAAGACCACCATGGCCACCAGGAAGGTCATTGTCACTGTCCAAGCACGTCCTG



CGGTGCCCATGTGTTGGACGGAAGGCCACATGTCAAAGGGCAACGATGTGGTGCTGA



AGTGCTTTGCCAACGGAGGCTCTCAGCCCCTCTCCTACAAGTGGGCCAAGATCAGTG



GGCACAGTCACCCCTACCGAGCTGGGGCTTACCACTCACAGCACAGCTTCCACTCTG



AGCTTTCTTACCAAGAGTCATTCCACAGCACCATCAACCAAGGCCTGGGCAACGGAG



ACCTGCTGTTGAAGGGCATCAACGCAGACGACGATGGGCTGTATCAGTGCACAGTGG



CCAACCATGTGGGCTACAGCGTCTGTGTGGTAGAGGTGAAAGTCTCAGACTCCCAGC



GAGTAGGCATGATCGTTGGAGCAGTGCTGGGCTCTTTGCTCATGCTGGCCTGCCTGG



CACTAGGCATCTGGGGGCTCATCTGCTGCTGCTGCGGAGGCGGCGGGGCCGGTGGTG



CCCGAGGTGCCTTCGGCTACGGGGTCGGCGGCGGGGTCGGCGGAGGGGCCTGCGGCG



ACTTGGCTAGTGAGATCAGAGTGGACGCCGAGGCGCCCGGGTGTAAGGCCAGCGGGC



GCGGCAGCCGCGTCACCCACCTCCTGGGGTACCCGACGCAGAACGTCAGCCGCTCCC



TGCGCCGCAAGTACGCGCCTCCGCCCTGCGGCGGCCCCGAGGACGTGGCCCTAGTGC



CCCGCACCGCCTCCGCCTCCTGCGAAGCGGGTCCCTCCCCCGTCTACATCAAGGTCA



AGAGCGCGGAGCCGGCCGACTGCGCCGACTGTGCCCAGGTCGAGCAGCGCTCGTGCA



AGGACGGCCTCTTAGTGTGAGCGCACAGCACCGGGCTGCGCCCCGGCTGGGAGGTGG



TTCGGGGGCTCTCTGCCCGCAGCTGGGGACAGGTTCGGGCCAGCAGACCTGGCTCTC



TCATTGGCCACCTAGCGGTGGTAAGGAAATTTCCCTCTGAGAAGCCAAGCCGGGCAG



ACCCTCCTCCCCTGTAGTGGGAGGAGAGGCGGGGGAGACAGAAAACAGTTCAGAGCT



CTCCCTCACCCCTGGTTTCCAGGGAGAGGAAGGGAGAGGAGAGCTGTCGGTATCCCA



GAACCGCAGAGGTACAACCCAGATGTCCCCAGCCAAGGCGAGGGCCCCCCAGCCCTG



GGTAGGTGGATGTCAGGGCTGAATTGCTCTGTGTGTGAGATCTGAGCTCCAAGGCAA



CAGTGTTAGCACAATAAAGAAACTTAAAGACTGAAAAAAAAAAAAAA (SEQ ID



NO: 71)






>NP_808391.2 V-set and immunoglobulin domain-containing



protein 8 precursor [Mus musculus]



MGVRGALHLLLVCLSPALLSAVRINGDGQEVMYLAEGDNVRLGCPYLLDPEDLGTNS



LDIEWMQVNSEPSHRENVFLTYQDKRIGHGNLPHLQQRVRFAASDPSQYDASINLMN



LQVSDTATYECRVKKTTMATRKVIVTVQARPAVPMCWTEGHMSKGNDVVLKCFANGG



SQPLSYKWAKISGHSHPYRAGAYHSQHSFHSELSYQESFHSTINQGLGNGDLLLKGI



NADDDGLYQCTVANHVGYSVCVVEVKVSDSQRVGMIVGAVLGSLLMLACLALGIWGL



ICCCCGGGGAGGARGAFGYGVGGGVGGGACGDLASEIRVDAEAPGCKASGRGSRVTH



LLGYPTQNVSRSLRRKYAPPPCGGPEDVALVPRTASASCEAGPSPVYIKVKSAEPAD



CADCAQVEQRSCKDGLLV (SEQ ID NO: 72)





Human VSIG3
>NM_001015887.3 Homosapiens immunoglobulin superfamily


(ISF11)
member 11 (IGSF11), transcript variant 2, mRNA



AGTCCTGGGGCAGGGCTGGGTGGCACGGCTGGCGAGCCCGGAACGCCTCTGGTCACA



GCTCAGCGTCCGCGGAGCCGGGCGGCGCTGCAGCTGCACTTGGCTCGTCTGTGGGTC



TGACAGTCCCAGCTCTGCGCGGGGAACAGCGGCCCGGCGCTGGGTGTGGGAGGACCA



GGCTGCCCCAAGAGCGCGGAGACTCACGCCCGCTCCTCTCCTGTTGCGACCGGGAGC



CGGGTAGGAGGCAGGCGCGCTCCCTGCGGCCCCGGGATGACTTCTCAGCGTTCCCCT



CTGGCGCCTTTGCTGCTCCTCTCTCTGCACGGTGTTGCAGCATCCCTGGAAGTGTCA



GAGAGCCCTGGGAGTATCCAGGTGGCCCGGGGTCAGCCAGCAGTCCTGCCCTGCACT



TTCACTACCAGCGCTGCCCTCATTAACCTCAATGTCATTTGGATGGTCACTCCTCTC



TCCAATGCCAACCAACCTGAACAGGTCATCCTGTATCAGGGTGGACAGATGTTTGAT



GGTGCCCCCCGGTTCCACGGTAGGGTAGGATTTACAGGCACCATGCCAGCTACCAAT



GTCTCTATCTTCATTAATAACACTCAGTTATCAGACACTGGCACCTACCAGTGCCTG



GTCAACAACCTTCCAGACATAGGGGGCAGGAACATTGGGGTCACCGGTCTCACAGTG



TTAGTTCCCCCTTCTGCCCCACACTGCCAAATCCAAGGATCCCAGGATATTGGCAGC



GATGTCATCCTGCTCTGTAGCTCAGAGGAAGGCATTCCTCGACCAACTTACCTTTGG



GAGAAGTTAGACAATACCCTCAAACTACCTCCAACAGCTACTCAGGACCAGGTCCAG



GGAACAGTCACCATCCGGAACATCAGTGCCCTGTCTTCAGGTTTGTACCAGTGCGTG



GCTTCTAATGCTATTGGAACCAGCACCTGTCTTCTGGATCTCCAGGTTATTTCACCC



CAGCCCAGGAACATTGGACTAATAGCTGGAGCCATTGGCACTGGTGCAGTTATTATC



ATTTTTTGCATTGCACTAATTTTAGGGGCATTCTTTTACTGGAGAAGCAAAAATAAA



GAGGAGGAAGAAGAAGAAATTCCTAATGAAATAAGAGAGGATGATCTTCCACCCAAG



TGTTCTTCTGCCAAAGCATTTCACACTGAGATTTCCTCCTCGGACAACAACACACTA



ACCTCTTCCAATGCCTACAACAGTCGATACTGGAGCAACAATCCAAAAGTTCATAGA



AACACAGAGTCAGTCAGCCACTTCAGTGACTTGGGCCAATCTTTCTCTTTCCACTCA



GGCAATGCCAACATACCATCCATTTATGCTAATGGGACCCATCTGGTCCCGGGTCAA



CATAAGACTCTGGTAGTGACAGCCAACAGAGGGTCATCACCACAGGTGATGTCCAGG



AGCAATGGCTCAGTCAGTAGGAAGCCTCGGCCTCCACACACTCATTCCTACACCATC



AGCCACGCAACACTGGAACGAATTGGTGCAGTACCTGTCATGGTACCAGCCCAGAGT



CGGGCCGGGTCCTTGGTATAGGACATGAGGAAATGTTGTGTTCAGAAATGAATAAAT



GGAATGCCCTCATACAAGGGGGAGGGTGGGGTGGGGAGTGCTGGGAAAGAAACACTT



CCTTATAATTATATTAGTAAAATGCACAAAGAAGAAGGCAGTGCTGTTACTTGGCCA



CTAAGATGTGTAAAATGGACTGAAATGCTCCATCATGAAGACTTGCTTCCCCACCAA



AGATGTCCTGGGATTCTGCTGGATCTCAAAGATGTGCCAAGCCAAGGAAAAAGATAC



AAGAGCAGAATAGTACTTAAAATCCAAACTGCCGCCCAGATGGGCTTGTTCTTCATG



CCTAACTTAATAATTTTTAAGAGATTAAAGTGCCAGATGGAGTTTAAATATTGAAAT



TATTTTAAAAGGTAGGTGTCTTTAAGAAAATAACAAGCAACCCTGTGATATGTTCCG



TCTCTCCCAATTCCCTCGTTATATAGAGGGCTTAATGGTATAAATGGTTAATATTGG



TCCCAACAGGGCTGACTCTTCTATCATATAATCAAAACTTTTTACATGAGCAAAATT



CAGTAAGAAATGGGGGAAGACAAAGGAAACGTCTTTGAGAAGCCCCTTCATATTTAT



TTATTTATCTCTTCCTGAACCATGAATTTCATATGTGGAATATTGCTATATTGACAG



ATTCTTGCCTGTCTGTGTTATTCTAGGATCTGTTACAGGTCCATGGCAATTACTGTT



TATTTTTTCCTGGAAAAATATTTTTTTATAAAAGGCTTTTTTTTTTTTTTAAATACA



TGAGAGGCATTGGGCTAAGAAAGAAAAGACTGTTGTATAATACCTTGTTCAATGGTT



GTATTTAGTGAGCTCATAGAGGTCCATCATATCATGACCGAGCTAGGTTGTGTGGGC



AGGAAGGTAGGGCTAAGGGGTTGTAGCCTTGCTGGGCAGCCTCTCAGAGCAAGGTTG



TTCAGATCTCCCTTGCTATTACAGTAGGTTACTATTAATGAGGGCAGCACCTGATGC



CTTTTGTACTGAGGTATGTAACTTTCTCCTTATTTGACAAGTAGAAGTTAACTTACT



TGTCAGGGAGGGCAGACGTTTTTTTGTTCTGTTTCGTTTTTCAAAATAATGCTTTTT



GCAAAAGAGGTAAGACTGAGACTAAAGGTGTTATCTTCTGGTGTGCTCCTGGAAGTG



TCTACCCTACATTTGTGTCAGCTCAGGGTTGCAGTGTTGCCCAGATGCATTTTACAT



CACTGTAAAGAGATTACTTTTGTGGTTACTACCTGGCTTGGCTGGCCTTGCGGTTCA



CCAGATTAATTTACAAACTCCCCCACTTTATTTTGTGCTATGTAGATCTGGCCATAC



TTGCATTAGTGACTGTCTTGCCTTAACCACACTTAAGCAACCCACAAATTTCTTCTC



AGATTTGTTTCCTAGATTACTTATGATACTCATCCCATGTCTCAATAAGAGTGTCTT



TTCTTTCTGGATGTGTTCTCTTACTCCCTCTTACCACCATACTTTTTGCTCTCTTCT



CCTGCAAGCGTAGTCTTCACAGGGAGTGGCTTCCTGACATTTTTTTCAGTTATGTGA



ATGAATGGAAACCAACAGCTGCTGCAAACACTGTTTTTCCAAGAAGGCTACACTCAG



AACCTAACCATTGCCAACCATTTCAGTATTGATAAAAAGCTGAATTTACTTTAGCAT



TACTTATTTTTTTTTCCATTTGATGGTTCTTACTTTGTAAAAATTTAAATAAATGAA



TGTCTATACTTTTTATAAAGAAAAGTGAAAATACCATGACACTGAAAAGATGATGCT



ATCAGATGCTGTTTAGAAAGCATTTATCTTGCATTTCTTTATTCTTTCTAATTATCT



AAAATTCAATAAAATTTTATTCATATAAAATAAGTTGTCATTAATTATCAATACTAA



CGAGTATGTCATTTTAAAACTTAGTATTCTCTTTAATGTTACAAGA (SEQ ID



NO: 73)






>NP_001015887.1 immunoglobulin superfamily member 11



isoform b precursor [Homo sapiens]



MTSQRSPLAPLLLLSLHGVAASLEVSESPGSIQVARGQPAVLPCTFTTSAALINLNV



IWMVTPLSNANQPEQVILYQGGQMFDGAPRFHGRVGFTGTMPATNVSIFINNTQLSD



TGTYQCLVNNLPDIGGRNIGVTGLTVLVPPSAPHCQIQGSQDIGSDVILLCSSEEGI



PRPTYLWEKLDNTLKLPPTATQDQVQGTVTIRNISALSSGLYQCVASNAIGTSTCLL



DLQVISPQPRNIGLIAGAIGTGAVIIIFCIALILGAFFYWRSKNKEEEEEEIPNEIR



EDDLPPKCSSAKAFHTEISSSDNNTLTSSNAYNSRYWSNNPKVHRNTESVSHFSDLG



QSFSFHSGNANIPSIYANGTHLVPGQHKTLVVTANRGSSPQVMSRSNGSVSRKPRPP



HTHSYTISHATLERIGAVPVMVPAQSRAGSLV (SEQ ID NO: 74)





Mouse VSIG3
>NM_170599.2 Mus musculus immunoglobulin superfamily,


(IGSF11)
member 11 (Igsf11), mRNA



CGGCTGGTGGTGGCCGCGGCGGCCGGCGAGCCCGGGACGCCCGAGCCTGCCCCGAGC



CTCGGCGGAGCGGAGTGGCCTCGGCGCTCCCGTGTCCCGCTTGGTCCCACGCTGCAC



CCCGCCGCCCAGGAGCCCGGCGGACGGCGGCTCCCCCGGCGGCTCCGGCATGACTCG



GCGGCGCTCCGCTCCGGCGTCCTGGCTGCTCGTGTCGCTGCTCGGTGTCGCAACATC



CCTGGAAGTGTCCGAGAGCCCAGGCAGTGTCCAGGTGGCCCGGGGCCAGACAGCAGT



CCTGCCCTGCGCCTTCTCCACCAGTGCTGCCCTCCTGAACCTCAATGTCATTTGGAT



GGTCATTCCCCTCTCCAATGCAAACCAGCCCGAACAGGTCATTCTTTATCAGGGTGG



ACAAATGTTTGACGGCGCCCTCCGGTTCCACGGGAGGGTAGGATTTACCGGCACCAT



GCCTGCTACCAATGTCTCGATCTTCATCAATAACACACAGCTGTCAGATACGGGCAC



GTACCAGTGCTTGGTGAATAACCTTCCAGACAGAGGGGGCAGAAACATCGGGGTCAC



TGGCCTCACAGTGTTAGTCCCCCCTTCTGCTCCACAATGCCAAATCCAAGGATCCCA



GGACCTCGGCAGTGACGTCATCCTTCTGTGTAGTTCAGAGGAAGGCATCCCTCGGCC



CACGTACCTTTGGGAGAAGTTAGATAATACGCTCAAGCTACCTCCAACAGCCACTCA



GGACCAGGTCCAGGGAACAGTCACCATCCGGAATATCAGTGCCCTCTCTTCCGGTCT



GTACCAGTGTGTGGCTTCTAATGCCATCGGGACCAGCACCTGTCTGCTGGACCTCCA



GGTTATCTCACCCCAGCCCCGGAGCGTTGGAGTAATAGCCGGAGCGGTTGGCACCGG



TGCTGTTCTTATCGTCATCTGCCTTGCACTAATTTCAGGGGCGTTCTTTTACTGGAG



AAGCAAAAACAAAGAGGAGGAGGAGGAAGAAATTCCTAATGAAATCAGAGAGGATGA



TCTTCCCCCTAAATGCTCTTCTGCCAAAGCCTTCCACACGGAGATATCCTCCTCAGA



AAATAACACGCTGACCTCTTCCAATACCTACAACAGTCGATACTGGAACAACAATCC



AAAACCCCATAGAAACACAGAGTCTTTCAACCACTTCAGTGACTTACGCCAGTCTTT



CTCTGGCAATGCAGTTATCCCATCAATCTATGCAAATGGGAACCATCTGGTTTTGGG



TCCACATAAGACTCTGGTAGTTACAGCCAACAGAGGGTCATCACCTCAGGTCTTGCC



CAGGAACAATGGTTCAGTCAGCAGGAAGCCTTGGCCTCAACACACTCATTCCTACAC



AGTAAGCCAAATGACCCTGGAGCGCATCGGTGCAGTGCCTGTCATGGTGCCTGCCCA



GAGTCGAGCAGGGTCCCTGGTATAGGATGACTGAGGAAACCATGTTCAGAAGAGAAT



AAATGGACCGCCTTCAGGCAAGGGGGGAGCACTGCCTTCAGGCAAGGGGGGAGCACT



GCCTTCAGGCAAGAGGGAGAGTGGGATGGGTGAGTGCTGAAAAATAAACTTTTGTTA



CGATTCCATTAGCAAAAAGCACAAAGAGGAGGCGTGTGTGAAGTGGCCTGGGGTTGT



TCCATAATGAAGACTCAAGAAGACTGTTTCCCCACCACAGATGTCCTGAGATTCAGT



TAAAACGAAACATGCTGCATCTCCAGAGATGTGCCAAGCCAAGGAGAATGCTAGAAG



CAGAGTAAAGCTTACCCCCCAAACTGTGGTCCAGCTGGACCCCTTCTTTAATTCTTG



CCTAACTTAATTATTTTCAGGACCCTTCAAGTGCCAGGTGGAATTTACATAATGAAA



TTATTTTTTAAAAATAGGTGTCCTTAGGGAGAGAAAACAGGAGCAAGCTCATGGTCT



GGCCTAGTCTCCCTCTCCCACTCCTTCTGATGACACTAGCAATGCATTCCATCTGAC



CTGACTTTATCATAGAGGCAAAATTGTTCAGAACACTGGCTGGAGATGGGGAGAAAT



AAGGAAACTTCTTGTGAACACCCTACACACACACACACACACACACACACACACACA



CACACACACACACACACACACACACACACATTTATTTACCTCCTCCTGAACCATGAA



TCGTATTGGTGATTTTGCTATATTGACAGATTCTCATCTGTTACACTCTAGGATCTC



TCACAGGTCTGTGGCAATTACTGTTCATGATTTCCTGAAAAAATATTTTTTTAAAAG



AAAACTATTTTTTTTAAATACTAGAGAGACAGTGGACTAGGAAAGCGAGAACTTGCC



GCCTTGTCTAGTGACTGTATTCAATGACTGAACAGAGGCCCCCCCCACCATACAAGA



GTTTTAGGTGATTGAGTGGGTGGAACCAGCTGGAGCCAGGTGGGAGGGGCCTTTACA



TTGCCAGCAGGGCCCCAAAGAATTGAGATTGTGTATGGCAACCGTTAATGAGGACAG



CGCCTGATGCCTTTTGTACCGAGGAAGATAATTGCCTCTTGTTTGACAAGTAGAGTT



TAGTAGGTTATTACAAAAAGGGCAAGAGTTGTTTTGGTTTTGTTTCTTTCAAAATAA



TTTTTTTTCAAAAGAATAACAAGGGTTAGGCAAATGGGGGACCTTCCTGTGTGCTCT



TGGGGGTCTGCTCAGCATCTGGAAATTTGGGTGTGCGATTTTCCCTGAACACATTGC



ATACCAGTGTAAAAAGACTCTGCCTCCCCCCTTTTTGGCTTTTTTACTGGGCTTGGC



TGGCCTTGCAGTTTACCAGATTCATTTACAGACTCTCTGCTCTGTATGGCGCCGCCT



GCCATGTCTGTCTTGGTGACTATCCTGCCTTAATCACTTTGCTTTAGGGCAACTCAT



GGTGATCTCTTCCAAGATCTGTTTTTAAATTGTTTGGACTACTTGAGCCACAACTCT



CAGAGGACATTCCTTTTTTTTTTTTTTTTTTTTTCTCCTTTCTTCCATTGCTTTGTC



CCTCTTCCCCTGTGCTTCCTGCCTTCTTTCCCTGTCCCATGGGCACAGTCCTCACAG



GGAGTGGCCTCCTCTCTCCAGTGATGTAAGTGAATGGAAGCCATCACTGGCTGCACA



TACCTTTTTCAAAAGGGACACTCGGGAAGTCACTGCTGTGACCGTTTCGATGTTGAT



AAGAAGGTGAATTTACTGTAGTGTTACCACCTTCTCCCCACTTGATGGTTCTTGACT



TTGTAAAAATTTAAATAAATGAATGTCTATACTTTTTAAGGAAAAGAGAAAATACCA



TGTCACAGAAAAGGTGAAACTATTAGATGCTGTTTAGAAAGCATTTATCTTGCATTT



CTTTATTCTTTCTAATTACCTAAAATTCAATAAAAGTTTATTCATATAAAAAAAAAA



AAAAAAAAAA (SEQ ID NO: 75)






>NP_733548.2 immunoglobulin superfamily member 11



precursor [Mus musculus]



MTRRRSAPASWLLVSLLGVATSLEVSESPGSVQVARGQTAVLPCAFSTSAALLNLNV



IWMVIPLSNANQPEQVILYQGGQMFDGALRFHGRVGFTGTMPATNVSIFINNTQLSD



TGTYQCLVNNLPDRGGRNIGVTGLTVLVPPSAPQCQIQGSQDLGSDVILLCSSEEGI



PRPTYLWEKLDNTLKLPPTATQDQVQGTVTIRNISALSSGLYQCVASNAIGTSTCLL



DLQVISPQPRSVGVIAGAVGTGAVLIVICLALISGAFFYWRSKNKEEEEEEIPNEIR



EDDLPPKCSSAKAFHTEISSSENNTLTSSNTYNSRYWNNNPKPHRNTESFNHFSDLR



QSFSGNAVIPSIYANGNHLVLGPHKTLVVTANRGSSPQVLPRNNGSVSRKPWPQHTH



SYTVSQMTLERIGAVPVMVPAQSRAGSLV (SEQ ID NO: 76)





Human VSIG4
>NM_007268.3 Homo sapiens V-set and immunoglobulin domain



containing 4 (VSIG4), transcript variant 1, mRNA



ACAGACGCTGGCGGCCACCAGAAGTTTGAGCCTCTTTGGTAGCAGGAGGCTGGAAGA



AAGGACAGAAGTAGCTCTGGCTGTGATGGGGATCTTACTGGGCCTGCTACTCCTGGG



GCACCTAACAGTGGACACTTATGGCCGTCCCATCCTGGAAGTGCCAGAGAGTGTAAC



AGGACCTTGGAAAGGGGATGTGAATCTTCCCTGCACCTATGACCCCCTGCAAGGCTA



CACCCAAGTCTTGGTGAAGTGGCTGGTACAACGTGGCTCAGACCCTGTCACCATCTT



TCTACGTGACTCTTCTGGAGACCATATCCAGCAGGCAAAGTACCAGGGCCGCCTGCA



TGTGAGCCACAAGGTTCCAGGAGATGTATCCCTCCAATTGAGCACCCTGGAGATGGA



TGACCGGAGCCACTACACGTGTGAAGTCACCTGGCAGACTCCTGATGGCAACCAAGT



CGTGAGAGATAAGATTACTGAGCTCCGTGTCCAGAAACTCTCTGTCTCCAAGCCCAC



AGTGACAACTGGCAGCGGTTATGGCTTCACGGTGCCCCAGGGAATGAGGATTAGCCT



TCAATGCCAGGCTCGGGGTTCTCCTCCCATCAGTTATATTTGGTATAAGCAACAGAC



TAATAACCAGGAACCCATCAAAGTAGCAACCCTAAGTACCTTACTCTTCAAGCCTGC



GGTGATAGCCGACTCAGGCTCCTATTTCTGCACTGCCAAGGGCCAGGTTGGCTCTGA



GCAGCACAGCGACATTGTGAAGTTTGTGGTCAAAGACTCCTCAAAGCTACTCAAGAC



CAAGACTGAGGCACCTACAACCATGACATACCCCTTGAAAGCAACATCTACAGTGAA



GCAGTCCTGGGACTGGACCACTGACATGGATGGCTACCTTGGAGAGACCAGTGCTGG



GCCAGGAAAGAGCCTGCCTGTCTTTGCCATCATCCTCATCATCTCCTTGTGCTGTAT



GGTGGTTTTTACCATGGCCTATATCATGCTCTGTCGGAAGACATCCCAACAAGAGCA



TGTCTACGAAGCAGCCAGGGCACATGCCAGAGAGGCCAACGACTCTGGAGAAACCAT



GAGGGTGGCCATCTTCGCAAGTGGCTGCTCCAGTGATGAGCCAACTTCCCAGAATCT



GGGCAACAACTACTCTGATGAGCCCTGCATAGGACAGGAGTACCAGATCATCGCCCA



GATCAATGGCAACTACGCCCGCCTGCTGGACACAGTTCCTCTGGATTATGAGTTTCT



GGCCACTGAGGGCAAAAGTGTCTGTTAAAAATGCCCCATTAGGCCAGGATCTGCTGA



CATAATTGCCTAGTCAGTCCTTGCCTTCTGCATGGCCTTCTTCCCTGCTACCTCTCT



TCCTGGATAGCCCAAAGTGTCCGCCTACCAACACTGGAGCCGCTGGGAGTCACTGGC



TTTGCCCTGGAATTTGCCAGATGCATCTCAAGTAAGCCAGCTGCTGGATTTGGCTCT



GGGCCCTTCTAGTATCTCTGCCGGGGGCTTCTGGTACTCCTCTCTAAATACCAGAGG



GAAGATGCCCATAGCACTAGGACTTGGTCATCATGCCTACAGACACTATTCAACTTT



GGCATCTTGCCACCAGAAGACCCGAGGGAGGCTCAGCTCTGCCAGCTCAGAGGACCA



GCTATATCCAGGATCATTTCTCTTTCTTCAGGGCCAGACAGCTTTTAATTGAAATTG



TTATTTCACAGGCCAGGGTTCAGTTCTGCTCCTCCACTATAAGTCTAATGTTCTGAC



TCTCTCCTGGTGCTCAATAAATATCTAATCATAACAGCAA (SEQ ID NO: 77)






>NP_009199.1 V-set and immunoglobulin domain-containing



protein 4 isoform 1 precursor [Homo sapiens]



MGILLGLLLLGHLTVDTYGRPILEVPESVTGPWKGDVNLPCTYDPLQGYTQVLVKWL



VQRGSDPVTIFLRDSSGDHIQQAKYQGRLHVSHKVPGDVSLQLSTLEMDDRSHYTCE



VTWQTPDGNQVVRDKITELRVQKLSVSKPTVTTGSGYGFTVPQGMRISLQCQARGSP



PISYIWYKQQTNNQEPIKVATLSTLLFKPAVIADSGSYFCTAKGQVGSEQHSDIVKF



VVKDSSKLLKTKTEAPTTMTYPLKATSTVKQSWDWTTDMDGYLGETSAGPGKSLPVF



AIILIISLCCMVVFTMAYIMLCRKTSQQEHVYEAARAHAREANDSGETMRVAIFASG



CSSDEPTSQNLGNNYSDEPCIGQEYQIIAQINGNYARLLDTVPLDYEFLATEGKSVC



(SEQ ID NO: 78)





Mouse VSIG4
>NM_177789.5 Mus musculus V-set and immunoglobulin domain



containing 4 (Vsig4), mRNA



AGCTACCAGCACTTCCAGGTTCTTCAGCAGCAAGAGGATGGAAGGATGAATAGAAGT



AGCTTCAAATAGGATGGAGATCTCATCAGGCTTGCTGTTCCTGGGCCACCTAATAGT



GCTCACCTATGGCCACCCCACCCTAAAAACACCTGAGAGTGTGACAGGGACCTGGAA



AGGAGATGTGAAGATTCAGTGCATCTATGATCCCCTGAGAGGCTACAGGCAAGTTTT



GGTGAAATGGCTGGTAAGACACGGCTCTGACTCCGTCACCATCTTCCTACGTGACTC



CACTGGAGACCATATCCAGCAGGCAAAGTACAGAGGCCGCCTGAAAGTGAGCCACAA



AGTTCCAGGAGATGTGTCCCTCCAAATAAATACCCTGCAGATGGATGACAGGAATCA



CTATACATGTGAGGTCACCTGGCAGACTCCTGATGGAAACCAAGTAATAAGAGATAA



GATCATTGAGCTCCGTGTTCGGAAATATAATCCACCTAGAATCAATACTGAAGCACC



TACAACCCTGCACTCCTCTTTGGAAGCAACAACTATAATGAGTTCAACCTCTGACTT



GACCACTAATGGGACTGGAAAACTTGAGGAGACCATTGCTGGTTCAGGGAGGAACCT



GCCAATCTTTGCCATAATCTTCATCATCTCCCTTTGCTGCATAGTAGCTGTCACCAT



ACCTTATATCTTGTTCCGCTGCAGGACATTCCAACAAGAGTATGTCTATGGAGTGAG



CAGGGTGTTTGCCAGGAAGACAAGCAACTCTGAAGAAACCACAAGGGTGACTACCAT



CGCAACTGATGAACCAGATTCCCAGGCTCTGATTAGTGACTACTCTGATGATCCTTG



CCTCAGCCAGGAGTACCAAATAACCATCAGATCAACAATGTCTATTCCTGCCTGCTG



AACACAGTTTCCAGAAACTAAGAAGTTCTTGCTACTGAAGAAAATAACATCTGCTAA



AATGCCCCTACTAAGTCAAGGTCTACTGGCGTAATTACCTGTTACTTATTTACTACT



TGCCTTCAACATAGCTTTCTCCCTGGCTTCCTTTCTTCTTAGACAACCTAAAGTATC



TATCTAGTCTGCCAATTCTGGGGCCATTGAGAAATCCTGGGTTTGGCTAAGAATATA



CTACATGCACCTCAAGAAATCTAGCTTCTGGGCTTCACCCAGAACAATTTTCTTCCT



AGGGCCTTCACAACTCTTCTCCAAACAGCAGAGAAATTCCATAGCAGTAGAGGTTCT



TTATCATGCCTCCAGACAGCGTGAGTCTCAGTCCTACAAACTCAGACAAGCACATGG



GTCTAGGATTACTCCTCTTTCTCTAGGGCCAGATGACTTTTAATTGATATTACTATT



GCTACATTATGAATCTAATGCACATGTATTCTTTTGTTGTTAATAAATGTTTAATCA



TGACATCAA(SEQ ID NO: 79)






>NP_808457.1 V-set and immunoglobulin domain-containing



protein 4 precursor [Mus musculus]



MEISSGLLFLGHLIVLTYGHPTLKTPESVTGTWKGDVKIQCIYDPLRGYRQVLVKWL



VRHGSDSVTIFLRDSTGDHIQQAKYRGRLKVSHKVPGDVSLQINTLQMDDRNHYTCE



VTWQTPDGNQVIRDKIIELRVRKYNPPRINTEAPTTLHSSLEATTIMSSTSDLTTNG



TGKLEETIAGSGRNLPIFAIIFIISLCCIVAVTIPYILFRCRTFQQEYVYGVSRVFA



RKTSNSEETTRVTTIATDEPDSQALISDYSDDPCLSQEYQITIRSTMSIPAC (SEQ



ID NO: 80)





Human Tim-3
>NM_032782.5 Homo sapiens hepatitis A virus cellular


(HAVCR2)
receptor 2 (HAVCR2), mRNA



ATTTGGAGAGTTAAAACTGTGCCTAACAGAGGTGTCCTCTGACTTTTCTTCTGCAAG



CTCCATGTTTTCACATCTTCCCTTTGACTGTGTCCTGCTGCTGCTGCTGCTACTACT



TACAAGGTCCTCAGAAGTGGAATACAGAGCGGAGGTCGGTCAGAATGCCTATCTGCC



CTGCTTCTACACCCCAGCCGCCCCAGGGAACCTCGTGCCCGTCTGCTGGGGCAAAGG



AGCCTGTCCTGTGTTTGAATGTGGCAACGTGGTGCTCAGGACTGATGAAAGGGATGT



GAATTATTGGACATCCAGATACTGGCTAAATGGGGATTTCCGCAAAGGAGATGTGTC



CCTGACCATAGAGAATGTGACTCTAGCAGACAGTGGGATCTACTGCTGCCGGATCCA



AATCCCAGGCATAATGAATGATGAAAAATTTAACCTGAAGTTGGTCATCAAACCAGC



CAAGGTCACCCCTGCACCGACTCGGCAGAGAGACTTCACTGCAGCCTTTCCAAGGAT



GCTTACCACCAGGGGACATGGCCCAGCAGAGACACAGACACTGGGGAGCCTCCCTGA



TATAAATCTAACACAAATATCCACATTGGCCAATGAGTTACGGGACTCTAGATTGGC



CAATGACTTACGGGACTCTGGAGCAACCATCAGAATAGGCATCTACATCGGAGCAGG



GATCTGTGCTGGGCTGGCTCTGGCTCTTATCTTCGGCGCTTTAATTTTCAAATGGTA



TTCTCATAGCAAAGAGAAGATACAGAATTTAAGCCTCATCTCTTTGGCCAACCTCCC



TCCCTCAGGATTGGCAAATGCAGTAGCAGAGGGAATTCGCTCAGAAGAAAACATCTA



TACCATTGAAGAGAACGTATATGAAGTGGAGGAGCCCAATGAGTATTATTGCTATGT



CAGCAGCAGGCAGCAACCCTCACAACCTTTGGGTTGTCGCTTTGCAATGCCATAGAT



CCAACCACCTTATTTTTGAGCTTGGTGTTTTGTCTTTTTCAGAAACTATGAGCTGTG



TCACCTGACTGGTTTTGGAGGTTCTGTCCACTGCTATGGAGCAGAGTTTTCCCATTT



TCAGAAGATAATGACTCACATGGGAATTGAACTGGGACCTGCACTGAACTTAAACAG



GCATGTCATTGCCTCTGTATTTAAGCCAACAGAGTTACCCAACCCAGAGACTGTTAA



TCATGGATGTTAGAGCTCAAACGGGCTTTTATATACACTAGGAATTCTTGACGTGGG



GTCTCTGGAGCTCCAGGAAATTCGGGCACATCATATGTCCATGAAACTTCAGATAAA



CTAGGGAAAACTGGGTGCTGAGGTGAAAGCATAACTTTTTTGGCACAGAAAGTCTAA



AGGGGCCACTGATTTTCAAAGAGATCTGTGATCCCTTTTTGTTTTTTGTTTTTGAGA



TGGAGTCTTGCTCTGTTGCCCAGGCTGGAGTGCAATGGCACAATCTCGGCTCACTGC



AAGCTCCGCCTCCTGGGTTCAAGCGATTCTCCTGCCTCAGCCTCCTGAGTGGCTGGG



ATTACAGGCATGCACCACCATGCCCAGCTAATTTGTTGTATTTTTAGTAGAGACAGG



GTTTCACCATGTTGGCCAGTGTGGTCTCAAACTCCTGACCTCATGATTTGCCTGCCT



CGGCCTCCCAAAGCACTGGGATTACAGGCGTGAGCCACCACATCCAGCCAGTGATCC



TTAAAAGATTAAGAGATGACTGGACCAGGTCTACCTTGATCTTGAAGATTCCCTTGG



AATGTTGAGATTTAGGCTTATTTGAGCACTGCCTGCCCAACTGTCAGTGCCAGTGCA



TAGCCCTTCTTTTGTCTCCCTTATGAAGACTGCCCTGCAGGGCTGAGATGTGGCAGG



AGCTCCCAGGGAAAAACGAAGTGCATTTGATTGGTGTGTATTGGCCAAGTTTTGCTT



GTTGTGTGCTTGAAAGAAAATATCTCTGACCAACTTCTGTATTCGTGGACCAAACTG



AAGCTATATTTTTCACAGAAGAAGAAGCAGTGACGGGGACACAAATTCTGTTGCCTG



GTGGAAAGAAGGCAAAGGCCTTCAGCAATCTATATTACCAGCGCTGGATCCTTTGAC



AGAGAGTGGTCCCTAAACTTAAATTTCAAGACGGTATAGGCTTGATCTGTCTTGCTT



ATTGTTGCCCCCTGCGCCTAGCACAATTCTGACACACAATTGGAACTTACTAAAAAT



TTTTTTTTACTGTT (SEQ ID NO: 81)






>NP_116171.3 hepatitis A virus cellular receptor 2



precursor [Homo sapiens]



MFSHLPFDCVLLLLLLLLTRSSEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGA



CPVFECGNVVLRTDERDVNYWTSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQI



PGIMNDEKFNLKLVIKPAKVTPAPTRQRDFTAAFPRMLTTRGHGPAETQTLGSLPDI



NLTQISTLANELRDSRLANDLRDSGATIRIGIYIGAGICAGLALALIFGALIFKWYS



HSKEKIQNLSLISLANLPPSGLANAVAEGIRSEENIYTIEENVYEVEEPNEYYCYVS



SRQQPSQPLGCRFAMP (SEQ ID NO: 82)





Mouse Tim-3
>NM_134250.2 Mus musculus hepatitis A virus cellular


(HAVCR2)
receptor 2 (Havcr2), mRNA



ACCATTTTAACCGAGGAGCTAAAGCTATCCCTACACAGAGCTGTCCTTGGATTTCCC



CTGCCAAGTACTCATGTTTTCAGGTCTTACCCTCAACTGTGTCCTGCTGCTGCTGCA



ACTACTACTTGCAAGGTCATTGGAAAATGCTTATGTGTTTGAGGTTGGTAAGAATGC



CTATCTGCCCTGCAGTTACACTCTATCTACACCTGGGGCACTTGTGCCTATGTGCTG



GGGCAAGGGATTCTGTCCTTGGTCACAGTGTACCAACGAGTTGCTCAGAACTGATGA



AAGAAATGTGACATATCAGAAATCCAGCAGATACCAGCTAAAGGGCGATCTCAACAA



AGGAGACGTGTCTCTGATCATAAAGAATGTGACTCTGGATGACCATGGGACCTACTG



CTGCAGGATACAGTTCCCTGGTCTTATGAATGATAAAAAATTAGAACTGAAATTAGA



CATCAAAGCAGCCAAGGTCACTCCAGCTCAGACTGCCCATGGGGACTCTACTACAGC



TTCTCCAAGAACCCTAACCACGGAGAGAAATGGTTCAGAGACACAGACACTGGTGAC



CCTCCATAATAACAATGGAACAAAAATTTCCACATGGGCTGATGAAATTAAGGACTC



TGGAGAAACGATCAGAACTGCTATCCACATTGGAGTGGGAGTCTCTGCTGGGTTGAC



CCTGGCACTTATCATTGGTGTCTTAATCCTTAAATGGTATTCCTGTAAGAAAAAGAA



GTTATCGAGTTTGAGCCTTATTACACTGGCCAACTTGCCTCCAGGAGGGTTGGCAAA



TGCAGGAGCAGTCAGGATTCGCTCTGAGGAAAATATCTACACCATCGAGGAGAACGT



ATATGAAGTGGAGAATTCAAATGAGTACTACTGCTACGTCAACAGCCAGCAGCCATC



CTGACCGCCTCTGGACTGCCACTTTTAAAGGCTCGCCTTCATTTCTGACTTTGGTAT



TTCCCTTTTTGAAAACTATGTGATATGTCACTTGGCAACCTCATTGGAGGTTCTGAC



CACAGCCACTGAGAAAAGAGTTCCAGTTTTCTGGGGATAATTAACTCACAAGGGGAT



TCGACTGTAACTCATGCTACATTGAAATGCTCCATTTTATCCCTGAGTTTCAGGGAT



CGGATCTCCCACTCCAGAGACTTCAATCATGCGTGTTGAAGCTCACTCGTGCTTTCA



TACATTAGGAATGGTTAGTGTGATGTCTTTGAGACATAGAGGTTTGTGGTATATCTG



CAAAGCTCCTGAACAGGTAGGGGGAATAAAGGGCTAAGATAGGAAGGTGAGGTTCTT



TGTTGATGTTGAAAATCTAAAGAAGTTGGTAGCTTTTCTAGAGATTTCTGACCTTGA



AAGATTAAGAAAAAGCCAGGTGGCATATGCTTAACACTATATAACTTGGGAACCTTA



GGCAGGAGGGTGATAAGTTCAAGGTCAGCCAGGGCTATGCTGGTAAGACTGTCTCAA



AATCCAAAGACGAAAATAAACATAGAGACAGCAGGAGGCTGGAGATGAGGCTCGGAC



AGTGAGGTGCATTTTGTACAAGCACGAGGAATCTATATTTGATCGTAGACCCCACAT



GAAAAAGCTAGGCCTGGTAGAGCATGCTTGTAGACTCAAGAGATGGAGAGGTAAAGG



CACAACAGATCCCCGGGGCTTGCGTGCAGTCAGCTTAGCCTAGGTGCTGAGTTCCAA



GTCCACAAGAGTCCCTGTCTCAAAGTAAGATGGACTGAGTATCTGGCGAATGTCCAT



GGGGGTTGTCCTCTGCTCTCAGAAGAGACATGCACATGAACCTGCACACACACACAC



ACACACACACACACACACACACACACACACACACACACACACATGAAATGAAGGTTC



TCTCTGTGCCTGCTACCTCTCTATAACATGTATCTCTACAGGACTCTCCTCTGCCTC



TGTTAAGACATGAGTGGGAGCATGGCAGAGCAGTCCAGTAATTAATTCCAGCACTCA



GAAGGCTGGAGCAGAAGCGTGGAGAGTTCAGGAGCACTGTGCCCAACACTGCCAGAC



TCTTCTTACAGAAGAAAAAGGTTACCCGCAAGCAGCCTGCTGTCTGTAAAAGGAAAC



CCTGCGAAAGGCAAACTTTGACTGTTGTGTGCTCAAGGGGAACTGACTCAGACAACT



TCTCCATTCCTGGAGGAAACTGGAGCTGTTTCTGACAGAAGAACAACCGGTGACTGG



GACATACGAAGGCAGAGCTCTTGCAGCAATCTATATAGTCAGCAAAATATTCTTTGG



GAGGACAGTCGTCACCAAATTGATTTCCAAGCCGGTGGACCTCAGTTTCATCTGGCT



TACAGCTGCCTGCCCAGTGCCCTTGATCTGTGCTGGCTCCCATCTATAACAGAATCA



AATTAAATAGACCCCGAGTGAAAATATTAAGTGAGCAGAAAGGTAGCTTTGTTCAAA



GATTTTTTTGCATTGGGGAGCAACTGTGTACATCAGAGGACATCTGTTAGTGAGGAC



ACCAAAACCTGTGGTACCGTTTTTTCATGTATGAATTTTGTTGTTTAGGTTGCTTCT



AGCTAGCTGTGGAGGTCCTGGCTTTCTTAGGTGGGTATGGAAGGGAGACCATCTAAC



AAAATCCATTAGAGATAACAGCTCTCATGCAGAAGGGAAAACTAATCTCAAATGTTT



TAAAGTAATAAAACTGTACTGGCAAAGTACTTTGAGCATATTTAAA (SEQ ID



NO: 83)






>NP_599011.2 hepatitis A virus cellular receptor 2



homolog precursor [Mus musculus]



MFSGLTLNCVLLLLQLLLARSLENAYVFEVGKNAYLPCSYTLSTPGALVPMCWGKGF



CPWSQCTNELLRTDERNVTYQKSSRYQLKGDLNKGDVSLIIKNVTLDDHGTYCCRIQ



FPGLMNDKKLELKLDIKAAKVTPAQTAHGDSTTASPRTLTTERNGSETQTLVTLHNN



NGTKISTWADEIKDSGETIRTAIHIGVGVSAGLTLALIIGVLILKWYSCKKKKLSSL



SLITLANLPPGGLANAGAVRIRSEENIYTIEENVYEVENSNEYYCYVNSQQPS



(SEQ ID NO: 84)





Human Tim-4
>NM_138379.3 Homo sapiens T cell immunoglobulin and mucin


(TIMD4)
domain containing 4 (TIMD4), transcript variant 1, mRNA



AGACTCCTGGGTCCGGTCAACCGTCAAAATGTCCAAAGAACCTCTCATTCTCTGGCT



GATGATTGAGTTTTGGTGGCTTTACCTGACACCAGTCACTTCAGAGACTGTTGTGAC



GGAGGTTTTGGGTCACCGGGTGACTTTGCCCTGTCTGTACTCATCCTGGTCTCACAA



CAGCAACAGCATGTGCTGGGGGAAAGACCAGTGCCCCTACTCCGGTTGCAAGGAGGC



GCTCATCCGCACTGATGGAATGAGGGTGACCTCAAGAAAGTCAGCAAAATATAGACT



TCAGGGGACTATCCCGAGAGGTGATGTCTCCTTGACCATCTTAAACCCCAGTGAAAG



TGACAGCGGTGTGTACTGCTGCCGCATAGAAGTGCCTGGCTGGTTCAACGATGTAAA



GATAAACGTGCGCCTGAATCTACAGAGAGCCTCAACAACCACGCACAGAACAGCAAC



CACCACCACACGCAGAACAACAACAACAAGCCCCACCACCACCCGACAAATGACAAC



AACCCCAGCTGCACTTCCAACAACAGTCGTGACCACACCCGATCTCACAACCGGAAC



ACCACTCCAGATGACAACCATTGCCGTCTTCACAACAGCAAACACGTGCCTTTCACT



AACCCCAAGCACCCTTCCGGAGGAAGCCACAGGTCTTCTGACTCCCGAGCCTTCTAA



GGAAGGGCCCATCCTCACTGCAGAATCAGAAACTGTCCTCCCCAGTGATTCCTGGAG



TAGTGTTGAGTCTACTTCTGCTGACACTGTCCTGCTGACATCCAAAGAGTCCAAAGT



TTGGGATCTCCCATCAACATCCCACGTGTCAATGTGGAAAACGAGTGATTCTGTGTC



TTCTCCTCAGCCTGGAGCATCTGATACAGCAGTTCCTGAGCAGAACAAAACAACAAA



AACAGGACAGATGGATGGAATACCCATGTCAATGAAGAATGAAATGCCCATCTCCCA



ACTACTGATGATCATCGCCCCCTCCTTGGGATTTGTGCTCTTCGCATTGTTTGTGGC



GTTTCTCCTGAGAGGGAAACTCATGGAAACCTATTGTTCGCAGAAACACACAAGGCT



AGACTACATTGGAGATAGTAAAAATGTCCTCAATGACGTGCAGCATGGAAGGGAAGA



CGAAGACGGCCTTTTTACCCTCTAACAACGCAGTAGCATGTTAGATTGAGGATGGGG



GCATGACACTCCAGTGTCAAAATAAGTCTTAGTAGATTTCCTTGTTTCATAAAAAAG



ACTCACTTATTCCATGGATGTCATTGATCCAGGCTTGCTTTAGTTTCATGAATGAAG



GGTACTTTAGAGACCACAA (SEQ ID NO: 85)






>NP_612388.2 T-cell immunoglobulin and mucin domain-



containing protein 4 isoform 1 precursor [Homo sapiens]



MSKEPLILWLMIEFWWLYLTPVTSETVVTEVLGHRVTLPCLYSSWSHNSNSMCWGKD



QCPYSGCKEALIRTDGMRVTSRKSAKYRLQGTIPRGDVSLTILNPSESDSGVYCCRI



EVPGWFNDVKINVRLNLQRASTTTHRTATTTTRRTTTTSPTTTRQMTTTPAALPTTV



VTTPDLTTGTPLQMTTIAVFTTANTCLSLTPSTLPEEATGLLTPEPSKEGPILTAES



ETVLPSDSWSSVESTSADTVLLTSKESKVWDLPSTSHVSMWKTSDSVSSPQPGASDT



AVPEQNKTTKTGQMDGIPMSMKNEMPISQLLMIIAPSLGFVLFALFVAFLLRGKLME



TYCSQKHTRLDYIGDSKNVLNDVQHGREDEDGLFTL (SEQ ID NO: 86)





Mouse Tim-4
>NM_178759.4 Mus musculus T cell immunoglobulin and mucin


(TIMD4)
domain containing 4 (Timd4), mRNA



AGATCCTATCAAAATGTCCAAGGGGCTTCTCCTCCTCTGGCTGGTGACGGAGCTCTG



GTGGCTTTATCTGACACCAGCTGCCTCAGAGGATACAATAATAGGGTTTTTGGGCCA



GCCGGTGACTTTGCCTTGTCATTACCTCTCGTGGTCCCAGAGCCGCAACAGTATGTG



CTGGGGCAAAGGTTCATGTCCCAATTCCAAGTGCAATGCAGAGCTTCTCCGTACAGA



TGGAACAAGAATCATCTCCAGGAAGTCAACAAAATATACACTTTTGGGGAAGGTCCA



GTTTGGTGAAGTGTCCTTGACCATCTCAAACACCAATCGAGGTGACAGTGGGGTGTA



CTGCTGCCGTATAGAGGTGCCTGGCTGGTTCAATGATGTCAAGAAGAATGTGCGCTT



GGAGCTGAGGAGAGCCACAACAACCAAAAAACCAACAACAACCACCCGGCCAACCAC



CACCCCTTATGTGACCACCACCACCCCAGAGCTGCTTCCAACAACAGTCATGACCAC



ATCTGTTCTCCCAACCACCACACCACCCCAGACACTAGCCACCACTGCCTTCAGTAC



AGCAGTGACCACGTGCCCCTCAACAACACCTGGCTCCTTCTCACAAGAAACCACAAA



AGGGTCCGCCTTCACTACAGAATCAGAAACTCTGCCTGCATCCAATCACTCTCAAAG



AAGCATGATGACCATATCTACAGACATAGCCGTACTCAGGCCCACAGGCTCTAACCC



TGGGATTCTCCCATCCACTTCACAGCTGACGACACAGAAAACAACATTAACAACAAG



TGAGTCTTTGCAGAAGACAACTAAATCACATCAGATCAACAGCAGACAGACCATCTT



GATCATTGCCTGCTGTGTGGGATTTGTGCTAATGGTGTTATTGTTTCTGGCGTTTCT



CCTTCGAGGGAAAGTCACAGGAGCCAACTGTTTGCAGAGACACAAGAGGCCAGACAA



CACTGAAGATAGTGACAGCGTCCTCAATGACATGTCACACGGGAGGGATGATGAAGA



CGGGATCTTCACTCTCTGACTCACCATCTTTATTTAGGATTAAGGATAGGGAATGGC



ACTTGAATTGTCAAAATAAGTTTGGGGACATTGTAATTTCCGTTTAAAGTCTCACTC



TGTTTACTGATGCTGTGGGTCCTGTCTGGTTGTATCTTCCCACATGAAGGTGCTTTA



GAGACACATTTTCCCTGCCTCGTGCCTTAGTCCTCTTTGTTGTTTTGTGGCTAGGTG



ACTTTTCACACTGGGCTTGAACACTGTCAGTGATGGTGAAATCCTTGCCACAGCTTT



GGGAGTCTCTTGCAGTCTCCCAGCAGTAGAGGGAGTTAGAAATATCCAGAGGGGAAA



AAAAAATCTCTCTTTTCAGACAGTATCTGCTTTATTGGTGGTAGCTGAACTTCATTT



ATACAGAGCTCCTTTAACCTGTCTGTCTTCTTCTTGGTATCTAAGCTGCCTTTTGTT



TTTGTTTTTGTTTTTGTTTTTATGATATTAACTTCTTTTCACATTCAAGTTTCTTTA



AAGTTGACTATAGTGCCTTCTGAACTCTTGCAGAGAGTTTGGATTTTGGAAGCTGCC



AGGTACCCATCACAGCAGGGGTGCCAGTGACAAGGATGGTGTACAAATGAAACACTG



AAGCTATCCAAATAAATTCCTCTAAGTGTAATTCATTTTACTGCAGCACAGGAAGAA



CAAATTTGTCTTACAACTTTAATAATTAGTACCATTATGAACCCTAGGAGAGAAATA



AGAGCAAATACCTGTTGAATAAATGAATGTAAGAAAATGTGTGTCTGAGCAAGAATA



CTCTGTCTGGCTACTATGGGAAGCTAGCTAGATCTGAAAGACATTCTCAGACTATCC



TCATGTTCAAGGCATTAAAGGAATAAGCCTCCAGCCCCTAACCTTAGGAGAATTCTG



CAGTCAAGTGAGGAGTTTTTAAAACAGGAATCTCTAGGTTCCAGTCCTCTAGCTATT



CTTTTATGCTTAGTCCAGGTAATGAGTTGAACATCCAAGTATTTTTTAAGGACCCAA



AGAAATGCAACCAGAGCTATTACCAGAATTTTGGAGTGGTCCTCCTAGAGTTGCCGC



ATGTTGCTGGGAAAATTGGGGTCTTAGAGTTCTTAGTCTACTTAATAAAAGAATTTT



AAAAAATGG (SEQ ID NO: 87)






>NP_848874.3 T-cell immunoglobulin and mucin domain-



containing protein 4 precursor [Mus musculus]



MSKGLLLLWLVTELWWLYLTPAASEDTIIGFLGQPVTLPCHYLSWSQSRNSMC



WGKGSCPNSKCNAELLRTDGTRIISRKSTKYTLLGKVQFGEVSLTISNTNRGD



SGVYCCRIEVPGWFNDVKKNVRLELRRATTTKKPTTTTRPTTTPYVTTTTPEL



LPTTVMTTSVLPTTTPPQTLATTAFSTAVTTCPSTTPGSFSQETTKGSAFTTE



SETLPASNHSQRSMMTISTDIAVLRPTGSNPGILPSTSQLTTQKTTLTTSESL



QKTTKSHQINSRQTILIIACCVGFVLMVLLFLAFLLRGKVTGANCLQRHKRPD



NTEDSDSVLNDMSHGRDDEDGIFTL (SEQ ID NO: 88)





Human
>NM_001712.5 Homo sapiens CEA cell adhesion molecule


CEACAM1
1 (CEACAM1), transcript variant 1, mRNA



AGCACAGAGAGTGGAAAACAGCAGAGGTGACAGAGCAGCCGTGCTCGAAGCGT



TCCTGGAGCCCAAGCTCTCCTCCACAGGTGAAGACAGGGCCAGCAGGAGACAC



CATGGGGCACCTCTCAGCCCCACTTCACAGAGTGCGTGTACCCTGGCAGGGGC



TTCTGCTCACAGCCTCACTTCTAACCTTCTGGAACCCGCCCACCACTGCCCAG



CTCACTACTGAATCCATGCCATTCAATGTTGCAGAGGGGAAGGAGGTTCTTCT



CCTTGTCCACAATCTGCCCCAGCAACTTTTTGGCTACAGCTGGTACAAAGGGG



AAAGAGTGGATGGCAACCGTCAAATTGTAGGATATGCAATAGGAACTCAACAA



GCTACCCCAGGGCCCGCAAACAGCGGTCGAGAGACAATATACCCCAATGCATC



CCTGCTGATCCAGAACGTCACCCAGAATGACACAGGATTCTACACCCTACAAG



TCATAAAGTCAGATCTTGTGAATGAAGAAGCAACTGGACAGTTCCATGTATAC



CCGGAGCTGCCCAAGCCCTCCATCTCCAGCAACAACTCCAACCCTGTGGAGGA



CAAGGATGCTGTGGCCTTCACCTGTGAACCTGAGACTCAGGACACAACCTACC



TGTGGTGGATAAACAATCAGAGCCTCCCGGTCAGTCCCAGGCTGCAGCTGTCC



AATGGCAACAGGACCCTCACTCTACTCAGTGTCACAAGGAATGACACAGGACC



CTATGAGTGTGAAATACAGAACCCAGTGAGTGCGAACCGCAGTGACCCAGTCA



CCTTGAATGTCACCTATGGCCCGGACACCCCCACCATTTCCCCTTCAGACACC



TATTACCGTCCAGGGGCAAACCTCAGCCTCTCCTGCTATGCAGCCTCTAACCC



ACCTGCACAGTACTCCTGGCTTATCAATGGAACATTCCAGCAAAGCACACAAG



AGCTCTTTATCCCTAACATCACTGTGAATAATAGTGGATCCTATACCTGCCAC



GCCAATAACTCAGTCACTGGCTGCAACAGGACCACAGTCAAGACGATCATAGT



CACTGAGCTAAGTCCAGTAGTAGCAAAGCCCCAAATCAAAGCCAGCAAGACCA



CAGTCACAGGAGATAAGGACTCTGTGAACCTGACCTGCTCCACAAATGACACT



GGAATCTCCATCCGTTGGTTCTTCAAAAACCAGAGTCTCCCGTCCTCGGAGAG



GATGAAGCTGTCCCAGGGCAACACCACCCTCAGCATAAACCCTGTCAAGAGGG



AGGATGCTGGGACGTATTGGTGTGAGGTCTTCAACCCAATCAGTAAGAACCAA



AGCGACCCCATCATGCTGAACGTAAACTATAATGCTCTACCACAAGAAAATGG



CCTCTCACCTGGGGCCATTGCTGGCATTGTGATTGGAGTAGTGGCCCTGGTTG



CTCTGATAGCAGTAGCCCTGGCATGTTTTCTGCATTTCGGGAAGACCGGCAGG



GCAAGCGACCAGCGTGATCTCACAGAGCACAAACCCTCAGTCTCCAACCACAC



TCAGGACCACTCCAATGACCCACCTAACAAGATGAATGAAGTTACTTATTCTA



CCCTGAACTTTGAAGCCCAGCAACCCACACAACCAACTTCAGCCTCCCCATCC



CTAACAGCCACAGAAATAATTTATTCAGAAGTAAAAAAGCAGTAATGAAACCT



GTCCTGCTCACTGCAGTGCTGATGTATTTCAAGTCTCTCACCCTCATCACTAG



GAGATTCCTTTCCCCTGTAGGGGTAGAGGGGTGGGGACAGAAACAACTTTCTC



CTACTCTTCCTTCCTAATAGGCATCTCCAGGCTGCCTGGTCACTGCCCCTCTC



TCAGTGTCAATAGATGAAAGTACATTGGGAGTCTGTAGGAAACCCAACCTTCT



TGTCATTGAAATTTGGCAAAGCTGACTTTGGGAAAGAGGGACCAGAACTTCCC



CTCCCTTCCCCTTTTCCCAACCTGGACTTGTTTTAAACTTGCCTGTTCAGAGC



ACTCATTCCTTCCCACCCCCAGTCCTGTCCTATCACTCTAATTCGGATTTGCC



ATAGCCTTGAGGTTATGTCCTTTTCCATTAAGTACATGTGCCAGGAAACAAGA



GAGAGAGAAAGTAAAGGCAGTAATGCCTTCTCCTATTTCTCCAAAGCCTTGTG



TGAACTCACCAAACACAAGAAAATCAAATATATAACCAATAGTGAAATGCCAC



ACCTTTGTCCACTGTCAGGGTTGTCTACCTGTAGGATCAGGGTCTAAGCACCT



TGGTGCTTAGCTAGAATACCACCTAATCCTTCTGGCAAGCCTGTCTTCAGAGA



ACCCACTAGAAGCAACTAGGAAAATCACTTGCCAAAATCCAAGGCAATTCCTG



ATGGAAAATGCAAAAGCACATATATGTTTTAATATCTTTATGGGCTCTGTTCA



AGGCAGTGCTGAGAGGGAGGGGTTATAGCTTCAGGAGGGAACCAGCTTCTGAT



AAACACAATCTGCTAGGAACTTGGGAAAGGAATCAGAGAGCTGCCCTTCAGCG



ATTATTTAAATTATTGTTAAAGAATACACAATTTGGGGTATTGGGATTTTTCT



CCTTTTCTCTGAGACATTCCACCATTTTAATTTTTGTAACTGCTTATTTATGT



GAAAAGGGTTATTTTTACTTAGCTTAGCTATGTCAGCCAATCCGATTGCCTTA



GGTGAAAGAAACCACCGAAATCCCTCAGGTCCCTTGGTCAGGAGCCTCTCAAG



ATTTTTTTTGTCAGAGGCTCCAAATAGAAAATAAGAAAAGGTTTTCTTCATTC



ATGGCTAGAGCTAGATTTAACTCAGTTTCTAGGCACCTCAGACCAATCATCAA



CTACCATTCTATTCCATGTTTGCACCTGTGCATTTTCTGTTTGCCCCCATTCA



CTTTGTCAGGAAACCTTGGCCTCTGCTAAGGTGTATTTGGTCCTTGAGAAGTG



GGAGCACCCTACAGGGACACTATCACTCATGCTGGTGGCATTGTTTACAGCTA



GAAAGCTGCACTGGTGCTAATGCCCCTTGGGGAAATGGGGCTGTGAGGAGGAG



GATTATAACTTAGGCCTAGCCTCTTTTAACAGCCTCTGAAATTTATCTTTTCT



TCTATGGGGTCTATAAATGTATCTTATAATAAAAAGGAAGGACAGGAGGAAGA



CAGGCAAATGTACTTCTCACCCAGTCTTCTACACAGATGGAATCTCTTTGGGG



CTAAGAGAAAGGTTTTATTCTATATTGCTTACCTGATCTCATGTTAGGCCTAA



GAGGCTTTCTCCAGGAGGATTAGCTTGGAGTTCTCTATACTCAGGTACCTCTT



TCAGGGTTTTCTAACCCTGACACGGACTGTGCATACTTTCCCTCATCCATGCT



GTGCTGTGTTATTTAATTTTTCCTGGCTAAGATCATGTCTGAATTATGTATGA



AAATTATTCTATGTTTTTATAATAAAAATAATATATCAGACATCGA (SEQ



ID NO: 89)






>NP_001703.2 carcinoembryonic antigen-related cell



adhesion molecule 1 isoform 1 precursor [Homo




sapiens]




MGHLSAPLHRVRVPWQGLLLTASLLTFWNPPTTAQLTTESMPFNVAEGKEVLL



LVHNLPQQLFGYSWYKGERVDGNRQIVGYAIGTQQATPGPANSGRETIYPNAS



LLIQNVTQNDTGFYTLQVIKSDLVNEEATGQFHVYPELPKPSISSNNSNPVED



KDAVAFTCEPETQDTTYLWWINNQSLPVSPRLQLSNGNRTLTLLSVTRNDTGP



YECEIQNPVSANRSDPVTLNVTYGPDTPTISPSDTYYRPGANLSLSCYAASNP 



PAQYSWLINGTFQQSTQELFIPNITVNNSGSYTCHANNSVTGCNRTTVKTIIV



TELSPVVAKPQIKASKTTVTGDKDSVNLTCSTNDTGISIRWFFKNQSLPSSER



MKLSQGNTTLSINPVKREDAGTYWCEVFNPISKNQSDPIMLNVNYNALPQENG



LSPGAIAGIVIGVVALVALIAVALACFLHFGKTGRASDQRDLTEHKPSVSNHT



QDHSNDPPNKMNEVTYSTLNFEAQQPTQPTSASPSLTATEIIYSEVKKQ



(SEQ ID NO: 90)





Mouse
>NM_001039185.1 Mus musculus carcinoembryonic


CEACAM1
antigen-related cell adhesion molecule 1 (Ceacam1),



transcript variant 1, mRNA



AAAGCTCCTTTAAGAAAAGCAGGGCAGATATCAGGGCAGCCTGGCTTAGCAGT



AGTGTTGGAGAAGAAGCTAGCAGGCAGGCAGCAGAGACATGGAGCTGGCCTCA



GCACATCTCCACAAAGGGCAGGTTCCCTGGGGAGGACTACTGCTCACAGCCTC



ACTTTTAGCCTCCTGGAGCCCTGCCACCACTGCTGAAGTCACCATTGAGGCTG



TGCCGCCCCAGGTTGCTGAAGACAACAATGTTCTTCTACTTGTTCACAATCTG



CCCCTGGCGCTTGGAGCCTTTGCCTGGTACAAGGGAAACACTACGGCTATAGA



CAAAGAAATTGCACGATTTGTACCAAATAGTAATATGAATTTCACGGGGCAAG



CATACAGCGGCAGAGAGATAATATACAGCAATGGATCCCTGCTCTTCCAAATG



ATCACCATGAAGGATATGGGAGTCTACACACTAGATATGACAGATGAAAACTA



TCGTCGTACTCAGGCGACTGTGCGATTTCATGTACACCCCATATTATTAAAGC



CCAACATCACAAGCAACAACTCCAATCCCGTGGAGGGTGACGACTCCGTATCA



TTAACCTGTGACTCTTACACTGACCCTGATAATATAAACTACCTGTGGAGCAG



AAATGGTGAAAGCCTTTCAGAAGGTGACAGGCTGAAGCTGTCTGAGGGCAACA



GGACTCTCACTTTACTCAATGTCACGAGGAATGACACAGGACCCTATGTGTGT



GAAACCCGGAATCCAGTGAGTGTCAACCGAAGTGACCCATTCAGCCTGAACAT



TATCTATGGTCCGGACACCCCGATTATATCCCCCTCAGATATTTATTTGCATC



CAGGGTCAAACCTCAACCTCTCCTGCCATGCAGCCTCTAACCCACCTGCACAG



TACTTTTGGCTTATCAATGAGAAGCCCCATGCATCCTCCCAAGAGCTCTTTAT



CCCCAACATCACTACTAATAATAGCGGAACCTATACCTGCTTCGTCAATAACT



CTGTCACTGGCCTCAGTAGGACCACAGTCAAGAACATTACAGTCCTTGAGCCA



GTGACTCAGCCCTTCCTCCAAGTCACCAACACCACAGTCAAAGAACTAGACTC



TGTGACCCTGACCTGCTTGTCGAATGACATTGGAGCCAACATCCAGTGGCTCT



TCAATAGCCAGAGTCTTCAGCTCACAGAGAGAATGACACTCTCCCAGAACAAC



AGCATCCTCAGAATAGACCCTATTAAGAGGGAAGATGCCGGCGAGTATCAGTG



TGAAATCTCGAATCCAGTCAGCGTCAGGAGGAGCAACTCAATCAAGCTGGACA



TAATATTTGACCCAACACAAGGAGGCCTCTCAGATGGCGCCATTGCTGGCATC



GTGATTGGAGTTGTGGCTGGGGTGGCTCTAATAGCAGGGCTGGCATATTTCCT



CTATTCCAGGAAGTCTGGCGGGGGAAGTGACCAGCGAGATCTCACAGAGCACA



AACCCTCAGCCTCCAACCACAATCTGGCTCCTTCTGACAACTCTCCTAACAAG



GTGGATGACGTCGCATACACTGTCCTGAACTTCAATTCCCAGCAACCCAACCG



GCCAACTTCAGCCCCTTCTTCTCCAAGAGCCACAGAAACAGTTTATTCAGAAG



TAAAAAAGAAGTGAGCATAATCTGTCCGTCTGTCCTGCTGGCTGCACCAGTGA



TGCATTCCCGGATTCTGTTCCTCACTGGAGGGTCTCAGCACACACACACACGT



ACACATGCGCGCGCGCACACACACACACACACACACACACACACACTTACACA



CACACTCATGCATTCACTCTATTGACTCCTTCAGTGTCTATAGAAGAAAAGGT



GGATCCTGGAGCCTACAGAAAACTCAACCCTTCTAGGCTTTCAAATTTGGCTG



AGAGTGAGGTATCAAAATTTCTCACCCTTTCACTTTCCTGACCCAGATTGTTG



AAAATTGACCTATTCAGAGCACCTTCATTCCCCTCCCAACTCCAAGTCCTGCC



CTATCAGAGTCTGACTTGAATTTCCATAAACCTTGGAGGTCACCTAAGTGCTT



ACGCCAAACAAAACAAAACAAAACAAAACAAAACAAAACAAAACAAAACAAAA



CAAACCAGAAGCAGGAAATGGCCAGTCCCATATCTTTAAAGGCTGATTGGAAG



CCACCATACATGAGAAGATCAAACCTCCATGGGCAATCTACACACCCGACAAC



TGTCATGCTTACCCATCTGGGACATTCGAGTCTCTGAACCTTGTGCCCTCACG



CCTGAGCCCTTCTCTGAGCCTTTCTCCAGAAAATCCACTCACAGCAACTAGAG



AGGCTCTTTGTCAGCAACTCCAAGCAAACTGCTAGGCAGGATTCAGAAGAAAA



GACAGCATCTCTAACATCCACCAGGAAGGTGCCCAGAAAAGCAGAGCTGGTGA



CTTTGGACTGACAGACATCTGGAGTGTGAAAAAGCAGCACAGAGCTAACCTTC



GGAGAGTGTTGAAATTATTTGAAAAGAAGCCATATTTGGAGGTATTGGAGTTT



TCCTCTTTCTGAGACAATCCACTATTTGAAAATTGTAGCTACTGAATTGCCTC



TCAGTATGCGAGCTGATCACTTTGCCTTAGGGCCACTAGATTTCTGTCTCCCT



TAGCCCCTCAAGCCCTTTTGATCATGAGTTCCAAACCAAAAATAAATAAATGA



ACAGTGAGGCAGTCCCTTGCAGTACCACTGTCATGGGTCAGGCTAAGCCTCCT



GCTTTTCTGAATTAGTCAAGAAAAGCCTTGGTTTCCCTTTTTCCATCTCTTTA



TCTTGTCTTTCAGATACTGGCCAGAGCCTGGACACTCTTCCTCTGAGATCTCC



AGCTTCTCTGCCTTCTTGTGTTTCTTTTAAACTCTAACAAAAACTGTTCTCAC



CTTCAAAAAATAAAATAATAACAAGCTTTCCACATCCCCACCAAAGAGGGACC



CAGCTAGGTTTCTGGAAACCCAGCACCAGCCTCCAGCTGCCCTTCTGCAGTGT



TTCTGCCTCTGTTTCCCTTTCGTTTTGACTTTTTTCCTTCTTTTGAGACAGAG



TTCCAGCATGGAGCCTGTGCAGGTTTCAATCCCACAGTAACACCTTCTGCAGC



ACCCCACCTGCTCAGACTGCAGCCCTGGCCACCAGGCCTGGCTACCTGGACAT



TCTGTCTGCCCTGCACTCTCAGGAAACCTTGGCCTCTGCTACTGTCTGTTTGG



CTCATTCAAAGTGTGTCCTTAAAGGAATGCAGTCACCCATGCCAGAGGCAGTG



TTTACAGCCTGGAATGCTCTGCACTTCCAGTGGACCAGTGCTCCACCGGAAGT



GGGCTGTTAGCAGGGTCCTCTCACCTGGCCCTGGCCTTTCTGTAGCCTTGAAT



CCTGCCTTCCCCACCAGGGCACCAGGGATGAGTGCAGCAGCAGGAGGAGAGGC



AAACAGTCACCTCAGGAACCTTCTGAGCTAAGGCACACCCTCTGTGCCTGTCA



AGCAAAGGTTGTATTGGATATCAAGTGTTTGGTCTCACGCCAAGCCAACAGGC



TTTGGAGAGAATTAATTAGTTCTCCTACTCAGGGATTTCTTTCAGTCCTAACA



CAGCCTGTGTATATTTTGCTTCACCCACGCAATGCTGGATTATTTAATTTTGC



CCGGCTTAAGACAAATCTGAGTTACTTGTAAATTTGCTCTATGTTCATAATAA



AAATGTATTATATATCACTGATAGCA (SEQ ID NO: 91)






>NP_001034274.1 carcinoembryonic antigen-related cell



adhesion molecule 1 isoform 1 precursor [Mus




musculus]




MELASAHLHKGQVPWGGLLLTASLLASWSPATTAEVTIEAVPPQVAEDNNVLL



LVHNLPLALGAFAWYKGNTTAIDKEIARFVPNSNMNFTGQAYSGREIIYSNGS



LLFQMITMKDMGVYTLDMTDENYRRTQATVRFHVHPILLKPNITSNNSNPVEG



DDSVSLTCDSYTDPDNINYLWSRNGESLSEGDRLKLSEGNRTLTLLNVTRNDT



GPYVCETRNPVSVNRSDPFSLNIIYGPDTPIISPSDIYLHPGSNLNLSCHAAS



NPPAQYFWLINEKPHASSQELFIPNITTNNSGTYTCFVNNSVTGLSRTTVKNI



TVLEPVTQPFLQVTNTTVKELDSVTLTCLSNDIGANIQWLENSQSLQLTERMT



LSQNNSILRIDPIKREDAGEYQCEISNPVSVRRSNSIKLDIIFDPTQGGLSDG



AIAGIVIGVVAGVALIAGLAYFLYSRKSGGGSDQRDLTEHKPSASNHNLAPSD



NSPNKVDDVAYTVLNFNSQQPNRPTSAPSSPRATETVYSEVKKK (SEQ ID



NO: 92)





Human
>NM_007048.6 Homo sapiens butyrophilin subfamily 3


BTN3A1
member A1 (BTN3A1), transcript variant 1, mRNA



ATTCCTCACGATGACCCGACAGTCTCTGCTTTCTTTTTCCTTTCTTCCAGAAG



GAGATTTAACCATAGTAGAAAGAATGGAGAACTATTAACTGCCTTTCTTCTGT



GGGCTGTGATTTTCAGAGGGGAATGCTAAGAGGTGATTTTCAATGTTGGGACT



CAAAGGTGAAGACACTGAAGGACAGAATTTTTGGCAGAGGAAAGATCTTCTTC



GGTCACCATACTTGAGTTAGCTCTAGGGAAGTGGAGGTTTCCATTTGGAATTC



TATAGCTTCTTCCAGGTCATAGTGTCTGCCCCCCACCTTCCAGTATCTCCTGA



TATGCAGCATGAATGAAAATGGCAAGTTTCCTGGCCTTCCTTCTGCTCAACTT



TCGTGTCTGCCTCCTTTTGCTTCAGCTGCTCATGCCTCACTCAGCTCAGTTTT



CTGTGCTTGGACCCTCTGGGCCCATCCTGGCCATGGTGGGTGAAGACGCTGAT



CTGCCCTGTCACCTGTTCCCGACCATGAGTGCAGAGACCATGGAGCTGAAGTG



GGTGAGTTCCAGCCTAAGGCAGGTGGTGAACGTGTATGCAGATGGAAAGGAAG



TGGAAGACAGGCAGAGTGCACCGTATCGAGGGAGAACTTCGATTCTGCGGGAT



GGCATCACTGCAGGGAAGGCTGCTCTCCGAATACACAACGTCACAGCCTCTGA



CAGTGGAAAGTACTTGTGTTATTTCCAAGATGGTGACTTCTATGAAAAAGCCC



TGGTGGAGCTGAAGGTTGCAGCACTGGGTTCTGATCTTCACGTTGATGTGAAG



GGTTACAAGGATGGAGGGATCCATCTGGAGTGCAGGTCCACTGGCTGGTACCC



CCAACCCCAAATACAGTGGAGCAACAACAAGGGAGAGAACATCCCGACTGTGG



AAGCACCTGTGGTTGCAGACGGAGTGGGCCTGTATGCAGTAGCAGCATCTGTG



ATCATGAGAGGCAGCTCTGGGGAGGGTGTATCCTGTACCATCAGAAGTTCCCT



CCTCGGCCTGGAAAAGACAGCCAGCATTTCCATCGCAGACCCCTTCTTCAGGA



GCGCCCAGAGGTGGATCGCCGCCCTGGCAGGGACCCTGCCTGTCTTGCTGCTG



CTTCTTGGGGGAGCCGGTTACTTCCTGTGGCAACAGCAGGAGGAAAAAAAGAC



TCAGTTCAGAAAGAAAAAGAGAGAGCAAGAGTTGAGAGAAATGGCATGGAGCA



CAATGAAGCAAGAACAAAGCACAAGAGTGAAGCTCCTGGAGGAACTCAGATGG



AGAAGTATCCAGTATGCATCTCGGGGAGAGAGACATTCAGCCTATAATGAATG



GAAAAAGGCCCTCTTCAAGCCTGCGGATGTGATTCTGGATCCAAAAACAGCAA



ACCCCATCCTCCTTGTTTCTGAGGACCAGAGGAGTGTGCAGCGTGCCAAGGAG



CCCCAGGATCTGCCAGACAACCCTGAGAGATTTAATTGGCATTATTGTGTTCT



CGGCTGTGAGAGCTTCATATCAGGGAGACATTACTGGGAGGTGGAGGTAGGGG



ACAGGAAAGAGTGGCATATAGGGGTGTGCAGTAAGAATGTGCAGAGAAAAGGC



TGGGTCAAAATGACACCTGAGAATGGATTCTGGACTATGGGGCTGACTGATGG



GAATAAGTATCGGACTCTAACTGAGCCCAGAACCAACCTGAAACTTCCTAAGC



CCCCTAAGAAAGTGGGGGTCTTCCTGGACTATGAGACTGGAGATATCTCATTC



TACAATGCTGTGGATGGATCGCATATTCATACTTTCCTGGACGTCTCCTTCTC



TGAGGCTCTATATCCTGTTTTCAGAATTTTGACCTTGGAGCCCACGGCCCTGA



CTATTTGTCCAGCGTGAAAAGAAGAAGAGAGTTCCTCCAATTCTGACCGAGTG



CTGATCATTCCCTAGAGACACCAGTAACCCCGGGCTTAGCTAACGAAAGTGGG



GAGCCTCAGGCTGAAGTAACTTTTCTCTGCTTCTCCCTGCCCAGCTCAGAGCT



GAGGGCCTCCCCCTCCACAGCAACCAATCACAACCATAAAGCTACAAGCACGC



ACTGAAGCACTTTACTGATACTCATTCAATTATTCATATGACAGTTGTTTGAG



TTTGGTACCATCTTATTTTCCCCTTATACAGATAAGGAAACTGGGGTGCAGAA



AAGTGAATTGACTACAAAGTAGACATGACTAGTTAACAACACAGCTGGGATCT



AAACAGCAATAACTAACATTAATGGAGAACTTAAAATGCTCTGAGTGCTGTGT



TATGAGCTTTGGTGGATGTCACTCCTTTAATCCTCGCAACACCCTGTCGGGTA



GTCTCATTTAGCAAGTATGGAAGTTGAGGCAGGGCAACATTAAGCAACTTACA



TAACTCATGCAGTAATTTCTGCAGTTGGGAGATGTTCAGCTTCAGTCCCCGGC



CCTATGGCCGTTCTTTTCCACCCTGTTTCTTCCCCCATAGGAAGAACCCACCT



GTAGCCCTGAGGTTCTTTTCCCAGGATGGCTCCAGGATAAGGATCACTGTAGG



TGGTTGTGGAGTTGACACCCCTGTTGACTCCTTCCCAGCTGATTGTCAGAGCC



TTAGACCCAGCACGCCTTGGATTAGCTCTGCAGAGTGTCTTGGTTGAGAGAAT



AACCTCACCGTACCCACATGACACGTGATTTGGAAAGAGACTAGAGGCCACAC



TTGATAAATCATGGGGAACAGATGTGTTCCACCCAACAAATGTGATAAGTGAT



CATGCAGCCAGAGCCAGCCTTCCTTCAATCAAGGTTTCCAGGCAGAGCAAATA



CCCTAGAGATTCTCTGTGATATAGGAAATTTGGATGAAGGGAGCTAGAAGAAA



TACAGGGATTTTTTTTTTTTTTTAAGATGGAGTCTTACTCTGTTGCTAGGCTG



GAGTGCAGTGGTGCGATCTCAGCTCCCTGCAACCTCCACCTCCTGGGTTCAAA



CAATTCTCCTGCCTCAGCCTCCCGAGTACTGGGAATATAGGTGCACGCCACCA



CACCCAACAAATTTTTGTACTTTTAGTACAGATGAGGGTTCACTATGTTGGCC



AGGATGGTCTCGATCTCTTGACCTCATGATCCACCCACCTCGGTCTCCCAAAG



TGCTGGGATTACAGGCTTGAGCCACCGGGTGACCGGCTTACAGGGATATTTTT



AATCCCGTTATGGACTCTGTCTCCAGGAGAGGGGTCTATCCACCCCTGCTCAT



TGGTGGATGTTAAACCAATATTCCTTTCAACTGCTGCCTGCTAGGGAAAAACT



ACTCCTCATTATCATCATTATTATTGCTCTCCACTGTATCCCCTCTACCTGGC



ATGTGCTTGTCAAGTTCTAGTTGTTCAATAAATTTGTTAATAATGCTGA



(SEQ ID NO: 93)






>NP_008979.3 butyrophilin subfamily 3 member Al



isoform a precursor [Homo sapiens]



MKMASFLAFLLLNFRVCLLLLQLLMPHSAQFSVLGPSGPILAMVGEDADLPCH



LFPTMSAETMELKWVSSSLRQVVNVYADGKEVEDRQSAPYRGRTSILRDGITA



GKAALRIHNVTASDSGKYLCYFQDGDFYEKALVELKVAALGSDLHVDVKGYKD



GGIHLECRSTGWYPQPQIQWSNNKGENIPTVEAPVVADGVGLYAVAASVIMRG



SSGEGVSCTIRSSLLGLEKTASISIADPFFRSAQRWIAALAGTLPVLLLLLGG



AGYFLWQQQEEKKTQFRKKKREQELREMAWSTMKQEQSTRVKLLEELRWRSIQ



YASRGERHSAYNEWKKALFKPADVILDPKTANPILLVSEDQRSVQRAKEPQDL



PDNPERFNWHYCVLGCESFISGRHYWEVEVGDRKEWHIGVCSKNVQRKGWVKM



TPENGFWTMGLTDGNKYRTLTEPRTNLKLPKPPKKVGVFLDYETGDISFYNAV



DGSHIHTFLDVSFSEALYPVFRILTLEPTALTICPA (SEQ ID NO: 94)





Human
>NM_007047.5 Homo sapiens butyrophilin subfamily 3


BTN3A2
member A2 (BTN3A2), transcript variant 1, mRNA



GACTCTTACTGTTTCTCATGGTGAGAAGACAATATTTGCTTTCTCTTTTTCCT



TTCTTCCGGATGAGAGGCTAAGCCATAATAGAAAGAATGGAGAATTATTGATT



GACCGTCTTTATTCTGTGGGCTCTGATTCTCCAATGGGAATACCAAGGGATGG



TTTTCCATACTGGAACCCAAAGGTAAAGACACTCAAGGACAGACATTTTTGGC



AGAGCATAGATGAAAATGGCAAGTTCCCTGGCTTTCCTTCTGCTCAACTTTCA



TGTCTCCCTCCTCTTGGTCCAGCTGCTCACTCCTTGCTCAGCTCAGTTTTCTG



TGCTTGGACCCTCTGGGCCCATCCTGGCCATGGTGGGTGAAGACGCTGATCTG



CCCTGTCACCTGTTCCCGACCATGAGTGCAGAGACCATGGAGCTGAAGTGGGT



AAGTTCCAGCCTAAGGCAGGTGGTGAACGTGTATGCAGATGGAAAGGAAGTGG



AAGACAGGCAGAGTGCACCGTATCGAGGGAGAACTTCGATTCTGCGGGATGGC



ATCACTGCAGGGAAGGCTGCTCTCCGAATACACAACGTCACAGCCTCTGACAG



TGGAAAGTACTTGTGTTATTTCCAAGATGGTGACTTCTATGAAAAAGCCCTGG



TGGAGCTGAAGGTTGCAGCACTGGGTTCTAATCTTCACGTCGAAGTGAAGGGT



TATGAGGATGGAGGGATCCATCTGGAGTGCAGGTCCACCGGCTGGTACCCCCA



ACCCCAAATACAGTGGAGCAACGCCAAGGGAGAGAACATCCCAGCTGTGGAAG



CACCTGTGGTTGCAGATGGAGTGGGCCTATATGAAGTAGCAGCATCTGTGATC



ATGAGAGGCGGCTCCGGGGAGGGTGTATCCTGCATCATCAGAAATTCCCTCCT



CGGCCTGGAAAAGACAGCCAGCATTTCCATCGCAGACCCCTTCTTCAGGAGCG



CCCAGCCCTGGATCGCAGCCCTGGCAGGGACCCTGCCTATCTTGCTGCTGCTT



CTCGCCGGAGCCAGTTACTTCTTGTGGAGACAACAGAAGGAAATAACTGCTCT



GTCCAGTGAGATAGAAAGTGAGCAAGAGATGAAAGAAATGGGATATGCTGCAA



CAGAGCGGGAAATAAGCCTAAGAGAGAGCCTCCAGGAGGAACTCAAGAGGAAA



AAAATCCAGTACTTGACTCGTGGAGAGGAGTCTTCGTCCGATACCAATAAGTC



AGCCTGATGCTCTAATGGAAAAATGGCCCTCTTCAAGCCTGGTGAGGAAATGC



TTCAGATGAGGCTCCACCTTGTTAAATAAATTGGATGTATGGAAAAATAGACT



GCAGAAAAGGGGAACTCATTTAGCTCACGAGTGGTCGAGTGAAGATTGAAAAT



TAACCTCTGAGGGCCAGCACAGCAGCTCATGCCTGTAATCCTAGCACTTTGGA



AGGCTGAGGAGGGCGGATCACAAGGTCAGGAGATCAAGACCATCCTGGCTAAC



ACGGTGAAACCCCGTCTCTACTAAAAATACAAAAAATAAAAAATTAGCCGGGC



ATGGTGACGGGCACCTGTAGTCCCAGCTACTCGGGAGGCTGAGGCAGGAGAAT



GGCATGAACCCGGAAGGCAGAGCTTGCAGTGAGCCGAGATCACGCCACTGCAC



TCCAGCCTGGGAGACAGAGCGAGACTCTGTCTCAAGAAAAAAAAAAAAAAAAA



AAAAGAAAAGAAAATTAACCTCTGAGTATAAAGCATCAGTGGGCAGAATCAAT



GTGGGGAGGGAAACAACAAAAATGTAGAAAGAGGATCCTTGTTGCTTCTTGGG



GCCGCATCAGGGTATTGGGTTAGGCAGATACTGACCTTACTTTCATTTCCCCT



CTGGTCACTAGACCCCTGGGGCTTTCACCAATGACATTGATGAGAGAATCACA



TTCAGGGCAGGCTAGGGACACGGGGTTCTGGAAGGACCTCCTCAGCATGGCCC



AAGCCTTGCATGCTGTGGCTCTTAAATCCAGGAAAAATGGCTGACCCCATGGA



CACCTCCTCAAACTCTCTGCAGCAGATGTAATTCTGTATCCAGACATGGCAAA



TGCCATCCTCCTTGTTTCTGAGGACCAGAGGAGTGTACAGCGTGCTGAGGAGC



CCCATGACCTACCAGACAACCCTGAGAGATTTGAATGGCGTTACTGTGTGCTT



GGCTGTGAAAGCTTCATGTCAGAGAGACACTACTGGGAGGTGGAAGTGGGGGA



CAGAAAAGAGTGGCATATTGGGGTATGTAGTAAGAACGTGGAGAGGAAAAAAG



TTTGGGTCAAAATGACACCGGAGAACGGATACTGGACTATGGGCCTGACTGAT



GGGAATAAGTATCGGGCTCTCACTGAGCCCAGAACCAACCTGAAACTTCCTGA



GCCTCCTAGGAAAGTGGGGGTCATCCTGGACTATGAGACTGGACATATCTCGT



TCTACAATGCCACGGATGGATCTCATATCTACACATTTCTGCACGCCTCTTCC



TCTGAGCCTCTGTATCCTGTATTCAGAATTTTGACCTTGGAGCCCACTGCCCT



GACCGTTTGCCCAATACCAAAAGTAGAGAGTTCCCCCGATCCCGACCTAGTGC



CTGATCATTCCCTGGAGATACCACTGACCCCAGGCTTAGCTAATGAAAGTGGG



GAGCCTCAGGCTGAAGTAACATCTCTGCTTCTCCCTGCCCAGCCTGGAGCTAA



GGGTCTCACCCTCCACAACAGCCAGTCAGAACCATAAAGCTACAGGCACACAC



TGAAGCACTTTACTGATATTCATTCAATTATTCCATAGGACAGTTGTTTGAGT



TTGGTGCCACCTTATTGGCCCCTTTATACAGATAAGGAAACTGGGGTGTAGAA



AAGTGTATTGACTTTACAAAGCAGACAGGAATAGTGAACAACAGAGCTGGGAT



CTGAACAACAATGACTAACATTAATGGAGAATTTAAAACGTTCTGAGTGCTGT



GTTATGAGCTTTGGTGGGTGTCACTCCTTTAATCCTCACAACACCCTGTCAGG



TAGTCTCATTTGGCAAGTATGGAAGCAGAGGCAGGGCAACATTAAGTAGCTTA



CATAACTCACACGGTAATTTGTGCAGTTGGGAGATGTTCAGCTTCAGTCCCTG



GCCAATTGCCCGTTCTTTTCCAGCCTGATTTTTCCTGCATGGGAAGAGCCCAC



ATGTAGCCCTGAGGTTCCCTTCCCAGGACAGCTCCAGGATCGAGATCACTGTG



AGTGGTTGTGGAGTTAAGACCCCTATGGACTCCTTCCCAGCTGATTATCAGAG



CCTTAGACCCAGCACTCCTTGGATTGGCTCTGCAGAGTGTCTTGGTTGAGAGA



ATAACGTTGCAGTTCCCACAGGGCATGTGACTTTGAAAGAGACTAGAGGCCAC



ACTCAGTTAATAATGGGGCACAGATGTGTTCCCACCCAACAAATGTGATAAGT



GATCGTGCAGCCAGAGCCAGCCTTCCTTCAGTCAAGGTTTCCAGGCAGAGCAA



ATACCCTAGAGATTCTCTGTAATATTGGTAATTTGGATGAAGGAAGCTAGAAG



AATTACAGGGATGTTTTTAATCCCACTATGGACTCAGTCTCCTGGAAAAGGAT



CTGTCCACTCCTGGTCATTGGTGGATGTTAAACCCATATTCCTTTCAACTGCT



GCCTGCTAGGGAAAACTGCTCCTCATTATCATCACTATTATTGCTCACCACTG



TATCCCCTCTACTGGGCAAGTGCTTGTCAAGTTCTAGTTGTTCAATAAATTTG



TTAATAATGCTGA (SEQ ID NO: 95)






>NP_008978.2 butyrophilin subfamily 3 member A2



isoform a precursor [Homo sapiens]



MKMASSLAFLLLNFHVSLLLVQLLTPCSAQFSVLGPSGPILAMVGEDADLPCH



LFPTMSAETMELKWVSSSLRQVVNVYADGKEVEDRQSAPYRGRTSILRDGITA



GKAALRIHNVTASDSGKYLCYFQDGDFYEKALVELKVAALGSNLHVEVKGYED



GGIHLECRSTGWYPQPQIQWSNAKGENIPAVEAPVVADGVGLYEVAASVIMRG



GSGEGVSCIIRNSLLGLEKTASISIADPFFRSAQPWIAALAGTLPILLLLLAG



ASYFLWRQQKEITALSSEIESEQEMKEMGYAATEREISLRESLQEELKRKKIQ



YLTRGEESSSDTNKSA (SEQ ID NO: 96)





Human
>NM_007049.5 Homo sapiens butyrophilin subfamily 2


BTN2A1
member A1 (BTN2A1), transcript variant 1, mRNA



AGATTTCGTTTCCTGCATCTCCAAACATGGCGACCTAGGAGAAGGGGAAGAAC



AATTTTTTCTCCTCTTTTGGGAAGGTTTGTGTCTAGTAGTGCCTGTGCCCCTG



GGCAGATTGGAGAGAAGAGGGACGACTGGAGAATCGTCGAGAACCAGCGGAGA



AAAGAAAAAGCAACGTTTAATTCTAGAAGGCCTCCTGTCCCTGCCTGCTCTGG



GTGCTCATGGAATCAGCTGCTGCCCTGCACTTCTCCCGGCCAGCCTCCCTCCT



CCTCCTCCTCCTCAGCCTGTGTGCACTGGTCTCAGCCCAGTTTATTGTCGTGG



GGCCCACTGATCCCATCTTGGCCACGGTTGGAGAAAACACTACGTTACGCTGC



CATCTGTCACCCGAGAAAAATGCTGAGGACATGGAGGTGCGGTGGTTCCGGTC



TCAGTTCTCCCCCGCAGTGTTTGTGTATAAAGGTGGCAGAGAGAGAACAGAGG



AGCAGATGGAGGAGTACCGAGGAAGAACCACCTTTGTGAGCAAAGACATCAGC



AGGGGCAGCGTGGCCCTGGTCATACACAACATCACAGCCCAGGAAAACGGCAC



CTACCGCTGTTACTTCCAAGAAGGCAGGTCCTACGATGAGGCCATCCTGCACC



TCGTAGTGGCAGGACTAGGCTCTAAGCCCCTCATTTCAATGAGGGGCCATGAA



GACGGGGGCATCCGGCTGGAGTGCATATCTAGAGGGTGGTACCCAAAGCCCCT



CACAGTGTGGAGGGACCCCTACGGTGGGGTTGCGCCTGCCCTGAAAGAGGTCT



CCATGCCTGATGCAGACGGCCTCTTCATGGTCACCACGGCTGTGATCATCAGA



GACAAGTCTGTGAGGAACATGTCCTGCTCTATCAACAACACCCTGCTCGGCCA



GAAGAAAGAAAGTGTCATTTTTATTCCAGAATCCTTTATGCCCAGTGTGTCTC



CCTGTGCAGTGGCCCTGCCTATCATTGTGGTTATTCTGATGATACCCATTGCC



GTATGCATCTATTGGATCAACAAACTCCAAAAGGAAAAAAAGATTCTGTCAGG



GGAAAAGGAGTTTGAACGGGAAACAAGAGAAATTGCTCTAAAGGAACTGGAGA



AAGAACGTGTGCAAAAAGAGGAAGAACTTCAAGTAAAAGAGAAACTTCAAGAA



GAATTGCGATGGAGAAGAACATTCTTACATGCTGTTGATGTGGTCCTGGATCC



AGACACCGCTCATCCCGATCTCTTCCTGTCAGAGGACCGGAGAAGTGTGAGAA



GGTGCCCCTTCAGGCACCTAGGGGAGAGCGTGCCTGACAACCCAGAGAGATTC



GACAGTCAGCCTTGTGTCCTAGGCCGGGAGAGCTTCGCTTCAGGGAAACATTA



CTGGGAGGTGGAGGTGGAAAACGTGATTGAGTGGACTGTGGGGGTCTGTAGAG



ACAGTGTTGAGAGGAAAGGGGAGGTCCTGCTGATTCCTCAGAATGGCTTCTGG



ACCTTGGAGATGCATAAAGGGCAATACCGGGCCGTGTCCTCCCCTGATAGGAT



TCTCCCTTTGAAGGAGTCCCTTTGCCGGGTGGGCGTCTTCCTGGACTATGAAG



CTGGAGATGTCTCCTTCTACAACATGAGGGACAGATCGCACATCTACACATGT



CCCCGTTCAGCCTTTTCCGTGCCTGTGAGGCCCTTCTTCAGGTTGGGGTGTGA



GGACAGCCCCATCTTCATCTGCCCTGCACTCACAGGAGCCAATGGGGTCACGG



TGCCTGAAGAGGGCCTGACACTTCACAGAGTGGGGACCCACCAGAGCCTATAG



AATCAATTCCTTGGTCTCACAGCCATGTAGACAAGCCCTGGTCATCTCAGCAG



CCACCGCACAACACCCCTGGTGGAAGACACGCCCTCCTCCCCTCTGGTCACAC



AAGAGAACATCTTCCAGCTGCCTCTTTCACACCCACTACAGACCTCAGCCCCA



GTTTTCTCCTCCTCACTAGGCTGTGTTTTTAGTAGTTCCTTTGCTTGTAACTA



TGGGATGGGATCCAGGCATAGGGAACTAGTTGTTACACAGCTCCCAGCCAAGA



AGAAAGTGTGAGAAGTTGATGGGCAGCAAACCTGCTGTTTAACATCAGGGTGA



CCACATTAAGCCCAGTATTCCAGTTGGCACCAGAAGATATGGACTTGGAATGA



GGCCTACAGGGTTCACCAGGATGTAAGAGGAGAGAGGAATCCACAGGACCACC



AGAGAGGAGAGGGAACCAGATATGCAGATCAGAGATAGAGGAAGTGGAACCAG



AGAGCTGGGAGGGACCAAGGTTGTAAGGGTGGCTAAGTCCCACCATAACAGCT



AAGGGGACCTGGGAGATGATGGCTCATTTCCACCCAGCCCCAGGATTTCCAGA



GCGCACATCCACAGGCCTGGACCTGGGATGAAGATGAATGAAGAACATGGATG



CACGTGGATGTAGTTTGGCTCAGGTGTCCCTGCAGTTGGCAAGGAGTCAGTAC



TCAGTCCCTGAGTGTGGCTGAAATTTGAGGTCCTGGCTGAGCCAAGGAGTAAT



GGACCAGATCTACCTCAGTATTCAAGTTCAGTGGGGACACCAGTGGCTTCAAA



CTTCCTGGTTTCATGATATCTTGAGACGCCTTACAAATGATGGAGGATTCCAA



AGAGTTTTTGTTTATTTGGGTTAATATTTGTTGGTATTTATGGCATTTGAGAT



TGAAACTAAGAAATGTTTTAATTTATTACCTTTACAACATTTATTTACATTAC



ATACATACATTTACAACATTTATTAATTTATATTAAAATAGCATGAATAAGCC



AATTATAGGTTAATATAAGTAGAATGTTTGTGAAAAATAAGTATGGTATCCAA



AGCAAAATAAATTTTATTGTGAAGTGTG (SEQ ID NO: 97)






>NP_008980.1 butyrophilin subfamily 2 member A1



isoform 1 precursor [Homo sapiens]



MESAAALHFSRPASLLLLLLSLCALVSAQFIVVGPTDPILATVGENTTLRCHL



SPEKNAEDMEVRWFRSQFSPAVFVYKGGRERTEEQMEEYRGRTTFVSKDISRG



SVALVIHNITAQENGTYRCYFQEGRSYDEAILHLVVAGLGSKPLISMRGHEDG



GIRLECISRGWYPKPLTVWRDPYGGVAPALKEVSMPDADGLFMVTTAVIIRDK



SVRNMSCSINNTLLGQKKESVIFIPESFMPSVSPCAVALPIIVVILMIPIAVC



IYWINKLQKEKKILSGEKEFERETREIALKELEKERVQKEEELQVKEKLQEEL



RWRRTFLHAVDVVLDPDTAHPDLFLSEDRRSVRRCPFRHLGESVPDNPERFDS



QPCVLGRESFASGKHYWEVEVENVIEWTVGVCRDSVERKGEVLLIPQNGFWTL



EMHKGQYRAVSSPDRILPLKESLCRVGVFLDYEAGDVSFYNMRDRSHIYTCPR



SAFSVPVRPFFRLGCEDSPIFICPALTGANGVTVPEEGLTLHRVGTHQSL



(SEQ ID NO: 98)





Human
>NM_001040462.3 Homo sapiens butyrophilin like 8


BTNL8
(BTNL8), transcript variant 2, mRNA



AGAACAGCGCAGTTTGCCCTCCGCTCACGCAGAGCCTCTCCGTGGCTTCCGCA



CCTTGAGCATTAGGCCAGTTCTCCTCTTCTCTCTAATCCATCCGTCACCTCTC



CTGTCATCCGTTTCCATGCCGTGAGGTCCATTCACAGAACACATCCATGGCTC



TCATGCTCAGTTTGGTTCTGAGTCTCCTCAAGCTGGGATCAGGGCAGTGGCAG



GTGTTTGGGCCAGACAAGCCTGTCCAGGCCTTGGTGGGGGAGGACGCAGCATT



CTCCTGTTTCCTGTCTCCTAAGACCAATGCAGAGGCCATGGAAGTGCGGTTCT



TCAGGGGCCAGTTCTCTAGCGTGGTCCACCTCTACAGGGACGGGAAGGACCAG



CCATTTATGCAGATGCCACAGTATCAAGGCAGGACAAAACTGGTGAAGGATTC



TATTGCGGAGGGGCGCATCTCTCTGAGGCTGGAAAACATTACTGTGTTGGATG



CTGGCCTCTATGGGTGCAGGATTAGTTCCCAGTCTTACTACCAGAAGGCCATC



TGGGAGCTACAGGTGTCAGCACTGGGCTCAGTTCCTCTCATTTCCATCACGGG



ATATGTTGATAGAGACATCCAGCTACTCTGTCAGTCCTCGGGCTGGTTCCCCC



GGCCCACAGCGAAGTGGAAAGGTCCACAAGGACAGGATTTGTCCACAGACTCC



AGGACAAACAGAGACATGCATGGCCTGTTTGATGTGGAGATCTCTCTGACCGT



CCAAGAGAACGCCGGGAGCATATCCTGTTCCATGCGGCATGCTCATCTGAGCC



GAGAGGTGGAATCCAGGGTACAGATAGGAGATACCTTTTTCGAGCCTATATCG



TGGCACCTGGCTACCAAAGTACTGGGAATACTCTGCTGTGGCCTATTTTTTGG



CATTGTTGGACTGAAGATTTTCTTCTCCAAATTCCAGTGGAAAATCCAGGCGG



AACTGGACTGGAGAAGAAAGCACGGACAGGCAGAATTGAGAGACGCCCGGAAA



CACGCAGTGGAGGTGACTCTGGATCCAGAGACGGCTCACCCGAAGCTCTGCGT



TTCTGATCTGAAAACTGTAACCCATAGAAAAGCTCCCCAGGAGGTGCCTCACT



CTGAGAAGAGATTTACAAGGAAGAGTGTGGTGGCTTCTCAGAGTTTCCAAGCA



GGGAAACATTACTGGGAGGTGGACGGAGGACACAATAAAAGGTGGCGCGTGGG



AGTGTGCCGGGATGATGTGGACAGGAGGAAGGAGTACGTGACTTTGTCTCCCG



ATCATGGGTACTGGGTCCTCAGACTGAATGGAGAACATTTGTATTTCACATTA



AATCCCCGTTTTATCAGCGTCTTCCCCAGGACCCCACCTACAAAAATAGGGGT



CTTCCTGGACTATGAGTGTGGGACCATCTCCTTCTTCAACATAAATGACCAGT



CCCTTATTTATACCCTGACATGTCGGTTTGAAGGCTTATTGAGGCCCTACATT



GAGTATCCGTCCTATAATGAGCAAAATGGAACTCCCATAGTCATCTGCCCAGT



CACCCAGGAATCAGAGAAAGAGGCCTCTTGGCAAAGGGCCTCTGCAATCCCAG



AGACAAGCAACAGTGAGTCCTCCTCACAGGCAACCACGCCCTTCCTCCCCAGG



GGTGAAATGTAGGATGAATCACATCCCACATTCTTCTTTAGGGATATTAAGGT



CTCTCTCCCAGATCCAAAGTCCCGCAGCAGCCGGCCAAGGTGGCTTCCAGATG



AAGGGGGACTGGCCTGTCCACATGGGAGTCAGGTGTCATGGCTGCCCTGAGCT



GGGAGGGAAGAAGGCTGACATTACATTTAGTTTGCTCTCACTCCATCTGGCTA



AGTGATCTTGAAATACCACCTCTCAGGTGAAGAACCGTCAGGAATTCCCATCT



CACAGGCTGTGGTGTAGATTAAGTAGACAAGGAATGTGAATAATGCTTAGATC



TTATTGATGACAGAGTGTATCCTAATGGTTTGTTCATTATATTACACTTTCAG



TAA (SEQ ID NO: 99)






>NP_001035552.1 butyrophilin-like protein 8 isoform 2



precursor [Homo sapiens]



MALMLSLVLSLLKLGSGQWQVFGPDKPVQALVGEDAAFSCFLSPKTNAEAMEV



RFFRGQFSSVVHLYRDGKDQPFMQMPQYQGRTKLVKDSIAEGRISLRLENITV



LDAGLYGCRISSQSYYQKAIWELQVSALGSVPLISITGYVDRDIQLLCQSSGW



FPRPTAKWKGPQGQDLSTDSRTNRDMHGLFDVEISLTVQENAGSISCSMRHAH



LSREVESRVQIGDTFFEPISWHLATKVLGILCCGLFFGIVGLKIFFSKFQWKI



QAELDWRRKHGQAELRDARKHAVEVTLDPETAHPKLCVSDLKTVTHRKAPQEV



PHSEKRFTRKSVVASQSFQAGKHYWEVDGGHNKRWRVGVCRDDVDRRKEYVTL



SPDHGYWVLRLNGEHLYFTLNPRFISVFPRTPPTKIGVFLDYECGTISFFNIN



DQSLIYTLTCRFEGLLRPYIEYPSYNEQNGTPIVICPVTQESEKEASWQRASA



IPETSNSESSSQATTPFLPRGEM (SEQ ID NO: 100)





Human
>NM_006995.5 Homo sapiens butyrophilin subfamily 2


BTN2A2
member A2 (BTN2A2), transcript variant 1, mRNA



GGGACTTTTTGGACACCCAGAGAACAGGTCCCAGATACCGAGTCCGCAACTCC



AAACATCGCGATTAATAGGAGGCCTCTGGTCTCTGCCTGCCCTGGGTGCTCAT



GGAACCAGCTGCTGCTCTGCACTTCTCCCTGCCAGCCTCCCTCCTCCTCCTCC



TGCTCCTCCTCCTTCTCAGCCTGTGTGCACTGGTCTCAGCCCAGTTTACTGTC



GTGGGGCCAGCTAATCCCATCCTGGCCATGGTGGGAGAAAACACTACATTACG



CTGCCATCTGTCACCCGAGAAAAATGCTGAGGACATGGAGGTGCGGTGGTTCC



GGTCTCAGTTCTCCCCCGCAGTGTTTGTGTATAAGGGTGGGAGAGAGAGAACA



GAGGAGCAGATGGAGGAGTACCGGGGAAGAATCACCTTTGTGAGCAAAGACAT



CAACAGGGGCAGCGTGGCCCTGGTCATACATAACGTCACAGCCCAGGAGAATG



GGATCTACCGCTGTTACTTCCAAGAAGGCAGGTCCTACGATGAGGCCATCCTA



CGCCTCGTGGTGGCAGGCCTTGGGTCTAAGCCCCTCATTGAAATCAAGGCCCA



AGAGGATGGGAGCATCTGGCTGGAGTGCATATCTGGAGGGTGGTACCCAGAGC



CCCTCACAGTGTGGAGGGACCCCTACGGTGAGGTTGTGCCCGCCCTGAAGGAG



GTTTCCATCGCTGATGCTGACGGCCTCTTCATGGTCACCACAGCTGTGATCAT



CAGAGACAAGTATGTGAGGAATGTGTCCTGCTCTGTCAACAACACCCTGCTCG



GCCAGGAGAAGGAAACTGTCATTTTTATTCCAGAATCCTTTATGCCCAGCGCA



TCTCCCTGGATGGTGGCCCTAGCTGTCATCCTGACCGCATCTCCCTGGATGGT



GTCCATGACTGTCATCCTGGCTGTTTTCATCATCTTCATGGCTGTCAGCATCT



GTTGCATCAAGAAACTTCAAAGGGAAAAAAAGATTCTGTCAGGGGAAAAGAAA



GTTGAACAAGAGGAAAAAGAAATTGCACAGCAACTTCAAGAAGAATTGCGATG



GAGAAGAACATTCTTACATGCTGCTGATGTGGTCCTGGATCCAGACACCGCTC



ATCCCGAGCTCTTCCTGTCAGAGGACCGGAGAAGTGTGAGGCGGGGCCCCTAC



AGGCAGAGAGTGCCTGACAACCCAGAGAGATTCGACAGTCAGCCTTGTGTCCT



GGGATGGGAGAGCTTCGCCTCAGGGAAACATTACTGGGAGGTGGAGGTGGAAA



ACGTGATGGTGTGGACTGTGGGGGTCTGCAGACACAGTGTTGAGAGGAAAGGG



GAGGTCCTGCTGATTCCTCAGAATGGCTTCTGGACCCTGGAGATGTTTGGAAA



CCAATACCGGGCCCTGTCCTCCCCTGAGAGGATTCTCCCTTTGAAGGAGTCCC



TTTGCCGGGTGGGCGTCTTCCTGGACTATGAAGCTGGAGATGTCTCCTTCTAC



AACATGAGGGACAGATCGCACATCTACACATGTCCCCGTTCAGCCTTTACTGT



GCCTGTGAGGCCCTTCTTCAGGTTAGGGTCTGATGACAGCCCCATCTTCATCT



GCCCTGCACTCACAGGAGCCAGTGGGGTCATGGTGCCTGAAGAGGGCCTGAAA



CTTCACAGAGTGGGGACCCACCAGAGCCTATAGAATCAATTCCTTGGACTCAC



AGCCATGCAGATAAGCCCTGGCCATCTCAGCAGCCACCGCACAACCCCCCTAA



TGAAAGACACGCCCTCCTCCCCTCTGGTCACGTAAGAGAACATCTTCCAGCTG



CCTTTTTCACACCCACTCCAGCCCTCTGCCCCAGTTTTCTCCTCCTCACTAGT



CTGTGGCTTTAGTAGTTCCTTTGCTTGTAATTATGGGATGGGATCCAGGCATA



GGGAACTAGTTGTTTCATAGCTCCCAGTCAAAAAGAAAGTGAGAGAAGCTGTT



GGGCAGCGAACCTACTGTTTAAAATCAGGATAACCACATTAAGCCCAATATGC



CAGTTGGCACCAGATGCTGTGGACTTGGAATGAGGCCAACAGGGTTCACCAGG



ATGAGAGAGGAGAGAGGAATCCACAGGACCACCAGAAGGGAGAGGGAACCAGA



TATGCAGATCAGAGATAGAGGAAGTGGAACCAGAGAGCTGGGAGGGACCAAGG



TTGTAAGGATGGCTAAGTCCCACCATAAGAGCTAAAGGGTCCTGGGAGATGAT



GGCTCATTTCCACCCAACCCCAGGATTTCCACAGCACACACCCACAGGCCTGG



ACCTGGGATGAAGATGAATGAAGAACATGGACTCATGTGGATGTGGTTTGGCT



CAGATGTCCCTGCAATAAACAAGGGGTCAGTACTTAGTCCCTGAGTGTGGTTG



AGGTTTGAGGTCCTGGTCGAGCAGGGCAGTACTGGACCAGGTCTACGTCAGCA



TTCAGGTTCAATGGGGACACCAGTGGCTTCAAACTTCCTGATCTAATTATGTT



TTTAGACACTTAGAAGTTATTGAGGACTTTAAAGAGCTTTTGTTTATTTGGGT



TAATATTTATGACATTTGACATTGAAACAAAAATTTAAAATGTTATCTTTTAA



TTTATGTTAAAATAGCATTAATAAATCAGTTATAGGTTAATGTAGATAGGATG



TTTTGTGAAAAAGCAATCTATTGTGTCCAAATAAAAAAACAAAAAGTGTGACA



CTGGTTAACTTTTTCCAGATCTCATGTCTGGCTTAATAAGAGATATTTGTATT



ATCATATCTGCCTTTGTATTAAACCTATTGGTATATCATAGGTCATGTTAGCT



CAAAAAAACTTTACTGCACACTACTGAGAGAATGAGATGAAAAACGATTAATG



TTTCATTATTATTATTGTGAAAATATTATTAACACTGGGGACTCCTTAAGAGT



ACATCAGAGTTCTCTCTAGGAATCCCAAAACCACATTTTGAAACTAGAATAGT



GGATCCTGGAAGTTAATCCATGTGCTGGTTAATTTTAGATGTCAACCTGACTG



GATTAAGGAATACCTAGACAGCTGGTACAACATTATTTCTGGGTGTGTCTGTG



AGTGTGTTTCCAGAAGAGATTGGCAAGTGAGTCAGTGGGAAATTCTCTCCTTC



TGTTGGCTGGGTGCCCAATACAACAAAAAGGCAGAGGAAAGGCAAATTCTTCT



CTCCTCTGGAGCTGAGACACTCTTCTTCTTCTGCCCTTGGACATCAGAACTCC



TGGCTCTCCGGCCTTTGAACTTCAGGACTTGTACCAGGAGGCCCTGGGTTCTC



AGGCCTTTGGCTTTGGACTGAGAGTTACACAATCAGCTTCCCTGGTTCTGAGG



CTTTCAGACTTAAACTGAGCCATGCTACCAGCATCCCAGGGTCTCCAGCCTAC



AGATGAGCTGTTGTGCGATTTCTTAGCCTCCATAATCACATGAGCCAATCTCC



TTAATAAATGCCTGCTCATAGATCTGTATCTACATCTATATCTGTATGTGCAT



CTATATCTATGCCTATATCTATATCTATATCATATTGATTTTGTCTCTCTGGA



GAACCCTGACTAATAAAATGAGGCATCTAAAA (SEQ ID NO: 101)






>NP_008926.2 butyrophilin subfamily 2 member A2



isoform a precursor [Homo sapiens]



MEPAAALHFSLPASLLLLLLLLLLSLCALVSAQFTVVGPANPILAMVGENTTL



RCHLSPEKNAEDMEVRWFRSQFSPAVFVYKGGRERTEEQMEEYRGRITFVSKD



INRGSVALVIHNVTAQENGIYRCYFQEGRSYDEAILRLVVAGLGSKPLIEIKA



QEDGSIWLECISGGWYPEPLTVWRDPYGEVVPALKEVSIADADGLFMVTTAVI



IRDKYVRNVSCSVNNTLLGQEKETVIFIPESFMPSASPWMVALAVILTASPWM



VSMTVILAVFIIFMAVSICCIKKLQREKKILSGEKKVEQEEKEIAQQLQEELR



WRRTFLHAADVVLDPDTAHPELFLSEDRRSVRRGPYRQRVPDNPERFDSQPCV



LGWESFASGKHYWEVEVENVMVWTVGVCRHSVERKGEVLLIPQNGFWTLEMFG



NQYRALSSPERILPLKESLCRVGVFLDYEAGDVSFYNMRDRSHIYTCPRSAFT



VPVRPFFRLGSDDSPIFICPALTGASGVMVPEEGLKLHRVGTHQSL (SEQ



ID NO: 102)





Mouse
>NM_175938.3 Mus musculus butyrophilin, subfamily 2,


BTN2A2
member A2 (Btn2a2), transcript variant 1, mRNA



GAAATTGTGAGACTTGCACGCGGAATGGGTCCTCCGAGGTCTGCTGTCGCGAG



TCCCAGCACTTTGCAAGTAATGGAGAACAGAAAATTCTTTCCTCTCTACTGTA



GCAGTTTGTTCTCTGGTGGCGACTGTGCTCAGCGACAAGTTGGAGAGTAGAGA



AAAGGCAAGATAATCAGCATTTGAGGGTCAGAGAAGAAAAGAAAACGCAGTTA



ATTCTAGAAGGTTTTCTGTCCACACGTGACCTAGGTGACTCTGTCCTGAAGAC



CTATGGAGCCTACAACTTCCCTGCGTTCTTGCCCGATAGCCTCCCTTCTCTTC



TTCTTGGTCCTCAGCCTGTTTGTGCTGGTCTCAGCCCAGTTTACTGTCATAGG



ACCAGCTGAGCCCATCCTGGCCATGGTAGGAGAGAATACCACACTACACTGCC



ACCTGTCACCAGAGAGAAATGCCGAAGAGATGGAGGTGCGGTGGTTCCGGTGG



CGTTTCTTCCCTGCAGTGCTGGTGTACAGAGGCCATCAAGAGAGACCAGAGGA



GCAGATGGTGGCATACCGAGGAAGAACCACCTTCATGCGCACAGACATCAGCA



AGGGAAGAGTTGCGCTCATTATCCACAATGTCACAGCCTATGACAATGGCATC



TACTGCTGTTACTTCCAGGAAGGCAGGTCCTATGACCAGGCAACCATGAAGCT



TATGGTGGCAAGCCTTGGCTCTGAGCCACTTATTAAAATGAAGACACTTGAGG



ATGGGAGCATCTTGCTAGAGTGCACATCTGAAGGGTGGTACCCAGAGCCCCGA



GCTGTGTGGAGAGACCCCTATGATGAAGTTGTACCTGCCCTGGAGGAGGAGTA



TACAGCTGACAGAGAAGGCCTCTTCACAGTCACCATGACTATAATCATCAGGG



ACTGCTCTGTGAGGAACATGACCTGCTCTGTCAATAACACTCTGCTCAGCCAG



GAGGTGGAAAGTGTGATTCTCATTCCAGAATCCTTCGTGCCCAGCCTTCCTCT



GTGGATGGTGGCTGTGGCTGTCACTCTGCCTGTAGTAATGCTGATTCTCCTCA



CATCTGGAAGCATCTGCCTTGTCAAGAAACACCGCAGGAAGAAATCTATTCTG



TCAGCTGAAAAAGAAGCCGAATATGAAGAGAAGGAAGCTGCACGGCAACTTCA



AGAGGAACTGCGATGGAGACGAACCCTCTTACATGCTGCTGACGTGGTCCTGG



ACCCAGATACAGCTCATCCTGAGCTCTTCCTGTCAGATGACCAGAGAAGTGTA



ATACGAGGCTCTTCGAGGCAGAGTGTGCCTGACAACCCTGAGAGATTTGACTG



CCGTCCATGTGTCCTGGGCAGGGAAAGCTTCTCCTCAGGGAAGCATTACTGGG



AGGTGGAGGTGGAAAATGTAATGGTGTGGGCCATTGGTGTTTGTAGAGACAGC



GTGGAAAGGAAAGGGGAGGCCCTGTTGGTTCCTCAGAATGGCTTCTGGACCCT



GGAGATGTTTGGAAGCCAGTATCGAGCCCTGTCCTCCCCAGAAAAGATCATAC



CTCTGAAAGAGCGTCTTCACCGTATAGCTGTCTTCCTGGACTGTGAGGGTGGA



GATATTTCTTTCTACAACATGAGAGACAGATCACACATTTACACATGTCCTCC



TGTGACTTTCACTGGGCCCCTGAGACCCTTCTTTAGGCTTGGTTCTGATGACA



GTCCCCTGTTCATCTGTCCAGCATTCACAGGGGCACAGGGAGTTACAATACCT



GAGGGTGGCTTATTCCTATATAAGACAAGACCAATTTCTCAGAGCCTTGTAAG



GAAGCCATAGCTCTCTACACAGTACCATCTGTTGGAGACTAGACCCCATGTCC



TTCAGATCACATGGAGCATCTTCCAGCTGCCACCTTCACACATACTTCAGGCC



CAGTCCTCAGATTACTACATCATTTCTTCTAACTATGGGCCTAGGTAGAGCCA



GTCTTAGGGGACTATTGCTGTAATACAGCTCTCTCCTGAGAAGAAAGTGTGAG



AAGGGCAGAAAACTTGGAGTTTCAACATGCTGCTCTGGTCACAGTGGATATCA



GGCAAGAGCAACAGGGTGGATCAGGATGTAAGAAGTGAGAACTACAGAGGAAG



GAGACAGATAAAGATGAATTGAGGCCGAAGATGGAGGAAATGGACTGAAGAGC



TCTGGGGTAAGCCCTATGTGACAGCTGTGGATAGGTAGGAGCTAATGGTCCAT



TGATATCCAAAGCCAAAGATTTAAATATCACATAGTGTGTCTGGAGTGTATAT



CTGTAGACCTACACATGAGAGGAAACAATCATAGTGATGAACTGGATGTAAGC



TGGCTCAGACGTCCCTACAATAAACACTTCTGAGTTCCATGTCTGTGCTCAGT



AAGAATGGCTTGAGGCTTGCGGTCCATGCTGAGCAGCCAGGTCCACATGAATC



GGATTTACTAGAGTAGGTAGCAGTTCAAGTTCCTTAGGCTCAGGATGTCTTCC



TTTCCCCCAAGCCCTTCCCCCTTCAAGATAGGTCTCACTATGTAGACCAGGCC



AGCCTCCACCTCCAGAGTTCTGGGATTAAAGACAAGCACAACCATGTCCAGTT



TATGAGCTTGTGATATATACAGAAGATTAAGTTCTGTGTTCTTGGGTTAGTAA



CTGTTGAGATTTGTTTTGAGTCATGCTCTCACTGGCTAGCACTGCTCTTGACT



TTCTCTCCCCATCTTTTTGTTATTGCTTTTCAAGACATGGTTTCACTGTGTAT



TTCTGGCTGATAAGCTGATTTTGAATTCACAGAGATCTGCCTCTGCCTCCTGA



GTGCTGGGATTAAAGGTGTGTTACACTACGCCTGGCTTCACTCTATCTCTTCA



GTGTGGGGATTATAGGTTTATACTATCATGCCTAACTAATGTCTGTTGCTGCA



TATGACATTTGAACTTTAGAACAGAAAAACAACTATACATATTAATATATATT



AAACTAATAATAAGC (SEQ ID NO: 103)






>NP_787952.2 butyrophilin subfamily 2 member A2



isoform 1 precursor [Mus musculus]



MEPTTSLRSCPIASLLFFLVLSLFVLVSAQFTVIGPAEPILAMVGENTTLHCH



LSPERNAEEMEVRWFRWRFFPAVLVYRGHQERPEEQMVAYRGRTTFMRTDISK



GRVALIIHNVTAYDNGIYCCYFQEGRSYDQATMKLMVASLGSEPLIKMKTLED



GSILLECTSEGWYPEPRAVWRDPYDEVVPALEEEYTADREGLFTVTMTIIIRD



CSVRNMTCSVNNTLLSQEVESVILIPESFVPSLPLWMVAVAVTLPVVMLILLT



SGSICLVKKHRRKKSILSAEKEAEYEEKEAARQLQEELRWRRTLLHAADVVLD



PDTAHPELFLSDDQRSVIRGSSRQSVPDNPERFDCRPCVLGRESFSSGKHYWE



VEVENVMVWAIGVCRDSVERKGEALLVPQNGFWTLEMFGSQYRALSSPEKIIP



LKERLHRIAVFLDCEGGDISFYNMRDRSHIYTCPPVTFTGPLRPFFRLGSDDS



PLFICPAFTGAQGVTIPEGGLFLYKTRPISQSLVRKP(SEQ ID NO: 104)





Human
>NM_001732.3 Homo sapiens butyrophilin subfamily 1


BTN1A1
member A1 (BTN1A1), mRNA



AGCTTTCTCACTTGGTAGCAGTGGCCTCTTGTGCCTTTTTCTCCAAGATCACC



CAGGCTGAAGCTCCTGAGGGGACTCACATCAGTTATCTTGCTGCTCCAGAAGG



GTGGGAGATGGCAGTTTTCCCAAGCTCCGGTCTCCCCAGATGTCTGCTCACCC



TCATTCTCCTCCAGCTGCCCAAACTGGATTCAGCTCCCTTTGACGTGATTGGA



CCCCCGGAGCCCATCCTGGCCGTTGTGGGTGAGGACGCCGAGCTGCCCTGTCG



CCTGTCTCCGAACGCGAGCGCCGAGCACTTGGAGCTACGCTGGTTCCGAAAGA



AGGTTTCGCCGGCCGTGCTGGTGCATAGGGACGGGCGCGAGCAGGAAGCCGAG



CAGATGCCCGAGTACCGCGGGCGGGCGACGCTGGTCCAGGACGGCATCGCCAA



GGGGCGCGTGGCCTTGAGGATCCGTGGCGTCAGAGTCTCTGACGACGGGGAGT



ACACGTGCTTTTTCAGGGAGGATGGAAGCTACGAAGAAGCCCTGGTGCATCTG



AAGGTGGCTGCTCTGGGCTCTGACCCTCACATCAGTATGCAAGTTCAAGAGAA



TGGAGAAATCTGTCTGGAGTGCACCTCAGTGGGATGGTACCCAGAGCCCCAGG



TGCAGTGGAGAACTTCCAAGGGAGAGAAGTTTCCATCTACATCAGAGTCCAGG



AATCCTGATGAAGAAGGTTTGTTCACTGTGGCTGCTTCAGTGATCATCAGAGA



CACTTCTGCGAAAAATGTGTCCTGCTACATCCAGAATCTCCTTCTTGGCCAGG



AGAAGAAAGTAGAAATATCCATACCAGCTTCCTCCCTCCCAAGGCTGACTCCC



TGGATAGTGGCTGTGGCTGTCATCCTGATGGTTCTAGGACTTCTCACCATTGG



GTCCATATTTTTCACTTGGAGACTATACAACGAAAGACCCAGAGAGAGGAGGA



ATGAATTCAGCTCTAAAGAGAGACTCCTGGAAGAACTCAAATGGAAAAAGGCT



ACCTTGCATGCAGTTGATGTGACTCTGGACCCAGACACAGCTCATCCCCACCT



CTTTCTTTATGAGGATTCAAAATCTGTTCGACTGGAAGATTCACGTCAGAAAC



TGCCTGAGAAAACAGAGAGATTTGACTCCTGGCCCTGTGTGTTGGGCCGTGAG



ACCTTCACCTCAGGAAGGCATTACTGGGAGGTGGAGGTGGGAGACAGGACTGA



CTGGGCAATCGGCGTGTGTAGGGAGAATGTGATGAAGAAAGGATTTGACCCCA



TGACTCCTGAGAATGGGTTCTGGGCTGTAGAGTTGTATGGAAATGGGTACTGG



GCCCTCACTCCTCTCCGGACCCCTCTCCCATTGGCAGGGCCCCCACGCCGGGT



TGGGATTTTCCTAGACTATGAATCAGGAGACATCTCCTTCTACAACATGAATG



ATGGATCTGATATCTATACTTTCTCCAATGTCACTTTCTCTGGCCCCCTCCGG



CCCTTCTTTTGCCTATGGTCTAGCGGTAAAAAGCCCCTGACCATCTGCCCAAT



TGCTGATGGGCCTGAGAGGGTCACAGTCATTGCTAATGCCCAGGACCTTTCTA



AGGAGATCCCATTGTCCCCCATGGGGGAGGACTCTGCCCCTAGGGATGCAGAC



ACTCTCCATTCTAAGCTAATCCCTACCCAACCCAGCCAAGGGGCACCTTAAGG



AATATCTCAGCTCATCTGTTTTCCTTTCCTCTAACCCCTCTCCTCCATAGCCT



TCTGAGGCTTCACCTGCTAGCTTTACCCAGTCTGTTTCTTCCTGTTGGGTGGC



AATTAATTAATCCTGTGAAGGTTACATTGCTGCTGCTAGAGAGGGTGGGGATT



GCACCTTCCAAATCTGTTTCTGTACCAATATTTGGGGGATGGAGGGGTGACTC



AAACTGCTTCTAGTGTTCTCCTAATCCCTTAAGACTAGAACCTATAGGAAACT



ACTTGGAGCAAACTCAAAGGACAGATTAGGGATCGAGATTGGGTCAGGTTAGC



ATGGGGTTGTGGTTGAAATATCTTGGTATCCAGGATAAGGGTATGTGGAAAAA



CAGGCTTTAGGCAAGTGGAAAATTCAAAATGTGCTGTGAAAGGACAATCTCAG



GCTGAAATCCCATAAAGGAACTTGGAGGGAATATTATGATGGAGGGAAGTGAG



GTGAATCCAGGCACATGATGAACACCTGGCTCATCCATAGAGTTTTCACAGCC



TATATCGCAAATTTTCTAAGCCACGTCCTATAGGACAGAGGAGACTGGCCCCA



CTTCTATGGGTCTGAGCTGTGGAAAAGGGAGAGCAGAGAGGAACTGAGATGAG



CAGGGATGAAGGGTCAGGCAGAAAGCGTGATAGAGGAGAGAATTTTTGACAAA



ACTCAAAAGTTGTTTGCACAGCTGTTCTTTGTACCCTGTTCCTTTCTCTGCGC



CCTCCTGTTTCTCCCTTGCCTGGAAGTCATTCCACCCTCAATTTGTTGATCCA



CAAGTTTCCAGTTGTCCTCTTCTTTTTGTTATAGCATCTCTCTATTTCAAAGA



CATTCCTAGAAGTCATCCTTCAGTGATATCACCACTTGCTCAGTCACCATCTC



AACCTTATGTCACCTCAGCCCTCATCTCAATGCCCAAACCCCTTACACACACC



TTCAGTTAGCTTCAACTGCCTCCGTTTCCACACTGTGCACCTTTCACTTTCCC



TACCCAGCTTTCCTACATGCTGCCTCTCCTCAGGGTCCCCTGAATGCTGCATC



ATTGTGTTCAGTGCAGCTGGACTGATTGCACCTGTGTATTTGCCCCTGAGCAC



TTTCCTTTACACATGTGGCTTGTCTTGCCAATAGACTCCAGGCTTATACCTTC



CATTTCCATCGTATTCTCCAGTTTCCAGGATAGACGTTGCTCATCGTCTTTAC



CTAATAAATAAGTTTGTCTGATTGCTGAAA (SEQ ID NO: 105)






>NP_001723.2 butyrophilin subfamily 1 member A1



precursor [Homo sapiens]



MAVFPSSGLPRCLLTLILLQLPKLDSAPFDVIGPPEPILAVVGEDAELPCRLS



PNASAEHLELRWFRKKVSPAVLVHRDGREQEAEQMPEYRGRATLVQDGIAKGR



VALRIRGVRVSDDGEYTCFFREDGSYEEALVHLKVAALGSDPHISMQVQENGE



ICLECTSVGWYPEPQVQWRTSKGEKFPSTSESRNPDEEGLFTVAASVIIRDTS



AKNVSCYIQNLLLGQEKKVEISIPASSLPRLTPWIVAVAVILMVLGLLTIGSI



FFTWRLYNERPRERRNEFSSKERLLEELKWKKATLHAVDVTLDPDTAHPHLFL



YEDSKSVRLEDSRQKLPEKTERFDSWPCVLGRETFTSGRHYWEVEVGDRTDWA



IGVCRENVMKKGFDPMTPENGFWAVELYGNGYWALTPLRTPLPLAGPPRRVGI



FLDYESGDISFYNMNDGSDIYTFSNVTFSGPLRPFFCLWSSGKKPLTICPIAD



GPERVTVIANAQDLSKEIPLSPMGEDSAPRDADTLHSKLIPTQPSQGAP



(SEQ ID NO: 106)





Mouse
>NM_013483.3 Mus musculus butyrophilin, subfamily 1,


BTN1A1
member A1 (Btn1a1), mRNA



AACAGCACACAGCCTTCTTCCTTCTGAAGAGCTCTCTCTTTGGCCCCGGGGTG



ACAAGCAGCCCTTTTCACTTGATCACTGTGGCTCTGGCTCCCTTTTCCTCTGG



GTCTGTCGAAATCGCCTGAAGCTCTTGGCGGGCTTCATTGCCCCAGTTAGCTC



AGAGATGGCAGTTCCCACCAACTCCTGCCTCCTGGTCTGTCTGCTCACCCTCA



CTGTCCTACAGCTGCCCACGCTGGATTCGGCAGCTCCCTTCGATGTGACCGCA



CCTCAGGAGCCAGTGTTGGCCCTAGTGGGCTCAGATGCCGAGCTGACCTGTGG



CTTTTCCCCAAACGCGAGCTCAGAATACATGGAGCTGCTGTGGTTTCGACAGA



CGAGGTCGACAGCGGTACTTCTATACCGGGATGGCCAGGAGCAGGAGGGCCAG



CAGATGACGGAGTACCGCGGGAGGGCGACGCTGGCGACAGCCGGGCTTCTAGA



CGGCCGCGCTACTCTGCTGATCCGAGATGTCAGGGTCTCAGACCAGGGGGAGT



ACCGGTGCCTTTTCAAAGACAACGACGACTTCGAGGAGGCCGCCGTATACCTC



AAAGTGGCTGCTGTGGGTTCAGATCCTCAAATCAGTATGACGGTTCAAGAGAA



TGGAGAAATGGAGCTGGAGTGCACCTCCTCTGGATGGTACCCAGAGCCTCAGG



TGCAGTGGAGAACAGGCAACAGAGAGATGCTACCATCCACGTCAGAGTCCAAG



AAGCATAATGAGGAAGGCCTGTTCACTGTGGCAGTTTCAATGATGATCAGAGA



CAGCTCCATAAAGAACATGTCCTGCTGCATCCAGAATATCCTCCTTGGCCAGG



GGAAGGAAGTAGAGATCTCCTTACCAGCTCCCTTCGTGCCAAGGCTGACTCCC



TGGATAGTAGCTGTGGCTATCATCTTACTGGCCTTAGGATTTCTCACCATTGG



GTCCATATTTTTCACTTGGAAACTATACAAGGAAAGATCCAGTCTGCGGAAGA



AGGAATTTGGCTCTAAAGAGAGACTTCTGGAAGAACTCAGATGCAAAAAGACT



GTACTGCATGAAGTTGACGTGACTCTGGATCCAGACACAGCCCACCCCCACCT



CTTCCTGTATGAAGATTCAAAGTCAGTTCGATTGGAAGATTCACGTCAGATCC



TGCCTGATAGACCAGAGAGATTTGACTCCTGGCCCTGTGTGTTGGGCCGTGAG



ACCTTTACTTCAGGGAGACATTACTGGGAGGTGGAGGTGGGAGATAGAACTGA



CTGGGCCATTGGTGTGTGTAGGGAGAATGTGGTGAAGAAAGGGTTTGACCCCA



TGACTCCTGATAATGGGTTCTGGGCTGTGGAGTTGTATGGAAATGGGTACTGG



GCCCTCACCCCACTCAGGACCTCTCTCCGATTAGCAGGGCCCCCTCGCAGAGT



TGGGGTTTTTCTGGACTATGACGCAGGAGACATTTCCTTCTACAACATGAGTA



ACGGATCTCTTATCTATACTTTCCCTAGCATCTCTTTCTCTGGCCCCCTCCGT



CCCTTCTTTTGTCTGTGGTCCTGTGGTAAAAAGCCCCTGACCATCTGTTCAAC



TGCCAATGGGCCTGAGAAAGTCACAGTCATTGCTAATGTCCAGGACGACATTC



CCTTGTCCCCGCTGGGGGAAGGCTGTACTTCTGGAGACAAAGACACTCTCCAT



TCTAAACTGATCCCGTTCTCACCTAGCCAAGCGGCACCATAACAAATATTCCA



GCTTCACGACTTTGCCTTCCTTTGACTAATCCCTCATGCCCCGAAGCTTCAGC



TGTTGGCTTCTTGCAGCCCTGCTTCTTCCTGGTGGATGGAGATTAATTCACAT



TGGGAAGGTTAGGTATGTTGCTGCCAGACAAGGCAGGAAGAAAGGCCATCCTA



GTTTGTTTCTGTACTAACAGTGGGGAGGAAGAGAGCTGAATCCTAAACTATTT



CCAGTGCTCATATTCCTTCAGGCCAGAGCCTATAGAGAAGGATTTGGTACAAT



CACTCGAGGGATCAAGAGGCAATTAGGTTGGCATGGAATTATGGCAGAAACAT



CTGGAATAGGGGTATGTGGAATGACAGGTTTTAGGTAAGGGAGAACAAAACCA



AACCATAGGATGCTGAGAAAGAAAGATCTTGGACTAAACTCCTAAAAAAGCAC



TTAGAGAAGATATGACAGGCAAATGAAGTGAATTTGGTCTAATTTGATACACT



TGCCCTGTCCCTAGGGTTTTTCAGTTATATCTCAATTTTTTTGTTGTTAATTA



CATTTTTGACAGCTTCATACATGTATATAATGCATTCTAATTACTCTCACTCT



CCTCTATTCTGTCTTATTTCCCTCCCCTCCCCTCATACCTTCCTTCTTGCTTC



AAACCTGGCACACTGAGTTTAATGGGCTATCATGGGAACATGGATTTAGAGCT



TTCCTCTGAGCTCAAGAGAGCAGGTGTGACTGAATACAGTGATTTCCCCTCTC



CTACAATCAATCAGCAGTCAATAGCTCAGCTGGGAGGGGTAGGGCCTCATGAG



ACTTCCCCTATCAAGGCTAAATGTTGAAAGGGCCAGTTTTTAGCACCTGTGAG



ATCATGATTGCAAGAGCCCAGAAGACAGCATTGCTCGGTCATTCTCCCTACCC



TTTGGCTTTTCTGGTOTTTTGTCCTCTCTTTCAGGATGTGTCTGAACTCTGTA



TCTTAAGTTTTCTATGTCATGTTCTATAAGATAGAGGAGACTGGCCCTGCTTG



TTTGAGAGCAATGTGAGCAAGCTAGCAAGAGACAGAAAGGAGCGGAGATGAAT



AGGGGTAGAGAAAATTTTTAAACAAACCCTCCAGGTGTGTGTGTGTGTGTGTG



TGTCTTCCTCTTTTTTGACCTCCCTAAAGGTCAATCCAACCTCACATTATTGA



CTCCACTAGGTGGGGGTTCTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG



TGTGTTTTAAGATAGAGGTTTACTATGTAGCTTAGGCTGGCTTTGAATTCCTG



ATCCTCCTGCCTCTACCTTCCAAGTGCTGGAAACATAGCCACATCCACCACCC



CTATCCAGTCCACCTGGTTTGATTCAGCAACGCTCAGGTAGCATCGCTGTTTG



ATCTGGAGCTGCCAGCTCCCTCGGCCCCCACTGCAATGCTTAACCCCCTCACA



GGCACCTTCCCTTGCCTAACACTGCCATCCTTTTCCACACTGAGCCATTTGCT



CAATGTAGCCTACCCAGGTATCCTGCTTTCTGGTCCCCAAAGTTACACCATGA



TGCTCAGCACAGCTGGACAGTTTGTCCCAATTTGTGTGTGTCCTCCTGTTTGT



ATGGGACTTCTTTTTGTCAATGGCCTGTGTGTGTATCCAAGCTCTTCCACTTC



TATTGTATTTTTCCGGCTTCTAAAACAGATGTTACCAAATAAAGAAAGAGAAA



GAAAAAAAA (SEQ ID NO: 107)






>NP_038511.1 butyrophilin subfamily 1 member A1



precursor [Mus musculus]



MAVPTNSCLLVCLLTLTVLQLPTLDSAAPFDVTAPQEPVLALVGSDAELTCGF



SPNASSEYMELLWFRQTRSTAVLLYRDGQEQEGQQMTEYRGRATLATAGLLDG



RATLLIRDVRVSDQGEYRCLFKDNDDFEEAAVYLKVAAVGSDPQISMTVQENG



EMELECTSSGWYPEPQVQWRTGNREMLPSTSESKKHNEEGLFTVAVSMMIRDS



SIKNMSCCIQNILLGQGKEVEISLPAPFVPRLTPWIVAVAIILLALGFLTIGS



IFFTWKLYKERSSLRKKEFGSKERLLEELRCKKTVLHEVDVTLDPDTAHPHLF



LYEDSKSVRLEDSRQILPDRPERFDSWPCVLGRETFTSGRHYWEVEVGDRTDW



AIGVCRENVVKKGFDPMTPDNGFWAVELYGNGYWALTPLRTSLRLAGPPRRVG



VFLDYDAGDISFYNMSNGSLIYTFPSISFSGPLRPFFCLWSCGKKPLTICSTA



NGPEKVTVIANVQDDIPLSPLGEGCTSGDKDTLHSKLIPFSPSQAAP (SEQ



ID NO: 108)





Human TIGIT
>NM_173799.4 Homo sapiens T cell immunoreceptor with



Ig and ITIM domains (TIGIT), mRNA



ACATCTGCTTCCTGTAGGCCCTCTGGGCAGAAGCATGCGCTGGTGTCTCCTCC



TGATCTGGGCCCAGGGGCTGAGGCAGGCTCCCCTCGCCTCAGGAATGATGACA



GGCACAATAGAAACAACGGGGAACATTTCTGCAGAGAAAGGTGGCTCTATCAT



CTTACAATGTCACCTCTCCTCCACCACGGCACAAGTGACCCAGGTCAACTGGG



AGCAGCAGGACCAGCTTCTGGCCATTTGTAATGCTGACTTGGGGTGGCACATC



TCCCCATCCTTCAAGGATCGAGTGGCCCCAGGTCCCGGCCTGGGCCTCACCCT



CCAGTCGCTGACCGTGAACGATACAGGGGAGTACTTCTGCATCTATCACACCT



ACCCTGATGGGACGTACACTGGGAGAATCTTCCTGGAGGTCCTAGAAAGCTCA



GTGGCTGAGCACGGTGCCAGGTTCCAGATTCCATTGCTTGGAGCCATGGCCGC



GACGCTGGTGGTCATCTGCACAGCAGTCATCGTGGTGGTCGCGTTGACTAGAA



AGAAGAAAGCCCTCAGAATCCATTCTGTGGAAGGTGACCTCAGGAGAAAATCA



GCTGGACAGGAGGAATGGAGCCCCAGTGCTCCCTCACCCCCAGGAAGCTGTGT



CCAGGCAGAAGCTGCACCTGCTGGGCTCTGTGGAGAGCAGCGGGGAGAGGACT



GTGCCGAGCTGCATGACTACTTCAATGTCCTGAGTTACAGAAGCCTGGGTAAC



TGCAGCTTCTTCACAGAGACTGGTTAGCAACCAGAGGCATCTTCTGGAAGATA



CACTTTTGTCTTTGCTATTATAGATGAATATATAAGCAGCTGTACTCTCCATC



AGTGCTGCGTGTGTGTGTGTGTGTGTATGTGTGTGTGTGTTCAGTTGAGTGAA



TAAATGTCATCCTCTTCTCCATCTTCATTTCCTTGGCCTTTTCGTTCTATTCC



ATTTTGCATTATGGCAGGCCTAGGGTGAGTAACGTGGATCTTGATCATAAATG



CAAAATTAAAAAATATCTTGACCTGGTTTTAAATCTGGCAGTTTGAGCAGATC



CTATGTCTCTGAGAGACACATTCCTCATAATGGCCAGCATTTTGGGCTACAAG



GTTTTGTGGTTGATGATGAGGATGGCATGACTGCAGAGCCATCCTCATCTCAT



TTTTTCACGTCATTTTCAGTAACTTTCACTCATTCAAAGGCAGGTTATAAGTA



AGTCCTGGTAGCAGCCTCTATGGGGAGATTTGAGAGTGACTAAATCTTGGTAT



CTGCCCTCAAGAACTTACAGTTAAATGGGGAGACAATGTTGTCATGAAAAGGT



ATTATAGTAAGGAGAGAAGGAGACATACACAGGCCTTCAGGAAGAGACGACAG



TTTGGGGTGAGGTAGTTGGCATAGGCTTATCTGTGATGAAGTGGCCTGGGAGC



ACCAAGGGGATGTTGAGGCTAGTCTGGGAGGAGCAGGAGTTTTGTCTAGGGAA



CTTGTAGGAAATTCTTGGAGCTGAAAGTCCCACAAAGAAGGCCCTGGCACCAA



GGGAGTCAGCAAACTTCAGATTTTATTCTCTGGGCAGGCATTTCAAGTTTCCT



TTTGCTGTGACATACTCATCCATTAGACAGCCTGATACAGGCCTGTAGCCTCT



TCCGGCCGTGTGTGCTGGGGAAGCCCCAGGAAACGCACATGCCCACACAGGGA



GCCAAGTCGTAGCATTTGGGCCTTGATCTACCTTTTCTGCATCAATACACTCT



TGAGCCTTTGAAAAAAGAACGTTTCCCACTAAAAAGAAAATGTGGATTTTTAA



AATAGGGACTCTTCCTAGGGGAAAAAGGGGGGCTGGGAGTGATAGAGGGTTTA



AAAAATAAACACCTTCAAACTAACTTCTTCGAACCCTTTTATTCACTCCCTGA



CGACTTTGTGCTGGGGTTGGGGTAACTGAACCGCTTATTTCTGTTTAATTGCA



TTCAGGCTGGATCTTAGAAGACTTTTATCCTTCCACCATCTCTCTCAGAGGAA



TGAGCGGGGAGGTTGGATTTACTGGTGACTGATTTTCTTTCATGGGCCAAGGA



ACTGAAAGAGAATGTGAAGCAAGGTTGTGTCTTGCGCATGGTTAAAAATAAAG



CATTGTCCTGCTTCCTAAGACTTAGACTGGGGTTGACAATTGTTTTAGCAACA



AGACAATTCAACTATTTCTCCTAGGATTTTTATTATTATTATTTTTTCACTTT



TCTACCAAATGGGTTACATAGGAAGAATGAACTGAAATCTGTCCAGAGCTCCA



AGTCCTTTGGAAGAAAGATTAGATGAACGTAAAAATGTTGTTGTTTGCTGTGG



CAGTTTACAGCATTTTTCTTGCAAAATTAGTGCAAATCTGTTGGAAATAGAAC



ACAATTCACAAATTGGAAGTGAACTAAAATGTAATGACGAAAAGGGAGTAGTG



TTTTGATTTGGAGGAGGTGTATATTCGGCAGAGGTTGGACTGAGAGTTGGGTG



TTATTTAACATAATTATGGTAATTGGGAAACATTTATAAACACTATTGGGATG



GTGATAAAATACAAAAGGGCCTATAGATGTTAGAAATGGGTCAGGTTACTGAA



ATGGGATTCAATTTGAAAAAAATTTTTTTAAATAGAACTCACTGAACTAGATT



CTCCTCTGAGAACCAGAGAAGACCATTTCATAGTTGGATTCCTGGAGACATGC



GCTATCCACCACGTAGCCACTTTCCACATGTGGCCATCAACCACTTAAGATGG



GGTTAGTTTAAATCAAGATGTGCTGTTATAATTGGTATAAGCATAAAATCACA



CTAGATTCTGGAGATTTAATATGAATAATAAGAATACTATTTCAGTAGTTTTG



GTATATTGTGTGTCAAAAATGATAATATTTTGGATGTATTGGGTGAAATAAAA



TATTAACATTA (SEQ ID NO: 109)






>NP_776160.2 T-cell immunoreceptor with Ig and ITIM



domains precursor [Homo sapiens]



MRWCLLLIWAQGLRQAPLASGMMTGTIETTGNISAEKGGSIILQCHLSSTTAQ



VTQVNWEQQDQLLAICNADLGWHISPSFKDRVAPGPGLGLTLQSLTVNDTGEY



FCIYHTYPDGTYTGRIFLEVLESSVAEHGARFQIPLLGAMAATLVVICTAVIV



VVALTRKKKALRIHSVEGDLRRKSAGQEEWSPSAPSPPGSCVQAEAAPAGLCG



EQRGEDCAELHDYFNVLSYRSLGNCSFFTETG (SEQ ID NO: 110)





Mouse TIGIT
>NM_001146325.1:98-823 Mus musculus T cell



immunoreceptor with Ig and ITIM domains (Tigit), mRNA



ATGCATGGCTGGCTGCTCCTGGTCTGGGTCCAGGGGCTGATACAGGCTGCCTT



CCTCGCTACAGGAGCCACAGCAGGCACGATAGATACAAAGAGGAACATCTCTG



CAGAGGAAGGTGGCTCTGTCATCTTACAGTGTCACTTCTCCTCTGACACAGCT



GAAGTGACCCAAGTCGACTGGAAGCAGCAGGACCAGCTTCTGGCCATTTATAG



TGTTGACCTGGGGTGGCATGTCGCTTCAGTCTTCAGTGATCGGGTGGTCCCAG



GCCCCAGCCTAGGCCTCACCTTCCAGTCTCTGACAATGAATGACACGGGAGAG



TACTTCTGTACCTATCATACGTATCCTGGTGGGATTTACAAGGGGAGAATATT



CCTGAAGGTCCAAGAAAGCTCAGTGGCTCAGTTCCAGACTGCCCCGCTTGGAG



GAACCATGGCTGCTGTGCTGGGACTCATTTGCTTAATGGTCACAGGAGTGACT



GTACTGGCTAGAAAGAAGTCTATTAGAATGCATTCTATAGAAAGTGGCCTTGG



GAGAACAGAAGCGGAGCCACAGGAATGGAACCTGAGGAGTCTCTCATCCCCTG



GAAGCCCTGTCCAGACACAAACTGCCCCTGCTGGTCCCTGTGGAGAGCAGGCA



GAAGATGACTATGCTGACCCACAGGAATACTTTAATGTCCTGAGCTACAGAAG



CCTAGAGAGCTTCATTGCTGTATCGAAGACTGGCTAA (SEQ ID NO: 111)






>NP_001139797.1 T-cell immunoreceptor with Ig and



ITIM domains precursor [Mus musculus]



MHGWLLLVWVQGLIQAAFLATGATAGTIDTKRNISAEEGGSVILQCHFSSDTA



EVTQVDWKQQDQLLAIYSVDLGWHVASVFSDRVVPGPSLGLTFQSLTMNDTGE



YFCTYHTYPGGIYKGRIFLKVQESSVAQFQTAPLGGTMAAVLGLICLMVTGVT



VLARKKSIRMHSIESGLGRTEAEPQEWNLRSLSSPGSPVQTQTAPAGPCGEQA



EDDYADPQEYFNVLSYRSLESFIAVSKTG (SEQ ID NO: 112)





Human
>NM_001252.5 Homo sapiens CD70 molecule (CD70),


CD27L (CD70)
transcript variant 1, mRNA



AGAGAGGGGCAGGCTGGTCCCCTGACAGGTTGAAGCAAGTAGACGCCCAGGAG



CCCCGGGAGGGGGCTGCAGTTTCCTTCCTTCCTTCTCGGCAGCGCTCCGCGCC



CCCATCGCCCCTCCTGCGCTAGCGGAGGTGATCGCCGCGGCGATGCCGGAGGA



GGGTTCGGGCTGCTCGGTGCGGCGCAGGCCCTATGGGTGCGTCCTGCGGGCTG



CTTTGGTCCCATTGGTCGCGGGCTTGGTGATCTGCCTCGTGGTGTGCATCCAG



CGCTTCGCACAGGCTCAGCAGCAGCTGCCGCTCGAGTCACTTGGGTGGGACGT



AGCTGAGCTGCAGCTGAATCACACAGGACCTCAGCAGGACCCCAGGCTATACT



GGCAGGGGGGCCCAGCACTGGGCCGCTCCTTCCTGCATGGACCAGAGCTGGAC



AAGGGGCAGCTACGTATCCATCGTGATGGCATCTACATGGTACACATCCAGGT



GACGCTGGCCATCTGCTCCTCCACGACGGCCTCCAGGCACCACCCCACCACCC



TGGCCGTGGGAATCTGCTCTCCCGCCTCCCGTAGCATCAGCCTGCTGCGTCTC



AGCTTCCACCAAGGTTGTACCATTGCCTCCCAGCGCCTGACGCCCCTGGCCCG



AGGGGACACACTCTGCACCAACCTCACTGGGACACTTTTGCCTTCCCGAAACA



CTGATGAGACCTTCTTTGGAGTGCAGTGGGTGCGCCCCTGACCACTGCTGCTG



ATTAGGGTTTTTTAAATTTTATTTTATTTTATTTAAGTTCAAGAGAAAAAGTG



TACACACAGGGGCCACCCGGGGTTGGGGTGGGAGTGTGGTGGGGGGTAGTGGT



GGCAGGACAAGAGAAGGCATTGAGCTTTTTCTTTCATTTTCCTATTAAAAAAT



ACAAAAATCA (SEQ ID NO: 113)






>NP_001243.1 CD70 antigen isoform 1 [Homo sapiens]



MPEEGSGCSVRRRPYGCVLRAALVPLVAGLVICLVVCIQRFAQAQQQLPLESL



GWDVAELQLNHTGPQQDPRLYWQGGPALGRSFLHGPELDKGQLRIHRDGIYMV



HIQVTLAICSSTTASRHHPTTLAVGICSPASRSISLLRLSFHQGCTIASQRLT



PLARGDTLCTNLTGTLLPSRNTDETFFGVQWVRP (SEQ ID NO: 114)





Mouse CD27L
>NM_011617.2 Mus musculus CD70 antigen (Cd70), mRNA


(CD70)
GAAGGTGCCAAAAGCTCCAGGGGATTTCCCTGCCCTCCGAGAAGAGGCCCAGT



TCTTCCCCTGCATCGGACATCCCCGAGGTTCTAAGGGCAGGTCAAGGCAGGCA



GAAGCTTCAAAAGCTCGGCTGAGGAGGCTACAGCTTCCCGCTGCCTTCAGGCC



GCTGCTTCCGTGCAGGGATGCCGGAGGAAGGTCGCCCTTGCCCCTGGGTTCGC



TGGAGCGGGACCGCGTTCCAGCGCCAATGGCCATGGCTGCTGCTGGTGGTGTT



TATTACTGTGTTTTGCTGTTGGTTTCATTGTAGCGGACTACTCAGTAAGCAGC



AACAGAGGCTGCTGGAGCACCCTGAGCCGCACACAGCTGAGTTACAGCTGAAT



CTCACAGTTCCTCGGAAGGACCCCACACTGCGCTGGGGAGCAGGCCCAGCCTT



GGGAAGGTCCTTCACACACGGACCAGAGCTGGAGGAGGGCCATCTGCGTATCC



ATCAAGATGGCCTCTACAGGCTGCATATCCAGGTGACACTGGCCAACTGCTCT



TCCCCAGGCAGCACCCTGCAGCACAGGGCCACCCTGGCTGTGGGCATCTGCTC



CCCCGCTGCGCACGGCATCAGCTTGCTGCGTGGGCGCTTTGGACAGGACTGTA



CAGTGGCATTACAGCGCCTGACATACCTGGTCCACGGAGATGTCCTCTGTACC



AACCTCACCCTGCCTCTGCTGCCGTCCCGCAACGCTGATGAGACCTTCTTTGG



AGTTCAGTGGATATGCCCTTGACCACAACTCCAGGATGACTTGTGAATATTTT



TTTTCTTTTCAAGTTCTACGTATTTATAAATGTATATAGTACACATA (SEQ



ID NO: 115)






>NP_035747.1 0D70 antigen [Mus musculus]



MPEEGRPCPWVRWSGTAFQRQWPWLLLVVFITVFCCWFHCSGLLSKQQQRLLE



HPEPHTAELQLNLTVPRKDPTLRWGAGPALGRSFTHGPELEEGHLRIHQDGLY



RLHIQVTLANCSSPGSTLQHRATLAVGICSPAAHGISLLRGRFGQDCTVALQR



LTYLVHGDVLCTNLTLPLLPSRNADETFFGVQWICP (SEQ ID NO: 116)





Human
>NM_001244.4 Homo sapiens TNF superfamily member 8


CD30L
(TNFSF8), transcript variant 1, mRNA


(CD153)
GTCATTTTCCTACGCGCCCTCTGACATCAGCCACCTTCTCTGTAGCTAGTTTC



TCTGCACACAACTTAATCCCTGGCAATGAAAAATGAACCTCTCCCCCACCCTT



GCTGCCGCCTCTCGCCTCACGCCCCCAGAGAAGAGTTTCTCCACCAGGCAGCA



GGTGAAGGTTTTTTTCCAAGTCACATGATTCAGGATTCAGGGGGAGAATCCTT



CTTGGAACAGAGATGGGCCCAGAACTGATCAGATGAAGAGAGATAAGGTGTG



ATGTGGGGAAGACTATATAAAGAATGGACCCAGGGCTGCAGCAAGCACTCAAC



GGAATGGCCCCTCCTGGAGACACAGCCATGCATGTGCCGGCGGGCTCCGTGGC



CAGCCACCTGGGGACCACGAGCCGCAGCTATTTCTATTTGACCACAGCCACTC



TGGCTCTGTGCCTTGTCTTCACGGTGGCCACTATTATGGTGTTGGTCGTTCAG



AGGACGGACTCCATTCCCAACTCACCTGACAACGTCCCCCTCAAAGGAGGAAA



TTGCTCAGAAGACCTCTTATGTATCCTGAAAAGGGCTCCATTCAAGAAGTCAT



GGGCCTACCTCCAAGTGGCAAAGCATCTAAACAAAACCAAGTTGTCTTGGAAC



AAAGATGGCATTCTCCATGGAGTCAGATATCAGGATGGGAATCTGGTGATCCA



ATTCCCTGGTTTGTACTTCATCATTTGCCAACTGCAGTTTCTTGTACAATGCC



CAAATAATTCTGTCGATCTGAAGTTGGAGCTTCTCATCAACAAGCATATCAAA



AAACAGGCCCTGGTGACAGTGTGTGAGTCTGGAATGCAAACGAAACACGTATA



CCAGAATCTCTCTCAATTCTTGCTGGATTACCTGCAGGTCAACACCACCATAT



CAGTCAATGTGGATACATTCCAGTACATAGATACAAGCACCTTTCCTCTTGAG



AATGTGTTGTCCATCTTCTTATACAGTAATTCAGACTGAACAGTTTCTCTTGG



CCTTCAGGAAGAAAGCGCCTCTCTACCATACAGTATTTCATCCCTCCAAACAC



TTGGGCAAAAAGAAAACTTTAGACCAAGACAAACTACACAGGGTATTAAATAG



TATACTTCTCCTTCTGTCTCTTGGAAAGATACAGCTCCAGGGTTAAAAAGAGA



GTTTTTAGTGAAGTATCTTTCAGATAGCAGGCAGGGAAGCAATGTAGTGTGGT



GGGCAGAGCCCCACACAGAATCAGAAGGGATGAATGGATGTCCCAGCCCAACC



TCTAATTCACTGTATGGTCTTGATCTATTTCTTCTGTTTTGAGAGCCTCCAGT



TAAAATGGGGCTCCAGTACCAGAGCAGCTAGCAACTCTGCCCTAATGGGAAAT



GAAGGGGAGCTGGGTGTGAGTGTTTACACTGTGCCCTTCACGGGATACTTCTT



TTATCTGCAGATGGCCTAATACTTAGTTGTCCAAGTCGCGATCAAGGACTCTC



TCACACAGGAAACTTCCCTATACTGGCAGATACACTTGTGACTGAACCATGCC



CAGTTTATGCCTGTCTGACTGTCACTCTGGCACTAGGAGGCTGATCTTGTACT



CCATATGACCCCACCCCTAGGAACCCCCAGGGAAAACCAGGCTGGGACAGCCC



CCTGTTCCTGAGATGGAAAGCACAAATTTAATACACCACCACAATGGAAAACA



AGTTCAAAGACTTTTACTTACAGATCCTGGACAGAAAGGGCATAATGAGTCTG



AAGGGCAGTCCTCCTTCTCTAGGTTACATGAGGCAGGAATAAGAAGTCAGACA



GAGACAGCAAGACAGTTAACAATGTAGGTAAAGAAATAGGGTGTGGTCACTCT



CAATTCACTGGCAAATGCCTGAATGGTCTGTCTGAAGGAAGCAACAGAGAAGT



GGGGAATCCAGTCTGCTAGGCAGGAAAGATGCCTCTAAGTTCTTGTCTCTGGC



CAGAGGTGTGGTATAGAACCAGAAACCCATATCAAGGGTGACTAAGCCCGGCT



TCTGGTATGAGAAATTAAACTTGTATACAAAATGGTTGCCAAGGCAACATAAA



ATTATAAGAATTCACTATACCTTCCCCTCCCTGGAACTCAGGATCCAAGTCTA



GAAAATGAAAGGACTGGGTTTGAATTGCTTCAAAACCTCTTCCATCTCAGAAG



ACCAGACCCTGGGAACTGAGATTCCAGACACAATTTTGGAAGCTCTCCAACCA



AAATAAGGCCCCCCTACCCCAGTATATAATTGAAGACACTAGTAACACCTGAC



TGCATCTCATCTCAGCAGAGCCAGAATATGGGGACAAGGTTCAGGGTGCCCTG



CTGAATGGTGTGAACAGCAGGATCTCAAGGATGTAATGGAAAGAACTACCACA



CTGACCATCCAGAATCTAAGAGACCATCTGGGTGTTTGGGAAACCATCTGACG



AGGCCTGACTCTATTCCAGTTAGATTGACAATAATTGAGCAGCAGGCATTTTT



CATTTCTGGTCAGGAAAGCATTGTGCCTTTAGCAAACAATCAGTGTGCAACAG



TGATGTGGTCATCTAGCCAGGGAATGGCTGCTCCATCCCCTGCATAATATATT



CCTGCTTCAAACACCTCTCAGAAAACCAGTTCCGCGAGGGTTTTTATATCCCC



ACAAAGTTGTTGAGAGACAATGATGACCCTGGAAGTGGGGAGGAGGACTTCTG



AGAAACAGCAACCTCTCTCCTGATTGGGGTAGCCATGAGATTTCTCTAGCTAT



ATCCAACTTGGCATCTGTACATCATCTTTGGAGGAACATCTTATTTGTGGAAG



GACCTTGACAAGCCGTTTGAGATGGAATGTAGGCCCTGATGTTATGCTTCAGT



AAAAAAAGATGGAAGCTTCCCTGCTATACCAAAACATGGAGCAAAATTTGCAT



TTTTCTCAAGAAGGAGAGAAAAGGAGTAGGACTCCAGCAAAGTTTGTCAGAAG



GAAAGCTAGAAAAGATTTAAAAGAAAAAAAGAAAGAACAAATCAGCAGTGGTG



GTATGGATGAAAGGGACTTGAGAGAACAAAAATGGCTAAGGGAAAATTTTAAG



TCATCTGCTGAGCAGTGTGCTGTGTCAACCTCCTCCTAGGTCTCCTCTATGAA



ATATTTAGTAAAGTCTACATTTCTCTTTAACTCTTTCTGTGAGTAGATTCTTT



GGGAGAAGCAGGCATTGGAAGAGGTGTTGAATTCAGCAAGCCAAATGGTCTGT



GGTAAAAAACAAAACAGACTTTGAGACTCAAGGCTAAAAAAACAGGGAAATGG



CTGGCATTTGAGTCACACACTAACTGCATAGGACAAATGAATCTTGCTTAAAC



CAACTCATGCATTCTTGAAAAGGTATATGCAACCCAACTGTGTGTTAACTAAG



CAATTTTTTTGCCATCTCACATTCTAACTCGAGAAAGATTCCATTTTCATTTT



TCACCAACTGTTCTCTGAGCAGAGGTACCTGACTTTTGCACTGTGAGTGGTTT



CTAATCTCAGTCTCTGTCAAGCAATGCTAAGAAAGCCAACACCTAAAGACACA



AGGGGTACATCATTTAAATGAATAATGTAACCAAACAAACAAAAAAAGAGAAT



AATCATTAATAACTCAACTGATAGATATGTAGGGAGTAGGCAACCCAGGAAGT



TTAAAACTAAATTCTGTTACTCTTGAGGGTTAACCAGCCCCTGGGAATGTTAT



GAGCAAATGATACTCCATGAGTAAAATGATATCTATGCAAGTAAAATAAATAA



TTTATCTAACTGGGAA (SEQ ID NO: 117)






>NP_001235.1 tumor necrosis factor ligand superfamily



member 8 isoform 1 [Homo sapiens]



MDPGLQQALNGMAPPGDTAMHVPAGSVASHLGTTSRSYFYLTTATLALCLVFT



VATIMVLVVQRTDSIPNSPDNVPLKGGNCSEDLLCILKRAPFKKSWAYLQVAK



HLNKTKLSWNKDGILHGVRYQDGNLVIQFPGLYFIICQLQFLVQCPNNSVDLK



LELLINKHIKKQALVTVCESGMQTKHVYQNLSQFLLDYLQVNTTISVNVDTFQ



YIDTSTFPLENVLSIFLYSNSD (SEQ ID NO: 118)





Mouse CD30L
>NM_009403.3 Mus musculus tumor necrosis factor


(CD153)
(ligand) superfamily, member 8 (Tnfsf8), mRNA



AGATTAATCCCAGGCGATGAAAAATGAACCTCTCCCCCACCCTTGCAGCCACC



CTTCGCCTCACGCCCCCAGAGAAGAGTTTCTCCATCCGGCAACTGGTGAAGGC



TTTTTTCCAAGTCACATGATCCAGGATGCAGGGGAAAATCCTTCTTGGAACAG



AGCTGGGTACAGAACCGAATCAGATGAGGAGAGATAAGGTGTGATGTGGGACA



GACTATATAAAGCATGGAGCCAGGGCTGCAACAAGCAGGCAGCTGTGGGGCTC



CTTCCCCTGACCCAGCCATGCAGGTGCAGCCCGGCTCGGTAGCCAGCCCCTGG



AGAAGCACGAGGCCCTGGAGAAGCACAAGTCGCAGCTACTTCTACCTCAGCAC



CACCGCACTGGTGTGCCTTGTTGTGGCAGTGGCGATCATTCTGGTACTGGTAG



TCCAGAAAAAGGACTCCACTCCAAATACAACTGAGAAGGCCCCCCTTAAAGGA



GGAAATTGCTCAGAGGATCTCTTCTGTACCCTGAAAAGTACTCCATCCAAGAA



GTCATGGGCCTACCTCCAAGTGTCAAAGCATCTCAACAATACCAAACTGTCAT



GGAACGAAGATGGCACCATCCACGGACTCATATACCAGGACGGGAACCTGATA



GTCCAATTCCCTGGCTTGTACTTCATCGTTTGCCAACTGCAGTTCCTCGTGCA



GTGCTCAAATCATTCTGTGGACCTGACATTGCAGCTCCTCATCAATTCCAAGA



TCAAAAAGCAGACGTTGGTAACAGTGTGTGAGTCTGGAGTTCAGAGTAAGAAC



ATCTACCAGAATCTCTCTCAGTTTTTGCTGCATTACTTACAGGTCAACTCTAC



CATATCAGTCAGGGTGGATAATTTCCAGTATGTGGATACAAACACTTTCCCTC



TTGATAATGTGCTATCCGTCTTCTTATATAGTAGCTCAGACTGAATAGTTGTT



CTTAACCTTTATGAAAATGCTGTCTACCATACAGTACTTCATCTGTCCAAACA



TGGGCCAAAGAAAATATTAGGACAACTCAAACTAAGCATGTGAGTTAGTGCAC



TTCTCTTTCTGTCCTTTGGAAAAATACAAACCCAGGATTTAGAAAGTGGAGTC



TCCTTCAGATGCACAAACAGGAAAGAATGTGATATGTGCACAGAGACCTACTT



GGGCACTAGAAGGGGTTGAGTTGTCCCAGTATAACCACTAATTCACTGACCTT



GAGCCATTTTTCCTTCCCCTGGAACTTGGGGTCTGAATCTGGAAAAGTAGGAG



ATGAGATTTACATTTCCCCAATATTTTCTTCAACTCAGAAGACGAGACTGTGG



AGCTGAGCTCCCTACACAGATGAAGGCCTCCCATGGCATGAGGAAAATGATGG



TACCAGTAATGTCTGTCTGACTGTCATCTCAGCAAGTCCTAAGGACTTCCATG



CTGCCTTGTTGAAAGATACTCTAACCTCTTGTAATGGGCAAAGTGATCCTGTC



TCTCACTGAGGGGAGTAGCTGCTGCCATCTCCTGAGACATACATGGAGACATT



TTCTGCCCAAATTCCATTCTGTGTGCAGTTTTTAAGTATTCCCCCAAAAGTTC



TTGACAATGAGAACTTTGAATGTGGGAAGAGCTTCTGGACAGCAAACATTAAC



AGCTTCTCCTGACCAGAGAGACCATGCAAGCTTGGTCTTAGACCCATCAAGCT



TGAGGTTTCTACATTGTGGGAGACAGACTTTTGACAAACCATTTGAGTTGATG



TCTGGGCCCCTGGGAGTTCTCCTTCAGTAAGGAGAGCAAGCCGTTCTAGTGCT



GTGTCAGAGGATGGAGTAAAATAGACACTTTTCTGAAGGAAAGGAGAACAAAG



TTCCAGAAAAAGGCTAGAAAATGTTTAAAAGGAAAAGAAAAAACTCAGCTTTT



CTCATATGAGAGGAACCCAGAAAAACAACACTGAAAAAGAAGAGTGGCTCTGT



CAACCTCCTCTTAGGTCTCCTCCTCTCTAGTTATTGGGAAAGGAGTTGCATGG



TACAGGACAAGTTCTGGTGTGTGGTCAAATAGAATCAGATGTGGAGAACACCA



TGCAGAGAATAAGGAGACCTGTCATATTTGTGTTGTACTCAAATGAGGGGCAA



ATGAATCTTAGGCTAAATCAAATAACAGTCTCTGTCAAGCTGTGCTCAGAAAG



TCAACCACTGAAGATGGAGGGTGAGGCACGTCATTTAAAAAAAGTGAAATGTA



GC (SEQ ID NO: 119)






>NP_033429.1 tumor necrosis factor ligand superfamily



member 8 [Mus musculus]



MEPGLQQAGSCGAPSPDPAMQVQPGSVASPWRSTRPWRSTSRSYFYLSTTALV



CLVVAVAIILVLVVQKKDSTPNTTEKAPLKGGNCSEDLFCTLKSTPSKKSWAY



LQVSKHLNNTKLSWNEDGTIHGLIYQDGNLIVQFPGLYFIVCQLQFLVQCSNH



SVDLTLQLLINSKIKKQTLVTVCESGVQSKNIYQNLSQFLLHYLQVNSTISVR



VDNFQYVDTNTFPLDNVLSVFLYSSSD (SEQ ID NO: 120)





Human
>NM_005092.4 Homo sapiens TNF superfamily member 18


GITRL
(TNFSF18), mRNA



ATCACTTGTGAATTTTTGTTTTCCACAGCTCTCATTTCTCCAAAAATGTGTTT



GAGCCACTTGGAAAATATGCCTTTAAGCCATTCAAGAACTCAAGGAGCTCAGA



GATCATCCTGGAAGCTGTGGCTCTTTTGCTCAATAGTTATGTTGCTATTTCTT



TGCTCCTTCAGTTGGCTAATCTTTATTTTTCTCCAATTAGAGACTGCTAAGGA



GCCCTGTATGGCTAAGTTTGGACCATTACCCTCAAAATGGCAAATGGCATCTT



CTGAACCTCCTTGCGTGAATAAGGTGTCTGACTGGAAGCTGGAGATACTTCAG



AATGGCTTATATTTAATTTATGGCCAAGTGGCTCCCAATGCAAACTACAATGA



TGTAGCTCCTTTTGAGGTGCGGCTGTATAAAAACAAAGACATGATACAAACTC



TAACAAACAAATCTAAAATCCAAAATGTAGGAGGGACTTATGAATTGCATGTT



GGGGACACCATAGACTTGATATTCAACTCTGAGCATCAGGTTCTAAAAAATAA



TACATACTGGGGTATCATTTTACTAGCAAATCCCCAATTCATCTCCTAGAGAC



TTGATTTGATCTCCTCATTCCCTTCAGCACATGTAGAGGTGCCAGTGGGTGGA



TTGGAGGGAGAAGATATTCAATTTCTAGAGTTTGTCTGTCTACAAAAATCAAC



ACAAACAGAACTCCTCTGCACGTGAATTTTCATCTATCATGCCTATCTGAAAG



AGACTCAGGGGAAGAGCCAAAGACTTTTGGTTGGATCTGCAGAGATACTTCAT



TAATCCATGATAAAACAAATATGGATGACAGAGGACATGTGCTTTTCAAAGAA



TCTTTATCTAATTCTTGAATTCATGAGTGGAAAAATGGAGTTCTATTCCCATG



GAAGATTTACCTGGTATGCAAAAAGGATCTGGGGCAGTAGCCTGGCTTTGTTC



TCATATTCTTGGGCTGCTGTAATTCATTCTTCTCATACTCCCATCTTCTGAGA



CCCTCCCAATAAAAAGTAGACTGATAGGATGGCCACAGATATGCCTACCATAC



CCTACTTTAGATATGGTGGTGTTAGAAGATAAAGAACAATCTGAGAACTATTG



GAATAGAGGTACAAGTGGCATAAAATGGAATGTACGCTATCTGGAAATTTCTC



TTGGTTTTATCTTCCTCAGGATGCAGGGTGCTTTAAAAAGCCTTATCAAAGGA



GTCATTCCGAACCCTCACGTAGAGCTTTGTGAGACCTTACTGTTGGTGTGTGT



GTCTAAACATTGCTAATTGTAAAGAAAGAGTAACCATTAGTAATCATTAGGTT



TAACCCCAGAATGGTATTATCATTACTGGATTATGTCATGTAATGATTTAGTA



TTTTTAGCTAGCTTTCCACAGTTTGCAAAGTGCTTTCGTAAAACAGTTAGCAA



TTCTATGAAGTTAATTGGGCAGGCATTTGGGGGAAAATTTTAGTGATGAGAAT



GTGATAGCATAGCATAGCCAACTTTCCTCAACTCATAGGACAAGTGACTACAA



GAGGCAATGGGTAGTCCCCTGCATTGCACTGTCTCAGCTTTAGAATTGTTATT



TCTGCTATCGTGTTATAAGACTCTAAAACTTAGCGAATTCACTTTTCAGGAAG



CATATTCCCCTTTAGCCCAAGGTGAGCAGAGTGAAGCTACAACAGATCTTTCC



TTTACCAGCACACTTTTTTTTTTTTTCCTGCCTGAATCAGGGAGATCCAGGAT



GCTGTTCAGGCCTTATCCCAACCAAATTCCCCTCTTCACTTTGCAGGGCCCAT



CTTAGTCAAATGTGCTAACTTCTAAAATAATAAATAGCACTAATTCAAAATTT



TTGGACTCTTAAATTAGCTACTTGCAGGTTCTTGTTGAAAGGTATATAATATT



ACATTGTAAACAAATTTAAAATATTTATGGATATTTGTGAAAAGCTGCATTAT



GTTAAATAATATTACATGTAAAGCTATTTAAAAGAGGTTTTTTTTGTATTTTG



TTTAACAAAAATTGCTCAGGAGCATGCTAAGCCTGAGGCCAAGTTGTTTCTTA



GTATGACTTTTTAAAAAAACATCTGCTGAGTAGCTACAGGGCCAAAGACTTGG



AGAGCTTGTTTCTGTTGCATTTGCATATCTTCTCAGGAAATTAAAGTGTGTCA



TACATATGTGTGTGTGTGTGTGTGTGTGTGTGTATATGTGTGTGTGTATATAT



ATGTATACTTATAAAATCTTGGTGTTCTTGATCTTTGTTGTGTTATAAGCAAT



GTGTGCTGGAGTGGGCTGGTGCTAGCTTATAAGCACATATTATTAAATTTTCA



GGAATGTTGCACTTTAGTTATTAACTATAGGCATTCTTGAAATTGGCTATGGT



GGGAGTATTTATACCATGTAAATTGGCAAACACTACACATTTTCCTTTTGGAC



AGCTAGTTCACCAGCACACCACTGTGAAACTCTCCTTAATGACTCCTCTCTGC



CCCCGCTTCATTCCTGGGATAATCATAGCAGACTAAGGGAGAAAATGAAATTG



TAAAAATTTGGCATACTGGTGATTTCTCAGGGCAAGCAGAGGTTACTACAGCT



GCAGCTAGAGGGATGACTACCAACAGGTGACCTTTACATTTTCCTGATGTTAT



AATTTTAGCTTTTGTTTTCAATGTATACTGTTTTCCTGTTTCTCCACATAGTA



GTCTGCATTTTAAATCTATAATAAAACATGCTGATAACTGG (SEQ ID NO:



121)






>NP_005083.3 tumor necrosis factor ligand superfamily



member 18 [Homo sapiens]



MCLSHLENMPLSHSRTQGAQRSSWKLWLFCSIVMLLFLCSFSWLIFIFLQLET



AKEPCMAKFGPLPSKWQMASSEPPCVNKVSDWKLEILQNGLYLIYGQVAPNAN



YNDVAPFEVRLYKNKDMIQTLTNKSKIQNVGGTYELHVGDTIDLIFNSEHQVL



KNNTYWGIILLANPQFIS (SEQ ID NO: 122)





Mouse GITRL
>NM_183391.3 Mus musculus tumor necrosis factor



(ligand) superfamily, member 18 (Tnfsf18), mRNA



TTGTGGGTATCTGCTTTCCCCAGTTCTCATTCCATCAGAGAACGAGTTCTAGC



CTCATGGAGGAAATGCCTTTGAGAGAATCAAGTCCTCAAAGGGCAGAGAGGTG



CAAGAAGTCATGGCTCTTGTGCATAGTGGCTCTGTTACTGATGTTGCTCTGTT



CTTTGGGTACACTGATCTATACTTCACTCAAGCCAACTGCCATCGAGTCCTGC



ATGGTTAAGTTTGAACTATCATCCTCAAAATGGCACATGACATCTCCCAAACC



TCACTGTGTGAATACGACATCTGATGGGAAGCTGAAGATACTGCAGAGTGGCA



CATATTTAATCTACGGCCAAGTGATTCCTGTGGATAAGAAATACATAAAAGAC



AATGCCCCCTTCGTAGTACAGATATATAAAAAGAATGATGTCCTACAAACTCT



AATGAATGATTTTCAAATCTTGCCTATAGGAGGGGTTTATGAACTGCATGCTG



GAGATAACATATATCTGAAGTTCAACTCTAAAGACCATATTCAGAAAACTAAC



ACATACTGGGGGATCATCTTAATGCCTGATCTACCATTCATCTCTTAGAGATT



GGGTTTGGTCTCCTCATCTTCTTCTTTGTATCCCGAGATGCTGGTGGGTGGGT



TGGAGGGGGATGATTGATGGCAATGCACACAGTTTGTGAGGGCTTACAAATTG



ACACAATCAGAGCCTCTTGGCATATAAAATTTTAGCCCTCATATCTGTCTGAA



GAGGACTCAGCAAATGGGCCAATCCCTAATGTTGGGTCTGCAAATGGACTTGT



ACAATCCATGATAAAAAGGAGTATGGGCCACAGAAGACAGAAACTCTTCCAAA



GAATGTCTTTCTAACCTTGATCCCTGGGTAGAATGAGATCCTGTTTCCATGGG



AGTCTTACTTGGCTTGCAAAAAAGGGTGTAGGGCAGTAGCTTGGCCTTTTTTC



CATCATAATTTCCTTGAGCTGTTTTACCTTAATCCCTCCAAACTCTCACCTTC



TGAGAGCCTCCTAATGAAACATTGTTAGACTGGTGGGGTGGCCAAGACATGCC



AACAACACCCTTCTTTAGAGGTGGTGTTTTTAGAGGACAGAGAACATTATGAA



GCCTAGAGCAGCAGAGGTCAAGATGCCACGAAATGGAATTGATCTGGGAATTT



TTTTTTTTTTTCATTCTCAGGATGCAGGTTCATTCTGAACTTTCCCCTAGGCC



TTCATTGCTTTTGTGTGTATGTGTGCATAAATTCTGCAAATAGAAAAATGAGA



GTTTGCACCAGTACTCACTAGATTTAACACCAGAAAGTGGTACTTTTCTGGCT



GTATTATGCCATGATAGCACATTTTCTGTTGGTGTTCCCTAACTGACAAGTAT



AACAGTTTTCCTAAACCACACAACAATGCTATGATGTTAATGGGGTAGATATT



TTTGGAAAAAAATTGCACAGTGAGAACATGGGTAGATGAACCCTAAGACTCTT



ACCTCAATTCAGAACTCGCAAGGAGTTAAGTGAGTGGGGTCTTCATTAGACCA



TTCACATGGTCTCTGCTTTGAAACTGGCGTTGCTACTGTCTCATTATACATCA



CTAAAATGGAATTAACTCAACTTTGAAATGGATGCATCGACTTTACCCCAAGG



TGTCCAGAATGAAGCTACAAGACTTTTACCAGCAGTCATTTTCCTTTTGCCTG



GAGCAAGAAGATCCAGGATACTGTTGGAAGAGTTCATCTCACTCAACCATGCT



GACTTTCCAAAGTAATAATGAACATTTGTGTTCAAATTTTGGATTCTGTTAAA



TTTAGCCAGCTTGTGAGTTCTTGTCGAAAAGTATTTTAAACCAATTTACACTA



TTTATGGGTATTTGTGAAAAGCTATATAGTGATATTTTATATATAACTAATTT



AAAATATTTTTATTTTATGTAACAAAAATACTATAGGCTAAGCTATTTCTTCT



TATTTTTTTATGAATACTTGCTGAATTGCCATAGGGCACAAAGACTCTTCTGT



TTGCATATCTTCTCAGGAAATTAAAATTGTATCACATGTATTTATAAGAA



(SEQ ID NO: 123)






>NP_899247.3 tumor necrosis factor ligand superfamily



member 18 [Mus musculus]



MEEMPLRESSPQRAERCKKSWLLCIVALLLMLLCSLGTLIYTSLKPTAIESCM



VKFELSSSKWHMTSPKPHCVNTTSDGKLKILQSGTYLIYGQVIPVDKKYIKDN



APFVVQIYKKNDVLQTLMNDFQILPIGGVYELHAGDNIYLKFNSKDHIQKTNT



YWGIILMPDLPFIS (SEQ ID NO: 124)





Human
>NM_000074.3 Homo sapiens CD40 ligand (CD40LG), mRNA


CD40L
AATCCTGAGTAAGGTGGCCACTTTGACAGTCTTCTCATGCTGCCTCTGCCACC


(CD154)
TTCTCTGCCAGAAGATACCATTTCAACTTTAACACAGCATGATCGAAACATAC



AACCAAACTTCTCCCCGATCTGCGGCCACTGGACTGCCCATCAGCATGAAAAT



TTTTATGTATTTACTTACTGTTTTTCTTATCACCCAGATGATTGGGTCAGCAC



TTTTTGCTGTGTATCTTCATAGAAGGTTGGACAAGATAGAAGATGAAAGGAAT



CTTCATGAAGATTTTGTATTCATGAAAACGATACAGAGATGCAACACAGGAGA



AAGATCCTTATCCTTACTGAACTGTGAGGAGATTAAAAGCCAGTTTGAAGGCT



TTGTGAAGGATATAATGTTAAACAAAGAGGAGACGAAGAAAGAAAACAGCTTT



GAAATGCAAAAAGGTGATCAGAATCCTCAAATTGCGGCACATGTCATAAGTGA



GGCCAGCAGTAAAACAACATCTGTGTTACAGTGGGCTGAAAAAGGATACTACA



CCATGAGCAACAACTTGGTAACCCTGGAAAATGGGAAACAGCTGACCGTTAAA



AGACAAGGACTCTATTATATCTATGCCCAAGTCACCTTCTGTTCCAATCGGGA



AGCTTCGAGTCAAGCTCCATTTATAGCCAGCCTCTGCCTAAAGTCCCCCGGTA



GATTCGAGAGAATCTTACTCAGAGCTGCAAATACCCACAGTTCCGCCAAACCT



TGCGGGCAACAATCCATTCACTTGGGAGGAGTATTTGAATTGCAACCAGGTGC



TTCGGTGTTTGTCAATGTGACTGATCCAAGCCAAGTGAGCCATGGCACTGGCT



TCACGTCCTTTGGCTTACTCAAACTCTGAACAGTGTCACCTTGCAGGCTGTGG



TGGAGCTGACGCTGGGAGTCTTCATAATACAGCACAGCGGTTAAGCCCACCCC



CTGTTAACTGCCTATTTATAACCCTAGGATCCTCCTTATGGAGAACTATTTAT



TATACACTCCAAGGCATGTAGAACTGTAATAAGTGAATTACAGGTCACATGAA



ACCAAAACGGGCCCTGCTCCATAAGAGCTTATATATCTGAAGCAGCAACCCCA



CTGATGCAGACATCCAGAGAGTCCTATGAAAAGACAAGGCCATTATGCACAGG



TTGAATTCTGAGTAAACAGCAGATAACTTGCCAAGTTCAGTTTTGTTTCTTTG



CGTGCAGTGTCTTTCCATGGATAATGCATTTGATTTATCAGTGAAGATGCAGA



AGGGAAATGGGGAGCCTCAGCTCACATTCAGTTATGGTTGACTCTGGGTTCCT



ATGGCCTTGTTGGAGGGGGCCAGGCTCTAGAACGTCTAACACAGTGGAGAACC



GAAACCCCCCCCCCCCCCCCGCCACCCTCTCGGACAGTTATTCATTCTCTTTC



AATCTCTCTCTCTCCATCTCTCTCTTTCAGTCTCTCTCTCTCAACCTCTTTCT



TCCAATCTCTCTTTCTCAATCTCTCTGTTTCCCTTTGTCAGTCTCTTCCCTCC



CCCAGTCTCTCTTCTCAATCCCCCTTTCTAACACACACACACACACACACACA



CACACACACACACACACACACACACACACAGAGTCAGGCCGTTGCTAGTCAGT



TCTCTTCTTTCCACCCTGTCCCTATCTCTACCACTATAGATGAGGGTGAGGAG



TAGGGAGTGCAGCCCTGAGCCTGCCCACTCCTCATTACGAAATGACTGTATTT



AAAGGAAATCTATTGTATCTACCTGCAGTCTCCATTGTTTCCAGAGTGAACTT



GTAATTATCTTGTTATTTATTTTTTGAATAATAAAGACCTCTTAACATTA



(SEQ ID NO: 125)






>NP_000065.1 CD40 ligand [Homo sapiens]



MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAVYLHRRLDKI



EDERNLHEDFVFMKTIQRCNTGERSLSLLNCEEIKSQFEGFVKDIMLNKEETK



KENSFEMQKGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGK



QLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTH



SSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL



(SEQ ID NO: 126)





Mouse CD40L
>NM_011616.2 Mus musculus CD40 ligand (Cd40lg), mRNA



CTTTCAGTCAGCATGATAGAAACATACAGCCAACCTTCCCCCAGATCCGTGGC



AACTGGACTTCCAGCGAGCATGAAGATTTTTATGTATTTACTTACTGTTTTCC



TTATCACCCAAATGATTGGATCTGTGCTTTTTGCTGTGTATCTTCATAGAAGA



TTGGATAAGGTCGAAGAGGAAGTAAACCTTCATGAAGATTTTGTATTCATAAA



AAAGCTAAAGAGATGCAACAAAGGAGAAGGATCTTTATCCTTGCTGAACTGTG



AGGAGATGAGAAGGCAATTTGAAGACCTTGTCAAGGATATAACGTTAAACAAA



GAAGAGAAAAAAGAAAACAGCTTTGAAATGCAAAGAGGTGATGAGGATCCTCA



AATTGCAGCACACGTTGTAAGCGAAGCCAACAGTAATGCAGCATCCGTTCTAC



AGTGGGCCAAGAAAGGATATTATACCATGAAAAGCAACTTGGTAATGCTTGAA



AATGGGAAACAGCTGACGGTTAAAAGAGAAGGACTCTATTATGTCTACACTCA



AGTCACCTTCTGCTCTAATCGGGAGCCTTCGAGTCAACGCCCATTCATCGTCG



GCCTCTGGCTGAAGCCCAGCAGTGGATCTGAGAGAATCTTACTCAAGGCGGCA



AATACCCACAGTTCCTCCCAGCTTTGCGAGCAGCAGTCTGTTCACTTGGGCGG



AGTGTTTGAATTACAAGCTGGTGCTTCTGTGTTTGTCAACGTGACTGAAGCAA



GCCAAGTGATCCACAGAGTTGGCTTCTCATCTTTTGGCTTACTCAAACTCTGA



ACAGTGCGCTGTCCTAGGCTGCAGCAGGGCTGATGCTGGCAGTCTTCCCTATA



CAGCAAGTCAGTTAGGACCTGCCCTGTGTTGAACTGCCTATTTATAACCCTAG



GATCCTCCTCATGGAGAACTATTTATTATGTACCCCCAAGGCACATAGAGCTG



GAATAAGAGAATTACAGGGCAGGCAAAAATCCCAAGGGACCCTGCTCCCTAAG



AACTTACAATCTGAAACAGCAACCCCACTGATTCAGACAACCAGAAAAGACAA



AGCCATAATACACAGATGACAGAGCTCTGATGAAACAACAGATAACTAATGAG



CACAGTTTTGTTGTTTTATGGGTGTGTCGTTCAATGGACAGTGTACTTGACTT



ACCAGGGAAGATGCAGAAGGGCAACTGTGAGCCTCAGCTCACAATCTGTTATG



GTTGACCTGGGCTCCCTGCGGCCCTAGTAGG (SEQ ID NO: 127)






>NP_035746.2 CD40 ligand [Mus musculus]



MIETYSQPSPRSVATGLPASMKIFMYLLTVFLITQMIGSVLFAVYLHRRLDKV



EEEVNLHEDFVFIKKLKRCNKGEGSLSLLNCEEMRRQFEDLVKDITLNKEEKK



ENSFEMQRGDEDPQIAAHVVSEANSNAASVLQWAKKGYYTMKSNLVMLENGKQ



LTVKREGLYYVYTQVTFCSNREPSSQRPFIVGLWLKPSSGSERILLKAANTHS



SSQLCEQQSVHLGGVFELQAGASVFVNVTEASQVIHRVGFSSFGLLKL (SEQ



ID NO: 128)





Human
>NM_003807.5 Homo sapiens TNF superfamily member 14


LIGHT
(TNFSF14), transcript variant 1, mRNA


(CD258)
CGAGACTCCATCTCAAAAACAAAACAAATAAACGAACAAAAAAACCCACAACG



TATTATTTTCTTGTTTACGAGGTTTCTTGTCTCTCTGGCTCCACCAGAAGAGG



AGCAGGGACCCTTCTTGCTGTTGTTCATTGCTGCATCCCCCACACCGAGAGCA



GAGCCTGGCATGGGCAGAAAGTCCTCAGTCGATATTTGGTGGCCCCAAGCGAA



TGAAGCATCCAAGAAGGGAAAGCTGGGGGCTCCCCACTGCACTTGCCACCTGA



GTCACATTTTCAGAAGCCTCTGGAAAGTCGTGCACAGCCCAGGAGTGTTGAGC



AATTTCGGTTTCCTCTGAGGTTGAAGGACCCAGGCGTGTCAGCCCTGCTCCAG



ACACCTTGGGCATGGAGGAGAGTGTCGTACGGCCCTCAGTGTTTGTGGTGGAT



GGACAGACCGACATCCCATTCACGAGGCTGGGACGAAGCCACCGGAGACAGTC



GTGCAGTGTGGCCCGGGTGGGTCTGGGTCTCTTGCTGTTGCTGATGGGGGCCG



GGCTGGCCGTCCAAGGCTGGTTCCTCCTGCAGCTGCACTGGCGTCTAGGAGAG



ATGGTCACCCGCCTGCCTGACGGACCTGCAGGCTCCTGGGAGCAGCTGATACA



AGAGCGAAGGTCTCACGAGGTCAACCCAGCAGCGCATCTCACAGGGGCCAACT



CCAGCTTGACCGGCAGCGGGGGGCCGCTGTTATGGGAGACTCAGCTGGGCCTG



GCCTTCCTGAGGGGCCTCAGCTACCACGATGGGGCCCTTGTGGTCACCAAAGC



TGGCTACTACTACATCTACTCCAAGGTGCAGCTGGGCGGTGTGGGCTGCCCGC



TGGGCCTGGCCAGCACCATCACCCACGGCCTCTACAAGCGCACACCCCGCTAC



CCCGAGGAGCTGGAGCTGTTGGTCAGCCAGCAGTCACCCTGCGGACGGGCCAC



CAGCAGCTCCCGGGTCTGGTGGGACAGCAGCTTCCTGGGTGGTGTGGTACACC



TGGAGGCTGGGGAGAAGGTGGTCGTCCGTGTGCTGGATGAACGCCTGGTTCGA



CTGCGTGATGGTACCCGGTCTTACTTCGGGGCTTTCATGGTGTGAAGGAAGGA



GCGTGGTGCATTGGACATGGGTCTGACACGTGGAGAACTCAGAGGGTGCCTCA



GGGGAAAGAAAACTCACGAAGCAGAGGCTGGGCGTGGTGGCTCTCGCCTGTAA



TCCCAGCACTTTGGGAGGCCAAGGCAGGCGGATCACCTGAGGTCAGGAGTTCG



AGACCAGCCTGGCTAACATGGCAAAACCCCATCTCTACTAAAAATACAAAAAT



TAGCCGGACGTGGTGGTGCCTGCCTGTAATCCAGCTACTCAGGAGGCTGAGGC



AGGATAATTTTGCTTAAACCCGGGAGGCGGAGGTTGCAGTGAGCCGAGATCAC



ACCACTGCACTCCAACCTGGGAAACGCAGTGAGACTGTGCCTCAAAAAAAAGA



AAGGAAGAAAAAAGAAAACTCAGGAAACAGATCTTGGGGGACACTCCAGGGAA



CCCAAAACTCAAAGGCGGAGAGCTCAGTGGGCACCACCAAGGCGAGATGAAGC



CCCAGCAGGCACCTTCAGAAGACCCACGTAGACTGCAGACCCTGCCACGGACA



ATACTAAGGACAAAAACCCAGAGACTTGGGGTCTGTGGGCCCCCAAACATGGG



GTAAAGTTGATTTGCCTGATATTCAGGAAGAAGGGGTGAGGGGTGGGTATTTA



TGCTTTTGATTCAGAAGAAAGTGGGGCTTGGGATTCCAGGGACTTGGCTGGGG



GTGGGAAACTTCATCCACTTCCCTACTCTCATCATGAGTACGGACAGGGTGGG



CGGGAGACTGATCATCGGGACTCATCATGAAGAGCCCAGCCCCACCCCACATA



CTCAGATCCCACCCACAGACTGGTGGCCACACCTCAGCCTGGTCACAAAGAGT



TACACTCAGATACATGAGCACGGCAGCGTGCTCATAACTGTTTAACAACCAGC



TGTCCTGGGAGGGGGACAGCTTTGTAATGTTTGCCAATTTCCATGGTGTAAAT



GCTACCACCATGGCTGATTTCATCACTGCCAAGCATAGACATCCCTAATAGGA



CACCACGGATCTGTCCCCGGCATCCGGCCCAGGGCCTGGCACAAAGCATGCTC



TAGGGAAATGCTTGCTGATTGAAAGGAAGGAAGAATGACTCTACAGTCACACC



TATGGCATCCCACAAAATCTGTCACATGGCTGCATAATCTCAGCCACTCTTTC



ACAACTATAGACTCATACACGCGAAGTGCCAGATTCATGCACAACCACACAAT



CACATGGAAGTCACAGACGGCATCACAGACAGTCACAGCACTGTGTGTATGTT



ATAACACAAGCACACAAAACTCAGACAGCATCCCAGCTACACAGCCACTCCCA



GAGGTGTCACCGTCACACTTGGTAATTAATACTCATTACATTAGACACAGACA



GACCAAGTTATAGTCAGACCTGGTTACACACATACACACACACAATATCACCA



TGACAAATACACATTACACACACACAACATCACAATGACAAACACACATTACA



CACACAACATCACGATGACAAACACACATTACACACACAACATCACGATGACA



AACACACATTACACACACATCACAATGACAAACACAACATTACACACACACAA



CATCACAATGACACACACATCACACACACATCACAATGACAAACACACAACAT



TACACACATATACACACAGCCTGAGGGCCCTCCCCAGCCCAGACTAACACATC



TCGGGGTGAGGACCAGACCTTGTTCATAACCCTGGGCCTCTTAACCACTGATC



TTTGAAATAAATGGCAAATAGTTGTACCTGGATCTGTCTAGTTCTTAGGGGAA



CAAACTGAAGAAGGGTGGAGAGGAATTGTCAGGCCTAAAGAGCCCCACAGGGA



AAGGGAGGAGTCGGATGGGGGGCAACCATCAGCAACAAGTGGTGGCTCCTAGA



GGCAGAGGGATGGAGGTAATGACCCATGGAGGTCATTCTACAGATGAGGAACC



TGGACCCAGTTGGCTCAAGTCCATGCAGGAAATGTGGGGGAAACCAGAGACCT



CACGTCTGGATCTGGCTTCCTCTCCAATCCACAATTCCTGAGGAAGTAGAGGC



TACATCCCGCAAGACGCCCTTATTAGACACATCCAGGACAGAATGACAATCCG



CCAAGCCAGCTGGAAGCATAAAACACAGGGAGCTGGTGGGTTGGGTGGGGGCA



GATAATGATATGCATACAAATTAGAGGGTCTATGCAAATGAGCATTGCTGCAG



TGTGGCTGGAGGGAATCCTTAGTTCCTAGGATTCTAGGATATGGGTTTCGACC



CCAGAGGTGAATGTATTGTTATTATTGTTTTGTTGTTGTTGTGAATGACAAGT



CAAAATTTGTGGGTTATTGTTGTTATCGCCAATAGTATTCTTGTCATTGTTGC



ACAGTACAGAGATGAAGGAAACAGATTTTGCAATCAGATGATCCTGGGTTCTG



AGTCCACTCTGCCACTCACCAGCTATATGACCTCCAGCAATTTCCATCACCTC



TCAATGCTTCAGTTTCCCCATCGGCAAGATGGTTGTGGGGGGAGAGGAACAAC



AGTACAGATTCACCATCCCAAATTCAAAATGCTCCAAAATCTAGGCCGGGCGT



GGTGGCTCATACCTGTAATCCCAGCACTTTGGGAGGTCAAAGTGGACGGATAA



CCTGAGGTCAGGAGCTCCAGACCAGCCTGGCCAACATGGCGAAACCCCATCTC



TACTAAAAATACAAAAAATTACCTGGGTGTGGTGGGGGGCACCTGTAACCCCA



GCTACTCGGGAGGCTGAGGCAGGAACCCTGGAGGTTGAGGTTGCAGTGAGCTG



AGATCACACCACTGCACTCCAGCCTGGGTGACAGAGCAAGGCTCCCATCTCAA



AAAACAAAAAAACATGCTCCAAAATCTGAAACTCTTTGAGCCCCAGTGTGATG



CCACAAGTGGGAAATTCCACAACTCATCACATGTGATAGATTGCAGTGGAAAT



GCAGGCACACACCACGAAGTTTACTCAGCATCCTCAAAGGAAATCCCCGTCAG



TAGCTATATATCATTTTCTCACATGCCAGATAGGTATCTCTCATCTTTTACTG



TTAGGTACTTCTGTGTTGAATAGGTGGAGGAAAATGATTGCTGGTTAGTAGTA



TATAAATTCAGAGTCAGGAAGGATGGTGATGTCGGCTGGGTGCAGTGGCTCAT



GCCTGTAATTCCAATGTGATACCCTACCTTGTGTTTAACGTGATTGACTCTCC



CTTAGCTGAGAGGGCCAGGCAGACTCTATTTTGGCTTCTTCGCTTGCAGTCTC



TCACCCACCCCCCTTCCTCAAGGACTTAAGCTGACTCCCAGCACATCCAAGAA



TGCGATTACTGATAAGATACTGTGACAAGCTATATCCACAATTCCCAGGAATT



CGTCCGGTTGATAGCACCCAAAGCCCCCGCGTCTATCACCTTGTGATAGATTT



AAAGCCCCTGCACCTGGAACTGTTTGTTTTTCTGTTACCATTTATCTTTTTCA



CTTTCTTGCCTGTTTTGCTTCTGTAAAATTGCTTCAGCTCGGCTCCCTCTTCC



CCTTCTAAACCAAGGTATAAAAAGAAACCTAGCCCCTTCTTTGGGGTGGAGAG



AATTTTGAGCGCTAGCCGTCTCTCAGTCGCCGGCTAATAAAGGACTCCTGAAT



TAGTCTAA (SEQ ID NO: 129)






>NP_003798.2 tumor necrosis factor ligand superfamily



member 14 isoform 1 [Homo sapiens]



MEESVVRPSVFVVDGQTDIPFTRLGRSHRRQSCSVARVGLGLLLLLMGAGLAV



QGWFLLQLHWRLGEMVTRLPDGPAGSWEQLIQERRSHEVNPAAHLTGANSSLT



GSGGPLLWETQLGLAFLRGLSYHDGALVVTKAGYYYIYSKVQLGGVGCPLGLA



STITHGLYKRTPRYPEELELLVSQQSPCGRATSSSRVWWDSSFLGGVVHLEAG



EKVVVRVLDERLVRLRDGTRSYFGAFMV (SEQ ID NO: 130)





Mouse LIGHT
>NM_019418.3 Mus musculus tumor necrosis factor



(ligand) superfamily, member 14 (Tnfsf14), mRNA



TTTTGCAGTTTGCACAGCCCGAGCGTGTTGGGCAATTGTGGTTTCCTCCGGAG



AGGAGGAACTCAGGCTTGCCAACCCTTTCCCTGGGCTTCGGAGCCTCAGCTGC



TCTGGCATGGAGAGTGTGGTACAGCCTTCAGTGTTTGTGGTGGATGGACAGAC



GGACATCCCATTCAGGCGGCTGGAACAGAACCACCGGAGACGGCGCTGTGGCA



CTGTCCAGGTCAGCCTGGCCCTGGTGCTGCTGCTAGGTGCTGGGCTGGCCACT



CAGGGCTGGTTTCTCCTGAGACTGCATCAACGTCTTGGAGACATAGTAGCTCA



TCTGCCAGATGGAGGCAAAGGCTCCTGGGAGAAGCTGATACAAGATCAACGAT



CTCACCAGGCCAACCCAGCAGCACATCTTACAGGAGCCAACGCCAGCTTGATA



GGTATTGGTGGACCTCTGTTATGGGAGACACGACTTGGCCTGGCCTTCTTGAG



GGGCTTGACGTATCATGATGGGGCCCTGGTGACCATGGAGCCCGGTTACTACT



ATGTGTACTCCAAAGTGCAGCTGAGCGGCGTGGGCTGCCCCCAGGGGCTGGCC



AATGGCCTCCCCATCACCCATGGACTATACAAGCGCACATCCCGCTACCCGAA



GGAGTTAGAACTGCTGGTCAGTCGGCGGTCACCCTGTGGCCGGGCCAACAGCT



CCCGAGTCTGGTGGGACAGCAGCTTCCTGGGCGGCGTGGTACATCTGGAGGCT



GGGGAAGAGGTGGTGGTCCGCGTGCCTGGAAACCGCCTGGTCAGACCACGTGA



CGGCACCAGGTCCTATTTCGGAGCTTTCATGGTCTGAAGGCTGCGGTGACAAT



GTATTTTGTGGAGGGACCTCTCCAGGACTCACCTCAAACCCAGCAATAGGGTT



TGAAGTCCTCCCTTTAAGGAGCCCTGAACTCTGCAGTGCTCGGGGCGGTGTAG



ACTGOTGACCTGCTTTGGGCAATCTTCAAATCAGAGACCTGGAGACTTGGGGC



GTGGAGCCCAGGAGCGAGGGGTCAGCTCATTTGCCTGATATTCAGGAAGAAAG



AATCAAGCTGGGGTATTTATGCTTCTGATGCAAACACTGAGATTTCGGCTTTC



TGGGTTTTGAGCTGGAGGCAAGAAACCTTCCCAGAGTGTCATCAGGACCATGT



TGGCAGGACTTGGGGCTCCAGACTTGCCACCACACTCTGGCCTCTCCCATCCA



TCCGCTGCATTGGTTTCCAGCCACCAAAACAGCACTGGCCCCCTGGCTGCAAC



TGGCCAGGTACGAGCTTCTGAGCACCTACATTCCTCAGGGACATCTTGATGAG



ATCTCAGTACTCAGTCCAATGCGCAGCAGCGACAGACATGCCAGGAATGGTTG



GTCAGAAGGGAAGGGAGGAAAGGGAGGAAAGAAGGGAATGCAGAAGAGAAGGG



GGGAAAACAAGACCAAAACAAAACAGCAACAACAAAGCGGCAGGGAGGAGGTG



ACACCCTTGGGGATACTTTAGTCAACACACTTAGAACAGATTGTGCCAGGCCT



GTTGGATTCCTGGAGTTGATGGGATCGTGGGAAGGCACAATGGGGAGCAAGTG



GGCTTGGGTTATGGCTCAGTGGGTAAAGTGCAATTATGGGGATCTGAGTTTGA



ATCCCTGGTACCCATATAAAGACACAGATGCGGTGATGGGCACTTGTGACAAT



GAGATCATCAATAGGGAATGGAGACAGGAGGGACCTCTGGGGTTCACTGGCCA



GGCAGTCTAGCTGAATCAAAGAGCTCCAAGTTCAGTCGATAGCTCCTGAAGAT



GACAACTGAGGCTATTCTCCAAACCCCACACGCAGGACACATGCGTAATAAAT



AAAATTTTAAAAAT (SEQ ID NO: 131)






>NP_062291.1 tumor necrosis factor ligand superfamily



member 14 [Mus musculus]



MESVVQPSVFVVDGQTDIPFRRLEQNHRRRRCGTVQVSLALVLLLGAGLATQG



WFLLRLHQRLGDIVAHLPDGGKGSWEKLIQDQRSHQANPAAHLTGANASLIGI



GGPLLWETRLGLAFLRGLTYHDGALVTMEPGYYYVYSKVQLSGVGCPQGLANG



LPITHGLYKRTSRYPKELELLVSRRSPCGRANSSRVWWDSSFLGGVVHLEAGE



EVVVRVPGNRLVRPRDGTRSYFGAFMV (SEQ ID NO: 132)





Human TL1
>NM_005118.4 Homo sapiens TNF superfamily member 15



(TNFSF15), transcript variant 1, mRNA



AGAGGTGCCTCCAGGAGCAGCAGGAGCATGGCCGAGGATCTGGGACTGAGCTT



TGGGGAAACAGCCAGTGTGGAAATGCTGCCAGAGCACGGCAGCTGCAGGCCCA



AGGCCAGGAGCAGCAGCGCACGCTGGGCTCTCACCTGCTGCCTGGTGTTGCTC



CCCTTCCTTGCAGGACTCACCACATACCTGCTTGTCAGCCAGCTCCGGGCCCA



GGGAGAGGCCTGTGTGCAGTTCCAGGCTCTAAAAGGACAGGAGTTTGCACCTT



CACATCAGCAAGTTTATGCACCTCTTAGAGCAGACGGAGATAAGCCAAGGGCA



CACCTGACAGTTGTGAGACAAACTCCCACACAGCACTTTAAAAATCAGTTCCC



AGCTCTGCACTGGGAACATGAACTAGGCCTGGCCTTCACCAAGAACCGAATGA



ACTATACCAACAAATTCCTGCTGATCCCAGAGTCGGGAGACTACTTCATTTAC



TCCCAGGTCACATTCCGTGGGATGACCTCTGAGTGCAGTGAAATCAGACAAGC



AGGCCGACCAAACAAGCCAGACTCCATCACTGTGGTCATCACCAAGGTAACAG



ACAGCTACCCTGAGCCAACCCAGCTCCTCATGGGGACCAAGTCTGTATGCGAA



GTAGGTAGCAACTGGTTCCAGCCCATCTACCTCGGAGCCATGTTCTCCTTGCA



AGAAGGGGACAAGCTAATGGTGAACGTCAGTGACATCTCTTTGGTGGATTACA



CAAAAGAAGATAAAACCTTCTTTGGAGCCTTCTTACTATAGGAGGAGAGCAAA



TATCATTATATGAAAGTCCTCTGCCACCGAGTTCCTAATTTTCTTTGTTCAAA



TGTAATTATAACCAGGGGTTTTCTTGGGGCCGGGAGTAGGGGGCATTCCACAG



GGACAACGGTTTAGCTATGAAATTTGGGGCCCAAAATTTCACACTTCATGTGC



CTTACTGATGAGAGTACTAACTGGAAAAAGGCTGAAGAGAGCAAATATATTAT



TAAGATGGGTTGGAGGATTGGCGAGTTTCTAAATATTAAGACACTGATCACTA



AATGAATGGATGATCTACTCGGGTCAGGATTGAAAGAGAAATATTTCAACACC



TTCCTGCTATACAATGGTCACCAGTGGTCCAGTTATTGTTCAATTTGATCATA



AATTTGCTTCAATTCAGGAGCTTTGAAGGAAGTCCAAGGAAAGCTCTAGAAAA



CAGTATAAACTTTCAGAGGCAAAATCCTTCACCAATTTTTCCACATACTTTCA



TGCCTTGCCTAAAAAAAATGAAAAGAGAGTTGGTATGTCTCATGAATGTTCAC



ACAGAAGGAGTTGGTTTTCATGTCATCTACAGCATATGAGAAAAGCTACCTTT



CTTTTGATTATGTACACAGATATCTAAATAAGGAAGTATGAGTTTCACATGTA



TATCAAAAATACAACAGTTGCTTGTATTCAGTAGAGTTTTCTTGCCCACCTAT



TTTGTGCTGGGTTCTACCTTAACCCAGAAGACACTATGAAAAACAAGACAGAC



TCCACTCAAAATTTATATGAACACCACTAGATACTTCCTGATCAAACATCAGT



CAACATACTCTAAAGAATAACTCCAAGTCTTGGCCAGGCGCAGTGGCTCACAC



CTGTAATCCCAACACTTTGGGAGGCCAAGGTGGGTGGATCATCTAAGGCCGGG



AGTTCAAGACCAGCCTGACCAACGTGGAGAAACCCCATCTCTACTAAAAATAC



AAAATTAGCCGGGCGTGGTAGCGCATGGCTGTAATCCTGGCTACTCAGGAGGC



CGAGGCAGAAGAATTGCTTGAACTGGGGAGGCAGAGGTTGCGGTGAGCCCAGA



TCGCGCCATTGCACTCCAGCCTGGGTAACAAGAGCAAAACTCTGTCCAAAAAA



AAAAAAATAAAATAATAACTCCAAGCCTTTAAAAAATATCATCTGAAACTGTT



ACATCAGATTTCTGGCACTCTACTGACTGTGGAAGATAGCCAGCTGACTGGAA



GATAGCCAGCTGATTAGTTCCCTGAAGAAACCTGAAGACAGATACCTGGTTAA



CTAGATCAACTACACTGCCAACTTGTTTGATGCTGAGAGACAATGGACTTATT



CCATGGGGGAAGGGAAAAAAGAAGTCAATCACCAAATCTGAAGAAGTTAACCT



AGATCTTTGAGGTTTGATTTGCAACTTTATATGCAGAGTATTATGTGGGTATT



TTCCCTTAAAATATTCAAAGGGATTTACATATGGGATTAGCTAATGAGCCTAG



CCAAGACCTTCCCTGGAGGACAGGCTGGTCATTGCGGAGGTCCCTTCTGTGCT



TCAGTGGGTTCATATCCTCTAGTCCGTATGATTTTCCTACGCTAATATGTCAA



GGGCAGGAGAGGCAGCTCTGTTCTCCTAGCCTTTGTTGACTTGTCTGCAAAGC



AGGAATCTGCCCATTTGTTTCCAAGGAGCAAATGAGCTCATGAGAATGAAAGA



TGTTAACTTCATGCATTCTGTGCCATCTGAGCATTTCGGTATTATATGACTGG



TGACCCTTGGCCCGTATTATAAATGCTTCCTATCCTGGGAGACCTCATGGATG



AGTCTGAGAGGAAATTTGGCACCAAAATCACTCTCACTCTGGTTTCCAGTAGA



CTATAGAGGCAGAGAGGCATTTGAGAGGCTCCTGAGCAAAGTGTCCAGTGTAG



CAGGAGCACTTCATTAATATTTATTGAGTTATAATTAAATAAAAATTAATTTC



TGATTTCTCAGTTTGGAGGTTAAGGCTCTAAATATATTTTCTAACCTCTGCTA



GGCTAACTTAAGCCAGGCCTTTTTCTTGCCTTCCCTTTCTCAAAACAGTCAGC



ACAGACTCAGTGGGAGCACAGAGGAGTGTGGTCACCTCCACCTGGCTCACCAG



AGTCTTCATAGAGGAAGTGAAGCCTGGAAGAAACTGGGCGGGCCCCAGATGAC



CACAGGGAAAGGGCATCTCAGATGGAGGAATTACCCTTGACTTAAAGCAGAAA



AGAAAGATTTCTCAGTAACTCCAAAACTTGCTTGATAGGAGAATATTCCCTCA



ACCAATTCCTAGGACAATATTTATTGGTAGATCAAGAATGTTTCCTCAATAAC



TCTAGTCTAGCTCCATGATCAGAACTAACACCCATTAAAAACATAAAATGTTC



TTTCTGAACCGGTCTTCATGGTGCGTGAGAGCACCAAGCAGCTTTGGTATGCA



GGAGGAGTTTTGCACAGAAGAGTGGCCTGCTCAAACCTGCCCACTGTTCTGTA



GGTGATCTGGTGGATCTGGAAATTTATCCCAAGACAGGAATTTCCTAATATTC



GAAGACATTTGAGGCTTTGGGAAATTCTCTGCTGTGCATTTATTTGGCTCCTG



TCATAAGCTTGTTTTTTAAAGAATGTATCATAGCTCAAGTTTTTACTGCTGAT



TTTGTTAAATTCTGTATAGTATATTTTTTACGGAAAGGCACAGTCAGACATTC



CTAATAGGGCTCATGTCAGAACTTCTGTTCCCAAGGCATTATCTCCATAGCAA



AAATTAGTGCACTGTTTTCAAAAGTGAGGTGGGAAAATGCTTTTAAGATCATG



TGATGTTCCCCTAAAAGGGGTTAATGGGGTGTATTCAGGGTTTGGGAGGGAGG



AAGAAGCATGCTTTAGAAAACAGTAAATTTAGGGAGAAAATGCTTTGTTGGTT



AAATGTCACTCAAAAGGCTGAATTCAAATCAATTCCACAAACATTTACTGAGT



ACCTACTGCCCCTGGGGACACAGAGATAAATTATTTAGTCTCAGACACACTCA



TTCTAACTTCCCAGCACCTCTACTGTCTGCAGATTCTTTAATTTATTTTGGTT



GTATTAGCTAATTAATTCGTAAACTTTAGGCACATGGATCTATTCTCATTATG



AAAATGGATGCCATTTGATTAAGGCTGATGACTAACAAAATGATTTGTGTTTA



CTCGAAGTGTTTTTTTAAAAATAGCTACTCAAGGATAGTTTTCCATAAATCAA



GAAGGTAAAAAAGTTCCCATTTTTTATTGTAGAATCCATTATTTAAACTACAT



GTAGAGACAGGTTATTATTTGCTATATTCAAGTTTGGTCATCAATACCCTTAA



AAATATTAGAATTTTATGGATGACCCAGAAATGCTTTGAAAATCTGTGTTCCT



CAGCAAATACAGAGACCATGATCAAAATGCACAGAATCACTAACATTTTGATG



CTAGCATGGTTTCAGTCTATTTGGCAGAACAGAATTGATTATGCTACTAAAAT



TTCTTTTTCTTTTTTTTTTTTTTTTTTTTTGAGACAGAGTCTTGCTTTGTCAC



CCAGGCTGAAGTGCAGTGGCAGGATCTCAGTTCACTGCAACCTCTGCCTCCCA



GGTTCACGCCATTCTCCTGCTTCAGCCTCCCGAGTAGCTGGGACTACAGGCTC



CCACCACCATGCCCGGCTAATTTTTTGCATTTTTAGTAGAGACGGGGTTTCAC



CGTGTTAGCCAGGATGGTCTCGATCTCCTGACCTCGTGATCCGCCCGCCTCAG



CCTTCCAAAGTGCTGGGATTACAGGCGTGAGCCACTGTGCCCGGACTCTGATT



TTTTTTTTACTAAGGTACAGTAAGAAAAGGGAAAAGTGTACGTTTTCACTTCC



TGAAATATGTCAGGTTGAATCAATAATAGAGCACACCAGAACTCTTGGCTCCA



TTTCAACCTAAACTATTCAGTTCTCATCACCCCAGAGGAAATTCCGCCTCTGT



GCTGGTCAGTAATCCCCCTGGATTATAAAAGTTTAACTAACTCACTGTGCACA



AGGCACGGCCATTGCCAACATTCTCTTGCAAGGTATTTTCCCAAGCCCTTACC



CAATTCTGTTTCCATGATTGTGACATTGGGGATTAATTCTGCAAGACAGAACT



GTTTATATTCTGTACCTTAAAAACACATGCAAACATCTCTTGCCTTAAGATTT



CTGGCTTTCCTATGGCCCAGAGTCCTAGAAGTGTTTTGATATTTGTAGCAGAA



TTTTCAAGTGTACATCCTTATCCTGGATATTAACATTTTTGCATCATATTGGC



AGCTGGACCTACAGAGAATTTAGTAGACTGTTAACCTAATAAGCCTTGAATCC



TTTTGCACCAGTGGTGAGAGAATGTGGATCAGAGCCATCACCTCCATGCCCCG



TCACCCTCTAACAACCACATTTACAACTTCCCCAGCTCTGAGACACACTTGCC



TCCACCCCTTCCATCACCCCATTTTAAGATGAAAATACCACACCAGCCTGGAA



GGAAGAAGTTACTTGCCCAGGGCCACATAGTGAGTTAAGGGCTGATCTAGAGC



TAGGAAGCTGTCTTCCTGAACCATAATCCTGGACTCTTCTAACCTCTCTACTC



ATCGCAAATAGAGTTCATTTTAGTGATTTGAAGGAAGATGGGACAAGTATTTT



CAAACACCTGTAGGACAACATGGAAGTGGGAGGAGACTTCTACTGTAGCTCCC



CAGAGAAGAGAGCTAGGGCTACAGAGTTGCAGTTACAAGGTTGCCCTCTCTGG



CTTGATCCCCAAAGGAATTTTCTACTCCAAAATAGAATTTTTCTAGGATGCTA



TTTCTCAGTCCCTGGAGATACTCAAACAAAGGGCTTGTCACAAGGGTTTTTGT



AGAAGCTATTCTTCACAGAGGTTGGGGGAGAGATTAAGCCAAAGGATCTCTGA



GGTCTTTTTCAAATCTATAATTATGTGGCCTTTTGTTCATTGACTTCCATGTG



TTCTAGTTGATCATTACAAACCTGGCAGGCCTTCTCAAGGGTTCAGTAATTAG



CTGTCATTTCCCATTTGTCCAGAGAGTGTCCAACACAAAATACCCCTAAGATC



TTGGCCAATAGAGAAATGTCATGGAATTTTAGAAATGACAGTATCTGCGGAGT



TTATTCCAAGTTATATCATTTCAAAGATGAAGAAACCCAGGCTCAGAGGGAGC



CATCACATCCACACCCTGTCACCCTTCGTGGCCAGTGCCAGACAGTAGCTAGT



TGGATGCTAAAAGTAGAATTTAGATATCTTAACAATAAGCCCAGCAGTCTTTC



AACTTCATTCGTAAATCATTTTTGTTTTGAGCATCTGTCACGTGGCAGCACTT



GCCTGGATACTGGAGAGCTGAGAAGGAATGCGACAGGCAAGTCCTACTCTCAC



AGTGTATACATTCAGGAGGAACAAGACACACAGTGCCAAGTAAATAAAGTAGC



TGAACTTCATCAAATGATTTTATTCTTAAAGTCATTAAAGCATGTAATGTTCC



CCTTTTTTTGTTTCAGGGGTGTACAGATTGAAGAAGTGTAGGTGTTTATGTGG



TTTTAGTGACAAACCCCATGTGCTTTCATTGATTTTATGTTTTATGTTAAAAC



ATCAACCGCAAGGTAAAATGCATATTGTATGTTGTTGGATACGTACTTAACTG



GTATGCATCCCATGTCTTTGGGTACTAGTGTATGAATTCTAATCTCTGTAAAT



GAAATGTTGTATGTGTTAATATATTTAATAGATGTAACTTAATAAACTGGCAT



TGAAGACTGAA (SEQ ID NO: 133)






>NP_005109.2 tumor necrosis factor ligand superfamily



member 15 isoform VEGI-251 precursor [Homo sapiens]



MAEDLGLSFGETASVEMLPEHGSCRPKARSSSARWALTCCLVLLPFLAGLTTY



LLVSQLRAQGEACVQFQALKGQEFAPSHQQVYAPLRADGDKPRAHLTVVRQTP



TQHFKNQFPALHWEHELGLAFTKNRMNYTNKFLLIPESGDYFIYSQVTFRGMT



SECSEIRQAGRPNKPDSITVVITKVTDSYPEPTQLLMGTKSVCEVGSNWFQPI



YLGAMFSLQEGDKLMVNVSDISLVDYTKEDKTFFGAFLL (SEQ ID NO:



134)





Mouse TL1
>NM_177371.4 Mus musculus tumor necrosis factor



(ligand) superfamily, member 15 (Tnfsf15), mRNA



ATCAGAAGTCTCTCCAAGACAGCAGAAGGATGGCAGAGGAGCTGGGGTTGGGC



TTCGGAGAAGGAGTCCCAGTGGAAGTGCTGCCGGAAGGCTGTAGACACAGGCC



AGAGGCCAGGGCCGGGCTAGCTGCCAGGAGCAAAGCCTGCCTGGCTCTCACCT



GCTGCCTGTTGTCATTTCCCATCCTCGCAGGACTTAGCACCCTCCTAATGGCT



GGCCAGCTCCGGGTCCCCGGAAAAGACTGTATGCTTCGGGCCATAACAGAAGA



GAGATCTGAGCCTTCACCACAGCAAGTTTACTCACCTCCCAGAGGCAAGCCGA



GAGCACACCTGACAATTAAGAAACAAACCCCAGCACCACATCTGAAAAATCAG



CTCTCTGCTCTACACTGGGAACATGACCTAGGGATGGCCTTCACCAAGAACGG



GATGAAGTACATCAACAAATCCCTGGTGATCCCAGAGTCAGGAGACTATTTCA



TCTACTCCCAGATCACATTCCGAGGGACCACATCTGTGTGTGGTGACATCAGT



CGGGGGAGACGACCAAACAAGCCAGACTCCATCACCATGGTTATCACCAAGGT



AGCAGACAGCTACCCTGAGCCTGCCCGCCTACTAACAGGGTCCAAGTCTGTGT



GTGAAATAAGCAACAACTGGTTCCAGTCCCTCTACCTTGGGGCCACGTTCTCC



TTGGAAGAAGGAGACAGACTAATGGTAAACGTCAGTGACATCTCCTTGGTGGA



TTACACAAAAGAAGATAAAACTTTCTTTGGAGCTTTCTTGCTATAAGGAGGAG



AAAACCATCATTCCAAGGGGCTCCCCTGCCTCCTACTTTCCAATTTCCTTTTC



TCATATGGATCTATAAACAGGGGCTTTAGAGGGATCAGGGAAGGGGACAGTGG



TTTAGCTATATAATTTAGGAACCCAATATTGATCCGTATATGCCTTATGGACT



AAAATAGTAAATGGAAAACCCAGTACAGCTCATGTTTGATAGAGACCTGCTGG



GTTTTAAAAATTGAAACACGCCTCATCCAATGGCACAATCTACTGATTTCAGG



ACAGAACCTTTCCACAGTGCCCTCTGTCCAAGTCCTTTCTGAATTCAGCAGTT



CAGTTAGAGCTGAATTCGACAATGAACTTACTCCAGATCAAGAGCTAAAGACA



GAATCCAAAGAAAGACTGAGAAAATGATGTTATTTCTCCAAGAGGCAATGCAT



TTCCACATTCTTTTGTGCCTAACCTAAAAAATAAGAAAGAAGAAAGGAAGGAA



GGAAGGAAGGAAGGAAGGAAGGAAGGAAGGAAGGAAGGAAGGAAGGAAGGAAG



GAAGGAAGGGACAAGAAAAGACAAGACAAGACAAGAAAAAAGAAAAAATGGTA



TTTCTCGTGAATATTCCCTAAAAGGAATTGGTTTTCTGCTGTGAAGGAGAAAC



CTCACCTTTCTTCTGATTGCATCCTTTAGTATCCAAACATACAAGTGGGAATT



CCAAATGCACATGGAACATAGAACACTTTTATTATTGTGAGAACATGTTTATT



GAGTACCTACTATGCTCTGGGCACTCAGCCCACAGGACCATGAAGAGAAAGTC



AAATTTTCTTAAAAACTAAATGAATCCTCAATACATACTTCCTGATCAACTAC



CACTCAAAATGTATAACTTCCAAAGTATAACTTCAAGTCAGCCATCTAGGTGG



TTTCTTGGGTAAAGGTGCTTGTCATTAAGCCTGACACCTGGGTTTGACCTCCC



AGAACCCAAAAGCTGGAAGGAGAGAATTGGTTCCCACAAATTATCCTCAAACC



CCCATACAAATGATGTGGCATGCACACATGTAACTAAATAAATAAGTGTAAAA



CAAAAACAAAAACAAAATTTTAAAGAAAAATTTCAAGTCCTGAAAGACAGCAT



TCCTGAGAATGTTGTCTCCATCGTTGTCCAGTATAGGCTAACCAGCTGATAGA



GACACTGAAGGAATTTAAAGACAGACATCAAGTGAAATGGAGCACTGTAGAAA



CACTTGATTCATGCCAGGAGTCAATGTACTATGAAGACCAACAACAAAGTGTC



AGTCATCAAATCCAGAGGTGTTTATCTAGATCTGCTTTCAAGTTTGGTTTGCA



GCCTTTATATAGTCTCTATTACAAATGCTCGTGTCATGGTAGATGCCACAAGG



AGTCAGAGGGTAAACTTAGCCCCAAACCACTGCTGAGCCATCTTCTAGGAAAC



CTTCGAAGCAGAGCTGGGCAGCGTGACTCCCACACAATGACTGGGAAAGTAGT



AGCTGATCAAAATTTGTTGAGTAATAATTTGTTAGAAAATTCATCTCCACTGC



CTACTAAACCTAAGTTGTATACTATCTAGCTTCTGCTAAGCCAACTTACATTG



GCCACTTTTTCTGTCTTCAACTTCTTGAAGTATCACAGGTCTCAGTGAGAACA



CAGGGAAAGGTGAGGTCGCCTTCCCCTGGTTCTTCATAGGGGAAACCACACCT



GAAAGAAGATGAGCAGCCTGAGGTGACCTGGAGGAAGGGCTGTCTCAGAAGAA



GGACTTATTTTTTGGCTTAGGTCTAAAACCTTGAGAGTAATGCTCACTGGTCA



ATTGAGGATGCTTTATCAATGACTCCAGTCTGACTCCAAGGTCAGAAAGGAGA



GTGAGATGCTCTCTCTGCCTGCATATATCTTCATGGAACATGAGAATATTGAG



CAACATAGACTTATAGGAAAACACTTGCCCAAAAGTAGCCAGAGTGACCTGGT



CATCCCCTCTACTAAACCCAAGCTTTGTGTCAAGGGCCTTCAAAGCTGCCCAG



AAGTGATCTGGATGGCTTGGGAATTTATCCAAGACAGGAATTTCCTGACAGCC



AAAGATGCTTGAGTCCTTGTGCCTGACATGCATTTATTTTGCCCCTGTTTATT



GAAGACTGTAACTGTTGATTTGTGGGTATACATACATACATACATACATACAT



ACATACATACATACATATGCTGTCATGAAGGCAGCATCAAACATTACTAATTG



GACTCAAACCAGCATTTCTGTTTCCAAGATACTAAGTATTCCCATGCAAACAG



GAGCATGCTATTTTTCTAAAGCAAAATGAAAAAAATAGTTTTGAAAGTATATA



TATGATGGAGTCAAGTGTAATGGCATACATCTGTAAACCCAGCACATGGGATG



CTGAGCCAGGAGGATTGCCGTGAGTTTGAGGAGAACAGGGGCTAAATAGTAAT



TTTCAGGAAAGCCTTGCCTATATAACAAGACCTTGTCTCAAATGAAAAAAAAA



AAAAAAATAGACCCCAGGCTGGTCCTTGGAGATAAGGTAATATATTCATTGGG



TGAGGGGGTGTGTGTTTTGGAAAATAGTTAATTTAGTGAGAAATGCTTTTCGG



TCAAATGCATCTCAAAGGCTGCTGAATTCAAATCGGGTCTGTAAATGCTTACC



TAGTGCTTGCTTGCCCTGGGGACAGAGACATAAATTACTTTAGTCTCAGATCC



ACTCGTTCTAACAGATTGGCATCTCCATCGTCTGTGGAGCTTTTAATCACTCT



GTTTGTATTAGCTAATTAATTAGCTAACTTGAGACACACTGATATTTTCTTAT



TATAAACATGGGTGCCATTTGATAAAAGACAATCATTAACAAAATGGTTCGAA



TTTCCGCTTAAGTGATCTTCTTTTTTCCTTTTCATTTTTTTTAACTAGCTAAT



CAAAGGTAGTTTCCCAAAAATAAATGCAAAGGGAGTATAAAGAAAAAATTCCC



TGTGGTGGGAGCTAGTATTGAAACAACAGTATCAAAGAGGCTGTTACCTACTG



GCCTCAAATTTTGGCAGGAACGCCTTTGAAAATGTTAGAACTTTACGGACAGC



CTAGAGGTGCTTTGAAAAGTCTCTGTTGCCAACAAAAGCCATTAATCAGCATG



CGGCACAGGTTACTCAAATTTTGACCTTGACTGTTTTTTAGATCTGTTACACA



GAACACAACTTCTGGGCTGTAATCTCTGATGTGGATTTGGTGATTTACTAAGG



TACCGTGGGAAACAAGGAAAGTGTACTTGTACCACATCGTTTCTCAGTGCATG



TCAGAGTCTACTCAACAGCAGGGCATGCCAGAGCCTTGGATACATTCCGGGAC



AAACTATGTCACTCCTAAGGAAATTCCAAGTGTGTGCCTGTCAAGCACTCTGG



ATCATAGAAGCCCACGAGTTCACTGTGCACAAGGCACAGCCATGGCCAGCACT



CTCTTGCATGGTATTTCTCTTAAGCTCTTACTCAATCACGGTCCCATGATTGT



GACATTGGGGATTAATTGCTTGAGCAGGTTTATTTACAGTCTGTTCCTTGCAA



AATACATGCAGATATGTCTGGCCTCAAAATCCCCTGATTGTTTTAGGGCTTAG



AGAATACTGGGGATGTTTTTGCTGTTTTCAGATGTACTTTATTTAAGCTTGCA



GAATTACCCTGAATATTAACAGTGTTCTAAGATATTGCCTGCTAGCTTCTGGC



TAATTTACTAGTGGTGACAGTATCAGATCAGAGTATCTATATTTATGTCTTGC



TATTATAGTTAAAACTTCCTGATCTCTGTAACACACTCACCCCTACCTCATCT



ATCTACCCATCTTGTGGATGTAGCTGTGAGAAGACTCACAAGCCCGAGTTGCA



GTTACTTTTCTGAAGCAACATAGTATGTTAATGGAATGGCCAGAACTCTACTC



TTGGCACATGGCACTGAATTTGATGCCACTAAAAGAAAAATTGAAGGCAGAAA



TATTTTTTACTATGCATGGGACAACGTAGAAGAGCAAGGAGACTGCTTACACA



TGGTGGTCACATCTCTGGCTTCATCCCTAAACCAATTTTCTGACCCCAAGTCG



ATTTTTTTTCATGTAGTTATTGTTCATTTTCTGGAAAGAGTCAAGCAAAAAGA



GAGTTTTATAGAAACCATTGCATCATGGAGGTCAGGGGAGGGATTAAGCCAAA



GAATTCCTTCTCCAAATCTATAGCCATATGGCCACCCTTTGGTGTACTTCTAT



TTGATCATGACAAACCTGAGAGCCCTGCCCAGAGTTCAGTGGATCCTAATGAA



CTCCAAGAGTAATTCATTCCCTCACCAACTCTAGGGGCTTGGCCAGTGCAGAA



AATGTCATGGGATTTTAAAGTTAACATGAGCTGCTATCCAAACTTATGTCTCT



TTAAGAATGGAGAGACACAGGCCAGGAGAGGTAACATATGAAGCCTGGTATTG



GGCAGTAGCTTGATGGAGTATTGAGGCTAAAAGTAGACTTCCTGCCCCTGACC



ATACACAACACCCTTTCAGTTTGATCCATGGTGGTCTTATTCTACTTTATTTT



GAGCACCTGTCACACCTAGTTACTGTCATGCCAAGAAGGTCCATAACAGGCAA



ATCCTACTCTGCTGTGTGCACACAAGAGGAAGGAGGCTCACAGTAGCAAGTAA



ACAGATAAGCAAACGTACACGATTTTCGTCTTAAAGTCATTAAGACACACGCG



TACCCCTCTTTTGTTTCAGAGGGTATACAGGCTGAACAGATGTCAGTGTTCAC



CTATTCTTATTGATAAGCCCCATGTGCTTTCATTGGTTGAATGTTTTATGTTA



AAACGTCATATTGCCATCGTAAAATGCATATTGTATGTTGTTGGGTATATAAT



TAACTAATATGCATCGCATGTATGAATTCTAATCTCTGTAAATGAAAACTTAT



ATATGTTAACATATGTAATAGTTATAATTTAATAAACTGACACTGGAGACTAC



(SEQ ID NO: 135)






>NP_796345.4 tumor necrosis factor ligand superfamily



member 15 [Mus musculus]



MAEELGLGFGEGVPVEVLPEGCRHRPEARAGLAARSKACLALTCCLLSFPILA



GLSTLLMAGQLRVPGKDCMLRAITEERSEPSPQQVYSPPRGKPRAHLTIKKQT



PAPHLKNQLSALHWEHDLGMAFTKNGMKYINKSLVIPESGDYFIYSQITFRGT



TSVCGDISRGRRPNKPDSITMVITKVADSYPEPARLLTGSKSVCEISNNWFQS



LYLGATFSLEEGDRLMVNVSDISLVDYTKEDKTFFGAFLL (SEQ ID NO:



136)





Human CD80
>NM_005191.4 Homo sapiens CD80 molecule (CD80), mRNA



AAACCCTCTGTAAAGTAACAGAAGTTAGAAGGGGAAATGTCGCCTCTCTGAAG



ATTACCCAAAGAAAAAGTGATTTGTCATTGCTTTATAGACTGTAAGAAGAGAA



CATCTCAGAAGTGGAGTCTTACCCTGAAATCAAAGGATTTAAAGAAAAAGTGG



AATTTTTCTTCAGCAAGCTGTGAAACTAAATCCACAACCTTTGGAGACCCAGG



AACACCCTCCAATCTCTGTGTGTTTTGTAAACATCACTGGAGGGTCTTCTACG



TGAGCAATTGGATTGTCATCAGCCCTGCCTGTTTTGCACCTGGGAAGTGCCCT



GGTCTTACTTGGGTCCAAATTGTTGGCTTTCACTTTTGACCCTAAGCATCTGA



AGCCATGGGCCACACACGGAGGCAGGGAACATCACCATCCAAGTGTCCATACC



TCAATTTCTTTCAGCTCTTGGTGCTGGCTGGTCTTTCTCACTTCTGTTCAGGT



GTTATCCACGTGACCAAGGAAGTGAAAGAAGTGGCAACGCTGTCCTGTGGTCA



CAATGTTTCTGTTGAAGAGCTGGCACAAACTCGCATCTACTGGCAAAAGGAGA



AGAAAATGGTGCTGACTATGATGTCTGGGGACATGAATATATGGCCCGAGTAC



AAGAACCGGACCATCTTTGATATCACTAATAACCTCTCCATTGTGATCCTGGC



TCTGCGCCCATCTGACGAGGGCACATACGAGTGTGTTGTTCTGAAGTATGAAA



AAGACGCTTTCAAGCGGGAACACCTGGCTGAAGTGACGTTATCAGTCAAAGCT



GACTTCCCTACACCTAGTATATCTGACTTTGAAATTCCAACTTCTAATATTAG



AAGGATAATTTGCTCAACCTCTGGAGGTTTTCCAGAGCCTCACCTCTCCTGGT



TGGAAAATGGAGAAGAATTAAATGCCATCAACACAACAGTTTCCCAAGATCCT



GAAACTGAGCTCTATGCTGTTAGCAGCAAACTGGATTTCAATATGACAACCAA



CCACAGCTTCATGTGTCTCATCAAGTATGGACATTTAAGAGTGAATCAGACCT



TCAACTGGAATACAACCAAGCAAGAGCATTTTCCTGATAACCTGCTCCCATCC



TGGGCCATTACCTTAATCTCAGTAAATGGAATTTTTGTGATATGCTGCCTGAC



CTACTGCTTTGCCCCAAGATGCAGAGAGAGAAGGAGGAATGAGAGATTGAGAA



GGGAAAGTGTACGCCCTGTATAACAGTGTCCGCAGAAGCAAGGGGCTGAAAAG



ATCTGAAGGTCCCACCTCCATTTGCAATTGACCTCTTCTGGGAACTTCCTCAG



ATGGACAAGATTACCCCACCTTGCCCTTTACGTATCTGCTCTTAGGTGCTTCT



TCACTTCAGTTGCTTTGCAGGAAGTGTCTAGAGGAATATGGTGGGCACAGAAG



TAGCTCTGGTGACCTTGATCAAGGTGTTTTGAAATGCAGAATTCTTGAGTTCT



GGAAGGGACTTTAGAGAATACCAGTGTTATTAATGACAAAGGCACTGAGGCCC



AGGGAGGTGACCCGAATTATAAAGGCCAGCGCCAGAACCCAGATTTCCTAACT



CTGGTGCTCTTTCCCTTTATCAGTTTGACTGTGGCCTGTTAACTGGTATATAC



ATATATATGTCAGGCAAAGTGCTGCTGGAAGTAGAATTTGTCCAATAACAGGT



CAACTTCAGAGACTATCTGATTTCCTAATGTCAGAGTAGAAGATTTTATGCTG



CTGTTTACAAAAGCCCAATGTAATGCATAGGAAGTATGGCATGAACATCTTTA



GGAGACTAATGGAAATATTATTGGTGTTTACCCAGTATTCCATTTTTTTCATT



GTGTTCTCTATTGCTGCTCTCTCACTCCCCCATGAGGTACAGCAGAAAGGAGA



ACTATCCAAAACTAATTTCCTCTGACATGTAAGACGAATGATTTAGGTACGTC



AAAGCAGTAGTCAAGGAGGAAAGGGATAGTCCAAAGACTTAACTGGTTCATAT



TGGACTGATAATCTCTTTAAATGGCTTTATGCTAGTTTGACCTCATTTGTAAA



ATATTTATGAGAAAGTTCTCATTTAAAATGAGATCGTTGTTTACAGTGTATGT



ACTAAGCAGTAAGCTATCTTCAAATGTCTAAGGTAGTAACTTTCCATAGGGCC



TCCTTAGATCCCTAAGATGGCTTTTTCTCCTTGGTATTTCTGGGTCTTTCTGA



CATCAGCAGAGAACTGGAAAGACATAGCCAACTGCTGTTCATGTTACTCATGA



CTCCTTTCTCTAAAACTGCCTTCCACAATTCACTAGACCAGAAGTGGACGCAA



CTTAAGCTGGGATAATCACATTATCATCTGAAAATCTGGAGTTGAACAGCAAA



AGAAGACAACATTTCTCAAATGCACATCTCATGGCAGCTAAGCCACATGGCTG



GGATTTAAAGCCTTTAGAGCCAGCCCATGGCTTTAGCTACCTCACTATGCTGC



TTCACAAACCTTGCTCCTGTGTAAAACTATATTCTCAGTGTAGGGCAGAGAGG



TCTAACACCAACATAAGGTACTAGCAGTGTTTCCCGTATTGACAGGAATACTT



AACTCAATAATTCTTTTCTTTTCCATTTAGTAACAGTTGTGATGACTATGTTT



CTATTCTAAGTAATTCCTGTATTCTACAGCAGATACTTTGTCAGCAATACTAA



GGGAAGAAACAAAGTTGAACCGTTTCTTTAATAA (SEQ ID NO: 137)






>NP__005182.1 T-lymphocyte activation antigen CD80



precursor [Homo sapiens]



MGHTRRQGTSPSKCPYLNFFQLLVLAGLSHFCSGVIHVTKEVKEVATLSCGHN



VSVEELAQTRIYWQKEKKMVLTMMSGDMNIWPEYKNRTIFDITNNLSIVILAL



RPSDEGTYECVVLKYEKDAFKREHLAEVTLSVKADFPTPSISDFEIPTSNIRR



IICSTSGGFPEPHLSWLENGEELNAINTTVSQDPETELYAVSSKLDFNMTTNH



SFMCLIKYGHLRVNQTFNWNTTKQEHFPDNLLPSWAITLISVNGIFVICCLTY



CFAPRCRERRRNERLRRESVRPV (SEQ ID NO: 138)





Mouse CD80
>NM_009855.2 Mus musculus CD80 antigen (Cd80),



transcript variant 2, mRNA



GAGTTTTATACCTCAATAGACTCTTACTAGTTTCTCTTTTTCAGGTTGTGAAA



CTCAACCTTCAAAGACACTCTGTTCCATTTCTGTGGACTAATAGGATCATCTT



TAGCATCTGCCGGGTGGATGCCATCCAGGCTTCTTTTTCTACATCTCTGTTTC



TCGATTTTTGTGAGCCTAGGAGGTGCCTAAGCTCCATTGGCTCTAGATTCCTG



GCTTTCCCCATCATGTTCTCCAAAGCATCTGAAGCTATGGCTTGCAATTGTCA



GTTGATGCAGGATACACCACTCCTCAAGTTTCCATGTCCAAGGCTCATTCTTC



TCTTTGTGCTGCTGATTCGTCTTTCACAAGTGTCTTCAGATGTTGATGAACAA



CTGTCCAAGTCAGTGAAAGATAAGGTATTGCTGCCTTGCCGTTACAACTCTCC



TCATGAAGATGAGTCTGAAGACCGAATCTACTGGCAAAAACATGACAAAGTGG



TGCTGTCTGTCATTGCTGGGAAACTAAAAGTGTGGCCCGAGTATAAGAACCGG



ACTTTATATGACAACACTACCTACTCTCTTATCATCCTGGGCCTGGTCCTTTC



AGACCGGGGCACATACAGCTGTGTCGTTCAAAAGAAGGAAAGAGGAACGTATG



AAGTTAAACACTTGGCTTTAGTAAAGTTGTCCATCAAAGCTGACTTCTCTACC



CCCAACATAACTGAGTCTGGAAACCCATCTGCAGACACTAAAAGGATTACCTG



CTTTGCTTCCGGGGGTTTCCCAAAGCCTCGCTTCTCTTGGTTGGAAAATGGAA



GAGAATTACCTGGCATCAATACGACAATTTCCCAGGATCCTGAATCTGAATTG



TACACCATTAGTAGCCAACTAGATTTCAATACGACTCGCAACCACACCATTAA



GTGTCTCATTAAATATGGAGATGCTCACGTGTCAGAGGACTTCACCTGGGAAA



AACCCCCAGAAGACCCTCCTGATAGCAAGAACACACTTGTGCTCTTTGGGGCA



GGATTCGGCGCAGTAATAACAGTCGTCGTCATCGTTGTCATCATCAAATGCTT



CTGTAAGCACAGAAGCTGTTTCAGAAGAAATGAGGCAAGCAGAGAAACAAACA



ACAGCCTTACCTTCGGGCCTGAAGAAGCATTAGCTGAACAGACCGTCTTCCTT



TAGTTCTTCTCTGTCCATGTGGGATACATGGTATTATGTGGCTCATGAGGTAC



AATCTTTCTTTCAGCACCGTGCTAGCTGATCTTTCGGACAACTTGACACAAGA



TAGAGTTAACTGGGAAGAGAAAGCCTTGAATGAGGATTTCTTTCCATCAGGAA



GCCTACGGGCAAGTTTGCTGGGCCTTTGATTGCTTGATGACTGAAGTGGAAAG



GCTGAGCCCACTGTGGGTGGTGCTAGCCCTGGGCAGGGGCAGGTGACCCTGGG



TGGTATAAGAAAAAGAGCTGTCACTAAAAGGAGAGGTGCCTAGTCTTACTGCA



ACTTGATATGTCATGTTTGGTTGGTGTCTGTGGGAGGCCTGCCCTTTTCTGAA



GAGAAGTGGTGGGAGAGTGGATGGGGTGGGGGCAGAGGAAAAGTGGGGGAGAG



GGCCTGGGAGGAGAGGAGGGAGGGGGACGGGGTGGGGGTGGGGAAAACTATGG



TTGGGATGTAAAAACGATAATAATATAAATATTAAATAAAAAGAGAGTATTGA



GCAAA (SEQ ID NO: 139)






>NP_033985.3 T-lymphocyte activation antigen CD80



precursor [Mus musculus]



MACNCQLMQDTPLLKFPCPRLILLFVLLIRLSQVSSDVDEQLSKSVKDKVLLP



CRYNSPHEDESEDRIYWQKHDKVVLSVIAGKLKVWPEYKNRTLYDNTTYSLII



LGLVLSDRGTYSCVVQKKERGTYEVKHLALVKLSIKADFSTPNITESGNPSAD



TKRITCFASGGFPKPRFSWLENGRELPGINTTISQDPESELYTISSQLDFNTT



RNHTIKCLIKYGDAHVSEDFTWEKPPEDPPDSKNTLVLFGAGFGAVITVVVIV



VIIKCFCKHRSCFRRNEASRETNNSLTFGPEEALAEQTVFL (SEQ ID NO:



140)





Human CD86
>NM_175862.5 Homo sapiens CD86 molecule (CD86),



transcript variant 1, mRNA



AGTCATTGCCGAGGAAGGCTTGCACAGGGTGAAAGCTTTGCTTCTCTGCTGCT



GTAACAGGGACTAGCACAGACACACGGATGAGTGGGGTCATTTCCAGATATTA



GGTCACAGCAGAAGCAGCCAAAATGGATCCCCAGTGCACTATGGGACTGAGTA



ACATTCTCTTTGTGATGGCCTTOCTGOTCTCTGGTGCTGCTCCTCTGAAGATT



CAAGCTTATTTCAATGAGACTGCAGACCTGCCATGCCAATTTGCAAACTCTCA



AAACCAAAGCCTGAGTGAGCTAGTAGTATTTTGGCAGGACCAGGAAAACTTGG



TTCTGAATGAGGTATACTTAGGCAAAGAGAAATTTGACAGTGTTCATTCCAAG



TATATGGGCCGCACAAGTTTTGATTCGGACAGTTGGACCCTGAGACTTCACAA



TCTTCAGATCAAGGACAAGGGCTTGTATCAATGTATCATCCATCACAAAAAGC



CCACAGGAATGATTCGCATCCACCAGATGAATTCTGAACTGTCAGTGCTTGCT



AACTTCAGTCAACCTGAAATAGTACCAATTTCTAATATAACAGAAAATGTGTA



CATAAATTTGACCTGCTCATCTATACACGGTTACCCAGAACCTAAGAAGATGA



GTGTTTTGCTAAGAACCAAGAATTCAACTATCGAGTATGATGGTGTTATGCAG



AAATCTCAAGATAATGTCACAGAACTGTACGACGTTTCCATCAGCTTGTCTGT



TTCATTCCCTGATGTTACGAGCAATATGACCATCTTCTGTATTCTGGAAACTG



ACAAGACGCGGCTTTTATCTTCACCTTTCTCTATAGAGCTTGAGGACCCTCAG



CCTCCCCCAGACCACATTCCTTGGATTACAGCTGTACTTCCAACAGTTATTAT



ATGTGTGATGGTTTTCTGTCTAATTCTATGGAAATGGAAGAAGAAGAAGCGGC



CTCGCAACTCTTATAAATGTGGAACCAACACAATGGAGAGGGAAGAGAGTGAA



CAGACCAAGAAAAGAGAAAAAATCCATATACCTGAAAGATCTGATGAAGCCCA



GCGTGTTTTTAAAAGTTCGAAGACATCTTCATGCGACAAAAGTGATACATGTT



TTTAATTAAAGAGTAAAGCCCATACAAGTATTCATTTTTTCTACCCTTTCCTT



TGTAAGTTCCTGGGCAACCTTTTTGATTTCTTCCAGAAGGCAAAAAGACATTA



CCATGAGTAATAAGGGGGCTCCAGGACTCCCTCTAAGTGGAATAGCCTCCCTG



TAACTCCAGCTCTGCTCCGTATGCCAAGAGGAGACTTTAATTCTCTTACTGCT



TCTTTTCACTTCAGAGCACACTTATGGGCCAAGCCCAGCTTAATGGCTCATGA



CCTGGAAATAAAATTTAGGACCAATACCTCCTCCAGATCAGATTCTTCTCTTA



ATTTCATAGATTGTGTTTTTTTTTTAAATAGACCTCTCAATTTCTGGAAAACT



GCCTTTTATCTGCCCAGAATTCTAAGCTGGTGCCCCACTGAATTTTGTGTGTA



CCTGTGACTAAACAACTACCTCCTCAGTCTGGGTGGGACTTATGTATTTATGA



CCTTATAGTGTTAATATCTTGAAACATAGAGATCTATGTACTGTAATAGTGTG



ATTACTATGCTCTAGAGAAAAGTCTACCCCTGCTAAGGAGTTCTCATCCCTCT



GTCAGGGTCAGTAAGGAAAACGGTGGCCTAGGGTACAGGCAACAATGAGCAGA



CCAACCTAAATTTGGGGAAATTAGGAGAGGCAGAGATAGAACCTGGAGCCACT



TCTATCTGGGCTGTTGCTAATATTGAGGAGGCTTGCCCCACCCAACAAGCCAT



AGTGGAGAGAACTGAATAAACAGGAAAATGCCAGAGCTTGTGAACCCTGTTTC



TCTTGAAGAACTGACTAGTGAGATGGCCTGGGGAAGCTGTGAAAGAACCAAAA



GAGATCACAATACTCAAAAGAGAGAGAGAGAGAAAAAAGAGAGATCTTGATCC



ACAGAAATACATGAAATGTCTGGTCTGTCCACCCCATCAACAAGTCTTGAAAC



AAGCAACAGATGGATAGTCTGTCCAAATGGACATAAGACAGACAGCAGTTTCC



CTGGTGGTCAGGGAGGGGTTTTGGTGATACCCAAGTTATTGGGATGTCATCTT



CCTGGAAGCAGAGCTGGGGAGGGAGAGCCATCACCTTGATAATGGGATGAATG



GAAGGAGGCTTAGGACTTTCCACTCCTGGCTGAGAGAGGAAGAGCTGCAACGG



AATTAGGAAGACCAAGACACAGATCACCCGGGGCTTACTTAGCCTACAGATGT



CCTACGGGAACGTGGGCTGGCCCAGCATAGGGCTAGCAAATTTGAGTTGGATG



ATTGTTTTTGCTCAAGGCAACCAGAGGAAACTTGCATACAGAGACAGATATAC



TGGGAGAAATGACTTTGAAAACCTGGCTCTAAGGTGGGATCACTAAGGGATGG



GGCAGTCTCTGCCCAAACATAAAGAGAACTCTGGGGAGCCTGAGCCACAAAAA



TGTTCCTTTATTTTATGTAAACCCTCAAGGGTTATAGACTGCCATGCTAGACA



AGCTTGTCCATGTAATATTCCCATGTTTTTACCCTGCCCCTGCCTTGATTAGA



CTCCTAGCACCTGGCTAGTTTCTAACATGTTTTGTGCAGCACAGTTTTTAATA



AATGCTTGTTACATTCA (SEQ ID NO: 141)






>NP_787058.5 T-lymphocyte activation antigen CD86



isoform 1 precursor [Homo sapiens]



MDPQCTMGLSNILFVMAFLLSGAAPLKIQAYFNETADLPCQFANSQNQSLSEL



VVFWQDQENLVLNEVYLGKEKFDSVHSKYMGRTSFDSDSWTLRLHNLQIKDKG



LYQCIIHHKKPTGMIRIHQMNSELSVLANFSQPEIVPISNITENVYINLTCSS



IHGYPEPKKMSVLLRTKNSTIEYDGVMQKSQDNVTELYDVSISLSVSFPDVTS



NMTIFCILETDKTRLLSSPFSIELEDPQPPPDHIPWITAVLPTVIICVMVFCL



ILWKWKKKKRPRNSYKCGTNTMEREESEQTKKREKIHIPERSDEAQRVFKSSK



TSSCDKSDTCF (SEQ ID NO: 142)





Mouse CD86
>NM_019388.3 Mus musculus CD86 antigen (Cd86), mRNA



ATTGCTGAGGAAGAAAGAGGAGCAAGCAGACGCGTAAGAGTGGCTCCTGTAGG



CAGCACGGACTTGAACAACCAGACTCCTGTAGACGTGTTCCAGAACTTACGGA



AGCACCCACGATGGACCCCAGATGCACCATGGGCTTGGCAATCCTTATCTTTG



TGACAGTCTTGCTGATCTCAGATGCTGTTTCCGTGGAGACGCAAGCTTATTTC



AATGGGACTGCATATCTGCCGTGCCCATTTACAAAGGCTCAAAACATAAGCCT



GAGTGAGCTGGTAGTATTTTGGCAGGACCAGCAAAAGTTGGTTCTGTACGAGC



ACTATTTGGGCACAGAGAAACTTGATAGTGTGAATGCCAAGTACCTGGGCCGC



ACGAGCTTTGACAGGAACAACTGGACTCTACGACTTCACAATGTTCAGATCAA



GGACATGGGCTCGTATGATTGTTTTATACAAAAAAAGCCACCCACAGGATCAA



TTATCCTCCAACAGACATTAACAGAACTGTCAGTGATCGCCAACTTCAGTGAA



CCTGAAATAAAACTGGCTCAGAATGTAACAGGAAATTCTGGCATAAATTTGAC



CTGCACGTCTAAGCAAGGTCACCCGAAACCTAAGAAGATGTATTTTCTGATAA



CTAATTCAACTAATGAGTATGGTGATAACATGCAGATATCACAAGATAATGTC



ACAGAACTGTTCAGTATCTCCAACAGCCTCTCTCTTTCATTCCCGGATGGTGT



GTGGCATATGACCGTTGTGTGTGTTCTGGAAACGGAGTCAATGAAGATTTCCT



CCAAACCTCTCAATTTCACTCAAGAGTTTCCATCTCCTCAAACGTATTGGAAG



GAGATTACAGCTTCAGTTACTGTGGCCCTCCTCCTTGTGATGCTGCTCATCAT



TGTATGTCACAAGAAGCCGAATCAGCCTAGCAGGCCCAGCAACACAGCCTCTA



AGTTAGAGCGGGATAGTAACGCTGACAGAGAGACTATCAACCTGAAGGAACTT



GAACCCCAAATTGCTTCAGCAAAACCAAATGCAGAGTGAAGGCAGTGAGAGCC



TGAGGAAAGAGTTAAAAATTGCTTTGCCTGAAATAAGAAGTGCAGAGTTTCTC



AGAATTCAAAAATGTTCTCAGCTGATTGGAATTCTACAGTTGAATAATTAAAG



AACAAAATACACAACAGTGTCCATATTTTATCCTGTTTCCTTTCCAAGTTTTT



GGGCAATGTCAATTGTGTCCCCTATGCCAGGAGCAGACATCTATTTTGTCTTG



CTTTGTTTAACTCAGTGCACACTCATAGGCCAAGAGCACTGAAATGGCTTCTT



TCCCAGGAATAACATTTTGGATCAATCTCTCCTACTTGAGATCAGATTCTTCT



TCTAATTTTGCATAGTGTGTTTTTATATGGAACTCCTTGTTGTAGGAATACTG



GCTTTTATCTGTCTTGCACACTTGCATACTTATATACTTATACCTGGACAGCT



ACCTCTTCAGTCAGGATGGGAGTGGTATATTTGGTGATGTTATTTGATGTGTT



CGTGTTGCTATCTTAAAACAGCAAAGAGCATATACTATAGTAGCTCAACTACA



ATGATCTAGAGAAAGACCCAGCACTTATAAGAAACACTGTCCCTCCATCAGGG



TCAATAATGAATACAATGACCTAAGTAATATACAGGTGACAGCAACAGCACAG



AGTTCTCAGTGCTGGCAAATCAAGAAACACAAATATGGAACCATCTCTAGATC



CAAGAGCCACTCCTACCTGGGCTGCCACAGATACTGGAAGAATCCACCTGCCT



GGCCAGCAAGTCACAACTTAGCAGGCAGCACTGAAGAAAGCAAGATGTACTGT



ATGCCCTTTTAAGAAAATGCCTGGAAAGGTCTGGAGAATGCTGTGCAAGGATA



AGACAGCCAAGCACTCAAAACCAGGAGACATCACTAGAATCCAACCAACAAAT



GTTTATGGAAGGACTGATCTGCCCAGTCCATTGAAAAGTCAAGAGGTCAGAGA



TAGACCAGTGTGTGTCTCAATGGATGTAGATATCAGCCACCTCGGTGCTCAAC



AGGTATTTTATGATCTCCTTGTTTCAAATTCATCTAGATGTAGAACTAGGGAG



AGAGCAGTCACATTGATGAAAGGCTAGGACTCTTTCAGCTCATGGCTTGTGTG



GAAGGAGGGAAAGCAGAAATCACAACACTCTGAGACTACTGTAGTCTGCAGAT



ACCTGAGTGGGTGTGGCTTGGCCTTTCAAAGGACAAAGAGCAACTAATGCTGA



AAGCACATAGTGTATCTATACGGCATGGAATAGTCATCACCCAGACTTAAAGA



GAACTTTGGCAGGTCTGAGCAGCAAAATATTGTTGTTTCCATTTTACATAAAG



GGCCCTGGAGGGCTATAGACTATTCCGCTGGCAGGGCTCATGCTTGTAATGTG



TCCATCTTGATTCACCCTGTGCAGACTCTTAAGATCTGGCCAGTTACCAACAT



GTTCTGTACAGAGTGGATTTCAATAAAGTTTTCTTGAATTTTTTCAAG



(SEQ ID NO: 143)






>NP_062261.3 T-lymphocyte activation antigen 0D86



precursor [Mus musculus]



MDPRCTMGLAILIFVTVLLISDAVSVETQAYFNGTAYLPCPFTKAQNISLSEL



VVFWQDQQKLVLYEHYLGTEKLDSVNAKYLGRTSFDRNNWTLRLHNVQIKDMG



SYDCFIQKKPPTGSIILQQTLTELSVIANFSEPEIKLAQNVTGNSGINLTCTS



KQGHPKPKKMYFLITNSTNEYGDNMQISQDNVTELFSISNSLSLSFPDGVWHM



TVVCVLETESMKISSKPLNFTQEFPSPQTYWKEITASVTVALLLVMLLIIVCH



KKPNQPSRPSNTASKLERDSNADRETINLKELEPQIASAKPNAE (SEQ ID



NO: 144)





Human LFA-3
>NM_001779.3 Homo sapiens CD58 molecule (CD58),


(CD58)
transcript variant 1, mRNA



GAACTTAGGGCTGCTTGTGGCTGGGCACTCGCGCAGAGGCCGGCCCGACGAGC



CATGGTTGCTGGGAGCGACGCGGGGCGGGCCCTGGGGGTCCTCAGCGTGGTCT



GCCTGCTGCACTGCTTTGGTTTCATCAGCTGTTTTTCCCAACAAATATATGGT



GTTGTGTATGGGAATGTAACTTTCCATGTACCAAGCAATGTGCCTTTAAAAGA



GGTCCTATGGAAAAAACAAAAGGATAAAGTTGCAGAACTGGAAAATTCTGAAT



TCAGAGCTTTCTCATCTTTTAAAAATAGGGTTTATTTAGACACTGTGTCAGGT



AGCCTCACTATCTACAACTTAACATCATCAGATGAAGATGAGTATGAAATGGA



ATCGCCAAATATTACTGATACCATGAAGTTCTTTCTTTATGTGCTTGAGTCTC



TTCCATCTCCCACACTAACTTGTGCATTGACTAATGGAAGCATTGAAGTCCAA



TGCATGATACCAGAGCATTACAACAGCCATCGAGGACTTATAATGTACTCATG



GGATTGTCCTATGGAGCAATGTAAACGTAACTCAACCAGTATATATTTTAAGA



TGGAAAATGATCTTCCACAAAAAATACAGTGTACTCTTAGCAATCCATTATTT



AATACAACATCATCAATCATTTTGACAACCTGTATCCCAAGCAGCGGTCATTC



AAGACACAGATATGCACTTATACCCATACCATTAGCAGTAATTACAACATGTA



TTGTGCTGTATATGAATGGTATTCTGAAATGTGACAGAAAACCAGACAGAACC



AACTCCAATTGATTGGTAACAGAAGATGAAGACAACAGCATAACTAAATTATT



TTAAAAACTAAAAAGCCATCTGATTTCTCATTTGAGTATTACAATTTTTGAAC



AACTGTTGGAAATGTAACTTGAAGCAGCTGCTTTAAGAAGAAATACCCACTAA



CAAAGAACAAGCATTAGTTTTGGCTGTCATCAACTTATTATATGACTAGGTGC



TTGCTTTTTTTGTCAGTAAATTGTTTTTACTGATGATGTAGATACTTTTGTAA



ATAAATGTAAATATGTACACAAGTGA (SEQ ID NO: 145)






>NP_001770.1 lymphocyte function-associated antigen 3



isoform 1 [Homo sapiens]



MVAGSDAGRALGVLSVVCLLHCFGFISCFSQQIYGVVYGNVTFHVPSNVPLKE



VLWKKQKDKVAELENSEFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYEME



SPNITDTMKFFLYVLESLPSPTLTCALTNGSIEVQCMIPEHYNSHRGLIMYSW



DCPMEQCKRNSTSIYFKMENDLPQKIQCTLSNPLFNTTSSIILTTCIPSSGHS



RHRYALIPIPLAVITTCIVLYMNGILKCDRKPDRTNSN (SEQ ID NO:



146)





Human SLAM
>NM_003037.5 Homo sapiens signaling lymphocytic


(CD150)
activation molecule family member 1 (SLAMF1),



transcript variant 1, mRNA



AGACAGCCTCTGCTGCATGACACGAAGCTTGCTTCTGCCTGGCATCTGTGAGC



AGCTGCCAGGCTCCGGCCAGGATCCCTTCCTTCTCCTCATTGGCTGATGGATC



CCAAGGGGCTCCTCTCCTTGACCTTCGTGCTGTTTCTCTCCCTGGCTTTTGGG



GCAAGCTACGGAACAGGTGGGCGCATGATGAACTGCCCAAAGATTCTCCGGCA



GTTGGGAAGCAAAGTGCTGCTGCCCCTGACATATGAAAGGATAAATAAGAGCA



TGAACAAAAGCATCCACATTGTCGTCACAATGGCAAAATCACTGGAGAACAGT



GTCGAGAACAAAATAGTGTCTCTTGATCCATCCGAAGCAGGCCCTCCACGTTA



TCTAGGAGATCGCTACAAGTTTTATCTGGAGAATCTCACCCTGGGGATACGGG



AAAGCAGGAAGGAGGATGAGGGATGGTACCTTATGACCCTGGAGAAAAATGTT



TCAGTTCAGCGCTTTTGCCTGCAGTTGAGGCTTTATGAGCAGGTCTCCACTCC



AGAAATTAAAGTTTTAAACAAGACCCAGGAGAACGGGACCTGCACCTTGATAC



TGGGCTGCACAGTGGAGAAGGGGGACCATGTGGCTTACAGCTGGAGTGAAAAG



GCGGGCACCCACCCACTGAACCCAGCCAACAGCTCCCACCTCCTGTCCCTCAC



CCTCGGCCCCCAGCATGCTGACAATATCTACATCTGCACCGTGAGCAACCCTA



TCAGCAACAATTCCCAGACCTTCAGCCCGTGGCCCGGATGCAGGACAGACCCC



TCAGAAACAAAACCATGGGCAGTGTATGCTGGGCTGTTAGGGGGTGTCATCAT



GATTCTCATCATGGTGGTAATACTACAGTTGAGAAGAAGAGGTAAAACGAACC



ATTACCAGACAACAGTGGAAAAAAAAAGCCTTACGATCTATGCCCAAGTCCAG



AAACCAGGTCCTCTTCAGAAGAAACTTGACTCCTTCCCAGCTCAGGACCCTTG



CACCACCATATATGTTGCTGCCACAGAGCCTGTCCCAGAGTCTGTCCAGGAAA



CAAATTCCATCACAGTCTATGCTAGTGTGACACTTCCAGAGAGCTGACACCAG



AGACCAACAAAGGGACTTTCTGAAGGAAAATGGAAAAACCAAAATGAACACTG



AACTTGGCCACAGGCCCCAAGTTTCCTCTGGCAGACATGCTGCACGTCTGTAC



CCTTCTCAGATCAACTCCCTGGTGATGTTTCTTCCACATACATCTGTGAAATG



AACAAGGAAGTGAGGCTTCCCAAGAATTTAGCTTGCTGTGCAGTGGCTGCAGG



CGCAGAACAGAGCGTTACTTGATAACAGCGTTCCATCTTTGTGTTGTAGCAGA



TGAAATGGACAGTAATGTGAGTTCAGACTTTGGGCATCTTGCTCTTGGCTGGA



ACTGGATAATAAAAATCAGACTGAAAGCCAGGACATCTGAGTACCTATCTCAC



ACACTGGACCACCAGTCACAAAGTCTGGAAAAGTTTACATTTTGGCTATCTTT



ACTTTGTTCTGGGAGCTGATCATGATAACCTGCAGACCTGATCAAGCCTCTGT



GCCTCAGTTTCTCTCTCAGGATAAAGAGTGAATAGAGGCTGAAGGGTGAATTT



CTTATTATACATAAAACACTCTGATATTATTGTATAAAGGAAGCTAAGAATAT



TATTTTATTTGCAAAACCCAGAAGCTAAAAAGTCAATAAACAGAAAGAATGAT



TTTGAGATCTCTGAGTTTTGAACAGTGGACTGGAAACCATGTAAGAGCCTTAA



AAGTACAGTTCTGTGCAAATGGCATTCAGTTTTAAAGAAAAACGTAGCAAATG



TTTGATGGTGCTGTTACAAAGGAGCTTGGAATACTCAGAGGAACTTGTCCCAT



GGTGATTTTTCACTTCTCAAAATGATGTTTAAATCCCAGTTCTCTGTTGATTC



CCTTGAACAACAAACCTGGAACCTCAGCTAAGACTCTCTGTGACCAGATTCTG



AACCTCTTATATCCAGGGCTTCAAGGGGTATTGCAGGTCAAGGTOTTTCCTAG



GCACTTTCTACTCCCTGCATACCTCTCCTCACACTAAATTTATCCTCTAGTAG



AAAATTAAGTTATTTTGGTCTAACAGCTTCAAATCTTTGAATGCTCAATAACT



TATTTTGCAAGCTGCAGGCAGAAAGAGACTTTTTAAGTAAAGTCCTTTGTTTT



TTCCTATTCTCTGCTTTTAGACAGGCTGTCCTCAATTTAAGCCCTGCTTTTTC



TTATTGTTTCTTATATAAACTTGGTAAGTACTGTAAGAAACAGCCACTATCAT



ACCATTGCATAATAAGGAGCACCAACTTCCCAGCTCAAAACTCAGGTCCTTAT



TGCCTTGTATCTTACCTCCTCTATGAGGTCAATTCACATTGTAAGCCTGTTGC



TTAGTGCATCTCGTTTCCTGGTACCAGCTTCTTTAATAGAGTTCTTAGTTGCA



ATCAACAGAAGCTGGCTTTGGCTTTTTTATGTAGAAAAGGAACCTATTGAAAA



GATACTGATTGGTTCCAATAACTGCTAGAAGTTTCTGCAAAACCATGCTTTGA



AAGTGAGCAGGAAAAGAAGAGACTAGGCTGTGGCTGGGAGCACAGCCAAAATT



ACAAAACCAGCCCAGGGATGATGATCCTGTTCATGCACAGCCACTGTCCCCAG



CACTAGGCACAGACTCTACCACTGCCTCACTGTCTCTGOTGGACTTGGAAACT



TGATATTACTGTTACTGCTGCACTGTCTGCCATGAAAATGAATTCTCCAGGGT



CCCTTCTTCATCCTTTCATCTCTAGCTTATAATTCAAAGTCTGGGATTGAGTG



GCCAATCCTAGGTCACATGTCCATGTCCTATCTCCAAGGGGGGCTGGGAATTG



AATATCTGGCATTTTCCACTTTCACTTCTTATGAATTAAGGAATTCTACAAAT



AATAGAAGTGGGATTCAGGTGGTAGGCAGACAAAAAAGCCTCACAATTATCCA



CTACGCCACCCTTGTATAACCTTACCCTCATTCACTGTCTACTCTCAAAACTG



TGGAGCTACTAATGAAGATTTGTAAACCCGGGCTTATGAGCACCCATTCCTTT



ACTACAACTCAGATTGCTCTAGAAGCTCAGTTCCCAGCACTTGGATTTTTCCA



GTAGCTGAATTCTACCTGAAGGAAGGGCAGAAACAAAGGGTGAAGAAGAGGCT



ATCACTTCCAAGTATCCTGCACCCCTGGGCTCAAGACCTCACTGGGGAGGGAG



TCTTTTGGGCCACCCACCAAACAGCACTGGCATTATGCCTCTCACCCTAGACC



ATGGTTACACGTGGTAAAACAACCCCTTCTGGTGATACATTCACAACTCTCTA



GTTTCCCCCAAATGGCACTATGGGGAGCGGGAGCTTGCCTTTTCCTCAGACTT



AAAACAATAAGTTTTCCCCGTGTTTCCCCTCTAATGCTGTTTTCTTTTGACCA



AGCATGTCTGAATTCTAGAGAAGTCAGGAGGAACACACCCATTCTCGGTTTGA



AGGGACTGATGTTCTGAAGTACAACTGGGCACAGTCCCAGGCTCTTCAGGACG



CTTCCTCCATTCACACAGCGGGGATGTGATTGTTACAGCGGGTGGTGTGTGCT



GGCTGAGAAGCCACTGTGAATTGATTCTTCTTCTGAAGTTTATGTTTCTACTT



TTTGGAAATGAATAAATTACAGCCAGTCCATCAAGGAAA (SEQ ID NO:



147)






>NP_003028.1 signaling lymphocytic activation



molecule isoform b precursor [Homo sapiens]



MDPKGLLSLTFVLFLSLAFGASYGTGGRMMNCPKILRQLGSKVLLPLTYERIN



KSMNKSIHIVVTMAKSLENSVENKIVSLDPSEAGPPRYLGDRYKFYLENLTLG



IRESRKEDEGWYLMTLEKNVSVQRFCLQLRLYEQVSTPEIKVLNKTQENGTCT



LILGCTVEKGDHVAYSWSEKAGTHPLNPANSSHLLSLTLGPQHADNIYICTVS



NPISNNSQTFSPWPGCRTDPSETKPWAVYAGLLGGVIMILIMVVILQLRRRGK



TNHYQTTVEKKSLTIYAQVQKPGPLQKKLDSFPAQDPCTTIYVAATEPVPESV



QETNSITVYASVTLPES (SEQ ID NO: 148)





Mouse SLAM
>NM_013730.4 Mus musculus signaling lymphocytic


(CD150)
activation molecule family member 1 (Slamf1),



transcript variant 1, mRNA



GAGCTTCTTCCTTGGGGGTAACAGTAAGCAGCTGTCCTGCCGAGCTGAGCTGA



GCTGAGCTCACAGCTGGGGACCCTGTCTGCGATTGCTGGCTAATGGATCCCAA



AGGATCCCTTTCCTGGAGAATACTTCTGTTTCTCTCCCTGGCTTTTGAGTTGA



GCTACGGAACAGGTGGAGGTGTGATGGATTGCCCAGTGATTCTCCAGAAGCTG



GGACAGGACACGTGGCTGCCCCTGACGAATGAACATCAGATAAATAAGAGCGT



GAACAAAAGTGTCCGCATCCTCGTCACCATGGCGACGTCCCCAGGAAGCAAAT



CCAACAAGAAAATTGTGTCTTTTGATCTCTCTAAAGGGAGCTATCCAGATCAC



CTGGAGGATGGCTACCACTTTCAATCAAAAAACCTGAGCCTGAAGATCCTCGG



GAACAGGCGGGAGAGTGAAGGATGGTACTTGGTGAGCGTGGAGGAGAACGTTT



CTGTTCAGCAATTCTGCAAGCAGCTGAAGCTTTATGAACAGGTCTCCCCTCCA



GAGATTAAAGTGCTAAACAAAACCCAGGAGAACGAGAATGGGACCTGCAGCTT



GCTGTTGGCCTGCACAGTGAAGAAAGGGGACCATGTGACTTACAGCTGGAGTG



ATGAGGCAGGCACCCACCTGCTGAGCCGAGCCAACCGCTCCCACCTCCTGCAC



ATCACTCTTAGCAACCAGCATCAAGACAGCATCTACAACTGCACCGCAAGCAA



CCCTGTCAGCAGTATCTCTAGGACCTTCAACCTATCATCGCAAGCATGCAAGC



AGGAATCCTCCTCAGAATCGAGTCCATGGATGCAATATACTCTTGTACCACTG



GGGGTCGTTATAATCTTCATCCTGGTTTTCACGGCAATAATAATGATGAAAAG



ACAAGGTAAATCAAATCACTGCCAGCCACCAGTGGAAGAAAAAAGCCTTACTA



TTTATGCCCAAGTACAGAAATCAGGGCCTCAAGAGAAGAAACTTCATGATGCC



CTAACAGATCAGGACCCCTGCACAACCATTTATGTGGCTGCCACAGAGCCTGC



CCCAGAGTCTGTCCAGGAACCAAACCCCACCACAGTTTATGCCAGTGTGACAC



TGCCAGAGAGCTGACCCATATACCCAGTGAAAGGACTTTTTGAAGGAGGATAG



AAGAACCAAAATCCACACTGAACTGGACCCCGGGTCCCAAGTTCTCTGTGACA



GAAACTGCACATCTGTAACCTTCTCCAATCAGTTCCCTGGTGACGGATCTGCA



CAGGCGTGCTTATGAAGTAGATGAGAAGTGAGGCTTCCTGGGCATGCAACCTG



CTCTGCTGCTGACACAGATATGAAGCAGAGATCCCGTGGTACAGTGTACCATC



TTTGCTGTAGCAGATAATGTGGGTTTAGGCATCTCACTCTTTGCTGGACTGGA



TAACAGAACTCAAAAAAAAACCAACAAGCCAAAGACATAGACTCCATCTCAGA



TGGCTGAGCACAAAGTATAAAAGCCATTTTGGCTCTCTGGACTTTATTCTGGA



AGCTGATCCTGATCACCTCAAGGCCAAGGGCTCCATGCCTCAGTTTCTCTCTC



ACCCTCTAGATGAAGAGGGAACAAAGCATAAAGAGTGAAATCCTTGTTGTCTG



AGATCATTCTATAAACGAACTGACATTTTATTTGCAAAACTCAAGCTAGTAAT



TCAGTAGACTTGAAGATGATTTTAGAGCCTCTTATGCTTCAAACAACAGAATG



AAATCCATCCAATGTTCTTCAAAGTGTGGTTCTCTGATTAAGTCAAAGCAACA



CTGTTTGGCAATGCTGCTGTAAAGTTGCCTGGAATACTCAGAGGAACTTGTCC



CAGGGAGGTTTTTTTCACTTCTTCAAAGAACTTTTGAATTTAAGTTCTCTGTT



TATTCCCTTGAGCAAAACTCTGGAACCTCAAGAGTCTCTCTCCGTTGGTTCTG



AGGCCATTTTATAGCCTAGGCCTCCTGTGGATCTACATGTGTATCACCCACTT



CCTATCTCACTGCATACCTCTGTGTAGTAGTAAATTTAACCTCAAGTAGAAAA



TTAAATTATTTTGGATGATCAGTTCCAAATGATTAGATGTTTAGTCTCTTATA



ATAGGATGTAGGTAGAGTCTATATAAAGTCCTATATTCTTCACGTTGTCTGTC



CTCAGAGAGACCATCTTTCAACCTATCTTCCTTCTTGCACAACTTTGGCAAAT



ACTTTAAAAATAACCATTGTGGAGATGGGGAGAGGTCTAAATGGATAATAGTA



CTTGCTTTGCAAACATGAAGATCTGGGTTCAAACTCCCAGTGTCCATGTAAAA



AGATAAGTGTGGTTGAGTGTGCCAGTAACATAGACACAGATAGGTCCTGAGAC



TTTGCTCCCTAGCCTTCCCAGCCAGGCATAAATGTCAAGTCCCCTGAGAGTGA



CAGAGGAAGATACTCCCCCCACACACACACACATACACGCACAGTGATACACA



TATACATGCATACAAAAAAAAAACTTATTGTAACAAAGAACACCAACTGCCTG



GCTCAAAACTCTCATGTCCCATTACTCTGTACCTTTCTGTATTTAGATAATTT



ACAGTGTGAGTTCTGOTGTTCCATGTATCCTATTTGTGTTACTAACTTATGTC



AAAGTATTTCTAATTATAATCAACAAAAGCTAACTTTG (SEQ ID NO:



149)






>NP_038758.2 signaling lymphocytic activation



molecule isoform 1 precursor [Mus musculus]



MDPKGSLSWRILLFLSLAFELSYGTGGGVMDCPVILQKLGQDTWLPLTNEHQI



NKSVNKSVRILVTMATSPGSKSNKKIVSFDLSKGSYPDHLEDGYHFQSKNLSL



KILGNRRESEGWYLVSVEENVSVQQFCKQLKLYEQVSPPEIKVLNKTQENENG



TCSLLLACTVKKGDHVTYSWSDEAGTHLLSRANRSHLLHITLSNQHQDSIYNC



TASNPVSSISRTFNLSSQACKQESSSESSPWMQYTLVPLGVVIIFILVFTAII



MMKRQGKSNHCQPPVEEKSLTIYAQVQKSGPQEKKLHDALTDQDPCTTIYVAA



TEPAPESVQEPNPTTVYASVTLPES (SEQ ID NO: 150)





Human CD40
>NM_001250.6 Homo sapiens CD40 molecule (CD40),



transcript variant 1, mRNA



AGTGGTCCTGCCGCCTGGTCTCACCTCGCTATGGTTCGTCTGCCTCTGCAGTG



CGTCCTCTGGGGCTGCTTGCTGACCGCTGTCCATCCAGAACCACCCACTGCAT



GCAGAGAAAAACAGTACCTAATAAACAGTCAGTGOTGTTCTTTGTGCCAGCCA



GGACAGAAACTGGTGAGTGACTGCACAGAGTTCACTGAAACGGAATGCCTTCC



TTGCGGTGAAAGCGAATTCCTAGACACCTGGAACAGAGAGACACACTGCCACC



AGCACAAATACTGCGACCCCAACCTAGGGCTTCGGGTCCAGCAGAAGGGCACC



TCAGAAACAGACACCATCTGCACCTGTGAAGAAGGCTGGCACTGTACGAGTGA



GGCCTGTGAGAGCTGTGTCCTGCACCGCTCATGCTCGCCCGGCTTTGGGGTCA



AGCAGATTGCTACAGGGGTTTCTGATACCATCTGCGAGCCCTGCCCAGTCGGC



TTCTTCTCCAATGTGTCATCTGCTTTCGAAAAATGTCACCCTTGGACAAGCTG



TGAGACCAAAGACCTGGTTGTGCAACAGGCAGGCACAAACAAGACTGATGTTG



TCTGTGGTCCCCAGGATCGGCTGAGAGCCCTGGTGGTGATCCCCATCATCTTC



GGGATCCTGTTTGCCATCCTCTTGGTGCTGGTCTTTATCAAAAAGGTGGCCAA



GAAGCCAACCAATAAGGCCCCCCACCCCAAGCAGGAACCCCAGGAGATCAATT



TTCCCGACGATCTTCCTGGCTCCAACACTGCTGCTCCAGTGCAGGAGACTTTA



CATGGATGCCAACCGGTCACCCAGGAGGATGGCAAAGAGAGTCGCATCTCAGT



GCAGGAGAGACAGTGAGGCTGCACCCACCCAGGAGTGTGGCCACGTGGGCAAA



CAGGCAGTTGGCCAGAGAGCCTGGTGCTGCTGCTGCTGTGGCGTGAGGGTGAG



GGGCTGGCACTGACTGGGCATAGCTCCCCGCTTCTGCCTGCACCCCTGCAGTT



TGAGACAGGAGACCTGGCACTGGATGCAGAAACAGTTCACCTTGAAGAACCTC



TCACTTCACCCTGGAGCCCATCCAGTCTCCCAACTTGTATTAAAGACAGAGGC



AGAAGTTTGGTGGTGGTGGTGTTGGGGTATGGTTTAGTAATATCCACCAGACC



TTCCGATCCAGCAGTTTGGTGCCCAGAGAGGCATCATGGTGGCTTCCCTGCGC



CCAGGAAGCCATATACACAGATGCCCATTGCAGCATTGTTTGTGATAGTGAAC



AACTGGAAGCTGCTTAACTGTCCATCAGCAGGAGACTGGCTAAATAAAATTAG



AATATATTTATACAACAGAATCTCAAAAACACTGTTGAGTAAGGAAAAAAAGG



CATGCTGCTGAATGATGGGTATGGAACTTTTTAAAAAAGTACATGCTTTTATG



TATGTATATTGCCTATGGATATATGTATAAATACAATATGCATCATATATTGA



TATAACAAGGGTTCTGGAAGGGTACACAGAAAACCCACAGCTCGAAGAGTGGT



GACGTCTGGGGTGGGGAAGAAGGGTCTGGGGGAGGGTTGGTTAAAGGGAGATT



TGGCTTTCCCATAATGCTTCATCATTTTTCCCAAAAGGAGAGTGAATTCACAT



AATGCTTATGTAATTAAAAAATCATCAAACATGTAAAAA (SEQ ID NO:



151)






>NP_001241.1 tumor necrosis factor receptor



superfamily member 5 isoform 1 precursor [Homo




sapiens]




MVRLPLQCVLWGCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQKLVSDCTE



FTETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCE



EGWHCTSEACESCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFE



KCHPWTSCETKDLVVQQAGTNKTDVVCGPQDRLRALVVIPIIFGILFAILLVL



VFIKKVAKKPTNKAPHPKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQED



GKESRISVQERQ (SEQ ID NO: 152)





Mouse CD40
>NM_170703.2 Mus musculus CD40 antigen (Cd40),



transcript variant 2, mRNA



AGCAGGGACTTTGGAGTGACTTGTGGCTTCAGCAGGAGCCCTGTGATTTGGCT



CTTCTGATCTCGCCCTGCGATGGTGTCTTTGCCTCGGCTGTGCGCGCTATGGG



GCTGCTTGTTGACAGCGGTCCATCTAGGGCAGTGTGTTACGTGCAGTGACAAA



CAGTACCTCCACGATGGCCAGTGCTGTGATTTGTGCCAGCCAGGAAGCCGACT



GACAAGCCACTGCACAGCTCTTGAGAAGACCCAATGCCACCCATGTGACTCAG



GCGAATTCTCAGCCCAGTGGAACAGGGAGATTCGCTGTCACCAGCACAGACAC



TGTGAACCCAATCAAGGGCTTCGGGTTAAGAAGGAGGGCACCGCAGAATCAGA



CACTGTCTGTACCTGTAAGGAAGGACAACACTGCACCAGCAAGGATTGCGAGG



CATGTGCTCAGCACACGCCCTGTATCCCTGGCTTTGGAGTTATGGAGATGGCC



ACTGAGACCACTGATACCGTCTGTCATCCCTGCCCAGTCGGCTTCTTCTCCAA



TCAGTCATCACTTTTCGAAAAGTGTTATCCCTGGACAAGGTTTAAAGTCCCGG



ATGCGAGCCCTGCTGGTCATTCCTGTCGTGATGGGCATCCTCATCACCATTTT



CGGGGTGTTTCTCTATATCAAAAAGGTGGTCAAGAAACCAAAGGATAATGAGA



TCTTACCCCCTGCGGCTCGACGGCAAGATCCCCAGGAGATGGAAGATTATCCC



GGTCATAACACCGCTGCTCCAGTGCAGGAGACGCTGCACGGGTGTCAGCCTGT



CACACAGGAGGATGGTAAAGAGAGTCGCATCTCAGTGCAGGAGCGGCAGGTGA



CAGACAGCATAGCCTTGAGGCCCCTGGTCTGAACCCTGGAACTGCTTTGGAGG



CGATGGCTCGGCTCGGGAGCAGGGGCCTGGCTCTGAGGACTGCTTGCTGACCT



TTGAAGTTTGAGATGAGCCAAGACAGAGCCCAGTGCAGCTAACTCTCATGCCT



GCCCCCTATCATTTCTCAACTTGCTTTTTAAGGATGGAGGGAGAGCTCGGGCA



TCGGGGGTCCACAGTGATACCTACCAAGTGCAGCAGTGCAGGACCCAGAGTCG



TCTTGCTGCGGCGTTCACTGTAAGGAGTCATGGACACAGGAGTCCGTGGCCCA



CAGCTTGTGCTGCTAGAGGGCACCTGGTTGCCCATCAGCAGGGTACTGGCTAA



ATAAATCTGTAATTATTTATACAATGACATCTCAGAAACTCTAGCAGGTGGGG



CAGAAAACAGGTAGTAGAATGATGGGTAGAGAAATAGCTTTTAAAACACATTC



CAAGGCAGGTAAGATGGCTTTTGTGAGTAAAGGAGCTTGCTGCCCAAACCCGG



TTACCTGATTTTGATCCCTGGGACTTCATGGTAAAAGGGAGAGAACCAAATCC



AGAGGGTTGTCATTTGACCTCCATGTGTGCTCTGTGGTAATGTACCCCGTGTG



TGCACATGTGCACATATCCTAAAATGGATGTGGTGGTGTATTGTAGAAATTAT



TTAATCCCGCCCTGGGGTTTCTACCTGTGTGTTACCATTTAGTTCTTGAATAA



AAGACACACTCAACCTTTATATTTACAATAA (SEQ ID NO: 153)






>NP_733804.1 tumor necrosis factor receptor



superfamily member 5 isoform 2 precursor [Mus




musculus]




MVSLPRLCALWGCLLTAVHLGQCVTCSDKQYLHDGQCCDLCQPGSRLTSHCTA



LEKTQCHPCDSGEFSAQWNREIRCHQHRHCEPNQGLRVKKEGTAESDTVCTCK



EGQHCTSKDCEACAQHTPCIPGFGVMEMATETTDTVCHPCPVGFFSNQSSLFE



KCYPWTRFKVPDASPAGHSCRDGHPHHHFRGVSLYQKGGQETKG (SEQ ID



NO: 154)





Human CD28
>NM_006139.4 Homo sapiens CD28 molecule (CD28),



transcript variant 1, mRNA



ACACTTCGGGTTCCTCGGGGAGGAGGGGCTGGAACCCTAGCCCATCGTCAGGA



CAAAGATGCTCAGGCTGCTCTTGGCTCTCAACTTATTCCCTTCAATTCAAGTA



ACAGGAAACAAGATTTTGGTGAAGCAGTCGCCCATGCTTGTAGCGTACGACAA



TGCGGTCAACCTTAGCTGCAAGTATTCCTACAATCTCTTCTCAAGGGAGTTCC



GGGCATCCCTTCACAAAGGACTGGATAGTGCTGTGGAAGTCTGTGTTGTATAT



GGGAATTACTCCCAGCAGCTTCAGGTTTACTCAAAAACGGGGTTCAACTGTGA



TGGGAAATTGGGCAATGAATCAGTGACATTCTACCTCCAGAATTTGTATGTTA



ACCAAACAGATATTTACTTCTGCAAAATTGAAGTTATGTATCCTCCTCCTTAC



CTAGACAATGAGAAGAGCAATGGAACCATTATCCATGTGAAAGGGAAACACCT



TTGTCCAAGTCCCCTATTTCCCGGACCTTCTAAGCCCTTTTGGGTGCTGGTGG



TGGTTGGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATT



ATTTTCTGGGTGAGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAA



CATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCC



CACCACGCGACTTCGCAGCCTATCGCTCCTGACACGGACGCCTATCCAGAAGC



CAGCCGGCTGGCAGCCCCCATCTGCTCAATATCACTGCTCTGGATAGGAAATG



ACCGCCATCTCCAGCCGGCCACCTCAGGCCCCTGTTGGGCCACCAATGCCAAT



TTTTCTCGAGTGACTAGACCAAATATCAAGATCATTTTGAGACTCTGAAATGA



AGTAAAAGAGATTTCCTGTGACAGGCCAAGTCTTACAGTGCCATGGCCCACAT



TCCAACTTACCATGTACTTAGTGACTTGACTGAGAAGTTAGGGTAGAAAACAA



AAAGGGAGTGGATTCTGGGAGCCTCTTCCCTTTCTCACTCACCTGCACATCTC



AGTCAAGCAAAGTGTGGTATCCACAGACATTTTAGTTGCAGAAGAAAGGCTAG



GAAATCATTCCTTTTGGTTAAATGGGTGTTTAATCTTTTGGTTAGTGGGTTAA



ACGGGGTAAGTTAGAGTAGGGGGAGGGATAGGAAGACATATTTAAAAACCATT



AAAACACTGTCTCCCACTCATGAAATGAGCCACGTAGTTCCTATTTAATGCTG



TTTTCCTTTAGTTTAGAAATACATAGACATTGTCTTTTATGAATTCTGATCAT



ATTTAGTCATTTTGACCAAATGAGGGATTTGGTCAAATGAGGGATTCCCTCAA



AGCAATATCAGGTAAACCAAGTTGCTTTCCTCACTCCCTGTCATGAGACTTCA



GTGTTAATGTTCACAATATACTTTCGAAAGAATAAAATAGTTCTCCTACATGA



AGAAAGAATATGTCAGGAAATAAGGTCACTTTATGTCAAAATTATTTGAGTAC



TATGGGACCTGGCGCAGTGGCTCATGCTTGTAATCCCAGCACTTTGGGAGGCC



GAGGTGGGCAGATCACTTGAGATCAGGACCAGCCTGGTCAAGATGGTGAAACT



CCGTCTGTACTAAAAATACAAAATTTAGCTTGGCCTGGTGGCAGGCACCTGTA



ATCCCAGCTGCCCAAGAGGCTGAGGCATGAGAATCGCTTGAACCTGGCAGGCG



GAGGTTGCAGTGAGCCGAGATAGTGCCACAGCTCTCCAGCCTGGGCGACAGAG



TGAGACTCCATCTCAAACAACAACAACAACAACAACAACAACAACAAACCACA



AAATTATTTGAGTACTGTGAAGGATTATTTGTCTAACAGTTCATTCCAATCAG



ACCAGGTAGGAGCTTTCCTGTTTCATATGTTTCAGGGTTGCACAGTTGGTCTC



TTTAATGTCGGTGTGGAGATCCAAAGTGGGTTGTGGAAAGAGCGTCCATAGGA



GAAGTGAGAATACTGTGAAAAAGGGATGTTAGCATTCATTAGAGTATGAGGAT



GAGTCCCAAGAAGGTTCTTTGGAAGGAGGACGAATAGAATGGAGTAATGAAAT



TCTTGCCATGTGCTGAGGAGATAGCCAGCATTAGGTGACAATCTTCCAGAAGT



GGTCAGGCAGAAGGTGCCCTGGTGAGAGCTCCTTTACAGGGACTTTATGTGGT



TTAGGGCTCAGAGCTCCAAAACTCTGGGCTCAGCTGCTCCTGTACCTTGGAGG



TCCATTCACATGGGAAAGTATTTTGGAATGTGTCTTTTGAAGAGAGCATCAGA



GTTCTTAAGGGACTGGGTAAGGCCTGACCCTGAAATGACCATGGATATTTTTC



TACCTACAGTTTGAGTCAACTAGAATATGCCTGGGGACCTTGAAGAATGGCCC



TTCAGTGGCCCTCACCATTTGTTCATGCTTCAGTTAATTCAGGTGTTGAAGGA



GCTTAGGTTTTAGAGGCACGTAGACTTGGTTCAAGTCTCGTTAGTAGTTGAAT



AGCCTCAGGCAAGTCACTGCCCACCTAAGATGATGGTTCTTCAACTATAAAAT



GGAGATAATGGTTACAAATGTCTCTTCCTATAGTATAATCTCCATAAGGGCAT



GGCCCAAGTCTGTCTTTGACTCTGCCTATCCCTGACATTTAGTAGCATGCCCG



ACATACAATGTTAGCTATTGGTATTATTGCCATATAGATAAATTATGTATAAA



AATTAAACTGGGCAATAGCCTAAGAAGGGGGGAATATTGTAACACAAATTTAA



ACCCACTACGCAGGGATGAGGTGCTATAATATGAGGACCTTTTAACTTCCATC



ATTTTCCTGTTTCTTGAAATAGTTTATCTTGTAATGAAATATAAGGCACCTCC



CACTTTTATGTATAGAAAGAGGTCTTTTAATTTTTTTTTAATGTGAGAAGGAA



GGGAGGAGTAGGAATCTTGAGATTCCAGATCGAAAATACTGTACTTTGGTTGA



TTTTTAAGTGGGCTTCCATTCCATGGATTTAATCAGTCCCAAGAAGATCAAAC



TCAGCAGTACTTGGGTGCTGAAGAACTGTTGGATTTACCCTGGCACGTGTGCC



ACTTGCCAGCTTCTTGGGCACACAGAGTTCTTCAATCCAAGTTATCAGATTGT



ATTTGAAAATGACAGAGCTGGAGAGTTTTTTGAAATGGCAGTGGCAAATAAAT



AAATACTTTTTTTTAAATGGAAAGACTTGATCTATGGTAATAAATGATTTTGT



TTTCTGACTGGAAAAATAGGCCTACTAAAGATGAATCACACTTGAGATGTTTC



TTACTCACTCTGCACAGAAACAAAGAAGAAATGTTATACAGGGAAGTCCGTTT



TCACTATTAGTATGAACCAAGAAATGGTTCAAAAACAGTGGTAGGAGCAATGC



TTTCATAGTTTCAGATATGGTAGTTATGAAGAAAACAATGTCATTTGCTGCTA



TTATTGTAAGAGTCTTATAATTAATGGTACTCCTATAATTTTTGATTGTGAGC



TCACCTATTTGGGTTAAGCATGCCAATTTAAAGAGACCAAGTGTATGTACATT



ATGTTCTACATATTCAGTGATAAAATTACTAAACTACTATATGTCTGCTTTAA



ATTTGTACTTTAATATTGTCTTTTGGTATTAAGAAAGATATGCTTTCAGAATA



GATATGCTTCGCTTTGGCAAGGAATTTGGATAGAACTTGCTATTTAAAAGAGG



TGTGGGGTAAATCCTTGTATAAATCTCCAGTTTAGCCTTTTTTGAAAAAGCTA



GACTTTCAAATACTAATTTCACTTCAAGCAGGGTACGTTTCTGGTTTGTTTGC



TTGACTTCAGTCACAATTTCTTATCAGACCAATGGCTGACCTCTTTGAGATGT



CAGGCTAGGCTTACCTATGTGTTCTGTGTCATGTGAATGCTGAGAAGTTTGAC



AGAGATCCAACTTCAGCCTTGACCCCATCAGTCCCTCGGGTTAACTAACTGAG



CCACCGGTCCTCATGGCTATTTTAATGAGGGTATTGATGGTTAAATGCATGTC



TGATCCCTTATCCCAGCCATTTGCACTGCCAGCTGGGAACTATACCAGACCTG



GATACTGATCCCAAAGTGTTAAATTCAACTACATGCTGGAGATTAGAGATGGT



GCCAATAAAGGACCCAGAACCAGGATCTTGATTGCTATAGACTTATTAATAAT



CCAGGTCAAAGAGAGTGACACACACTCTCTCAAGACCTGGGGTGAGGGAGTCT



GTGTTATCTGCAAGGCCATTTGAGGCTCAGAAAGTCTCTCTTTCCTATAGATA



TATGCATACTTTCTGACATATAGGAATGTATCAGGAATACTCAACCATCACAG



GCATGTTCCTACCTCAGGGCCTTTACATGTCCTGTTTACTCTGTCTAGAATGT



CCTTCTGTAGATGACCTGGCTTGCCTCGTCACCCTTCAGGTCCTTGCTCAAGT



GTCATCTTCTCCCCTAGTTAAACTACCCCACACCCTGTCTGCTTTCCTTGCTT



ATTTTTCTCCATAGCATTTTACCATCTCTTACATTAGACATTTTTCTTATTTA



TTTGTAGTTTATAAGCTTCATGAGGCAAGTAACTTTGCTTTGTTTCTTGCTGT



ATCTCCAGTGCCCAGAGCAGTGCCTGGTATATAATAAATATTTATTGACTGAG



TGAA (SEQ ID NO: 155)






>NP_006130.1 T-cell-specific surface glycoprotein



CD28 isoform 1 precursor [Homo sapiens]



MLRLLLALNLFPSIQVTGNKILVKQSPMLVAYDNAVNLSCKYSYNLFSREFRA



SLHKGLDSAVEVCVVYGNYSQQLQVYSKTGFNCDGKLGNESVTFYLQNLYVNQ



TDIYFCKIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVV



GGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPP



RDFAAYRS (SEQ ID NO: 156)





Mouse CD28
>NM_007642.4 Mus musculus CD28 antigen (Cd28), mRNA



AGACCTTGGCAGATGTGACTTCAGTTCACACCACACTCTGCCTTGCTCACAGA



GGAGGGGCTGCAGCCCTGGCCCTCATCAGAACAATGACACTCAGGCTGCTGTT



CTTGGCTCTCAACTTCTTCTCAGTTCAAGTAACAGAAAACAAGATTTTGGTAA



AGCAGTCGCCCCTGCTTGTGGTAGATAGCAACGAGGTCAGCCTCAGCTGCAGG



TATTCCTACAACCTTCTCGCAAAGGAATTCCGGGCATCCCTGTACAAGGGCGT



GAACAGCGACGTGGAAGTCTGTGTCGGGAATGGGAATTTTACCTATCAGCCCC



AGTTTCGCTCGAATGCCGAGTTCAACTGCGACGGGGATTTCGACAACGAAACA



GTGACGTTCCGTCTCTGGAATCTGCACGTCAATCACACAGATATTTACTTCTG



CAAAATTGAGTTCATGTACCCTCCGCCTTACCTAGACAACGAGAGGAGCAATG



GAACTATTATTCACATAAAAGAGAAACATCTTTGTCATACTCAGTCATCTCCT



AAGCTGTTTTGGGCACTGGTCGTGGTTGCTGGAGTCCTGTTTTGTTATGGCTT



GCTAGTGACAGTGGCTCTTTGTGTTATCTGGACAAATAGTAGAAGGAACAGAC



TCCTTCAAAGTGACTACATGAACATGACTCCCCGGAGGCCTGGGCTCACTCGA



AAGCCTTACCAGCCCTACGCCCCTGCCAGAGACTTTGCAGCGTACCGCCCCTG



ACAGGGACCCCTATCCAGAAGCCCGCCGGCTGGTACCCGTCTACCTGCTCATC



ATCACTGCTCTGGATAGGAAAGGACAGCCTCATCTTCAGCCGGCCACTTTGGA



CCTCTACTGGGCCACCAATGCCAACTATTTTAGAGTGTCTAGATCTAACATCA



TGATCATCTTGAGACTCTGGAATGAATGACAGAAGCTTCTATGGCAGGATAAA



GTCTGTGTGGCTTGACCCAAACTCAAGCTTAATACATTTATTGACTTGATTGG



GGAAGTTAGAGTAGAGCAATCAAAAAGATCATTCATTCAGCCTTGGGAAGTCA



ATTTGCAGGCTCCTGGATGAGCCCTGCCCCGTTTTCACTTGCCAGCACATTTC



AGTCATGTGGTGTGATAGCCAAAGATGTTTTGGACAGAGAAGAAAGGATAGAA



AAACCTTCTCTTTGGCTAAGTTGGTGTTTGGGGTGGGGATAGGTTAGAGTATA



GTACTTAACTATTTGAAAAATAATGAAAACACTTTTTTCACTCATGAAATGAG



CCACTTAGCTCCTAAATAGTGTTTTCCTGTTAGTTTAGAAAGTTGTGGACATA



TTTTTTTAATGATTTCTGACCATTTTTAATCACATTGACTCATGGAATGGCCT



CAAAGCACCCCCCAGTGCTTCTTTCCTCATTCCCGGTCATGGGAACTCAGTAT



TATTAATAGTCACAACATGATTTCAGAACTAGATAGCCCTCCCACACCAAGAA



GAATGTGAGAGGAAGTAAGGTCACTTTATGTAAAAAAAAAAAAAAACAAACGC



GTACACATATGTATGTATACATACATACCTATGTGCACACACACACACATATA



CATACACACAAAATGCTATGAAGAGTTATCTGTTTAGTAGCCTGTTATAGTCA



AATCATTTTAAGTTTCAACTTCTTACAGTTGGGCCACTTGTTGTCCTTTGTGG



ATGGATATCTGAAATTGTGTCTATATATTGCTAGTCATGATACTGTGAACAAA



AAGGGTAGTGTTAGTATTTGTCAGGGTGGTAAGGATGCATTCCAGGAAGCTTC



CTCTGAGGAAGGGAATGAGGTCATTCTTGCCATGTATGAAAGACATAGATGTT



TTCCAGAAGGCACCATTGGGAGCCCCAGTATAAGTTCCTTTAGACTCTACAGT



TTAGAGGGATTTTATATGTCCTAGGACTCAGGACTCCAGAACTTTGTGGGCTC



AGCTGCTTCATACCATGGGGATACATTGACATGAACAATTATTTTGGAATGTG



TCTTTAGGGACGACATCAAAGTTCTCAAGTACCTACAAGACCTGATACTGGAA



TGAAGGTGGACTTTCTTTTTTGCTTCCAGTTCGGATCAACTGGAATGTATCTG



GGGACCTTGAAGAACGGCTGTCCAGCTGTCTTCACCATTTGTATAGTGCTTTG



AATTATTCAGAGGTTTTAAAGTCAGGAAGACCTGGTTTAAAAAACATTTCATT



ATGAGTTAAATGGCCTCAGGCAAGTCACTGTTCATCCAAGTCTATGACTCCTC



AACTGTAAGATGGCCACACTGAAACTTGCTAAGATCCTCTGGCCTCTGCCTCC



CAAGAGTTGGGATTTCAGGAGTGCACAATCATGACCCAAACTCGTGATAATCT



CTCAGCTTCAATAACTTTCCAGCTAATTGGAATATCCTGTAATCAAACATGAG



GCATTTCCCCTCCCCCCACTGTTTTTGTGTATAAAGAGATCTTTAAACTTTTT



TTTTAATATGAGGGGTAAGAAAAGATAGGAATCTTTTAATTCTAGACAGAAGA



TATTGTGCTTTGGTTTTTTTTTTTTTTAATGGCTTCTATTCTGTGCTTTTAAT



TAAACCAGAGAAGGCCAAGATTAGCCCTACTTGTGTGATAAAAGAATGCTGGC



CCTTGTGATTGCAGTCAGCCTCTTGACACATAGAGTTCTTGAATCTAAGTTAT



AAAATTATATTTGAAAATGACAGAGCTGGAGAATTTATAGAAAGGGTCATAGC



AAATAACAAACCATTTTTTTTTAAACGGAAAGATTTGGTCTTTGGCAATCAAT



AACTTTGTTTTCTAACTGGAAAAGGAGGTTTACTGGAGATGAATCACACCTGA



AAGTTTTCATACCTCCTCTGAACACAACCGAAACATAGGTGTCCAAAGCCTTT



CGCTCTCGGTATGAACCAACAGGCGGGTTAAAAACACTGGGTCAGAGTAAAGC



TTTTGCAGTTTCAGATGTAGTGTGTATGAAGAAAACTATGTCACTTGCTGCTA



TTATTGTAAGAGTCTAAGAACTAAAGGTGTGCCTGTAATTTCTAATTATGAGC



TCACCTATTTGGTACCGAGCATGCCAATTTTAAAGAGACCCGGTGTACCTTAT



AGCTACATCCAATGATAAAATTACCACACTAGCACATGCCTGTGTTTAAACTC



GTGCTTTAATGTTTTTCTTAGGGCAGGTATGCACCCCCTTTGCAGTGAGTTGG



GAGAGATTTTGAAAAAGTGTATGACAAACATTTTTAACACCTTTGGTTTCCTC



TCTCTGTGTCTCTTTGTCTCTGTCTCTCTCTTTCTCTCCTGTGCATATGTCTC



CCCTCCCTCACTTCTCTGTCTCTTCCTCTCTCCCTCTCTCTGTCTTTCTCTGT



GTGTCTCTCTGTCTCTGTGTATCTCTCTGTCTGTCTCTTTCTCTGCAGATTTT



CAAAACGTTGTTTTTCTATGGAAGAAATACAAGCTGTGGTTGGTTTGCTACGA



GTCAGTAGCAGTTTATCAGTAGGCCAATGTTTTATCTCTTGGAGATTTCAGTC



TGGGTTTACCCAATGTATTCTCTGTAATGTGACTGCTGGGGACAGATATAACT



TGATTGAGCCTTCAAATCATTTAGGTCTTCAATCATTTAGTCAACGGAGTGAG



CCACTAATCTGCAATGGCTATTTTAATATGCATACTGATGGTCAAATGGATGT



CTGATCTCTCATCCCAGCTTTCTGTACTACCATATGGGAACTATATGTAACTT



GTATACTTACCTGAATATGTTAAATTCAACTACATGGTAAGATGGACCAGAAA



TTGCAATGTTCATGTCCATATAGCCACCATTAACCCAAGTTAAGCACAGTAGT



GTGGGTTCTCTCAGGACTTGTGAATGAGTTTATGCTCTCTACAAAGACAGGTG



AAGCTTAAATCTCTCTTGCACTGCTATGTTTATGCAAATATCAAGATTGTTTC



TGTACCAGGGACTTAACACATTCTATTCATACTATTTTCCCTGTCTACAATGT



TATTTCATAGATATCTACTTGGTTTGCTCTTACTTCCTTGACATATTTGCCCA



AATGCCACCTTCAACTGTAGTTAATTACCTGTACAACCTGTCTCCATGCCTTG



TTTTATTTTCTCTATAACTCTACTAATAGGTATTTTTCTTATTTATTGGTTTA



TTGCCTGTTTTTTTTCCTAAATCTACACCGGATCTCCAAAGGGAAAGAACTCC



ATTTGCTTTGATTTTATTGCTGTATCCCCAGTGCCTAGAATAATGCTTAGCCT



GCAATAAATATTTATTCATTGACT (SEQ ID NO: 157)






>NP_031668.3 T-cell-specific surface glycoprotein



CD28 precursor [Mus musculus]



MTLRLLFLALNFFSVQVTENKILVKQSPLLVVDSNEVSLSCRYSYNLLAKEFR



ASLYKGVNSDVEVCVGNGNFTYQPQFRSNAEFNCDGDFDNETVTFRLWNLHVN



HTDIYFCKIEFMYPPPYLDNERSNGTIIHIKEKHLCHTQSSPKLFWALVVVAG



VLFCYGLLVTVALCVIWTNSRRNRLLQSDYMNMTPRRPGLTRKPYQPYAPARD



FAAYRP (SEQ ID NO: 158)





Human
>NM_144615.2 Homo sapiens transmembrane and


CD28H
immunoglobulin domain containing 2 (TMIGD2),



transcript variant 1, mRNA



GGAAGTCTGTCAACTGGGAGGGGGAGAGGGGGGTGATGGGCCAGGAATGGGGT



CCCCGGGCATGGTGCTGGGCCTCCTGGTGCAGATCTGGGCCCTGCAAGAAGCC



TCAAGCCTGAGCGTGCAGCAGGGGCCCAACTTGCTGCAGGTGAGGCAGGGCAG



TCAGGCGACCCTGGTCTGCCAGGTGGACCAGGCCACAGCCTGGGAACGGCTCC



GTGTTAAGTGGACAAAGGATGGGGCCATCCTGTGTCAACCGTACATCACCAAC



GGCAGCCTCAGCCTGGGGGTCTGCGGGCCCCAGGGACGGCTCTCCTGGCAGGC



ACCCAGCCATCTCACCCTGCAGCTGGACCCTGTGAGCCTCAACCACAGCGGGG



CGTACGTGTGCTGGGCGGCCGTAGAGATTCCTGAGTTGGAGGAGGCTGAGGGC



AACATAACAAGGCTCTTTGTGGACCCAGATGACCCCACACAGAACAGAAACCG



GATCGCAAGCTTCCCAGGATTCCTCTTCGTGCTGCTGGGGGTGGGAAGCATGG



GTGTGGCTGCGATCGTGTGGGGTGCCTGGTTCTGGGGCCGCCGCAGCTGCCAG



CAAAGGGACTCAGGTAACAGCCCAGGAAATGCATTCTACAGCAACGTCCTATA



CCGGCCCCGGGGGGCCCCAAAGAAGAGTGAGGACTGCTCTGGAGAGGGGAAGG



ACCAGAGGGGCCAGAGCATTTATTCAACCTCCTTCCCGCAACCGGCCCCCCGC



CAGCCGCACCTGGCGTCAAGACCCTGCCCCAGCCCGAGACCCTGCCCCAGCCC



CAGGCCCGGCCACCCCGTCTCTATGGTCAGGGTCTCTCCTAGACCAAGCCCCA



CCCAGCAGCCGAGGCCAAAAGGGTTCCCCAAAGTGGGAGAGGAGTGAGAGATC



CCAGGAGACCTCAACAGGACCCCACCCATAGGTACACACAAAAAAGGGGGGAT



CGAGGCCAGACACGGTGGCTCACGCCTGTAATCCCAGCAGTTTGGGAAGCCGA



GGCGGGTGGAACACTTGAGGTCAGGGGTTTGAGACCAGCCTGGCTTGAACCTG



GGAGGCGGAGGTTGCAGTGAGCCGAGATTGCGCCACTGCACTCCAGCCTGGGC



GACAGAGTGAGACTCCGTCTCAAAAAAAACAAAAAGCAGGAGGATTGGGAGCC



TGTCAGCCCCATCCTGAGACCCCGTCCTCATTTCTGTAATGATGGATCTCGCT



CCCACTTTCCCCCAAGAACCTAATAAAGGCTTGTGAAGAAAAAGCAAAAAAAA



AAAAAAAAAA (SEQ ID NO: 159)






>NP_653216.2 transmembrane and immunoglobulin domain-



containing protein 2 isoform 1 precursor [Homo




sapiens]




MGSPGMVLGLLVQIWALQEASSLSVQQGPNLLQVRQGSQATLVCQVDQATAWE



RLRVKWTKDGAILCQPYITNGSLSLGVCGPQGRLSWQAPSHLTLQLDPVSLNH



SGAYVCWAAVEIPELEEAEGNITRLFVDPDDPTQNRNRIASFPGFLFVLLGVG



SMGVAAIVWGAWFWGRRSCQQRDSGNSPGNAFYSNVLYRPRGAPKKSEDCSGE



GKDQRGQSIYSTSFPQPAPRQPHLASRPCPSPRPCPSPRPGHPVSMVRVSPRP



SPTQQPRPKGFPKVGEE (SEQ ID NO: 160)





Human CD2
>NM_001328609.2 Homo sapiens CD2 molecule (CD2),



transcript variant 1, mRNA



AGTCTCACTTCAGTTCCTTTTGCATGAAGAGCTCAGAATCAAAAGAGGAAACC



AACCCCTAAGATGAGCTTTCCATGTAAATTTGTAGCCAGCTTCCTTCTGATTT



TCAATGTTTCTTCCAAAGGTGCAGTCTCCAAAGAGATTACGAATGCCTTGGAA



ACCTGGGGTGCCTTGGGTCAGGACATCAACTTGGACATTCCTAGTTTTCAAAT



GAGTGATGATATTGACGATATAAAATGGGAAAAAACTTCAGACAAGAAAAAGA



TTGCACAATTCAGAAAAGAGAAAGAGACTTTCAAGGAAAAAGATACATATAAG



CTATTTAAAAATGGAACTCTGAAAATTAAGCATCTGAAGACCGATGATCAGGA



TATCTACAAGGTATCAATATATGATACAAAAGGAAAAAATGTGTTGGAAAAAA



TATTTGATTTGAAGATTCAAGAGAGGGTCTCAAAACCAAAGATCTCCTGGACT



TGTATCAACACAACCCTGACCTGTGAGGTAATGAATGGAACTGACCCCGAATT



AAACCTGTATCAAGATGGGAAACATCTAAAACTTTCTCAGAGGGTCATCACAC



ACAAGTGGACCACCAGCCTGAGTGCAAAATTCAAGTGCACAGCAGGGAACAAA



GTCAGCAAGGAATCCAGTGTCGAGCCTGTCAGCTGTCCAGGAGGCAGCATCCT



TGGCCAGAGTAATGGGCTCTCTGCCTGGACCCCTCCCAGCCATCCCACTTCTC



TTCCTTTTGCAGAGAAAGGTCTGGACATCTATCTCATCATTGGCATATGTGGA



GGAGGCAGCCTCTTGATGGTCTTTGTGGCACTGCTCGTTTTCTATATCACCAA



AAGGAAAAAACAGAGGAGTCGGAGAAATGATGAGGAGCTGGAGACAAGAGCCC



ACAGAGTAGCTACTGAAGAAAGGGGCCGGAAGCCCCACCAAATTCCAGCTTCA



ACCCCTCAGAATCCAGCAACTTCCCAACATCCTCCTCCACCACCTGGTCATCG



TTCCCAGGCACCTAGTCATCGTCCCCCGCCTCCTGGACACCGTGTTCAGCACC



AGCCTCAGAAGAGGCCTCCTGCTCCGTCGGGCACACAAGTTCACCAGCAGAAA



GGCCCGCCCCTCCCCAGACCTCGAGTTCAGCCAAAACCTCCCCATGGGGCAGC



AGAAAACTCATTGTCCCCTTCCTCTAATTAAAAAAGATAGAAACTGTCTTTTT



CAATAAAAAGCACTGTGGATTTCTGCCCTCCTGATGTGCATATCCGTACTTCC



ATGAGGTGTTTTCTGTGTGCAGAACATTGTCACCTCCTGAGGCTGTGGGCCAC



AGCCACCTCTGCATCTTCGAACTCAGCCATGTGGTCAACATCTGGAGTTTTTG



GTCTCCTCAGAGAGCTCCATCACACCAGTAAGGAGAAGCAATATAAGTGTGAT



TGCAAGAATGGTAGAGGACCGAGCACAGAAATCTTAGAGATTTCTTGTCCCCT



CTCAGGTCATGTGTAGATGCGATAAATCAAGTGATTGGTGTGCCTGGGTCTCA



CTACAAGCAGCCTATCTGCTTAAGAGACTCTGGAGTTTCTTATGTGCCCTGGT



GGACACTTGCCCACCATCCTGTGAGTAAAAGTGAAATAAAAGCTTTGACTAGA



(SEQ ID NO: 161)






>NP_001315538.1 T-cell surface antigen CD2 isoform 1



precursor [Homo sapiens]



MSFPCKFVASFLLIFNVSSKGAVSKEITNALETWGALGQDINLDIPSFQMSDD



IDDIKWEKTSDKKKIAQFRKEKETFKEKDTYKLFKNGTLKIKHLKTDDQDIYK



VSIYDTKGKNVLEKIFDLKIQERVSKPKISWTCINTTLTCEVMNGTDPELNLY



QDGKHLKLSQRVITHKWTTSLSAKFKCTAGNKVSKESSVEPVSCPGGSILGQS



NGLSAWTPPSHPTSLPFAEKGLDIYLIIGICGGGSLLMVFVALLVFYITKRKK



QRSRRNDEELETRAHRVATEERGRKPHQIPASTPQNPATSQHPPPPPGHRSQA



PSHRPPPPGHRVQHQPQKRPPAPSGTQVHQQKGPPLPRPRVQPKPPHGAAENS



LSPSSN (SEQ ID NO: 162)





Mouse CD2
>NM_013486.2 Mus musculus CD2 antigen (Cd2), mRNA



GCCTCACCACAGTCCTGACAGAAAGAACTCAGAGTCACCCCTGGGAAAAGAAC



TCTAAAGATGAAATGTAAATTCCTGGGTAGCTTCTTTCTGCTCTTCAGCCTTT



CCGGCAAAGGGGCGGACTGCAGAGACAATGAGACCATCTGGGGTGTCTTGGGT



CATGGCATCACCCTGAACATCCCCAACTTTCAAATGACTGATGATATTGATGA



GGTGCGATGGGTAAGGAGGGGCACCCTGGTCGCAGAGTTTAAAAGGAAGAAGC



CACCTTTTTTGATATCAGAAACGTATGAGGTCTTAGCAAACGGATCCCTGAAG



ATAAAGAAGCCGATGATGAGAAACGACAGTGGCACCTATAATGTAATGGTGTA



TGGCACAAATGGGATGACTAGGCTGGAGAAGGACCTGGACGTGAGGATTCTGG



AGAGGGTCTCAAAGCCCATGATCCACTGGGAATGCCCCAACACAACCCTGACC



TGTGCGGTCTTGCAAGGGACAGATTTTGAACTGAAGCTGTATCAAGGGGAAAC



ACTACTCAATAGTCTCCCCCAGAAGAACATGAGTTACCAGTGGACCAACCTGA



ACGCACCATTCAAGTGTGAGGCGATAAACCCGGTCAGCAAGGAGTCTAAGATG



GAAGTTGTTAACTGTCCAGAGAAAGGTCTGTCCTTCTATGTCACAGTGGGGGT



CGGTGCAGGAGGACTCCTCTTGGTGCTCTTGGTGGCGCTTTTTATTTTCTGTA



TCTGCAAGAGGAGAAAACGGAACAGGAGGAGAAAAGATGAAGAGCTGGAAATA



AAAGCTTCCAGAACAAGCACTGTGGAAAGGGGCCCCAAGCCGCACTCAACCCC



AGCCGCAGCAGCGCAGAATTCAGTGGCGCTCCAAGCTCCTCCTCCACCTGGCC



ATCACCTCCAGACACCTGGCCATCGTCCCTTGCCTCCAGGCCACCGTACCCGT



GAGCACCAGCAGAAGAAGAGACCTCCTCCATCAGGCACACAGATTCACCAGCA



GAAAGGCCCTCCTTTACCCAGACCCCGAGTTCAGCCAAAACCTCCCTGTGGGA



GTGGAGATGGTGTTTCACTGCCGCCCCCTAATTAAGAAGGCAGAGTTCGTCAT



TTCCAATAAAAAGCTGTGTGGATTTATCTTC (SEQ ID NO: 163)






>NP_038514.1 T-cell surface antigen CD2 precursor



[Mus musculus]



MKCKFLGSFFLLFSLSGKGADCRDNETIWGVLGHGITLNIPNFQMTDDIDEVR



WVRRGTLVAEFKRKKPPFLISETYEVLANGSLKIKKPMMRNDSGTYNVMVYGT



NGMTRLEKDLDVRILERVSKPMIHWECPNTTLTCAVLQGTDFELKLYQGETLL



NSLPQKNMSYQWTNLNAPFKCEAINPVSKESKMEVVNCPEKGLSFYVTVGVGA



GGLLLVLLVALFIFCICKRRKRNRRRKDEELEIKASRTSTVERGPKPHSTPAA



AAQNSVALQAPPPPGHHLQTPGHRPLPPGHRTREHQQKKRPPPSGTQIHQQKG



PPLPRPRVQPKPPCGSGDGVSLPPPN (SEQ ID NO: 164)





Human LFA-3
>NM_001779.3 Homo sapiens CD58 molecule (CD58),


(CD58)
transcript variant 1, mRNA



GAACTTAGGGCTGCTTGTGGCTGGGCACTCGCGCAGAGGCCGGCCCGACGAGC



CATGGTTGCTGGGAGCGACGCGGGGCGGGCCCTGGGGGTCCTCAGCGTGGTCT



GCCTGCTGCACTGCTTTGGTTTCATCAGCTGTTTTTCCCAACAAATATATGGT



GTTGTGTATGGGAATGTAACTTTCCATGTACCAAGCAATGTGCCTTTAAAAGA



GGTCCTATGGAAAAAACAAAAGGATAAAGTTGCAGAACTGGAAAATTCTGAAT



TCAGAGCTTTCTCATCTTTTAAAAATAGGGTTTATTTAGACACTGTGTCAGGT



AGCCTCACTATCTACAACTTAACATCATCAGATGAAGATGAGTATGAAATGGA



ATCGCCAAATATTACTGATACCATGAAGTTCTTTCTTTATGTGCTTGAGTCTC



TTCCATCTCCCACACTAACTTGTGCATTGACTAATGGAAGCATTGAAGTCCAA



TGCATGATACCAGAGCATTACAACAGCCATCGAGGACTTATAATGTACTCATG



GGATTGTCCTATGGAGCAATGTAAACGTAACTCAACCAGTATATATTTTAAGA



TGGAAAATGATCTTCCACAAAAAATACAGTGTACTCTTAGCAATCCATTATTT



AATACAACATCATCAATCATTTTGACAACCTGTATCCCAAGCAGCGGTCATTC



AAGACACAGATATGCACTTATACCCATACCATTAGCAGTAATTACAACATGTA



TTGTGCTGTATATGAATGGTATTCTGAAATGTGACAGAAAACCAGACAGAACC



AACTCCAATTGATTGGTAACAGAAGATGAAGACAACAGCATAACTAAATTATT



TTAAAAACTAAAAAGCCATCTGATTTCTCATTTGAGTATTACAATTTTTGAAC



AACTGTTGGAAATGTAACTTGAAGCAGCTGCTTTAAGAAGAAATACCCACTAA



CAAAGAACAAGCATTAGTTTTGGCTGTCATCAACTTATTATATGACTAGGTGC



TTGCTTTTTTTGTCAGTAAATTGTTTTTACTGATGATGTAGATACTTTTGTAA



ATAAATGTAAATATGTACACAAGTGA (SEQ ID NO: 165)






>NP_001770.1 lymphocyte function-associated antigen 3



isoform 1 [Homo sapiens]



MVAGSDAGRALGVLSVVCLLHCFGFISCFSQQIYGVVYGNVTFHVPSNVPLKE



VLWKKQKDKVAELENSEFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYEME



SPNITDTMKFFLYVLESLPSPTLTCALTNGSIEVQCMIPEHYNSHRGLIMYSW



DCPMEQCKRNSTSIYFKMENDLPQKIQCTLSNPLFNTTSSIILTTCIPSSGHS



RHRYALIPIPLAVITTCIVLYMNGILKCDRKPDRTNSN (SEQ ID NO:



166)





Human CD48
>NM_001778.4 Homo sapiens CD48 molecule (CD48),



transcript variant 1, mRNA



CTTTTTCTAGCCAGGCTCTCAACTGTCTCCTGCGTTGCTGGGAAGTTCTGGAA



GGAAGCATGTGCTCCAGAGGTTGGGATTCGTGTCTGGCTCTGGAATTGCTACT



GCTGCCTCTGTCACTCCTGGTGACCAGCATTCAAGGTCACTTGGTACATATGA



CCGTGGTCTCCGGCAGCAACGTGACTCTGAACATCTCTGAGAGCCTGCCTGAG



AACTACAAACAACTAACCTGGTTTTATACTTTCGACCAGAAGATTGTAGAATG



GGATTCCAGAAAATCTAAGTACTTTGAATCCAAATTTAAAGGCAGGGTCAGAC



TTGATCCTCAGAGTGGCGCACTGTACATCTCTAAGGTCCAGAAAGAGGACAAC



AGCACCTACATCATGAGGGTGTTGAAAAAGACTGGGAATGAGCAAGAATGGAA



GATCAAGCTGCAAGTGCTTGACCCTGTACCCAAGCCTGTCATCAAAATTGAGA



AGATAGAAGACATGGATGACAACTGTTATCTGAAACTGTCATGTGTGATACCT



GGCGAGTCTGTAAACTACACCTGGTATGGGGACAAAAGGCCCTTCCCAAAGGA



GCTCCAGAACAGTGTGCTTGAAACCACCCTTATGCCACATAATTACTCCAGGT



GTTATACTTGCCAAGTCAGCAATTCTGTGAGCAGCAAGAATGGCACGGTCTGC



CTCAGTCCACCCTGTACCCTGGCCCGGTCCTTTGGAGTAGAATGGATTGCAAG



TTGGCTAGTGGTCACGGTGCCCACCATTCTTGGCCTGTTACTTACCTGAGATG



AGCTCTTTTAACTCAAGCGAAACTTCAAGGCCAGAAGATCTTGCCTGTTGGTG



ATCATGCTCCTCACCAGGACAGAGACTGTATAGGCTGACCAGAAGCATGCTGC



TGAATTATCAACGAGGATTTTCAAGTTAACTTTTAAATACTGGTTATTATTTA



ATTTTATATCCCTTTGTTGTTTTCTAGTACACAGAGATATAGAGATACACATG



CTTTTTTCCCACCCAAAATTGTGACAACATTATGTGAATGTTTTATTATTTTT



TAAAATAAACATTTGATATAATTGTCAATTAACTGAA (SEQ ID NO: 167)






>NP_001769.2 CD48 antigen isoform 1 precursor [Homo




sapiens]




MCSRGWDSCLALELLLLPLSLLVTSIQGHLVHMTVVSGSNVTLNISESLPENY



KQLTWFYTFDQKIVEWDSRKSKYFESKFKGRVRLDPQSGALYISKVQKEDNST



YIMRVLKKTGNEQEWKIKLQVLDPVPKPVIKIEKIEDMDDNCYLKLSCVIPGE



SVNYTWYGDKRPFPKELQNSVLETTLMPHNYSRCYTCQVSNSVSSKNGTVCLS



PPCTLARSFGVEWIASWLVVTVPTILGLLLT (SEQ ID NO: 168)





Mouse CD48
>NM_007649.5 Mus musculus CD48 antigen (Cd48),



transcript variant 1, mRNA



ATACGACTTCCGGTTTTGGGTTTTGCTTCCTGATTGAAGGGCAGGCGCCCTGA



CTTCTCTTACAGTTGTCTCCAGTGTTCTGGGGAAGCTTCTCTAAGTATTATGT



GCTTCATAAAACAGGGATGGTGTCTGGTCCTGGAACTGCTACTGCTGCCCTTG



GGAACTGGATTTCAAGGTCATTCAATACCAGATATAAATGCCACCACCGGCAG



CAATGTAACCCTGAAAATCCATAAGGACCCACTTGGACCATATAAACGTATCA



CCTGGCTTCATACTAAAAATCAGAAGATTTTAGAGTACAACTATAATAGTACA



AAGACAATCTTCGAGTCTGAATTTAAAGGCAGGGTTTATCTTGAAGAAAACAA



TGGTGCACTTCATATCTCTAATGTCCGGAAAGAGGACAAAGGTACCTACTACA



TGAGAGTGCTGCGTGAAACTGAGAACGAGTTGAAGATAACCCTGGAAGTATTT



GATCCTGTGCCCAAGCCTTCCATAGAAATCAATAAGACTGAAGCGTCGACTGA



TTCCTGTCACCTGAGGCTATCGTGTGAGGTAAAGGACCAGCATGTTGACTATA



CTTGGTATGAGAGCTCGGGACCTTTCCCCAAAAAGAGTCCAGGATATGTGCTC



GATCTCATCGTCACACCACAGAACAAGTCTACATTTTACACCTGCCAAGTCAG



CAATCCTGTAAGCAGCAAGAACGACACAGTGTACTTCACTCTACCTTGTGATC



TAGCCAGATCTTCTGGAGTATGTTGGACTGCAACTTGGCTAGTGGTCACAACA



CTCATCATTCACAGGATCCTGTTAACCTGACAAGAACTCTTCTCACCCAAGAA



GGCAACTTGGAAGCACAGAGTCTTGCCTTCATCCCTAGCAGTGTTCCTAGCCA



GCGAAGCAACTCTGGCTCTATTGGACAAAGGAAAATGTGTTACTGAACGTCTG



CGAGAGTTTGCATGCATGCTCTATGAAACAAGCACAGGACCTTGTACAGTGCT



CCACCACTGACCTGTGTGCCCAGTCCTTTACAAAGATTTCAAATCAACCTTTT



AAAAACTGTGCATAATATCTAATTTTATATACCCTAGTTGTTTCCCAACATAT



ATTAAAGATAAATGCATTCTTTTTACCAAAATGTGACTATATTATTTTCATGT



TTTCATATCTCTTTTTAAAATAAATTCTTTTAAAAAACT (SEQ ID NO:



169)






>NP_031675.1 0048 antigen isoform 1 precursor [Mus




musculus]




MCFIKQGWCLVLELLLLPLGTGFQGHSIPDINATTGSNVTLKIHKDPLGPYKR



ITWLHTKNQKILEYNYNSTKTIFESEFKGRVYLEENNGALHISNVRKEDKGTY



YMRVLRETENELKITLEVFDPVPKPSIEINKTEASTDSCHLRLSCEVKDQHVD



YTWYESSGPFPKKSPGYVLDLIVTPQNKSTFYTCQVSNPVSSKNDTVYFTLPC



DLARSSGVCWTATWLVVTTLIIHRILLT (SEQ ID NO: 170)





Human CD226
>NM_006566.4 Homo sapiens CD226 molecule (CD226),



transcript variant 1, mRNA



GCAGATGGGAAGAAGCGTTAGAGCGAGCAGCACTCACATCTCAAGAACCAGCC



TTTCAAACAGTTTCCAGAGATGGATTATCCTACTTTACTTTTGGCTCTTCTTC



ATGTATACAGAGCTCTATGTGAAGAGGTGCTTTGGCATACATCAGTTCCCTTT



GCCGAGAACATGTCTCTAGAATGTGTGTATCCATCAATGGGCATCTTAACACA



GGTGGAGTGGTTCAAGATCGGGACCCAGCAGGATTCCATAGCCATTTTCAGCC



CTACTCATGGCATGGTCATAAGGAAGCCCTATGCTGAGAGGGTTTACTTTTTG



AATTCAACGATGGCTTCCAATAACATGACTCTTTTCTTTCGGAATGCCTCTGA



AGATGATGTTGGCTACTATTCCTGCTCTCTTTACACTTACCCACAGGGAACTT



GGCAGAAGGTGATACAGGTGGTTCAGTCAGATAGTTTTGAGGCAGCTGTGCCA



TCAAATAGCCACATTGTTTCGGAACCTGGAAAGAATGTCACACTCACTTGTCA



GCCTCAGATGACGTGGCCTGTGCAGGCAGTGAGGTGGGAAAAGATCCAGCCCC



GTCAGATCGACCTCTTAACTTACTGCAACTTGGTCCATGGCAGAAATTTCACC



TCCAAGTTCCCAAGACAAATAGTGAGCAACTGCAGCCACGGAAGGTGGAGCGT



CATCGTCATCCCCGATGTCACAGTCTCAGACTCGGGGCTTTACCGCTGCTACT



TGCAGGCCAGCGCAGGAGAAAACGAAACCTTCGTGATGAGATTGACTGTAGCC



GAGGGTAAAACCGATAACCAATATACCCTCTTTGTGGCTGGAGGGACAGTTTT



ATTGTTGTTGTTTGTTATCTCAATTACCACCATCATTGTCATTTTCCTTAACA



GAAGGAGAAGGAGAGAGAGAAGAGATCTATTTACAGAGTCCTGGGATACACAG



AAGGCACCCAATAACTATAGAAGTCCCATCTCTACCAGTCAACCTACCAATCA



ATCCATGGATGATACAAGAGAGGATATTTATGTCAACTATCCAACCTTCTCTC



GCAGACCAAAGACTAGAGTTTAAGCTTATTCTTGACATGAGTGCATTAGTAAT



GACTCTTATGTACTCATGCATGGATCTTTATGCAATTTTTTTCCACTACCCAA



GGTCTACCTTAGATACTAGTTGTCTGAATTGAGTTACTTTGATAGGAAAAATA



CTTCATTACCTAAAATCATTTTTCATAGAACTGTTTCAGAAAACCTGACTCTA



ACTGGTTTATATACAAAAGAAAACTTACTGTATCATATAACAGAATGATCCAG



GGGAGATTAAGCTTTGGGCAAGGGCTATTTACCAGGGCTTAAATGTTGTGTCT



AGAATTAAGTATGGGCATAAACTGGCTTCTGAATCCCTTTCCAGAGTGTTGGA



TCCATTTCCCTGGTCTTGGCCTCACTCTCATGCAGGCTTTCCTCTTGTGTTGG



CAAGATGGCTGCCAACTCTTGGCAATTCATACATCCTTGTTTCTGTCTGGTAG



AGAGTTTGCTTCTCAAATGGAGCAAACAAATTTGATTATTTTTTCATTGTTAA



ATAGGCAACATGACCAGAAAGGATGGAATGGCTTAAGTAAACTAAGGGTTCAC



TTCTAGAGCTGAGAAGCAGGGTCAAAGCACAATACTGGGCAATTCAGAGCATG



GTTAGAAGAGGAAAGGGGAGTCTCAAAGCTGGAGAGTTTACCAACAAATATTG



ACTGCAGTGATTAACCAAGACATTTTTGTTAACTAAAAAGTGAAATATGGGAT



GGATTCTAGAAATGGGGTATCTCTGTCCATACTTCTAGAATCCACTCTATCAG



CATAGTCCAGAAGAATACCTGGCAGTAGAAGAAATGAATATTCAAGAGGAAGA



TAAATGCGAGAGGGCAATCCTTTACTATTCTCATATTTATTTATCTCTCATTC



TGTATAGAATTCTTGCCGCCATCCCAGGTCTAGCCTTAGGAGCAAATGTAGTA



GATAGTCGAATAATAAATAACTTAATGTTTTGGACATATTTTGTCTACTTTTG



AGAATTATTTTTAATATGTAAATTCTCTCAAAAGGGTCAGGCACCTAGTTATT



ATTTTTTAATGATTATGTGAAAGTTGAATATAATATACCACTAAAAGTGACAG



TTGAAAGTGGTGGCATAGGACGGTAGGGTAGAAATTTGGGAGGGAAAAAAGAA



ATTGGGAGGGTACAGGCAACAGGAGAAAGGAATCAAACCACAGAAAAATACAA



AGGGAAACTTCTGCTTCACTATTCAGACAAAGACAGCCCTAATGACATCACCA



ACAGTCAAAGCAATTAGAGACCATACCTAATATTGTTTAAATTCTAGATGTAG



GCTAACAATGAAAAGTATTTGCCAAACTGAATAAAACTGTCATGGTTACCTTG



AAAGGACAATGGTTATTGTTAAATATAGTGATCATTCATGTCTAAAAGATTCA



TTATTTATCTCTAAAGATTTCTAAAGACCACCATCTAGAAAAGATTCATTATG



AAGGCTGTATTTAAATATCAAAGTTGTGGACTTCATGATAATCTTAAATAAAG



CAAATCCAAATTCTCCTGTTGCCTAGACAGATTCTAAGATGTAATTTACACTT



TTAAGCTAATTAGTGAGTATTTTATGATTTTAGCCTTAAACACCATGTATGCC



AAATAATGCACTTGTTTTGTGAATTACAGAAATGGTAAGTGCCCACATTTCTG



TGAATTATAAAATTTGTGAGTTTCTTTTAACCCTTTTCAGGAGTGAAAAAATA



AAAACGACCATTTCCTGGTTGTGCTTAAGTATATGCAAGAAGGGTAAACTCTC



ATTTTTATTATGTTTGCTTAAAGATCTTTTTATACCTGGATTCATGAAATGTT



TCCACAAATATATTAGTGTAACAAACTTGAAAGGCAGTTTACAAGAAAGCACT



CTACTATCAGATCAATCAAAGATTCTGTGAGTGAATTTATTGGTTTGCATGGT



GAAGCAAGCTTAGCATCAATTAAAAGGTAAATAATTTCTTTTCTGAATGGTAA



AGACAATCAAAATATTACTTTCTGGAAAACTCCAATAACCAAATTCTCAATGA



TTAGTGTATGTGAGCAGGAAAACATTTTTACAGTTGTAGTATGGGGAAATATA



AATCCAATTTTAAGAGAGAAAATTATGACTGGGTGTGGAAGGGACAGTATAGT



CAGATACCATTGTCATGGTGGTTTTTACTGGGAACTTCATGAAAGACTTTTGT



AGCAAACCACTGCAGTATTGCAAAGCCTCCAGAACATTTGGAACTTGTCTCTT



TTTCCTTGTGTGTGTTTGTGTTTTTGGTCTCTCATTCAAAATATTGATGAGAA



CTATTTACTCTGTCCTTTCTTCTCTATATATTCTTCCTCTACAGAGTGTAGGG



TTTTTTCAGGAATTTGGAGCCATCTGAAGTCCTCCCAAAAATTCTCTGACGTC



TTCTGATGCTCCTGTTATACCCTCAGGGGTAATGCTTGTGAAATTCCATTCAT



TCATTTTCTTTCTCTGGACATCTTTACTTACCAAAGCACTTTCATTGTCATCT



TTTTAACATCATTCTTAATTCGTGATAGTTTTGGGACTCTCCCTAGTGTATGT



TTCTCCCCCTCTACTCTTTTGCACCTATGATTCTGATTGTTACTAAGAAAGCA



GATGAAAAACAGATCCACAGAATAAACGATCAGAATTCCAGTAAATTCTATTT



TAAATACAGATACTTTTTACAAGTTGCTGCTTTGGAAGCAAAATGCTTCTTAA



GTTTTACATATATATATATATATATACATATATATATACACATATAATTTATA



TCGATGGATAATACATTAAGAATCTATGCTTCCTTTGAATGCCATTAATATTT



ATGTTAAAGTAACCAATGAAAGGAAATTACTTTGTTATAATAAGATAGGAAGA



CTTGTTAATGGAGTACACAGTTTTGTCAGGGAAAGAACACATCTTATTGAACT



ATGATGACTATGCATTGACTATATTATTATAAGAGATACCTTCAAACTTTATT



TAAAGAACTTTAGGTATAATATGTTGAGAAAATAAAATAGAAATTTCATTTAC



TTGTAATCATGCTTAAAATGGGAGGCAGGTAGGTGAAGATATAATTTTTAGTA



AAAACTCCAATTTATGTTTTAAGTAATTCAGTGTATTACTAAAATACTATATA



TATAAACTTAAAATACATGGGTTATCAATTTAAAAGACAAAGTAAGTAAAAAT



ACTTTTAGTAGGCATTCGTGGATTGTGAACATCCAAGTTATATTGGTTTGTAT



AGAATGGCATTAAGTAAAAATTACAGCTGTATAACAGTAGTTTTCTAAATTGA



GAGAGTCCACATTGTAATTAGAGATCACTGTGACCAAAATGCTTCTCCTTGAT



TTATAATGATGTACTGTATTTTGTACTGCTTATATGAAATTTCAGCAAGATTG



ACGATATTATAAAGATGCTTATAAAGTGTAAGTGGAGACGCTAAATTGTGAGT



ACAAAGTTTCTTTTTCACAACAGTGATAAGAAAATATCTTTAAAAAATATAAG



ACAATATAAACATGTCATCATTAGTTTAGCTACTATTAAAATGTAACATCTAG



AAAGTACTGATCTCCACCTTCAGACTTCTGTATAAGTATATTTTTTCACTGAT



CTGTTCATTAGAGTTCTTCCAGCCAAGACTCTGGGCTCTTAAAACATGTATCT



GAAAACTAAAAACAAGTTAATTTTTTTAAAAGCTTCTCTATTTCTAGTGATTC



AATAGGTAGAAAAATAGCTTCTAGAATTAACTGCAATGCTTTCTAAGGAAATT



TTATAAATCCTCAAGGTCGGTTTACACATATTTTTCCAGATTCAGAGCACTAA



CTATCTTGTAAGATGTAAGAAAAGGTCCATTTGGAAGTATGAGTAATAAATGT



CTGGGATAATTCTGGTTTATTTCGTATTATCCTTGTTAGAATAAGTTATATGG



TCAACCTGTTCAGAACACTTTTTCTAGTGTTAGTGTGTACTTTTGGATTTTTG



GTTCTTGTAGGGTATAGAAATATTTTCCTTTGTCTTGTATTCTGTTGTTTTGA



ATGAATAAAACACAATGTTTCACGATCACTACTTTCATTTGCCATGGAGAAAT



AGCAGGGAAAAATTTCTACAGAATAAAATTAACTGATGAATTACATGCAGAAA



AAATTCAAATCAATGATACATTGTAATTTTTATCTCAATGCAATGTTCTTTGT



ATTTTATTTTATTATTATTTTTTTGAGACGGAGTTTCACTTTTGTTGCCCGGG



CTGGAGTGCAATGGCACAATCTCGGCTCACCACAACCTCTGCCTCCCGGATTC



AAGTGATTCTCCTGCCTCAGCCTCCTGAATAGCTGGGATTACAGGCATATGCC



AACATGCCTGGCTAATTTTGTATTTTTAGTGGAGACGGGGTTTCTCCACGTTG



GTCAGACTTGTCTTGAACTCTGGACCTCAGGTGATCCACCTGCCTCAGCCTCC



TAAATTGCTGGGATTACAGGCATGAGCGACCACTCCTGGCCTTGTTCTTTGTA



TTTTATAAGTGCATGTAGTGCAAAGGGTCAAAGGGCTTTACAGGTTTTTTGTT



TGTTTGTTTTTGTTTTTCCCGAAACATAGTAGTCCCTTGCCCTTCCTCATTTT



TGTTACCTTGAGACAACAAATTTTACTACTTCTAACTCATTATTTTATTTATG



TTCACTTTTCTGAATAGCATGCTTATGACACTAATACTTTTTTTTTCAATTTT



AGACATTCATTATTCATTTAGATGTCTTTCTCTCCCCAAACTCACCACATAAA



ATACTCTTCTCATGTCTCTTTCAGAAATATTTGTATTAAAATATGATTATATC



AATATTTGGCATTTATTTCTTATGACCTTGCCAGTACTCTTAGTTAAACTACA



TGGTAAAAATGATTTTGCTTTCCCTCCTACATAACTTTTTTTCCACCTAGAGC



TAATAATTGTCATTCTGGGGACTGACTTTTTCTGTATTTACCATAAATTGACC



TGAAACTCCCCTGTGATGCAGCAGGAATTCTACCAACGTCAACTTCCTTAGAA



AGACTCCATTAGAAGCTTGACTTGGGGCTAGAAGGAGAGGCACACAACTGCCA



TCCTGGTGTCTCCCTTCATCCAGAAAAAGGGGGAGGAATACATGAAACCTAGA



ATCCACTCTAAAACATTTTCCAGAACAAAAGGACATGTGTTTCCGTGTTGTAA



ATGTTTAACGAGTGCCCATAACAAGGAATAATAAGTCTATTATGTTTGCTTTT



GTGTCTGTAAAAGTTGGGGGTATTGGTTGTAAGCACGAAAACAGATACTGACT



GTTGAAGAAAAAAAAAAATACGAGGTCAGGAGTTTGAGACCAACTTGGCCAAT



ATGGTGAAACCCTGTCTTAGTAAAAATAGAAAAATTAGCCAGGCCTGGTGGCA



CGCACCTGTAGTCCCAGCTACTTGGGAGGCTGAGGCAGAAGAATCGCTTGAAC



CCGGGAGGCAGAGGTTGCAGTGAGCCAAGATCGCACCACTGCACTCCACCCTG



GGCAACAGAGCGAGACTCCGTCTCAAAAAAAAAAAAAAAAAAAAAAAAAAAAA



GTTAAGTATTTGAACATAGGGGTGGCTCATAGAATTCCCAGGACACCCGATGG



AGTAGGCTTGCAAAACACAACATGTGGCAACTCCAGTGGGAAACGAGGCAGGA



AACACTCGTTTCCTGCAGAAAGCAACAATTTGGGCTTCGATACCCTCCCTAGA



ACACAGGGCAGTGAATCTGAGCAGCATCAGTACCCCACGTTCGGATGAGTCCT



GAGCCCCTATTTTTATTCACTGACTTATTCCAAAATCAGTGTCTCTTAAATAT



ATCTGGAAGGCAGCAGCTTGTATCTCCCCCTTCAGCTTCCATAGTGGCAGTCA



GGGTACAACTTACTTTCCAAACAGAACACACTGCGACATTCCCTCCAGGCTCG



TTGAAGAACTTCAACTGACAAATGTCCCTCCTCGACCAGATGATAGTTTTCTT



AAAGGCAGGGTTTAATATACCCTTTTATAAATGTTTCAAGGCCCTGTGTAATA



CCTGAGTTTATTCCAGATGTAACTAAATATATCCAAGATTGTTTTAAAATAAA



TTGCTGAAAAAACAAATAAATACAGTTAGTATCTATATCAATATTCTCAGTTG



GCAGTTTTGCAATAATGGCCGATAGTTCATTTTTAGTAACACTATTGACATTG



CATTTGGATATTAGGGTTTACTAATCATCCGCATGTATACATTGCATATTTTT



CTAGACTTTAACTTTATTCAAATCTATTGATTTTTAAACCTGCAACTTATGTC



TAGACACAGGTATACCTTTACAAGAACTACCATTTTTTTTGGTAACATACTAC



CTCCAAAATTTCAAGTAAGAAGTTGATTTTTGTCCATTTTTAAATGGAAAACT



TGTAATCAAAATGCCACAAAATTATACTGTGTATCATTTGACCTATAGAAACC



AATATTATTACAGGAAGAAAGCAGAGCCAATCTTCTACCTGTGGTCAAATAAG



TGGAGGCCCTTTCTAGACTAAGTTCTCATGAGTTTAAAATACCAAGCATAAGT



TCTCCAAATTCCTGAAAAGGAAGCCTTGTGTTGTATTGCCCAGCCATATTTGT



AAGACATAAAAATAAAACTTGAGAAGAAGCTATGATAACTTACTTTCTTCATT



CTTCAAAATTTACATAATCTCAACTGATTTTATGTTTTTATGAAAATGCATTC



TTAAGATATATCCTTATTCAATCATGTATTCATTACATCCTTTATGCCAGGTA



TCCAAAAGTACTTACAGTGACTAAGACCATTATTCTTTGATCAGCTGCCTGAG



TAAGACTTTGAGCTCTCCAATATACTCTCAGTGATACTAAGTTTTCTGAGTAA



CAGCTTTGGATGTGGCTTCAGTTGAGCTGATTTATCCCACACTTTATTTTTAT



CGTATAATGGTCCTCAGAAGCAAATTTTGATTTTAGCTCACATAAAAAATGTA



CAAAGAAATGTAATGGCTCAGTAGCTTCTAGAGATAGAGATTACTCTTCTAAC



CTTTCTGTAATTTTGTATGTCTATTTTATAATTCTTTCAATGTCTAATGAATA



GCTATCTTTTTTTGAGACGGAGTCTCGCTCTGTCGCCCAGGCTGGAGTGCAGT



GGTGCGACCTCGGCTCACCGCAAGCTGCGTCTTCCAGGTTCACGCCATTCTCC



TGCCTCAGCCTCCCGAGTAGCTGGGACTTCAGGCGCCCACCACCATGCCCAGC



TAATTTTTTTGTATTTTTAGTAGAGACGGGGTTTCACCGTGTTAGCCAGGGTG



GTCTCGATCTCCTGACCTCGTGATCCGCCCGCCTCGGCCTCCCAACGTGCTGG



GATTACAGGAGTGAGCCACCGCGCCCGGCCTCCTTAGTTTCTTAAGGTGGAAG



CCTAGATTATTGATTTTATATGTTGTTTTCTTTTCCAATAGTGGCACTTAATG



CTATAAATTTCACTTTGTTCCACAAGTTTTGGTAAGCTCTATTTTTATTTTCA



TTTAGTCCAAAATATTTTAAAATTTCTTTTGATATTTCTTCTTTGAGCCATGA



ATTATTTACAATGTGTTGTTTAATCTCTATATATTTTGGGATTTTTCTACTTT



ATATCTCTTACAGATTTCTAACTTAATTTCATCATGTTTTAAAAACATTCTTT



GTATAATTTCTATTCTTTTAAATTTTTCAGGTGTATTTTATGGCCCAGAATAT



GGTCTATCTTGTAGAATGTTTCATGTGATCTTAAGAAGAATGTTCATTCTGCT



GTTGAGTGTAATATTCTACAAATGTCCATTAGATTAAACTGATTGATACCACC



GTTCAGATTATCTATATCCTTTCTGATTTTCCCTCTTCTTGATCTATCACATA



CTGACAGATCAAGTGATCAAGTCTCGTTAAAGACTGCAAGTAAAATAGTGGAT



TTTTCTATTTCTCCTTGCAGTTTTGTTAGTTTTTGTCTCATGTATCTTGATAC



TCTTGTTAGTACATATACTTTCAGAATCGTTAGGTTTTCTTGGAGAATTGACC



CCTTTACCACATGTAATGTCCCTTTTATTCTTGATAATCTTTCTTGTTCTGTC



TGCTTTTTCTGATATTAACATAACTTTCAGTTTTTTAAAAAATTAACATTAGC



ATCTCACATCTTTATCCTTTTAATTTTAAATTATCTAAATATTTATATTTAAT



GTGCCTTTCTTATAGACAATGTATAGTTGCGTCTATTTGTAATTTCCCCACTT



TTCTTACTTAAAAATGTTGTAGATATATAGGAGTTGTATATATTTGGGGGGTA



CATGTGATGTTTTGATACCTGTATACAATATGTAATGATCATATTGGGTAATC



GTGATATCTGTCACCTCTAACATTCATCTTTTTTGTGTGTTTAAACCCACCAC



TTCTAATTGGTACATTTAGATTATTCAAATTTAAGTGATTATTGATATAGTTG



GATTAATATCTACTATGTTTGTAACTTTTCTATCCTTGCACTCGTTCTTTCTT



TTTTATCCTCCTTTTTCTGTGTTCTCTGATTTTAACTGGGGTTTTTACATGAT



TTAATTTTCTCTCGTGGCATATCTTTCATTGATCAACCTAGGTTTTTCTCCTT



TTCCCCTCTTTTTTTTGGTATTTATTCTATTTAGTGTTATCTGAGCTACCTGA



GTTGGTGTCTATCACTAATTTTGGCAAGTTCCCAGACGTTATTACTTCTAACA



TTCTTTTGCTCCATTCTTTCTTCTTCTTCAATTATTCCATAGTCTTGAATATT



CTGGGTTTTTCCCACTCTTTGAATTTTAGTTTGAAAAGTTTCTATTGGCCTAG



CTTCAAAGTCATTCATTCTTCCTTCGGGGTTCCAAGTCAACTGATAATTGCAT



CAAAGATATCCTTCCTTTCTATTACTATGTTTTTTATTGCTACCATTTCTTTT



TTATTCCTTCTTAGTGTTTCCATCTTTCTTCTTACATTATCCATCTGTTGTCT



ATTTTTTTCATGAGAGCTCTTAACATATTAATGATAAGTTCCATGTCTGATAA



TTCTGACACGTGTCATGTCTCTATCTGGTTCCAATGATTGCTTTATCTCTTCA



GACCATGACTTTTCTTGCCTTTTGACGTTCTTTGACATTTTTTTTGAATTTTT



TGTTGCAAGCCAGATCTGGTGTGTTATGTAATAGGAACAGGTAAATAAGTCTT



TAGCTTGCAGACTTATCTTAATCTGACTAACTATTAGACTGTGTTTAAAGTCT



GTTATAACCATAGGTGCTAAATTTCTTCAAATTCCTCTAGTGTCTTTGTTTTG



TTTGTTCATGTGTTTTTCCCCTTCTTGAGTTCAGGCTTCCCTAAGTGCTCCTC



TTCAGAGAGACTTTCTGTCTTTCAGCTCTTTCCTCTGCAATTCACTGTTACTA



TACTGGAGCCCTGTTGGTGTAGTACTAAGCTGTGGGAAAGGAGAGTGCTCTGT



AATCTTACAGTGAAATCTCAGTOTTTTAGTGGGTCTGTGTCTGGGACATTCAC



AGAGCTTCTCCAGTGGTATTGCTTCCTCATCCTCAACTCTCTTTCCTGGCTGC



AGCATTCCCAATGTATTTCTTTGAAGGCCTGCCCCCTGTTGACTGTTATTTTC



CCTCTTTCCTTAAGTGGGACAGGGAGACTTCAGGGGCTGGGATGAGGTTTGGG



AATTGTGCTTGGCAGAGTCCTTTCCATCTTTGTTACCAAGAAGGTTCATGGCT



TATTTCTCAATGGATGTCCCTCTCTATCTGTTGCCAGAGCCACGAGGAAATTT



TTCTTGGATCCTCATAATGAGAACCTTGGAGTTTCCTACTGGAAAAGCCCTTG



AATGTGTGGAGTGCCTCAAGAGCACAGCCCCCATGGGTTTCTTGCTCACACCA



GTCCACAAACAGATGCCAGCAATTCACCCAACTTACCATATAAAGGCTCATAC



TAGTTTATGGCTCCAGTGCTTTGACTCCAGATAAATGGCTATTGGTTGCGTAT



CTCTCTGGATGTATCTGTATCTCCAGATTTTGGGGTGGCAGTTTGCTCAGGAC



CTTGGTTCTCTAATAGGTCTAATAAGAAAAGTCATTGATTTTCAGCTTTCCAA



CTTTCCAGCTTTGTCTTGTTATAAGCATGGCAGCAACATCTTCCATGCCTTAA



CATGATGACACTAAAGGCAGAAGTCGATCTCCATGTATAAACATTTTAACACA



TATGTTTTTTGTTATCGTGGTTTCTGACCTGTCTCTTTGCCCTGACTTTCTGA



TACTGCACTAGGGTTCCTGTTGCTGGACTCCATTCCATATGACTTGCTCTCGT



CTAGGCTGCTCTTTGGCTCATCTTTATAAATCATGATCCAAAATGAAGCACAT



ATTTATTTTTTAAATAAATATGAAATGAAGTATAGACATCAAACTGAAGATGA



GTAGATCATACTGAGTTTCACTGTCTGTGCTTGGATCAACATCAGGCCTTATA



CAAATATTCAAGTCCAGAGGCAAAAGGTAATAAGGAAAATTTGTAGCACAAGC



CACAAGGAGATAACATGTCAAGTCTATGCGATTGGAAATAAACTAAAGATGAA



CTGCTGGGGATGCTCACTCATCACAGAGCTCAGTCTAAAGCACCAGATTTCAC



AAGCATTTTTTGGGGGAAATTCTGTTAAAATGAAATATGAGTCACATGGTGGT



GTTTCACTCATCATATGTGTTCAATATTAATTCATTTTAAGGTTTAGTTGCAC



AAAAGGTAAATGAGAATTAGAAGACTCCATGGGTAAGAGGAGCCACAGAAGTA



AAGCATTGTCAAGGGTTCTATGTCTATATATTTAGATATTAGGCTTCTGAGAA



AAAAACACAATAGGAAGGAAGATGAACACAACAGAGGGCAGAAGGTCTATACG



TCCTGAGGCCTTTTATGCAACGTTTGTTTGTGGAATGTTTTTTAAGAATGTGT



GAGAGTCATTTTAATGTGAAATAAAGACCTACGTCTACA (SEQ ID NO:



171)






>NP_006557.2 CO226 antigen isoform a precursor [Homo




sapiens]




MDYPTLLLALLHVYRALCEEVLWHTSVPFAENMSLECVYPSMGILTQVEWFKI



GTQQDSIAIFSPTHGMVIRKPYAERVYFLNSTMASNNMTLFFRNASEDDVGYY



SCSLYTYPQGTWQKVIQVVQSDSFEAAVPSNSHIVSEPGKNVTLTCQPQMTWP



VQAVRWEKIQPRQIDLLTYCNLVHGRNFTSKFPRQIVSNCSHGRWSVIVIPDV



TVSDSGLYRCYLQASAGENETFVMRLTVAEGKTDNQYTLFVAGGTVLLLLFVI



SITTIIVIFLNRRRRRERRDLFTESWDTQKAPNNYRSPISTSQPTNQSMDDTR



EDIYVNYPTFSRRPKTRV (SEQ ID NO: 172)





Mouse CD226
>NM_178687.2 Mus musculus CD226 antigen (Cd226),



transcript variant 1, mRNA



ACACAGAAGACTTCTTGACTTCAGGAGACACTGCTGTATGAAACAGTGCTTGC



TATCAGTGGCTGCTGGAAGAGGCTGTGGTGGAAAGAAAACCTCAACTGCAGGC



CAGAGTTGGTTCCCCAAAAGAGGCAAACTCCCAGTGCTAGCCAGAGGCTAGGA



AGCTCTAAGCAACCCACTTATCTGCAAGGAGAGTTACGCCCAAAGAGCATCAA



GTCCAACCTCCTGAACTGTTTCCAGAGATGGCTTATGTTACTTGGCTTTTGGC



TATTCTTCATGTGCACAAAGCACTGTGTGAAGAGACATTGTGGGACACAACAG



TTCGGCTTTCTGAGACTATGACTCTGGAATGTGTATATCCATTGACGCATAAC



TTAACCCAGGTGGAGTGGACCAAGAACACTGGCACAAAGACAGTGAGCATAGC



AGTTTACAACCCTAACCATAATATGCATATAGAATCTAACTACCTCCATAGAG



TACACTTCCTAAACTCAACAGTGGGGTTCCGCAACATGAGCCTTTCCTTTTAC



AATGCCTCAGAAGCAGACATTGGCATCTACTCCTGCTTGTTTCATGCTTTCCC



AAATGGACCTTGGGAAAAGAAGATAAAAGTAGTCTGGTCAGATAGTTTTGAGA



TAGCAGCACCCTCGGATAGCTACCTGTCTGCAGAACCTGGACAAGATGTCACA



CTCACTTGCCAGCTTCCAAGGACTTGGCCAGTGCAACAAGTCATATGGGAAAA



AGTCCAGCCCCATCAGGTAGACATCTTAGCTTCCTGTAACCTATCTCAAGAGA



CAAGATACACTTCAAAGTACCTAAGACAAACAAGGAGCAACTGTAGCCAGGGG



AGCATGAAGAGCATCCTCATCATTCCAAATGCCATGGCCGCTGACTCAGGACT



TTACAGATGTCGCTCAGAGGCCATTACAGGAAAAAACAAGTCCTTTGTCATAA



GGCTGATCATAACTGATGGTGGAACCAATAAACATTTTATCCTTCCCATCGTT



GGAGGGTTAGTTTCACTGTTACTTGTCATCCTAATTATCATCATTTTCATTTT



ATATAACAGGAAGAGACGGAGACAGGTGAGAATTCCACTTAAAGAGCCCAGGG



ATAAACAGAGTAAGGTAGCCACCAACTGCAGAAGTCCTACTTCTCCCATCCAG



TCTACAGATGATGAAAAAGAGGACATTTATGTAAACTATCCAACTTTCTCTCG



AAGACCAAAACCAAGACTCTAAGCTGCTCTTTTGGCCTGAACACATTAGTGAT



GACTTCTATGGCATGGAATTTTACCCATGATTTCCTTACCACTAGGATCTACA



TTGATAAAAAAAATTGATTAAATTTATTTCATCTCATATATAGAAGTACTTTA



TTACCTGGAAACATTCTTAATAGAGATTCATTAGAAAACCCAAATCTAATGTT



CATGTGTTCAAGGAACCTTCTTCCATTATGTAACAGAACAGTCTAGAGAAGAT



TAAGGACCACATGGCTTTCTTGCTCTACTTGAAATTAATTGTGAGCATAAGCT



TGTTTCTGGAGTCTTCTTACATTGTTGGTTCTACTTACATACTACTGGTCCAA



CTCTCATGCTGTTTCTCTCAGATGTTCCCATGATGGTTGCCAAGGACACTTGA



TAGAAAGACTACTGGTTAAACACAATAAACAAAGTTCATTATTCACTTATTAG



CAAGAAGGTAGCATTATCATAAAGGATTAGATGACTTAAGTTAGCTATAGGTT



CAAGACCTGGACTAAAGTATTACTTGGAAATTCTGAGTATTGCTAAAAAGGAG



GATGAAAGGGACCTAGAAGTTGAGTTATTACTAAAAACTTTGAGTGCGAAGAT



ATTACTCATTAACCAGATAACAAGTGAATATGCTGTAGCATCAACATAATTCA



AAAGAGTAAAGAAATGGCTAGGAATGAGGTAGTTGTGTAATTATTTCTTCTCT



TACTAGTTTCAAATAAATTCATCTCTAATTCTATAGAGAATTCTTGCCTCCCA



TTCAGGACTGGCCTTCTATACAGTGAGATGGTCCAGTAAGAAATAATTTTTAT



TAGTGTTTTTTCTATTTTGAGAATTATTTTAATATATATTTTAATATATAAAC



TTGTGAGTTAAATTTTTTTTTTGCAAAATTAGCACATGAAAAGAGATTGATGG



TTTTAAGTAGTAGAACACAGTAGTGTAGGAATCTGAGAGCAGAGAGTTTGGGA



GGGGGTGAAGAGAAAACAACATCACCAAATAGTGATATATAAGAGAAAATCTG



TGCTTCAGAGTTTGATCAGGGCCATCTCTCCCAACTCTGCTGGAACTGAGAGA



ATGCACCTGATGTTGTCTCCATTTTAGATAGAGAAAAAAAAAACCCGAATATT



TATAAAACTAAATAAAACTATAGTTACCTCAAAACTATGGGGATCACTATAAC



ATAGAATAGAATAGAATAGAATAGAATAGAATAGAATAGAATAGAATAG



(SEQ ID NO: 173)






>NP_848802.2 CD226 antigen isoform a precursor [Mus




musculus]




MAYVTWLLAILHVHKALCEETLWDTTVRLSETMTLECVYPLTHNLTQVEWTKN



TGTKTVSIAVYNPNHNMHIESNYLHRVHFLNSTVGFRNMSLSFYNASEADIGI



YSCLFHAFPNGPWEKKIKVVWSDSFEIAAPSDSYLSAEPGQDVTLTCQLPRTW



PVQQVIWEKVQPHQVDILASCNLSQETRYTSKYLRQTRSNCSQGSMKSILIIP



NAMAADSGLYRCRSEAITGKNKSFVIRLIITDGGTNKHFILPIVGGLVSLLLV



ILIIIIFILYNRKRRRQVRIPLKEPRDKQSKVATNCRSPTSPIQSTDDEKEDI



YVNYPTFSRRPKPRL (SEQ ID NO: 174)





Human DR3
>NM_003790.3 Homo sapiens TNF receptor superfamily



member 25 (TNFRSF25), transcript variant 2, mRNA



GAAGGCGGAACCACGACGGGCAGAGAGCACGGAGCCGGGAAGCCCCTGGGCGC



CCGTCGGAGGGCTATGGAGCAGCGGCCGCGGGGCTGCGCGGCGGTGGCGGCGG



CGCTCCTCCTGGTGCTGCTGGGGGCCCGGGCCCAGGGCGGCACTCGTAGCCCC



AGGTGTGACTGTGCCGGTGACTTCCACAAGAAGATTGGTCTGTTTTGTTGCAG



AGGCTGCCCAGCGGGGCACTACCTGAAGGCCCCTTGCACGGAGCCCTGCGGCA



ACTCCACCTGCCTTGTGTGTCCCCAAGACACCTTCTTGGCCTGGGAGAACCAC



CATAATTCTGAATGTGCCCGCTGCCAGGCCTGTGATGAGCAGGCCTCCCAGGT



GGCGCTGGAGAACTGTTCAGCAGTGGCCGACACCCGCTGTGGCTGTAAGCCAG



GCTGGTTTGTGGAGTGCCAGGTCAGCCAATGTGTCAGCAGTTCACCCTTCTAC



TGCCAACCATGCCTAGACTGCGGGGCCCTGCACCGCCACACACGGCTACTCTG



TTCCCGCAGAGATACTGACTGTGGGACCTGCCTGCCTGGCTTCTATGAACATG



GCGATGGCTGCGTGTCCTGCCCCACGAGCACCCTGGGGAGCTGTCCAGAGCGC



TGTGCCGCTGTCTGTGGCTGGAGGCAGATGTTCTGGGTCCAGGTGCTCCTGGC



TGGCCTTGTGGTCCCCCTCCTGCTTGGGGCCACCCTGACCTACACATACCGCC



ACTGCTGGCCTCACAAGCCCCTGGTTACTGCAGATGAAGCTGGGATGGAGGCT



CTGACCCCACCACCGGCCACCCATCTGTCACCCTTGGACAGCGCCCACACCCT



TCTAGCACCTCCTGACAGCAGTGAGAAGATCTGCACCGTCCAGTTGGTGGGTA



ACAGCTGGACCCCTGGCTACCCCGAGACCCAGGAGGCGCTCTGCCCGCAGGTG



ACATGGTCCTGGGACCAGTTGCCCAGCAGAGCTCTTGGCCCCGCTGCTGCGCC



CACACTCTCGCCAGAGTCCCCAGCCGGCTCGCCAGCCATGATGCTGCAGCCGG



GCCCGCAGCTCTACGACGTGATGGACGCGGTCCCAGCGCGGCGCTGGAAGGAG



TTCGTGCGCACGCTGGGGCTGCGCGAGGCAGAGATCGAAGCCGTGGAGGTGGA



GATCGGCCGCTTCCGAGACCAGCAGTACGAGATGCTCAAGCGCTGGCGCCAGC



AGCAGCCCGCGGGCCTCGGAGCCGTTTACGCGGCCCTGGAGCGCATGGGGCTG



GACGGCTGCGTGGAAGACTTGCGCAGCCGCCTGCAGCGCGGCCCGTGACACGG



CGCCCACTTGCCACCTAGGCGCTCTGGTGGCCCTTGCAGAAGCCCTAAGTACG



GTTACTTATGCGTGTAGACATTTTATGTCACTTATTAAGCCGCTGGCACGGCC



CTGCGTAGCAGCACCAGCCGGCCCCACCCCTGCTCGCCCCTATCGCTCCAGCC



AAGGCGAAGAAGCACGAACGAATGTCGAGAGGGGGTGAAGACATTTCTCAACT



TCTCGGCCGGAGTTTGGCTGAGATCGCGGTATTAAATCTGTGAAAGAAAACAA



AACAAAACAAAAACGGCTTCTTGGCGTTTCTGCGGGGCTGGGGTGTTAAGTGG



ACTGGACTTTTCTCGAGGGATTCGAAGGGGACGGGAATCTTGTCACCCCGGGA



TCTGGCACCCATGGTGGAGTCCAGTGTGGCCTTAGCTCCCAAGCCTGCCCCTC



CCGAGTCCACTCTGGCTCAATTACCCCGAGAAGGAGAGAGCAAGTCGCGGCCA



CAGCGAGTGAGTGAACCGGAGCCCAGATGAGAGCGCTTTAATGGGGCTGCGAG



GTGGCGGAGACAGGGTCGGGATGGGGTGCAGCAGTTGGAGACACAGGGTCAGG



GCCCCTCATCCTCTATTCACTCCACCGGGGCAGTGAAAGGGTCCCGGCAGCGA



GTGGGTC (SEQ ID NO: 175)






>NP_003781.1 tumor necrosis factor receptor



superfamily member 25 isoform 2 precursor [Homo




sapiens]




MEQRPRGCAAVAAALLLVLLGARAQGGTRSPRCDCAGDFHKKIGLFCCRGCPA



GHYLKAPCTEPCGNSTCLVCPQDTFLAWENHHNSECARCQACDEQASQVALEN



CSAVADTRCGCKPGWFVECQVSQCVSSSPFYCQPCLDCGALHRHTRLLCSRRD



TDCGTCLPGFYEHGDGCVSCPTSTLGSCPERCAAVCGWRQMFWVQVLLAGLVV



PLLLGATLTYTYRHCWPHKPLVTADEAGMEALTPPPATHLSPLDSAHTLLAPP



DSSEKICTVQLVGNSWTPGYPETQEALCPQVTWSWDQLPSRALGPAAAPTLSP



ESPAGSPAMMLQPGPQLYDVMDAVPARRWKEFVRTLGLREAEIEAVEVEIGRF



RDQQYEMLKRWRQQQPAGLGAVYAALERMGLDGCVEDLRSRLQRGP (SEQ



ID NO: 176)





Mouse DR3
>NM_033042.4 Mus musculus tumor necrosis factor



receptor superfamily, member 25 (Tnfrsf25),



transcript variant 2, mRNA



CTGCGTGGAGGGGAAATGGGCCAGAGGCTGCTGGCAGGGGGCCTCCTCTGCTG



TACACAAGCTGGTTTTGTAGACAGTGAGAGGGAAGCTGATCCCAGTCCCCTAA



CCCTGTTCTGCCCAGGAGCCTGAGAACTGAGCTTACTCGGGCAAATGCTAGGG



CTTCAGAAATGGAGGAGCTGCCTAGGAGGGAGAGGTCACCTCCTGGGGCAGCC



ACACCAGGGTCAACTGCACGTGTTCTCCAGCCTCTGTTCCTACCACTGCTGCT



GCTGCTGCTGCTGCTGCTTGGTGGCCAGGGCCAGGGCGGCATGTCTGGCAGGT



GTGACTGTGCCAGTGAGTCCCAGAAGAGGTATGGCCCGTTTTGTTGCAGGGGC



TGCCCAAAGGGACACTACATGAAGGCCCCCTGCGCAGAACCCTGTGGCAACTC



CACCTGCCTTCCCTGTCCCTCGGACACCTTCTTGACCAGAGACAACCACTTTA



AGACTGACTGTACCCGCTGCCAAGTCTGTGATGAAGAGGCCCTTCAAGTGACC



CTTGAGAACTGCTCGGCAAAGTCGGACACCCACTGTGGCTGCCAGTCAGGCTG



GTGTGTTGACTGCTCCACCGAGCCATGTGGGAAAAGCTCACCTTTCTCTTGTG



TCCCATGCGGGGCTACAACACCAGTCCATGAGGCTCCAACCCCCCTGTTTTGG



GTCCAGGTGCTTCTAGGAGTCGCGTTCCTTTTTGGGGCTATCCTGATCTGTGC



ATATTGTCGATGGCAGCCTTGTAAGGCCGTGGTCACTGCAGACACAGCTGGGA



CGGAGACCCTGGCCTCACCACAGACTGCCCATCTCTCAGCCTCAGACAGCGCC



CACACCCTCCTGGCACCTCCAAGCAGTACTGGGAAAATCTGTACCACTGTOCA



GTTGGTAGGCAACAACTGGACCCCTGGCTTATCCCAGACTCAGGAGGTGGTCT



GCGGACAGGCCTCACAACCCTGGGATCAGCTGCCAAACAGAACTCTTGGAACT



CCTCTGGCATCTCCGCTCTCGCCAGCGCCCCCTGCGGGCTCTCCGGCTGCTGT



GCTCCAGCCTGGCCCGCAGCTCTACGATGTGATGGATGCGGTCCCAGCACGAA



GGTGGAAGGAGTTCGTGCGCACGCTGGGGCTGCGGGAAGCGGAAATTGAAGCC



GTGGAGGTGGAAATCTGCCGCTTCCGAGACCAGCAGTATGAGATGCTCAAGCG



CTGGCGTCAGCAGCAGCCTGCAGGCCTCGGTGCCATCTATGCGGCTCTGGAGC



GCATGGGTCTGGAAGGCTGTGCCGAGGACCTGCGCAGCCGCCTGCAGCGTGGC



CCGTGATGGAAGGTCCATCAGCCACTTTGACACCCTAGTGACCCTTGAAGGAG



CCTTAAGTATTGTTACTTATGCGTGTAGACATTTTATGTCAATTACTAACCCC



CTGCCGTGGTCCTGCGTAGCAGGGCTGGCTGCCTCACTTTTGCTTATCTGCAG



CACGGAGCTCCTGCTAAGGGAAGCGTCATGGAGAAATACCAGAAGGGGCCAAG



TGATTGGTTGCTCAGCTGTTAATTAGCCCGAGTTTGGACTTGGTATTAAATTT



CGTAAGAAAAGCAGCTGCTTG (SEQ ID NO: 177)






>NP_149031.2 tumor necrosis factor receptor



superfamily member 25 isoform 2 precursor [Mus




musculus]




MEELPRRERSPPGAATPGSTARVLQPLFLPLLLLLLLLLGGQGQGGMSGRCDC



ASESQKRYGPFCCRGCPKGHYMKAPCAEPCGNSTCLPCPSDTFLTRDNHFKTD



CTRCQVCDEEALQVTLENCSAKSDTHCGCQSGWCVDCSTEPCGKSSPFSCVPC



GATTPVHEAPTPLFWVQVLLGVAFLFGAILICAYCRWQPCKAVVTADTAGTET



LASPQTAHLSASDSAHTLLAPPSSTGKICTTVQLVGNNWTPGLSQTQEVVCGQ



ASQPWDQLPNRTLGTPLASPLSPAPPAGSPAAVLQPGPQLYDVMDAVPARRWK



EFVRTLGLREAEIEAVEVEICRFRDQQYEMLKRWRQQQPAGLGAIYAALERMG



LEGCAEDLRSRLQRGP (SEQ ID NO: 178)





Human DcR3
>NM_003823.4 Homo sapiens TNF receptor superfamily



member 6b (TNFRSF6B), mRNA



GGACTTGGGCGGCCCCTCCGCAGGCGGACCGGGGGCAAAGGAGGTGGCATGTC



GGTCAGGCACAGCAGGGTCCTGTGTCCGCGCTGAGCCGCGCTCTCCCTGCTCC



AGCAAGGACCATGAGGGCGCTGGAGGGGCCAGGCCTGTCGCTGCTGTGCCTGG



TGTTGGCGCTGCCTGCCCTGCTGCCGGTGCCGGCTGTACGCGGAGTGGCAGAA



ACACCCACCTACCCCTGGCGGGACGCAGAGACAGGGGAGCGGCTGGTGTGCGC



CCAGTGCCCCCCAGGCACCTTTGTGCAGCGGCCGTGCCGCCGAGACAGCCCCA



CGACGTGTGGCCCGTGTCCACCGCGCCACTACACGCAGTTCTGGAACTACCTA



GAGCGCTGCCGCTACTGCAACGTCCTCTGCGGGGAGCGTGAGGAGGAGGCACG



GGCTTGCCACGCCACCCACAACCGTGCCTGCCGCTGCCGCACCGGCTTCTTCG



CGCACGCTGGTTTCTGCTTGGAGCACGCATCGTGTCCACCTGGTGCCGGCGTG



ATTGCCCCGGGCACCCCCAGCCAGAACACGCAGTGCCAGCCGTGCCCCCCAGG



CACCTTCTCAGCCAGCAGCTCCAGCTCAGAGCAGTGCCAGCCCCACCGCAACT



GCACGGCCCTGGGCCTGGCCCTCAATGTGCCAGGCTCTTCCTCCCATGACACC



CTGTGCACCAGCTGCACTGGCTTCCCCCTCAGCACCAGGGTACCAGGAGCTGA



GGAGTGTGAGCGTGCCGTCATCGACTTTGTGGCTTTCCAGGACATCTCCATCA



AGAGGCTGCAGCGGCTGCTGCAGGCCCTCGAGGCCCCGGAGGGCTGGGGTCCG



ACACCAAGGGCGGGCCGCGCGGCCTTGCAGCTGAAGCTGCGTCGGCGGCTCAC



GGAGCTCCTGGGGGCGCAGGACGGGGCGCTGCTGGTGCGGCTGCTGCAGGCGC



TGCGCGTGGCCAGGATGCCCGGGCTGGAGCGGAGCGTCCGTGAGCGCTTCCTC



CCTGTGCACTGATCCTGGCCCCCTCTTATTTATTCTACATCCTTGGCACCCCA



CTTGCACTGAAAGAGGCTTTTTTTTAAATAGAAGAAATGAGGTTTCTTAAAGC



TTATTTTTATAAAGCTTTTTCATAAAA (SEQ ID NO: 179)






>NP_003814.1 tumor necrosis factor receptor



superfamily member 6B precursor [Homo sapiens]



MRALEGPGLSLLCLVLALPALLPVPAVRGVAETPTYPWRDAETGERLVCAQCP



PGTFVQRPCRRDSPTTCGPCPPRHYTQFWNYLERCRYCNVLCGEREEEARACH



ATHNRACRCRTGFFAHAGFCLEHASCPPGAGVIAPGTPSQNTQCQPCPPGTFS



ASSSSSEQCQPHRNCTALGLALNVPGSSSHDTLCTSCTGFPLSTRVPGAEECE



RAVIDFVAFQDISIKRLQRLLQALEAPEGWGPTPRAGRAALQLKLRRRLTELL



GAQDGALLVRLLQALRVARMPGLERSVRERFLPVH (SEQ ID NO: 180)





Human FasL
>NM_000639.3 Homo sapiens Fas ligand (FASLG),



transcript variant 1, mRNA



AGCAGTCAGCAACAGGGTCCCGTCCTTGACACCTCAGCCTCTACAGGACTGAG



AAGAAGTAAAACCGTTTGCTGGGGCTGGCCTGACTCACCAGCTGCCATGCAGC



AGCCCTTCAATTACCCATATCCCCAGATCTACTGGGTGGACAGCAGTGCCAGC



TCTCCCTGGGCCCCTCCAGGCACAGTTCTTCCCTGTCCAACCTCTGTGCCCAG



AAGGCCTGGTCAAAGGAGGCCACCACCACCACCGCCACCGCCACCACTACCAC



CTCCGCCGCCGCCGCCACCACTGCCTCCACTACCGCTGCCACCCCTGAAGAAG



AGAGGGAACCACAGCACAGGCCTGTGTCTCCTTGTGATGTTTTTCATGGTTCT



GGTTGCCTTGGTAGGATTGGGCCTGGGGATGTTTCAGCTCTTCCACCTACAGA



AGGAGCTGGCAGAACTCCGAGAGTCTACCAGCCAGATGCACACAGCATCATCT



TTGGAGAAGCAAATAGGCCACCCCAGTCCACCCCCTGAAAAAAAGGAGCTGAG



GAAAGTGGCCCATTTAACAGGCAAGTCCAACTCAAGGTCCATGCCTCTGGAAT



GGGAAGACACCTATGGAATTGTCCTGCTTTCTGGAGTGAAGTATAAGAAGGGT



GGCCTTGTGATCAATGAAACTGGGCTGTACTTTGTATATTCCAAAGTATACTT



CCGGGGTCAATCTTGCAACAACCTGCCCCTGAGCCACAAGGTCTACATGAGGA



ACTCTAAGTATCCCCAGGATCTGGTGATGATGGAGGGGAAGATGATGAGCTAC



TGCACTACTGGGCAGATGTGGGCCCGCAGCAGCTACCTGGGGGCAGTGTTCAA



TCTTACCAGTGCTGATCATTTATATGTCAACGTATCTGAGCTCTCTCTGGTCA



ATTTTGAGGAATCTCAGACGTTTTTCGGCTTATATAAGCTCTAAGAGAAGCAC



TTTGGGATTCTTTCCATTATGATTCTTTGTTACAGGCACCGAGAATGTTGTAT



TCAGTGAGGGTCTTCTTACATGCATTTGAGGTCAAGTAAGAAGACATGAACCA



AGTGGACCTTGAGACCACAGGGTTCAAAATGTCTGTAGCTCCTCAACTCACCT



AATGTTTATGAGCCAGACAAATGGAGGAATATGACGGAAGAACATAGAACTCT



GGGCTGCCATGTGAAGAGGGAGAAGCATGAAAAAGCAGCTACCAGGTGTTCTA



CACTCATCTTAGTGCCTGAGAGTATTTAGGCAGATTGAAAAGGACACCTTTTA



ACTCACCTCTCAAGGTGGGCCTTGCTACCTCAAGGGGGACTGTCTTTCAGATA



CATGGTTGTGACCTGAGGATTTAAGGGATGGAAAAGGAAGACTAGAGGCTTGC



ATAATAAGCTAAAGAGGCTGAAAGAGGCCAATGCCCCACTGGCAGCATCTTCA



CTTCTAAATGCATATCCTGAGCCATCGGTGAAACTAACAGATAAGCAAGAGAG



ATGTTTTGGGGACTCATTTCATTCCTAACACAGCATGTGTATTTCCAGTGCAA



TTGTAGGGGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTATGACTAAAGAGA



GAATGTAGATATTGTGAAGTACATATTAGGAAAATATGGGTTGCATTTGGTCA



AGATTTTGAATGCTTCCTGACAATCAACTCTAATAGTGCTTAAAAATCATTGA



TTGTCAGCTACTAATGATGTTTTCCTATAATATAATAAATATTTATGTAGATG



TGCATTTTTGTGAAATGAAAACATGTAATAAAAAGTATATGTTAGGATACAAA



TAA (SEQ ID NO: 181)






>NP_000630.1 tumor necrosis factor ligand superfamily



member 6 isoform 1 [Homo sapiens]



MQQPFNYPYPQIYWVDSSASSPWAPPGTVLPCPTSVPRRPGQRRPPPPPPPPP



LPPPPPPPPLPPLPLPPLKKRGNHSTGLCLLVMFFMVLVALVGLGLGMFQLFH



LQKELAELRESTSQMHTASSLEKQIGHPSPPPEKKELRKVAHLTGKSNSRSMP



LEWEDTYGIVLLSGVKYKKGGLVINETGLYFVYSKVYFRGQSCNNLPLSHKVY



MRNSKYPQDLVMMEGKMMSYCTTGQMWARSSYLGAVFNLTSADHLYVNVSELS



LVNFEESQTFFGLYKL (SEQ ID NO: 182)





Mouse FasL
>NM_010177.4 Mus musculus Fas ligand (TNF



superfamily, member 6) (Fasl), transcript variant 1,



mRNA



TGAGGCTTCTCAGCTTCAGATGCAAGTGAGTGGGTGTCTCACAGAGAAGCAAA



GAGAAGAGAACAGGAGAAAGGTGTTTCCCTTGACTGCGGAAACTTTATAAAGA



AAACTTAGCTTCTCTGGAGCAGTCAGCGTCAGAGTTCTGTCCTTGACACCTGA



GTCTCCTCCACAAGGCTGTGAGAAGGAAACCCTTTCCTGGGGCTGGGTGCCAT



GCAGCAGCCCATGAATTACCCATGTCCCCAGATCTTCTGGGTAGACAGCAGTG



CCACTTCATCTTGGGCTCCTCCAGGGTCAGTTTTTCCCTGTCCATCTTGTGGG



CCTAGAGGGCCGGACCAAAGGAGACCGCCACCTCCACCACCACCTGTGTCACC



ACTACCACCGCCATCACAACCACTCCCACTGCCGCCACTGACCCCTCTAAAGA



AGAAGGACCACAACACAAATCTGTGGCTACCGGTGGTATTTTTCATGGTTCTG



GTGGCTCTGGTTGGAATGGGATTAGGAATGTATCAGCTCTTCCACCTGCAGAA



GGAACTGGCAGAACTCCGTGAGTTCACCAACCAAAGCCTTAAAGTATCATCTT



TTGAAAAGCAAATAGCCAACCCCAGTACACCCTCTGAAAAAAAAGAGCCGAGG



AGTGTGGCCCATTTAACAGGGAACCCCCACTCAAGGTCCATCCCTCTGGAATG



GGAAGACACATATGGAACCGCTCTGATCTCTGGAGTGAAGTATAAGAAAGGTG



GCCTTGTGATCAACGAAACTGGGTTGTACTTCGTGTATTCCAAAGTATACTTC



CGGGGTCAGTCTTGCAACAACCAGCCCCTAAACCACAAGGTCTATATGAGGAA



CTCTAAGTATCCTGAGGATCTGGTGCTAATGGAGGAGAAGAGGTTGAACTACT



GCACTACTGGACAGATATGGGCCCACAGCAGCTACCTGGGGGCAGTATTCAAT



CTTACCAGTGCTGACCATTTATATGTCAACATATCTCAACTCTCTCTGATCAA



TTTTGAGGAATCTAAGACCTTTTTCGGCTTGTATAAGCTTTAAAAGAAAAAGC



ATTTTAAAATGATCTACTATTCTTTATCATGGGCACCAGGAATATTGTCTTGA



ATGAGAGTCTTCTTAAGACCTATTGAGATTAATTAAGACTACATGAGCCACAA



AGACCTCATGACCGCAAGGTCCAACAGGTCAGCTATCCTTCATTTTCTCGAGG



TCCATGGAGTGGTCCTTAATGCCTGCATCATGAGCCAGATGGAAGGAGGTCTG



TGACTGAGGGACATAAAGCTTTGGGCTGCTGTGTGACAATGCAGAGGCACAGA



GAAAGAACTGTCTGATGTTAAATGGCCAAGAGAATTTTAACCATTGAAGAAGA



CACCTTTACACTCACTTCCAGGGTGGGTCTACTTACTACCTCACAGAGGCCGT



TTTTGAGACATAGTTGTGGTATGAATATACAAGGGTGAGAAAGGAGGCTCATT



TGACTGATAAGCTAGAGACTGAAAAAAAGACAGTGTCTCATTGGCACCATCTT



TACTGTTACCTAATGTTTTCTGAGCCGACCTTTGATCCTAACGGAGAAGTAAG



AGGGATGTTTGAGGCACAAATCATTCTCTACATAGCATGCATACCTCCAGTGC



AATGATGTCTGTGTGTTTGTATGTATGAGAGCAAACAGATTCTAAGGAGTCAT



ATAAATAAAATATGTACATTATGGAGTACATATTAGAAACCTGTTACATTTGA



TGCTAGATATCTGAATGTTTCTTGGCAATAAACTCTAATAGTCTTCAAAATCT



TTTATTATCAGCTACTGATGCTGTTTTTCTTTAATACAACTAGTATTTATGCT



CTGAACATCCTAATGAGGAAAAGACAAATAAAATTATGTTATAGAATACAGAA



ATGCCTTAAGGACATAGACTTTGGAAA (SEQ ID NO: 183)






>NP_034307.1 tumor necrosis factor ligand superfamily



member 6 isoform 1 [Mus musculus]



MQQPMNYPCPQIFWVDSSATSSWAPPGSVFPCPSCGPRGPDQRRPPPPPPPVS



PLPPPSQPLPLPPLTPLKKKDHNTNLWLPVVFFMVLVALVGMGLGMYQLFHLQ



KELAELREFTNQSLKVSSFEKQIANPSTPSEKKEPRSVAHLTGNPHSRSIPLE



WEDTYGTALISGVKYKKGGLVINETGLYFVYSKVYFRGQSCNNQPLNHKVYMR



NSKYPEDLVLMEEKRLNYCTTGQIWAHSSYLGAVFNLTSADHLYVNISQLSLI



NFEESKTFFGLYKL (SEQ ID NO: 184)





Human TIM-1
>NM_012206.3 Homo sapiens hepatitis A virus cellular


(CD365)
receptor 1 (HAVCR1), transcript variant 1, mRNA



GACCAGGAGTCAGTTTGGCGGTTATGTGTGGGGAAGAAGCTGGGAAGTCAGGG



GCTGTTTCTGTGGACAGCTTTCCCTGTCCTTTGGAAGGCACAGAGCTCTCAGC



TGCAGGGAACTAACAGAGCTCTGAAGCCGTTATATGTGGTCTTCTCTCATTTC



CAGCAGAGCAGGCTCATATGAATCAACCAACTGGGTGAAAAGATAAGTTGCAA



TCTGAGATTTAAGACTTGATCAGATACCATCTGGTGGAGGGTACCAACCAGCC



TGTCTGCTCATTTTCCTTCAGGCTGATCCCATAATGCATCCTCAAGTGGTCAT



CTTAAGCCTCATCCTACATCTGGCAGATTCTGTAGCTGGTTCTGTAAAGGTTG



GTGGAGAGGCAGGTCCATCTGTCACACTACCCTGCCACTACAGTGGAGCTGTC



ACATCCATGTGCTGGAATAGAGGCTCATGTTCTCTATTCACATGCCAAAATGG



CATTGTCTGGACCAATGGAACCCACGTCACCTATCGGAAGGACACACGCTATA



AGCTATTGGGGGACCTTTCAAGAAGGGATGTCTCTTTGACCATAGAAAATACA



GCTGTGTCTGACAGTGGCGTATATTGTTGCCGTGTTGAGCACCGTGGGTGGTT



CAATGACATGAAAATCACCGTATCATTGGAGATTGTGCCACCCAAGGTCACGA



CTACTCCAATTGTCACAACTGTTCCAACCGTCACGACTGTTCGAACGAGCACC



ACTGTTCCAACGACAACGACTGTTCCAATGACGACTGTTCCAACGACAACTGT



TCCAACAACAATGAGCATTCCAACGACAACGACTGTTCTGACGACAATGACTG



TTTCAACGACAACGAGCGTTCCAACGACAACGAGCATTCCAACAACAACAAGT



GTTCCAGTGACAACAACTGTCTCTACCTTTGTTCCTCCAATGCCTTTGCCCAG



GCAGAACCATGAACCAGTAGCCACTTCACCATCTTCACCTCAGCCAGCAGAAA



CCCACCCTACGACACTGCAGGGAGCAATAAGGAGAGAACCCACCAGCTCACCA



TTGTACTCTTACACAACAGATGGGAATGACACCGTGACAGAGTCTTCAGATGG



CCTTTGGAATAACAATCAAACTCAACTGTTCCTAGAACATAGTCTACTGACGG



CCAATACCACTAAAGGAATCTATGCTGGAGTCTGTATTTCTGTCTTGGTGCTT



CTTGCTCTTTTGGGTGTCATCATTGCCAAAAAGTATTTCTTCAAAAAGGAGGT



TCAACAACTAAGTGTTTCATTTAGCAGCCTTCAAATTAAAGCTTTGCAAAATG



CAGTTGAAAAGGAAGTCCAAGCAGAAGACAATATCTACATTGAGAATAGTCTT



TATGCCACGGACTAAGACCCAGTGGTGCTCTTTGAGAGTTTACGCCCATGAGT



GCAGAAGACTGAACAGACATCAGCACATCAGACGTCTTTTAGACCCCAAGACA



ATTTTTCTGTTTCAGTTTCATCTGGCATTCCAACATGTCAGTGATACTGGGTA



GAGTAACTCTCTCACTCCAAACTGTGTATAGTCAACCTCATCATTAATGTAGT



CCTAATTTTTTATGCTAAAACTGGCTCAATCCTTCTGATCATTGCAGTTTTCT



CTCAAATATGAACACTTTATAATTGTATGTTCTTTTTAGACCCCATAAATCCT



GTATACATCAAAGAGAA (SEQ ID NO: 185)






>NP_036338.2 hepatitis A virus cellular receptor 1



isoform a precursor [Homo sapiens]



MHPQVVILSLILHLADSVAGSVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCS



LFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCR



VEHRGWFNDMKITVSLEIVPPKVTTTPIVTTVPTVTTVRTSTTVPTTTTVPMT



TVPTTTVPTTMSIPTTTTVLTTMTVSTTTSVPTTTSIPTTTSVPVTTTVSTFV



PPMPLPRQNHEPVATSPSSPQPAETHPTTLQGAIRREPTSSPLYSYTTDGNDT



VTESSDGLWNNNQTQLFLEHSLLTANTTKGIYAGVCISVLVLLALLGVIIAKK



YFFKKEVQQLSVSFSSLQIKALQNAVEKEVQAEDNIYIENSLYATD (SEQ



ID NO: 186)





Mouse TIM-1
>NM_134248.2 Mus musculus hepatitis A virus cellular



receptor 1 (Havcr1), transcript variant 1, mRNA



GTCAGTACCATGAATCAGATTCAAGTCTTCATTTCAGGCCTCATACTGCTTCT



CCCAGGCGCTGTGGATTCTTATGTGGAAGTAAAGGGGGTGGTGGGTCACCCTG



TCACACTTCCATGTACTTACTCAACATATCGTGGAATCACAACGACATGTTGG



GGCCGAGGGCAATGCCCATCTTCTGCTTGTCAAAATACACTTATTTGGACCAA



TGGACATCGTGTCACCTATCAGAAGAGCAGTCGGTACAACTTAAAGGGGCATA



TTTCAGAAGGAGATGTGTCCTTGACGATAGAGAACTCTGTTGAGAGTGACAGT



GOTCTGTATTGTTGTCGAGTGGAGATTOCTGOATGGTTTAATGATCAGAAAGT



GACCTTTTCATTGCAAGTTAAACCAGAGATTCCCACACGTCCTCCAAGAAGAC



CCACAACTACAAGGCCCACAGCTACAGGAAGACCCACGACTATTTCAACAAGA



TCCACACATGTACCAACATCAACCAGAGTCTCTACCTCCACTCCTCCAACATC



TACACACACATGGACTCACAAACCAGAACCCACTACATTTTGTCCCCATGAGA



CAACAGCTGAGGTGACAGGAATCCCATCCCATACTCCTACAGACTGGAATGGC



ACTGTGACATCCTCAGGAGATACCTGGAGTAATCACACTGAAGCAATCCCTCC



AGGGAAGCCGCAGAAAAACCCTACTAAGGGCTTCTATGTTGGCATCTGCATCG



CAGCCCTGCTGCTACTGCTCCTTGTGAGCACCGTGGCTATCACCAGGTACATA



CTTATGAAAAGGAAGTCAGCATCTCTAAGCGTGGTTGCCTTCCGTGTCTCTAA



GATTGAAGCTTTGCAGAACGCAGCGGTTGTGCATTCCCGAGCTGAAGACAACA



TCTACATTGTTGAAGATAGACCTTGAGGGGCAGAATGAGTACCAGTGGCCCTC



TGAGGGACCTTCTGCCTGAGATTTATAGAGACTGTCACTGATGTCATAGAGTC



ACACCCATTACAGCGCCAAGGCGATTTTCTGTGTTGGTTCTTCCAGCTGCAGC



AGAGAGGGTAACCCTCTACTGTGTATACTCAAAACTCAGATTAACATCATCCT



AATTTTGGTATCTGCACCACCTCCGTGTCTCTGCTCACTACAGAGATTCTCTC



AAACATGAACGTTTTAGAAGTTTGTGTTTCCCTTAGTCAATGTAATCATTGGT



AATACTATTCTATTCTTGGTTACTAAAACCATTACTAAGAGAGGGATAGGAAT



TAAAAGTTGGTGTGAGGGGCCTCCTGAATTTAGAAGCACTTGATTCTGTTTTA



TCTACTTTCTTGAAATGTTACTTCTACCCTTCCCAATGGGTAAAATCATGGGA



GCATGGTGCCCTCATAGATAAATAGAAGAGAGTCTATTGCTGCCAATATAGAT



GGTTATGCTTTCTCATAGCTCTGAAAATATGACACATTTATTATGAGGTTGAT



CTTAGGATAAGGATAGGTGTTTTATGTCAGGAGAGGTTATCATGGTGAATATG



GACCAGCAGACAGCAGTGGAGGAAAATAATGAACCAAGGGATTGAGTTCATTA



GTGCTAATTCTACTCCACTCCTGTCTTTATGCTCCTAAACTTACTGACTGAGC



TCTGAATTAGGTGCTAGGAGGAGACAATGCAGACATGAAAGGGGAAGGAGCGC



CTTCAGGACACAGGCTCTCTGCTGAGAGAAGTCCTATTTGCAGGTGTGATAGA



GGTTGGGACAATCTCTGAGTTGTAAATTTCTAATTGTCTTCAGGCCATATTTA



TAGTTAAATTCATTTCCGAAAGACATAGCATCTTCCCCAATGGGTCAGTTTGT



CAAAATCAATAAAATATTTTGTTTTGCTAAGAATTAAAAAAAAAAAAAAAAAA



A (SEQ ID NO: 187)






>NP_599009.2 hepatitis A virus cellular receptor 1



homolog isoform a precursor [Mus musculus]



MNQIQVFISGLILLLPGAVDSYVEVKGVVGHPVTLPCTYSTYRGITTTCWGRG



QCPSSACQNTLIWTNGHRVTYQKSSRYNLKGHISEGDVSLTIENSVESDSGLY



CCRVEIPGWFNDQKVTFSLQVKPEIPTRPPRRPTTTRPTATGRPTTISTRSTH



VPTSTRVSTSTPPTSTHTWTHKPEPTTFCPHETTAEVTGIPSHTPTDWNGTVT



SSGDTWSNHTEAIPPGKPQKNPTKGFYVGICIAALLLLLLVSTVAITRYILMK



RKSASLSVVAFRVSKIEALQNAAVVHSRAEDNIYIVEDRP (SEQ ID NO:



188)





Human PD-1
>NM_005018.3 Homo sapiens programmed cell death 1



(PDCD1), mRNA



GCTCACCTCCGCCTGAGCAGTGGAGAAGGCGGCACTCTGGTGGGGCTGCTCCA



GGCATGCAGATCCCACAGGCGCCCTGGCCAGTCGTCTGGGCGGTGCTACAACT



GGGCTGGCGGCCAGGATGGTTCTTAGACTCCCCAGACAGGCCCTGGAACCCCC



CCACCTTCTCCCCAGCCCTGCTCGTGGTGACCGAAGGGGACAACGCCACCTTC



ACCTGCAGCTTCTCCAACACATCGGAGAGCTTCGTGCTAAACTGGTACCGCAT



GAGCCCCAGCAACCAGACGGACAAGCTGGCCGCCTTCCCCGAGGACCGCAGCC



AGCCCGGCCAGGACTGCCGCTTCCGTGTCACACAACTGCCCAACGGGCGTGAC



TTCCACATGAGCGTGGTCAGGGCCCGGCGCAATGACAGCGGCACCTACCTCTG



TGGGGCCATCTCCCTGGCCCCCAAGGCGCAGATCAAAGAGAGCCTGCGGGCAG



AGCTCAGGGTGACAGAGAGAAGGGCAGAAGTGCCCACAGCCCACCCCAGCCCC



TCACCCAGGCCAGCCGGCCAGTTCCAAACCCTGGTGGTTGGTGTCGTGGGCGG



CCTGCTGGGCAGCCTGGTGCTGCTAGTCTGGGTCCTGGCCGTCATCTGCTCCC



GGGCCGCACGAGGGACAATAGGAGCCAGGCGCACCGGCCAGCCCCTGAAGGAG



GACCCCTCAGCCGTGCCTGTGTTCTCTGTGGACTATGGGGAGCTGGATTTCCA



GTGGCGAGAGAAGACCCCGGAGCCCCCCGTGCCCTGTGTCCCTGAGCAGACGG



AGTATGCCACCATTGTCTTTCCTAGCGGAATGGGCACCTCATCCCCCGCCCGC



AGGGGCTCAGCTGACGGCCCTCGGAGTGCCCAGCCACTGAGGCCTGAGGATGG



ACACTGCTCTTGGCCCCTCTGACCGGCTTCCTTGGCCACCAGTGTTCTGCAGA



CCCTCCACCATGAGCCCGGGTCAGCGCATTTCCTCAGGAGAAGCAGGCAGGGT



GCAGGCCATTGCAGGCCGTCCAGGGGCTGAGCTGCCTGGGGGCGACCGGGGCT



CCAGCCTGCACCTGCACCAGGCACAGCCCCACCACAGGACTCATGTCTCAATG



CCCACAGTGAGCCCAGGCAGCAGGTGTCACCGTCCCCTACAGGGAGGGCCAGA



TGCAGTCACTGCTTCAGGTCCTGCCAGCACAGAGCTGCCTGCGTCCAGCTCCC



TGAATCTCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCCTGCGGCCCGGGGCT



GAAGGCGCCGTGGCCCTGCCTGACGCCCCGGAGCCTCCTGCCTGAACTTGGGG



GCTGGTTGGAGATGGCCTTGGAGCAGCCAAGGTGCCCCTGGCAGTGGCATCCC



GAAACGCCCTGGACGCAGGGCCCAAGACTGGGCACAGGAGTGGGAGGTACATG



GGGCTGGGGACTCCCCAGGAGTTATCTGCTCCCTGCAGGCCTAGAGAAGTTTC



AGGGAAGGTCAGAAGAGCTCCTGGCTGTGGTGGGCAGGGCAGGAAACCCCTCC



ACCTTTACACATGCCCAGGCAGCACCTCAGGCCCTTTGTGGGGCAGGGAAGCT



GAGGCAGTAAGCGGGCAGGCAGAGCTGGAGGCCTTTCAGGCCCAGCCAGCACT



CTGGCCTCCTGCCGCCGCATTCCACCCCAGCCCCTCACACCACTCGGGAGAGG



GACATCCTACGGTCCCAAGGTCAGGAGGGCAGGGCTGGGGTTGACTCAGGCCC



CTCCCAGCTGTGGCCACCTGGGTGTTGGGAGGGCAGAAGTGCAGGCACCTAGG



GCCCCCCATGTGCCCACCCTGGGAGCTCTCCTTGGAACCCATTCCTGAAATTA



TTTAAAGGGGTTGGCCGGGCTCCCACCAGGGCCTGGGTGGGAAGGTACAGGCG



TTCCCCCGGGGCCTAGTACCCCCGCCGTGGCCTATCCACTCCTCACATCCACA



CACTGCACCCCCACTCCTGGGGCAGGGCCACCAGCATCCAGGCGGCCAGCAGG



CACCTGAGTGGCTGGGACAAGGGATCCCCCTTCCCTGTGGTTCTATTATATTA



TAATTATAATTAAATATGAGAGCATGCTAA (SEQ ID NO: 189)






>NP_005009.2 programmed cell death protein 1



precursor [Homo sapiens]



MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFT



CSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDF



HMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPS



PRPAGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRAARGTIGARRTGQPLKED



PSAVPVFSVDYGELDFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARR



GSADGPRSAQPLRPEDGHCSWPL (SEQ ID NO: 190)





Mouse PD-1
>NM_008798.3 Mus musculus programmed cell death 1



(Pdcd1), mRNA



TGAGCAGCGGGGAGGAGGAAGAGGAGACTGCTACTGAAGGCGACACTGCCAGG



GGCTCTGGGCATGTGGGTCCGGCAGGTACCCTGGTCATTCACTTGGGCTGTGC



TGCAGTTGAGCTGGCAATCAGGGTGGCTTCTAGAGGTCCCCAATGGGCCCTGG



AGGTCCCTCACCTTCTACCCAGCCTGGCTCACAGTGTCAGAGGGAGCAAATGC



CACCTTCACCTGCAGCTTGTCCAACTGGTCGGAGGATCTTATGCTGAACTGGA



ACCGCCTGAGTCCCAGCAACCAGACTGAAAAACAGGCCGCCTTCTGTAATGGT



TTGAGCCAACCCGTCCAGGATGCCCGCTTCCAGATCATACAGCTGCCCAACAG



GCATGACTTCCACATGAACATCCTTGACACACGGCGCAATGACAGTGGCATCT



ACCTCTGTGGGGCCATCTCCCTGCACCCCAAGGCAAAAATCGAGGAGAGCCCT



GGAGCAGAGCTCGTGGTAACAGAGAGAATCCTGGAGACCTCAACAAGATATCC



CAGCCCCTCGCCCAAACCAGAAGGCCGGTTTCAAGGCATGGTCATTGGTATCA



TGAGTGCCCTAGTGGGTATCCCTGTATTGCTGCTGCTGGCCTGGGCCCTAGCT



GTCTTCTGCTCAACAAGTATGTCAGAGGCCAGAGGAGCTGGAAGCAAGGACGA



CACTCTGAAGGAGGAGCCTTCAGCAGCACCTGTCCCTAGTGTGGCCTATGAGG



AGCTGGACTTCCAGGGACGAGAGAAGACACCAGAGCTCCCTACCGCCTGTGTG



CACACAGAATATGCCACCATTGTCTTCACTGAAGGGCTGGGTGCCTCGGCCAT



GGGACGTAGGGGCTCAGCTGATGGCCTGCAGGGTCCTCGGCCTCCAAGACATG



AGGATGGACATTGTTCTTGGCCTCTTTGACCAGATTCTTCAGCCATTAGCATG



CTGCAGACCCTCCACAGAGAGCACCGGTCCGTCCCTCAGTCAAGAGGAGCATG



CAGGCTACAGTTCAGCCAAGGCTCCCAGGGTCTGAGCTAGCTGGAGTGACAGC



CCAGCGCCTGCACCAATTCCAGCACATGCACTGTTGAGTGAGAGCTCACTTCA



GGTTTACCACAAGCTGGGAGCAGCAGGCTTCCCGGTTTCCTATTGTCACAAGG



TGCAGAGCTGGGGCCTAAGCCTATGTCTCCTGAATCCTACTGTTGGGCACTTC



TAGGGACTTGAGACACTATAGCCAATGGCCTCTGTGGGTTCTGTGCCTGGAAA



TGGAGAGATCTGAGTACAGCCTGCTTTGAATGGCCCTGTGAGGCAACCCCAAA



GCAAGGGGGTCCAGGTATACTATGGGCCCAGCACCTAAAGCCACCCTTGGGAG



ATGATACTCAGGTGGGAAATTCGTAGACTGGGGGACTGAACCAATCCCAAGAT



CTGGAAAAGTTTTGATGAAGACTTGAAAAGCTCCTAGCTTCGGGGGTCTGGGA



AGCATGAGCACTTACCAGGCAAAAGCTCCGTGAGCGTATCTGCTGTCCTTCTG



CATGCCCAGGTACCTCAGTTTTTTTCAACAGCAAGGAAACTAGGGCAATAAAG



GGAACCAGCAGAGCTAGAGCCACCCACACATCCAGGGGGGCACTTGACTCTCC



CTACTCCTCCTAGGAACCAAAAGGACAAAGTCCATGTTGACAGCAGGGAAGGA



AAGGGGGATATAACCTTGACGCAAACCAACACTGGGGTGTTAGAATCTCCTCA



TTCACTCTGTCCTGGAGTTGGGTTCTGGCTCTCCTTCACACCTAGGACTCTGA



AATGAGCAAGCACTTCAGACAGTCAGGGTAGCAAGAGTCTAGCTGTCTGGTGG



GCACCCAAAATGACCAGGGCTTAAGTCCCTTTCCTTTGGTTTAAGCCCGTTAT



AATTAAATGGTACCAAAAGCTTTAA (SEQ ID NO: 191)






>NP_032824.1 programmed cell death protein 1



precursor [Mus musculus]



MWVRQVPWSFTWAVLQLSWQSGWLLEVPNGPWRSLTFYPAWLTVSEGANATFT



CSLSNWSEDLMLNWNRLSPSNQTEKQAAFCNGLSQPVQDARFQIIQLPNRHDF



HMNILDTRRNDSGIYLCGAISLHPKAKIEESPGAELVVTERILETSTRYPSPS



PKPEGRFQGMVIGIMSALVGIPVLLLLAWALAVFCSTSMSEARGAGSKDDTLK



EEPSAAPVPSVAYEELDFQGREKTPELPTACVHTEYATIVFTEGLGASAMGRR



GSADGLQGPRPPRHEDGHCSWPL (SEQ ID NO: 317)





mScarlet
>KY021423.1 Synthetic construct mScarlet gene,



partial cds, mRNA



ATGGTGAGCAAGGGCGAGGCAGTGATCAAGGAGTTCATGCGGTTCAAGGTGCA



CATGGAGGGCTCCATGAACGGCCACGAGTTCGAGATCGAGGGCGAGGGCGAGG



GCCGCCCCTACGAGGGCACCCAGACCGCCAAGCTGAAGGTGACCAAGGGTGGC



CCCCTGCCCTTCTCCTGGGACATCCTGTCCCCTCAGTTCATGTACGGCTCCAG



GGCCTTCACCAAGCACCCCGCCGACATCCCCGACTACTATAAGCAGTCCTTCC



CCGAGGGCTTCAAGTGGGAGCGCGTGATGAACTTCGAGGACGGCGGCGCCGTG



ACCGTGACCCAGGACACCTCCCTGGAGGACGGCACCCTGATCTACAAGGTGAA



GCTCCGCGGCACCAACTTCCCTCCTGACGGCCCCGTAATGCAGAAGAAGACAA



TGGGCTGGGAAGCGTCCACCGAGCGGTTGTACCCCGAGGACGGCGTGCTGAAG



GGCGACATTAAGATGGCCCTGCGCCTGAAGGACGGCGGCCGCTACCTGGCGGA



CTTCAAGACCACCTACAAGGCCAAGAAGCCCGTGCAGATGCCCGGCGCCTACA



ACGTCGACCGCAAGTTGGACATCACCTCCCACAACGAGGACTACACCGTGGTG



GAACAGTACGAACGCTCCGAGGGCCGCCACTCCACCGGCGGCATGGACGAGCT



GTACAAG (SEQ ID NO: 192)






>APD76535.1 mScarlet, partial [synthetic construct]



MVSKGEAVIKEFMRFKVHMEGSMNGHEFEIEGEGEGRPYEGTQTAKLKVTKGG



PLPFSWDILSPQFMYGSRAFTKHPADIPDYYKQSFPEGFKWERVMNFEDGGAV



TVTQDTSLEDGTLIYKVKLRGTNFPPDGPVMQKKTMGWEASTERLYPEDGVLK



GDIKMALRLKDGGRYLADFKTTYKAKKPVQMPGAYNVDRKLDITSHNEDYTVV



EQYERSEGRHSTGGMDELYK (SEQ ID NO: 193)





Nanoluciferase
>JQ513379. 1 NanoLuc reporter vector



pNL1.1.CMV[Nluc/CMV], complete sequence, mRNA



GGCCTAACTGGCCTCAATATTGGCCATTAGCCATATTATTCATTGGTTATATA



GCATAAATCAATATTGGCTATTGGCCATTGCATACGTTGTATCTATATCATAA



TATGTACATTTATATTGGCTCATGTCCAATATGACCGCCATGTTGGCATTGAT



TATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCA



TATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACC



GCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAA



CGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACT



GCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTCCGCCCCCTATTGA



CGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTAC



GGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATG



GTGATGCGGTTTTGGCAGTACACCAATGGGCGTGGATAGCGGTTTGACTCACG



GGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACC



AAAATCAACGGGACTTTCCAAAATGTCGTAATAACCCCGCCCCGTTGACGCAA



ATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTCGTTTAGT



GAACCGTCAGATCACTAGAAGCTTTATTGCGGTAGTTTATCACAGTTAAATTG



CTAACGCAGTCAGTGGGCCTCGGCGGCCAAGCTTGGCAATCCGGTACTGTTGG



TAAAGCCACCATGGTCTTCACACTCGAAGATTTCGTTGGGGACTGGCGACAGA




CAGCCGGCTACAACCTGGACCAAGTCCTTGAACAGGGAGGTGTGTCCAGTTTG





TTTCAGAATCTCGGGGTGTCCGTAACTCCGATCCAAAGGATTGTCCTGAGCGG





TGAAAATGGGCTGAAGATCGACATCCATGTCATCATCCCGTATGAAGGTCTGA





GCGGCGACCAAATGGGCCAGATCGAAAAAATTTTTAAGGTGGTGTACCCTGTG





GATGATCATCACTTTAAGGTGATCCTGCACTATGGCACACTGGTAATCGACGG





GGTTACGCCGAACATGATCGACTATTTCGGACGGCCGTATGAAGGCATCGCCG





TGTTCGACGGCAAAAAGATCACTGTAACAGGGACCCTGTGGAACGGCAACAAA





ATTATCGACGAGCGCCTGATCAACCCCGACGGCTCCCTGCTGTTCCGAGTAAC





CATCAACGGAGTGACCGGCTGGCGGCTGTGCGAACGCATTCTGGCGTAATTCT




AGAGTCGGGGCGGCCGGCCGCTTCGAGCAGACATGATAAGATACATTGATGAG



TTTGGACAAACCACAACTAGAATGCAGTGAAAAAAATGCTTTATTTGTGAAAT



TTGTGATGCTATTGCTTTATTTGTAACCATTATAAGCTGCAATAAACAAGTTA



ACAACAACAATTGCATTCATTTTATGTTTCAGGTTCAGGGGGAGGTGTGGGAG



GTTTTTTAAAGCAAGTAAAACCTCTACAAATGTGGTAAAATCGATAAGGATCC



GTCGACCGATGCCCTTGAGAGCCTTCAACCCAGTCAGCTCCTTCCGGTGGGCG



CGGGGCATGACTATCGTCGCCGCACTTATGACTGTCTTCTTTATCATGCAACT



CGTAGGACAGGTGCCGGCAGCGCTCTTCCGCTTCCTCGCTCACTGACTCGCTG



CGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAAT



ACGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAAAG



GCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCAT



AGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTG



GCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCC



TCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTT



CTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAG



TTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTC



AGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTA



AGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGC



GAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCT



ACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTC



GGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGG



TGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAG



AAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCA



CGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCT



TTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTT



GGTCTGACAGCGGCCGCAAATGCTAAACCACTGCAGTGGTTACCAGTGCTTGA



TCAGTGAGGCACCGATCTCAGCGATCTGCCTATTTCGTTCGTCCATAGTGGCC



TGACTCCCCGTCGTGTAGATCACTACGATTCGTGAGGGCTTACCATCAGGCCC



CAGCGCAGCAATGATGCCGCGAGAGCCGCGTTCACCGGCCCCCGATTTGTCAG



CAATGAACCAGCCAGCAGGGAGGGCCGAGCGAAGAAGTGGTCCTGCTACTTTG



TCCGCCTCCATCCAGTCTATGAGCTGCTGTCGTGATGCTAGAGTAAGAAGTTC



GCCAGTGAGTAGTTTCCGAAGAGTTGTGGCCATTGCTACTGGCATCGTGGTAT



CACGCTCGTCGTTCGGTATGGCTTCGTTCAACTCTGGTTCCCAGCGGTCAAGC



CGGGTCACATGATCACCCATATTATGAAGAAATGCAGTCAGCTCCTTAGGGCC



TCCGATCGTTGTCAGAAGTAAGTTGGCCGCGGTGTTGTCGCTCATGGTAATGG



CAGCACTACACAATTCTCTTACCGTCATGCCATCCGTAAGATGCTTTTCCGTG



ACCGGCGAGTACTCAACCAAGTCGTTTTGTGAGTAGTGTATACGGCGACCAAG



CTGCTCTTGCCCGGCGTCTATACGGGACAACACCGCGCCACATAGCAGTACTT



TGAAAGTGCTCATCATCGGGAATCGTTCTTCGGGGCGGAAAGACTCAAGGATC



TTGCCGCTATTGAGATCCAGTTCGATATAGCCCACTCTTGCACCCAGTTGATC



TTCAGCATCTTTTACTTTCACCAGCGTTTCGGGGTGTGCAAAAACAGGCAAGC



AAAATGCCGCAAAGAAGGGAATGAGTGCGACACGAAAATGTTGGATGCTCATA



CTCGTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTACTAGTACGTCTC



TCAAGGATAAGTAAGTAATATTAAGGTACGGGAGGTATTGGACAGGCCGCAAT



AAAATATCTTTATTTTCATTACATCTGTGTGTTGGTTTTTTGTGTGAATCGAT



AGTACTAACATACGCTCTCCATCAAAACAAAACGAAACAAAACAAACTAGCAA



AATAGGCTGTCCCCAGTGCAAGTGCAGGTGCCAGAACATTTCTCT (SEQ ID



NO: 194)






>AFJ15599.1 NanoLuc luciferase [NanoLuc reporter



vector pNL1.1.CMV[Nluc/CMV]]



MVFTLEDFVGDWRQTAGYNLDQVLEQGGVSSLFQNLGVSVTPIQRIVLSGENG



LKIDIHVIIPYEGLSGDQMGQIEKIFKVVYPVDDHHFKVILHYGTLVIDGVTP



NMIDYFGRPYEGIAVFDGKKITVTGTLWNGNKIIDERLINPDGSLLFRVTING



VTGWRLCERILA (SEQ ID NO: 195)









The polypeptides provided in Table 1 above are involved in a range of biological processes, including but not limited to, suppressing the adaptive arm of the immune system (e.g., PD-L1); cellular adhesion (e.g., nectin), immune activation (e.g., HVEM), and the like. The POI domains can also be used to track, purify, or identify the engineered EVs from native EVs (e.g., mScarlet and nanoluciferase). The genes, transcripts, polypeptides, variants, and fragments thereof can be used in any combination from Table 1 to be expressed by an engineered EV provided herein. In some embodiments, the POI domain is the human polypeptide. In some embodiments, the POI domain is a homologue of the human polypeptide (e.g., mouse).


In some embodiments of any of the aspects, the engineered cell or EV provided herein comprises an exogenous nucleic acid encoding one or more exogenous polypeptide(s) selected from the group consisting of: the polypeptides listed in Table 1.


In some embodiments of any of the aspects, the POI domain is PD-L1 or a fragment thereof. In some embodiments of any of the aspects, the POI domain is PD-L2 or a fragment thereof. In some embodiments of any of the aspects, the POI domain is FGL1 or a fragment thereof. In some embodiments of any of the aspects, the POI domain is 4-1BBL or a fragment thereof. In some embodiments of any of the aspects, the POI domain is CTLA or a fragment thereof.


In some embodiments of any of the aspects, the POI domain substantially binds to one or more of a target polypeptide. In some embodiments of any of the aspects, the target polypeptide is a cellular receptor. In some embodiments of any of the aspects, the target polypeptide is an immunosuppressive polypeptide. In some embodiments of any of the aspects, the target polypeptide is an immunostimulatory polypeptide. The engineered exosomes provided herein can be designed to activate, block, or modulate a given target polypeptide with the appropriate POI domain that binds to or modulates the function or expression of the target polypeptide. Non-limiting examples of target polypeptides include those listed in Table 2 (below).









TABLE 2





Exemplary Target Polypeptides


















PD-1
VISTA
LAG-3
CD44


CD80
BTLA
CD112
IL10RA


CD86
CD160
CD200R
IL10RB


CD28
HVEM
CD200
Tim-3


ICOS
CD2
Galectin 9
TNFRSF25


CD28H
SLAM CD150
TIM-3
TNFRSF6B


PD-Ll
CD58
CD226
CD113


CTLA-4
TIM-1
CD155
CD27


4-1BB (CD137)
TIM-4
CD112
CD30


GITR
CD40
DR3
LFA-3 (CD58)


CD27L
CD30L
GITRL
CD40L


CD48
CD244
DcR3
CD28H


LFA-3 (CD58)
CD98
TNF Receptor
TNF receptor




Superfamily
associated factor




members
(TRAF) family





members


Butyrophilin family
PD-L2
Nectin
TIM family


members


members


B7/CD28 family
SLAM family
Nectin-like
Collagen


members
members
binding receptors
family proteins


LAIR-1 (CD305)









The EVs provided herein further comprise at least one fusion protein comprising a vesicle targeting domain. In various embodiments, the vesicle targeting domain provided herein is capable of binding or anchoring the fusion polypeptide provided herein to an extracellular vesicle, e.g., via targeting of the phospholipid bilayer membrane. In various embodiments, the vesicle targeting domain is a GPI domain (i.e., GPI linker, GPI anchor), fatty acylation site, or prenylation site. One of skill in the art can appreciate that the aforementioned refer to peptide or protein sites, wherein covalent lipid attachment supports embedding of the lipid in a cell membrane (i.e., phospholipid bilayer). Biochemical forces that anchor EV targeting domains to the EV phospholipid bilayer may include, but are not limited to, electrostatic forces, affinity for EVs through protein-protein interactions with natively resident proteins (e.g., CD81, CD63, CD9, ALIX, TSG101. CD98, CD298, MARCKS, PTGFRN, Lactadherin (MFGe8)), association or affinity for negatively or positively curved phospholipids, association or affinity for negatively or positively charged domains of resident membrane associated proteins, etc., or the like.


Additional non-limiting examples of membrane targeting domains that can be used and their properties are further described in detail, e.g., Alberts B, Johnson A, Lewis J, et at, Molecular Biology of the Cell. 4th edition, New York: Garland Science, 2002. Membrane Proteins, https://www.ncbi.nlm.nih.gov/books/NBK268781; Marilyn D. Resh, Fatty acylation of proteins: new insights into membrane targeting of myristoylated and palmitoylated proteins. Biochimica et Biophysica Acta (BBA)—Molecular Cell Research. Volume 1451, Issue 1, 12 Aug. 1999, Pages 1-16, doi.org/10.1016/S0167-4889(99)00075-0; Ann Apolloni, et. al., H-ras but Not K-ras Traffics to the Plasma Membrane through the Exocytic Pathway, Molecular and Cellular Biology April 2000, 20 (7) 2475-2487, DOI: 10.1128/MCB.20.7.2475-2487.2000; Rosie Dawaliby et. al., Phosphatidylethanolamine Is a Key Regulator of Membrane Fluidity in Eukaryotic Cells, Membrane Biology, VOLUME 291, ISSUE 7, doi.org/10.1074/jbc.M115.706523; R. J. Deschenes, Protein Palmitoylation, Encyclopedia of Biological Chemistry (Second Edition), Academic Press, 2013, Pages 645-647, ISBN 9780123786319, https://doi.org/10.1016/B978-0-12-378630-2.00022-0; Charuta C. Palsuledesai and Mark D. Distefano, Protein Prenylation: Enzymes, Therapeutics, and Biotechnology Applications, ACS Chemical Biology 2015 10 (1), 51-62, DOI: 10.1021/cb500791f; Hung M E, Leonard J N. Stabilization of exosome-targeting peptides via engineered glycosylation, J Biol Chem, 2015 Mar. 27; 290(13):8166-72, doi: 10.1074/jbc.M114.621383; Udenwobele Daniel Ikenna, et. al., Myristoylation: An Important Protein Modification in the Immune Response, Frontiers in Immunology, Vol: 8, 2017, DOI=10.3389/fimmu.2017.00751; Kinoshita Taroh 2020Biosynthesis and biology of mammalian GPI-anchored proteins Open Biol. 10190290, http://doi.org/10.1098/rsob.190290, the contents of which are incorporated herein by reference in their entireties.


In some embodiments, the fusion polypeptide comprises one or more, two or more, three or more, four or more, five or more, or six or more vesicle targeting domains on the same polypeptide or nucleic acid construct encoding said polypeptide. For example, the fusion polypeptides provided herein can comprise PD-L1 and Glycosylphosphatidylinositol (GPI).


In some embodiments, the vesicle targeting domain is a prenylated protein. Prenylated proteins are proteins that have at least one prenylation site. Prenylation occurs when a 15-carbon or 20-carbon, farnesyl or geranylgeranyl isoprenoid, respectively, is covalently bound via a thioether bond to a cysteine at or near the carboxy terminus of a protein. In general, a prenylation site comprises an amino acid sequence CAAX, wherein C represents cysteine, A represents an aliphatic amino acid (glycine, alanine, valine, leucine, or isoleucine), and X represents alanine, methionine, serine, leucine, or glutamine.


In some embodiments, the vesicle targeting domain is a fatty acylated protein. Fatty acylated proteins are proteins that have been modified post-translationally by covalent attachment of one or more fatty acids, generally with a saturated fatty acid that comprises 14-carbon (e.g. myristic acid) via myristoylation or 16-carbons (e.g. palmitic acid) via palmitoylation. For example, proteins destined to become myristoylated begin with the amino acids Met-Gly-X-X-X followed by a serine or threonine at position 6 and lysine or arginine at position 7 and/or 8 wherein X can be any amino acid. The methionine is removed and a myristate is linked to the glycine via an amide bond. Palmitoylation herein means a posttranslational covalent attachment of fatty acids (e.g. palmitic acid) to cysteine (S-palmitoylation), serine and/or threonine (0-palmitoylation), and to the amino group of lysine (N-palmitoylation) of proteins.


Palmitoylated proteins may be acylated by attachment of a thioester linkage to a sulfhydryl group of cysteine, or via a palmitate linked to the amino group of an N-terminal cysteine. Palmitoylation sites may be present near the N- or C-terminus of a protein.


In some embodiments, the vesicle targeting domain is a glycosylphosphatidylinositol (GPI) anchor. A glycosylphosphatidylinositol (GPI) anchor (“GPI anchor”) or “GPI sticky binder” are used interchangeably and refer to a means of stably anchoring a protein to an outer leaflet (e.g. exterior layer of a phospholipid bilayer) of a cell membrane. A GPI anchor comprises a glycan, a phosphoethanolamine linker, a phospholipid tail, and may be modified by various glycan sidechains. The glycan core comprises phophoinositol, glucosamine, and mannose residues wherein said mannose residues may be modified for example with phosphoethanolamine or carbohydrates. The phosphoethanolamine is amide-bonded to the carboxyl terminus of a protein during the process of GPI attachment. In some embodiments, the vesicle targeting domain may have affinity to EV resident proteins, e.g., CD81, CD63, CD9, ALIX, TSG101, CD98, CD298, MARCKS, PTGFRN, Lactadherin (MFGe8)


Sticky binders can include a sequence for one or more myristoylation and/or palmitoylation (Myr/Palm) sites fused to a transmembrane domain from 4F2 (CD98). For example, the myristoylation sequence from the MARCKS protein may be modified to encode for one or more myristoylation and palmitoylation sites, wherein the modified MARCKS protein sequence is fused to a protein sequence of the transmembrane domain from 4F2 via a covalent peptide bond. A Myr/Palm followed by the 4F2 transmembrane domain can improve loading of the fusion proteins provided herein when compared with 4F2 transmembrane domain alone or Myr/Palm alone.


Non-limiting examples of vesicle targeting domains that enhance fusion polypeptide structure and function on the extracellular vesicles are provided in Table 3 (below).









TABLE 3







Exosome Targeting Domain








Exosome Targeting



Domain/Sticky
Nucleic Acid Sequence (SEQ ID NO:)


Binder
Amino Acid Sequence (SEQ ID NO:)





Human CD55
>NM_000574.5 Homo sapiens CD55 molecule (Cromer blood


(DAF)
group) (CD55), transcript variant 1, mRNA


Glycosylphosphatidylinositol
CTGCTTACTGCAACTCGCTCCGGCCGCTGGGCGTAGCTGCGACTCGGCGGAGTCCCG


(GPI)
GCGGCGCGTCCTTGTTCTAACCCGGCGCGCCATGACCGTCGCGCGGCCGAGCGTGCC



CGCGGCGCTGCCCCTCCTCGGGGAGCTGCCCCGGCTGCTGCTGCTGGTGCTGTTGTG



CCTGCCGGCCGTGTGGGGTGACTGTGGCCTTCCCCCAGATGTACCTAATGCCCAGCC



AGCTTTGGAAGGCCGTACAAGTTTTCCCGAGGATACTGTAATAACGTACAAATGTGA



AGAAAGCTTTGTGAAAATTCCTGGCGAGAAGGACTCAGTGATCTGCCTTAAGGGCAG



TCAATGGTCAGATATTGAAGAGTTCTGCAATCGTAGCTGCGAGGTGCCAACAAGGCT



AAATTCTGCATCCCTCAAACAGCCTTATATCACTCAGAATTATTTTCCAGTCGGTAC



TGTTGTGGAATATGAGTGCCGTCCAGGTTACAGAAGAGAACCTTCTCTATCACCAAA



ACTAACTTGCCTTCAGAATTTAAAATGGTCCACAGCAGTCGAATTTTGTAAAAAGAA



ATCATGCCCTAATCCGGGAGAAATACGAAATGGTCAGATTGATGTACCAGGTGGCAT



ATTATTTGGTGCAACCATCTCCTTCTCATGTAACACAGGGTACAAATTATTTGGCTC



GACTTCTAGTTTTTGTCTTATTTCAGGCAGCTCTGTCCAGTGGAGTGACCCGTTGCC



AGAGTGCAGAGAAATTTATTGTCCAGCACCACCACAAATTGACAATGGAATAATTCA



AGGGGAACGTGACCATTATGGATATAGACAGTCTGTAACGTATGCATGTAATAAAGG



ATTCACCATGATTGGAGAGCACTCTATTTATTGTACTGTGAATAATGATGAAGGAGA



GTGGAGTGGCCCACCACCTGAATGCAGAGGAAAATCTCTAACTTCCAAGGTCCCACC



AACAGTTCAGAAACCTACCACAGTAAATGTTCCAACTACAGAAGTCTCACCAACTTC



TCAGAAAACCACCACAAAAACCACCACACCAAATGCTCAAGCAACACGGAGTACACC



TGTTTCCAGGACAACCAAGCATTTTCATGAAACAACCCCAAATAAAGGAAGTGGAAC




CACTTCAGGTACTACCCGTCTTCTATCTGGGCAGACGTGTTTCACGTTGACAGGTTT





GCTTGGGACGCTAGTAACCATGGGCTTGCTGACTTAGCCAAAGAAGAGTTAAGAAGA




AAATACACACAAGTATACAGACTGTTCCTAGTTTCTTAGACTTATCTGCATATTGGA



TAAAATAAATGCAATTGTGCTCTTCATTTAGGATGCTTTCATTGTCTTTAAGATGTG



TTAGGAATGTCAACAGAGCAAGGAGAAAAAAGGCAGTCCTGGAATCACATTCTTAGC



ACACCTACACCTCTTGAAAATAGAACAACTTGCAGAATTGAGAGTGATTCCTTTCCT



AAAAGTGTAAGAAAGCATAGAGATTTGTTCGTATTTAGAATGGGATCACGAGGAAAA



GAGAAGGAAAGTGATTTTTTTCCACAAGATCTGTAATGTTATTTCCACTTATAAAGG



AAATAAAAAATGAAAAACATTATTTGGATATCAAAAGCAAATAAAAACCCAATTCAG



TCTCTTCTAAGCAAAATTGCTAAAGAGAGATGAACCACATTATAAAGTAATCTTTGG



CTGTAAGGCATTTTCATCTTTCCTTCGGGTTGGCAAAATATTTTAAAGGTAAAACAT



GCTGGTGAACCAGGGGTGTTGATGGTGATAAGGGAGGAATATAGAATGAAAGACTGA



ATCTTCCTTTGTTGCACAAATAGAGTTTGGAAAAAGCCTGTGAAAGGTGTCTTCTTT



GACTTAATGTCTTTAAAAGTATCCAGAGATACTACAATATTAACATAAGAAAAGATT



ATATATTATTTCTGAATCGAGATGTCCATAGTCAAATTTGTAAATCTTATTCTTTTG



TAATATTTATTTATATTTATTTATGACAGTGAACATTCTGATTTTACATGTAAAACA



AGAAAAGTTGAAGAAGATATGTGAAGAAAAATGTATTTTTCCTAAATAGAAATAAAT



GATCCCATTTTTTGGTATCATGTAGTATGTGAAATTTATTCTTAAACGTGACTACTT



TATTTCTAAATAAGAAATTCCCTACCTGCTTCCTACAAGCAGTTCAGAATGCCATGC



CTTGGTTGTCCTAGTGTGAATAATTTTCAGCTACTTTAAAATTATATTGTACTTTCT



CAAGCATGTCATATCCTTTCCTATTAGAGTATCTATATTACTTGTTACTGATTTACC



TGAAGGCAATCTGATTAATTTCTAGGTTTTTACCATATTCTTGTCATCTTGCCAATT



ACATTTTAAGTGTTAGACTAGACTAAGATGTACTAGTTGTATAGAATATAACTAGA



TTTATTATGGCAATGTTTATTTTGTCATTTTGCTTCATCTGTTTTGTTGTTGAAGTA



CTTTAAATTTCATACGTTCATGGCATTTCACTGTAAAGACTTTAATGTGTATTTCTT



AAAATAAAACTTTTTTTCCTCCTTAA (SEQ ID NO: 196)



>NP_000565.1 complement decay-accelerating factor isoform



1 preproprotein [Homo sapiens]



MTVARPSVPAALPLLGELPRLLLLVLLCLPAVWGDCGLPPDVPNAQPALEGRTSFPE



DTVITYKCEESFVKIPGEKDSVICLKGSQWSDIEEFCNRSCEVPTRLNSASLKQPYI



TQNYFPVGTVVEYECRPGYRREPSLSPKLTCLQNLKWSTAVEFCKKKSCPNPGEIRN



GQIDVPGGILFGATISFSCNTGYKLFGSTSSFCLISGSSVQWSDPLPECREIYCPAP



PQIDNGIIQGERDHYGYRQSVTYACNKGFTMIGEHSIYCTVNNDEGEWSGPPPECRG



KSLTSKVPPTVQKPTTVNVPTTEVSPTSQKTTTKTTTPNAQATRSTPVSRTTKHFHE



TTPNKGSGTTSGTTRLLSGHTCFTLTGLLGTLVTMGLLT (SEQ ID NO: 197)





Human CD59
>NM_203330.2 Homo sapiens CD59 molecule (CD59 blood


Glycosylphosphatidylinositol
group) (CD59), transcript variant 1, mRNA


(GPI)
GGGGCCGGGGGGCGGAGCCTTGCGGGCTGGAGCGAAAGAATGCGGGGGCTGA



GCGCAGAAGCGGCTCGAGGCTGGAAGAGGATCTTGGGCGCCGCCAGTCTCTC



TCTGTTGCCCAAGCTGGAGTGCAGTGGCACAGTCTTGGCTCACTGCAACCTC



CACCTCCTGGGTGCAAGCGATTCTCGTGTCTCAGCCTCTCAAGTAGCTGGGA



TTACAGTCTTTAGCACCAGTTGGTGTAGGAGTTGAGACCTACTTCACAGTAG



TTCTGTGGACAATCACAATGGGAATCCAAGGAGGGTCTGTCCTGTTCGGGCT



GCTGCTCGTCCTGGCTGTCTTCTGCCATTCAGGTCATAGCCTGCAGTGCTAC



AACTGTCCTAACCCAACTGCTGACTGCAAAACAGCCGTCAATTGTTCATCTG



ATTTTGATGCGTGTCTCATTACCAAAGCTGGGTTACAAGTGTATAACAAGTG



TTGGAAGTTTGAGCATTGCAATTTCAACGACGTCACAACCCGCTTGAGGGAA



AATGAGCTAACGTACTACTGCTGCAAGAAGGACCTGTGTAACTTTAACGAAC




AGCTTGAAAATGGTGGGACATCCTTATCAGAGAAAACAGTTCTTCTGCTGGT





GACTCCATTTCTGGCAGCAGCCTGGAGCCTTCATCCCTAAGTCAACACCAGG




AGAGCTTCTCCCAAACTCCCCGTTCCTGCGTAGTCCGCTTTCTCTTGCTGCC



ACATTCTAAAGGCTTGATATTTTCCAAATGGATCCTGTTGGGAAAGAATAAA



ATTAGCTTGAGCAACCTGGCTAAGATAGAGGGGCTCTGGGAGACTTTGAAGA



CCAGTCCTGTTTGCAGGGAAGCCCCACTTGAAGGAAGAAGTCTAAGAGTGAA



GTAGGTGTGACTTGAACTAGATTGCATGCTTCCTCCTTTGCTCTTGGGAAGA



CCAGCTTTGCAGTGACAGCTTGAGTGGGTTCTCTGCAGCCCTCAGATTATTT



TTCCTCTGGCTCCTTGGATGTAGTCAGTTAGCATCATTAGTACATCTTTGGA



GGGTGGGGCAGGAGTATATGAGCATCCTCTCTCACATGGAACGCTTTCATAA



ACTTCAGGGATCCCGTGTTGCCATGGAGGCATGCCAAATGTTCCATATGTGG



GTGTCAGTCAGGGACAACAAGATCCTTAATGCAGAGCTAGAGGACTTCTGGC



AGGGAAGTGGGGAAGTGTTCCAGATAGCAGGGCATGAAAACTTAGAGAGGTA



CAAGTGGCTGAAAATCGAGTTTTTCCTCTGTCTTTAAATTTTATATGGGCTT



TGTTATCTTCCACTGGAAAAGTGTAATAGCATACATCAATGGTGTGTTAAAG



CTATTTCCTTGCCTTTTTTTTATTGGAATGGTAGGATATCTTGGCTTTGCCA



CACACAGTTACAGAGTGAACACTCTACTACATGTGACTGGCAGTATTAAGTG



TGCTTATTTTAAATGTTACTGGTAGAAAGGCAGTTCAGGTATGTGTGTATAT



AGTATGAATGCAGTGGGGACACCCTTTGTGGTTACAGTTTGAGACTTCCAAA



GGTCATCCTTAATAACAACAGATCTGCAGGGGTATGTTTTACCATCTGCATC



CAGCCTCCTGCTAACTCCTAGCTGACTCAGCATAGATTGTATAAAATACCTT



TGTAACGGCTCTTAGCACACTCACAGATGTTTGAGGCTTTCAGAAGCTCTTC



TAAAAAATGATACACACCTTTCACAAGGGCAAACTTTTTCCTTTTCCCTGTG



TATTCTAGTGAATGAATCTCAAGATTCAGTAGACCTAATGACATTTGTATTT



TATGATCTTGGCTGTATTTAATGGCATAGGCTGACTTTTGCAGATGGAGGAA



TTTCTTGATTAATGTTGAAAAAAAACCCTTGATTATACTCTGTTGGACAAAC



CGAGTGCAATGAATGATGCTTTTCTGAAAATGAAATATAACAAGTGGGTGAA



TGTGGTTATGGCCGAAAAGGATATGCAGTATGCTTAATGGTAGCAACTGAAA



GAAGACATCCTGAGCAGTGCCAGCTTTCTTCTGTTGATGCCGTTCCCTGAAC



ATAGGAAAATAGAAACTTGCTTATCAAAACTTAGCATTACCTTGGTGCTCTG



TGTTCTCTGTTAGCTCAGTGTCTTTCCTTACATCAATAGGTTTTTTTTTTTT



TTTTTGGCCTGAGGAAGTACTGACCATGCCCACAGCCACCGGCTGAGCAAAG



AAGCTCATTTCATGTGAGTTCTAAGGAATGAGAAACAATTTTGATGAATTTA



AGCAGAAAATGAATTTCTGGGAACTTTTTTGGGGGCGGGGGGGTGGGGAATT



CAGCCACACTCCAGAAAGCCAGGAGTCGACAGTTTTGGAAGCCTCTCTCAGG



ATTGAGATTCTAGGATGAGATTGGCTTACTGCTATCTTGTGTCATGTACCCA



CTTTTTGGCCAGACTACACTGGGAAGAAGGTAGTCCTCTAAAGCAAAATCTG



AGTGCCACTAAATGGGGAGATGGGGCTGTTAAGCTGTCCAAATCAACAAGGG



TCATATAAATGGCCTTAAACTTTGGGGTTGCTTTCTGCAAAAAGTTGCTGTG



ACTCATGCCATAGACAAGGTTGAGTGCCTGGACCCAAAGGCAATACTGTAAT



GTAAAGACATTTATAGTACTAGGCAAACAGCACCCCAGGTACTCCAGGCCCT



CCTGGCTGGAGAGGGCTGTGGCAATAGAAAATTAGTGCCAACTGCAGTGAGT



CAGCCTAGGTTAAATAGAGAGTGTAAGAGTGCTGGACAGGAACCTCCACCCT



CATGTCACATTTCTTCAATGTGACCCTTCTGGCCCCTCTCCTCCTGACAGCG



GAACAATGACTGCCCCGATAGGTGAGGCTGGAGGAAGAATCAGTCCTGTCCT



TGGCAAGCTCTTCACTATGACAGTAAAGGCTCTCTGCCTGCTGCCAAGGCCT



GTGACTTTCTAACCTGGCCTCACGCTGGGTAAGCTTAAGGTAGAGGTGCAGG



ATTAGCAAGCCCACCTGGCTACCAGGCCGACAGCTACATCCTCCAACTGACC



CTGATCAACGAAGAGGGATTCATGTGTCTGTCTCAGTTGGTTCCAAATGAAA



CCAGGGAGCAGGGGAGTTAGGAATCGAACACCAGTCATGCCTACTGGCTCTC



TGCTCGAGAGCCAATACCCTGTGCCCTCCACTCATCTGGATTTACAGGAACT



GTCATAGTGTTCAGTATTGGGTGGTGATAAGCCCATTGGATTGTCCCCTTGG



GGGGATGAGCTAGGGGTGCAAGGAACACCTGATGAGTAGATAAGTGGAGCTC



ATGGTATTTCCTGAAAGATGCTAATCTATTTGCCAAACTTGGTCTTGAATGT



ACTGGGGGCTTCAAGGTATGGGTATATTTTTCTTGTGTCCTTGCAGTTAGCC



CCCATGTCTTATGTGTGTCCTGAAAAAATAAGAGCCTGCCCAAGACTTTGGG



CCTCTTGACAGAATTAACCACTTTTATACATCTGAGTTCTCTTGGTAAGTTC



TTTAGCAGTGTTCAAAGTCTACTAGCTCGCATTAGTTTCTGTTGCTGCCAAC



AGATCTGAACTAATGCTAACAGATCCCCCTGAGGGATTCTTGATGGGCTGAG



CAGCTGGCTGGAGCTAGTACTGACTGACATTCATTGTGATGAGGGCAGCTTT



CTGGTACAGGATTCTAAGCTCTATGTTTTATATACATTTTCATCTGTACTTG



CACCTCACTTTACACAAGAGGAAACTATGCAAAGTTAGCTGGATCGCTCAAG



GTCACTTAGGTAAGTTGGCAAGTCCATGCTTCCCACTCAGCTCCTCAGGTCA



GCAAGTCTACTTCTCTGCCTATTTTGTATACTCTCTTTAATATGTGCCTAGC



TTTGGAAAGTCTAGAATGGGTCCCTGGTGCCTTTTTACTTTGAAGAAATCAG



TTTCTGCCTCTTTTTGGAAAAGAAAACAAAGTGCAATTGTTTTTTACTGGAA



AGTTACCCAATAGCATGAGGTGAACAGGACGTAGTTAGGCCTTCCTGTAAAC



AGAAAATCATATCAAAACACTATCTTCCCATCTGTTTCTCAATGCCTGCTAC



TTCTTGTAGATATTTCATTTCAGGAGAGCAGCAGTTAAACCCGTGGATTTTG



TAGTTAGGAACCTGGGTTCAAACCCTCTTCCACTAATTGGCTATGTCTCTGG



ACAAGTTTTTTTTTTTTTTTTTTTTTAAACCCTTTCTGAACTTTCACTTTCT



ATGTCTACCTCAAAGAATTGTTGTGAGGCTTGAGATAATGCATTTGTAAAGG



GTCTGCCAGATAGGAAGATGCTAGTTATGGATTTACAAGGTTGTTAAGGCTG



TAAGAGTCTAAAACCTACAGTGAATCACAATGCATTTACCCCCACTGACTTG



GACATAAGTGAAAACTAGCCAGAAGTCTCTTTTTCAAATTACTTACAGGTTA



TTCAATATAAAATTTTTGTAATGGATAATCTTATTTATCTAAACTAAAGCTT



CCTGTTTATACACACTCCTGTTATTCTGGGATAAGATAAATGACCACAGTAC



CTTAATTTCTAGGTGGGTGCCTGTGATGGTTCATTGTAGGTAAGGACATTTT



CTCTTTTTCAGCAGCTGTGTAGGTCCAGAGCCTCTGGGAGAGGAGGGGGGTA



GCATGCACCCAGCAGGGGACTGAACTGGGAAACTCAAGGTTCTTTTTACTGT



GGGGTAGTGAGCTGCCTTTCTGTGATCGGTTTCCCTAGGGATGTTGCTGTTC



CCCTCCTTGCTATTCGCAGCTACATACAACGTGGCCAACCCCAGTAGGCTGA



TCCTATATATGATCAGTGCTGGTGCTGACTCTCAATAGCCCCACCCAAGCTG



GCTATAGGTTTACAGATACATTAATTAGGCAACCTAAAATATTGATGCTGGT



GTTGGTGTGACATAATGCTATGGCCAGAACTGAAACTTAGAGTTATAATTCA



TGTATTAGGGTTCTCCAGAGGGACAGAATTAGTAGGATATATGTATATATGA



AAGGGAGGTTATTAGGGAGAACTGGCTCCCACAGTTAGAAGGCGAAGTCGCA



CAATAGGCCGTCTGCAAGCTGGGTTAGAGAGAAGCCAGTAGTGGCTCAGCCT



GAGTTCAAAAACCTCAAAACTGGGGAAGCTGACAGTGCAGCCAGCCTTCAGT



CTGTGGCCAAAGGCCCAAGAGCCCCTGGCAACCAACCCACTGGTGCAAGTCC



TAGATTCCAAAGGCTGAAGAACCTGGAGTCTGATGTCCAAGAGCAGGAAGAG



TGGAAGAAAGCCAGAAGACTCAGCAAACAAGGTAGACAGTGTCTACCACCAT



AGTGGCCATACCAAAGAGGCTACCGATTCCTTCCTGCTACCTGGATCCCTGA



AGTTGCCCTGGTCTCTGCACCTTCTAAACCTAGTTCTTAAGAGCTTTCCATT



ACATGAGCTGTCTCAAAGCCCTCCAATAAATTCTCAGTGTAAGCTTCTGTTG



CTTGTGGACAGAAAATTCTGACAGACCTACCCTATAAGTGTTACTGTCAGGA



TAACATGAGAACGCACAACAGTAAGTGGTCACTAAGTGTTAGCTACGGTTAT



TTTGCCCAAGGTAGCATGGCTAGTTGATGCCGGTTGATGGGGCTTAAACCCA



GCTCCCTCATCTTCCAGGCCTCTGTACTCCCTATTCCACTAAACTACCTCTC



AGGTTTATTTTTTTAAATTCTTACTCTGCAAGTACATAGGACCACATTTACC



TGGGAAAACAAGAATAAAGGCTGCTCTGCATTTTTTAGAAACTTTTTTGAAA



GGGAGATGGGAATGCCTGCACCCCCAAGTCCAGACCAACACAATGGTTAATT



GAGATGAATAATAAAGGAAAGACTGTTCTGGGCTTCCCAGAATAGCTTGGTC



CTTAAATTGTGGCACAAACAACCTCCTGTCAGAGCCAGCCTCCTGCCAGGAA



GAGGGGTAGGAGACTAGAGGCCGTGTGTGCAGCCTTGCCCTGAAGGCTAGGG



TGACAATTTGGAGGCTGTCCAAACACCCTGGCCTCTAGAGCTGGCCTGTCTA



TTTGAAATGCCGGCTCTGATGCTAATCGGCGACCCTCAGGCAAGTTACTTAA



CCTTACATGCCTCAGTTTTCTCATCTGGAAAATGAGAACCCTAGGTTTAGGG



TTGTTAGAAAAGTTAAATGAGTTAAGACAAGTGCCTGGGACACAGTAGCCTC



TTGTGTGTGTTTATCATTATGTCCTCAGCAGGTCGTAGAAGCAGCTTCTCAG



GTGTGAGGCTGGCGCGATTATCTGGAGTGGGTTGGGTTTTCTAGGATGGACC



CCCTGCTGCATTTTCCTCATTCATCCACCAGGGCTTAATGGGGAATCAAGGA



ATCCATGTGTAACTGTATAATAACTGTAGCCACACTCCAATGACCACCTACT



AGTTGTCCCTGGCACTGCTTATACATATGTCCATCAAATCAATCCTATGAAG



TAGATACTGTCTTCATTTTATAGATCAGAGACAATTGGGGTTCAGAGAGCTG



ATGTGATTTTCCCAGGGTCACAGAGAGTCCCAGATTCAGGCACAACTCTTGT



ATTCCAAGACACAACCACTACATGTCCAAAGGCTGCCCAGAGCCACCGGGCA



CGGCAAATTGTGACATATCCCTAAAGAGGCTGAGCACCTGGTCAGGATCTGA



TGGCTGACAGTGTGTCCAGATGCAGAGCTGGAGTGGGGGAGGGGAAGGGGGG



CTCCTTGGGACAGAGAAGGCTTTCTGTGCTTTCTCTGAAGGGAGCAGTCTGA



GGACCAAGGGAACCCGGCAAACAGCACCTCAGGTACTCCAGGCCCTCCTGGC



TGGAGAGGGCTGTGGCAATGGAAAATTAGTGCCAACTGCAATGAGTCAGCCT



CGGTTAAATAGAGAGTGAAGAATGCTGGACAGGAACCTCCACCCTCATGTCA



CATTTCTTCAGTGTGACCCTTCTGGCCCCTCTCCTCCTGACAGCGGAACAAT



GACTGCCCCGATAGGTGAGGCTGGAGGAAGAATCAGTCCTGTCCTTGGCAAG



CTCTTCACTATGACAGTAAAGGCTCTCTGCCTGCTGCCAAGGCCTGTGACTT



TCTAACCTGGCCTCACGCTGGGTAAGCTTAAGGTAGAGGTGCAGGATTAGCA



AGCCCACCTGGCTACCAGGCCGACAGCTACATCTTTCAACTGACCCTGATCA



ACGAAGAGGGACTTGTGTCTCTCAGTTGGTTCCAAATGAAACCAGGGAGCAG



GGGCGTTAGGAAGCTCCAACAGGATGGTACTTAATGGGGCATTTGAGTGGAG



AGGTAGGTGACATAGTGCTTTGGAGCCCAGGGAGGGAAAGGTTCTGCTGAAG



TTGAATTCAAGACTGTTCTTTCATCACAAACTTGAGTTTCCTGGACATTTGT



TTGCAGAAACAACCGTAGGGTTTTGCCTTAACCTCGTGGGTTTATTATTACC



TCATAGGGACTTTGCCTCCTGACAGCAGTTTATGGGTGTTCATTGTGGCACT



TGAGTTTTCTTGCATACTTGTTAGAGAAACCAAGTTTGTCATCAACTTCTTA



TTTAACCCCCTGGCTATAACTTCATGGATTATGTTATAATTAAGCCATCCAG



AGTAAAATCTGTTTAGATTATCTTGGAGTAAGGGGGAAAAAATCTGTAATTT



TTTCTCCTCAACTAGATATATACATAAAAAATGATTGTATTGCTTCATTTAA



AAAATATAACGCAAAATCTCTTTTCCTTCTAAAAAAAAAAAAAAAAAA 



(SEQ ID NO: 321)



>NP_976075.1 CD59 glycoprotein preproprotein [Homo




sapiens]




MGIQGGSVLFGLLLVLAVFCHSGHSLQCYNCPNPTADCKTAVNCSSDFDACL



ITKAGLQVYNKCWKFEHCNFNDVTTRLRENELTYYCCKKDLCNFNEQLENGG




TSLSEKTVLLLVTPFLAAAWSLHP (SEQ ID NO: 198)






Human C1C2 from
NM_005928.4 Homo sapiens milk fat globule-EGF factor 8


MFGE8
protein (MFGE8), transcript variant 1, mRNA



AGAACCCCGCGGGGTCTGAGCAGCCCAGCGTGCCCATTCCAGCGCCCGCGTCCCCGC



AGCATGCCGCGCCCCCGCCTGCTGGCCGCGCTGTGCGGCGCGCTGCTCTGCGCCCCC



AGCCTCCTCGTCGCCCTGGATATCTGTTCCAAAAACCCCTGCCACAACGGTGGTTTA



TGCGAGGAGATTTCCCAAGAAGTGCGAGGAGATGTCTTCCCCTCGTACACCTGCACG



TGCCTTAAGGGCTACGCGGGCAACCACTGTGAGACGAAATGTGTCGAGCCACTGGGC




CTGGAGAATGGGAACATTGCCAACTCACAGATCGCCGCCTCGTCTGTGCGTGTGACC





TTCTTGGGTTTGCAGCATTGGGTCCCGGAGCTGGCCCGCCTGAACCGCGCAGGCATG





GTCAATGCCTGGACACCCAGCAGCAATGACGATAACCCCTGGATCCAGGTGAACCTG





CTGCGGAGGATGTGGGTAACAGGTGTGGTGACGCAGGGTGCCAGCCGCTTGGCCAGT





CATGAGTACCTGAAGGCCTTCAAGGTGGCCTACAGCCTTAATGGACACGAATTCGAT





TTCATCCATGATGTTAATAAAAAACACAAGGAGTTTGTGGGTAACTGGAACAAAAAC





GCGGTGCATGTCAACCTGTTTGAGACCCCTGTGGAGGCTCAGTACGTGAGATTGTAC





CCCACGAGCTGCCACACGGCCTGCACTCTGCGCTTTGAGCTACTGGGCTGTGAGCTG





AACGGATGCGCCAATCCCCTGGGCCTGAAGAATAACAGCATCCCTGACAAGCAGATC





ACGGCCTCCAGCAGCTACAAGACCTGGGGCTTGCATCTCTTCAGCTGGAACCCCTCC





TATGCACGGCTGGACAAGCAGGGCAACTTCAACGCCTGGGTTGCGGGGAGCTACGGT





AACGATCAGTGGCTGCAGGTGGACCTGGGCTCCTCGAAGGAGGTGACAGGCATCATC





ACCCAGGGGGCCCGTAACTTTGGCTCTGTCCAGTTTGTGGCATCCTACAAGGTTGCC





TACAGTAATGACAGTGCGAACTGGACTGAGTACCAGGACCCCAGGACTGGCAGCAGT





AAGATCTTCCCTGGCAACTGGGACAACCACTCCCACAAGAAGAACTTGTTTGAGACG





CCCATCCTGGCTCGCTATGTGCGCATCCTGCCTGTAGCCTGGCACAACCGCATCGCC





CTGCGCCTGGAGCTGCTGGGCTGTTAGTGGCCACCTGCCACCCCCAGGTCTTCCTGC




TTTCCATGGGCCCGCTGCCTCTTGGCTTCTCAGCCCCTTTAAATCACCATAGGGCTG



GGGACTGGGGAAGGGGAGGGTGTTCAGAGGCAGCACCACCACACAGTCACCCCTCCC



TCCCTCTTTCCCACCCTCCACCTCTCACGGGCCCTGCCCCAGCCCCTAAGCCCCGTC



CCCTAACCCCCAGTCCTCACTGTCCTGTTTTCTTAGGCACTGAGGGATCTGAGTAGG



TCTGGGATGGACAGGAAAGGGCAAAGTAGGGCGTGTGGTTTCCCTGCCCCTGTCCGG



ACCGCCGATCCCAGGTGCGTGTGTCTCTGTCTCTCCTAGCCCCTCTCTCACACATCA



CATTCCCATGGTGGCCTCAAGAAAGGCCCGGAAGCGCCAGGCTGGAGATAACAGCCT



CTTGCCCGTCGGCCCTGCGTCGGCCCTGGGGTACCATGTGGCCACAACTGCTGTGGC



CCCCTGTCCCCAAGACACTTCCCCTTGTCTCCCTGGTTGCCTCTCTTGCCCCTTGTC



CTGAAGCCCAGCGACACAGAAGGGGGTGGGGCGGGTCTATGGGGAGAAAGGGAGCGA



GGTCAGAGGAGGGCATGGGTTGGCAGGGTGGGCGTTTGGGGCCCTCTATGCTGGCTT



TTCACCCCAGAGGACACAGGCAGCTTCCAAAATATATTTATCTTCTTCACGGGAA



(SEQ ID NO: 199)



>NP_005919.2 lactadherin isoform a preproprotein [Homo




sapiens]




MPRPRLLAALCGALLCAPSLLVALDICSKNPCHNGGLCEEISQEVRGDVFPSYTCTC



LKGYAGNHCETKCVEPLGLENGNIANSQIAASSVRVTFLGLQHWVPELARLNRAGMV




NAWTPSSNDDNPWIQVNLLRRMWVTGVVTQGASRLASHEYLKAFKVAYSLNGHEFDF





IHDVNKKHKEFVGNWNKNAVHVNLFETPVEAQYVRLYPTSCHTACTLRFELLGCELN





GCANPLGLKNNSIPDKQITASSSYKTWGLHLFSWNPSYARLDKQGNFNAWVAGSYGN





DQWLQVDLGSSKEVTGIITQGARNFGSVQFVASYKVAYSNDSANWTEYQDPRTGSSK





IFPGNWDNHSHKKNLFETPILARYVRILPVAWHNRIALRLELLGC (SEQ ID NO:




200)





Human 4F2 (CD98)
>NM_002394.6 Homo sapiens solute carrier family 3



member 2 (SLC3A2), transcript variant 3, mRNA



GCATTGCGGCTTGGTTTTCTCACCCAGTGCATGTGGCAGGAGCGGTGAGATC



ACTGCCTCACGGCGATCCTGGACTGACGGTCACGACTGCCTACCCTCTAACC



CTGTTCTGAGCTGCCCCTTGCCCACACACCCCAAACCTGTGTGCAGGATCCG



CCTCCATGGAGCTACAGCCTCCTGAAGCCTCGATCGCCGTCGTGTCGATTCC



GCGCCAGTTGCCTGGCTCACATTCGGAGGCTGGTGTCCAGGGTCTCAGCGCG



GGGGACGACTCAGAGTTGGGGTCTCACTGTGTTGCCCAGACTGGTCTCGAAC



TCTTGGCCTCAGGTGATCCTCTTCCCTCAGCTTCCCAGAATGCCGAGATGAT



AGAGACGGGGTCTGACTGTGTTACCCAGGCTGGTCTTCAACTCTTGGCCTCA



AGTGATCCTCCTGCCTTAGCTTCCAAGAATGCTGAGGTTACAGGCACCATGA




GCCAGGACACCGAGGTGGATATGAAGGAGGTGGAGCTGAATGAGTTAGAGCC





CGAGAAGCAGCCGATGAACGCGGCGTCTGGGGCGGCCATGTCCCTGGCGGGA





GCCGAGAAGAATGGTCTGGTGAAGATCAAGGTGGCGGAAGACGAGGCGGAGG





CGGCAGCCGCGGCTAAGTTCACGGGCCTGTCCAAGGAGGAGCTGCTGAAGGT





GGCAGGCAGCCCCGGCTGGGTACGCACCCGCTGGGCACTGCTGCTGCTCTTC




TGGCTCGGCTGGCTCGGCATGCTTGCTGGTGCCGTGGTCATAATCGTGCGAG



CGCCGCGTTGTCGCGAGCTACCGGCGCAGAAGTGGTGGCACACGGGCGCCCT



CTACCGCATCGGCGACCTTCAGGCCTTCCAGGGCCACGGCGCGGGCAACCTG



GCGGGTCTGAAGGGGCGTCTCGATTACCTGAGCTCTCTGAAGGTGAAGGGCC



TTGTGCTGGGTCCAATTCACAAGAACCAGAAGGATGATGTCGCTCAGACTGA



CTTGCTGCAGATCGACCCCAATTTTGGCTCCAAGGAAGATTTTGACAGTCTC



TTGCAATCGGCTAAAAAAAAGAGCATCCGTGTCATTCTGGACCTTACTCCCA



ACTACCGGGGTGAGAACTCGTGGTTCTCCACTCAGGTTGACACTGTGGCCAC



CAAGGTGAAGGATGCTCTGGAGTTTTGGCTGCAAGCTGGCGTGGATGGGTTC



CAGGTTCGGGACATAGAGAATCTGAAGGATGCATCCTCATTCTTGGCTGAGT



GGCAAAATATCACCAAGGGCTTCAGTGAAGACAGGCTCTTGATTGCGGGGAC



TAACTCCTCCGACCTTCAGCAGATCCTGAGCCTACTCGAATCCAACAAAGAC



TTGCTGTTGACTAGCTCATACCTGTCTGATTCTGGTTCTACTGGGGAGCATA



CAAAATCCCTAGTCACACAGTATTTGAATGCCACTGGCAATCGCTGGTGCAG



CTGGAGTTTGTCTCAGGCAAGGCTCCTGACTTCCTTCTTGCCGGCTCAACTT



CTCCGACTCTACCAGCTGATGCTCTTCACCCTGCCAGGGACCCCTGTTTTCA



GCTACGGGGATGAGATTGGCCTGGATGCAGCTGCCCTTCCTGGACAGCCTAT



GGAGGCTCCAGTCATGCTGTGGGATGAGTCCAGCTTCCCTGACATCCCAGGG



GCTGTAAGTGCCAACATGACTGTGAAGGGCCAGAGTGAAGACCCTGGCTCCC



TCCTTTCCTTGTTCCGGCGGCTGAGTGACCAGCGGAGTAAGGAGCGCTCCCT



ACTGCATGGGGACTTCCACGCGTTCTCCGCTGGGCCTGGACTCTTCTCCTAT



ATCCGCCACTGGGACCAGAATGAGCGTTTTCTGGTAGTGCTTAACTTTGGGG



ATGTGGGCCTCTCGGCTGGACTGCAGGCCTCCGACCTGCCTGCCAGCGCCAG



CCTGCCAGCCAAGGCTGACCTCCTGCTCAGCACCCAGCCAGGCCGTGAGGAG



GGCTCCCCTCTTGAGCTGGAACGCCTGAAACTGGAGCCTCACGAAGGGCTGC



TGCTCCGCTTCCCCTACGCGGCCTGACTTCAGCCTGACATGGACCCACTACC



CTTCTCCTTTCCTTCCCAGGCCCTTTGGCTTCTGATTTTTCTCTTTTTTAAA



AACAAACAAACAAACTGTTGCAGATTATGAGTGAACCCCCAAATAGGGTGTT



TTCTGCCTTCAAATAAAAGTCACCCCTGCATGGTGAA (SEQ ID NO: 201)



>NP_002385.3 4F2 cell-surface antigen heavy chain



isoform c [Homo sapiens]




MELQPPEASIAVVSIPRQLPGSHSEAGVQGLSAGDDSELGSHCVAQTGLELL





ASGDPLPSASQNAEMIETGSDCVTQAGLQLLASSDPPALASKNAEVTGTMSQ





DTEVDMKEVELNELEPEKQPMNAASGAAMSLAGAEKNGLVKIKVAEDEAEAA





AAAKFTGLSKEELLKVAGSPGWVRTRWALLLLFWLGWLGMLAGAVVIIVRAP




RCRELPAQKWWHTGALYRIGDLQAFQGHGAGNLAGLKGRLDYLSSLKVKGLV



LGPIHKNQKDDVAQTDLLQIDPNFGSKEDFDSLLQSAKKKSIRVILDLTPNY



RGENSWFSTQVDTVATKVKDALEFWLQAGVDGFQVRDIENLKDASSFLAEWQ



NITKGFSEDRLLIAGTNSSDLQQILSLLESNKDLLLTSSYLSDSGSTGEHTK



SLVTQYLNATGNRWCSWSLSQARLLTSFLPAQLLRLYQLMLFTLPGTPVFSY



GDEIGLDAAALPGQPMEAPVMLWDESSFPDIPGAVSANMTVKGQSEDPGSLL



SLFRRLSDQRSKERSLLHGDFHAFSAGPGLFSYIRHWDQNERFLVVLNFGDV



GLSAGLQASDLPASASLPAKADLLLSTQPGREEGSPLELERLKLEPHEGLLL



RFPYAA (SEQ ID NO: 202)





Human TFR2
>NM_003227.4 Homo sapiens transferrin receptor 2



(TFR2), transcript variant 1, mRNA



ATCGCTGGGGGACAGCCTGCAGGCTTCAGGAGGGGACACAAGCATGGAGCGG




CTTTGGGGTCTATTCCAGAGAGCGCAACAACTGTCCCCAAGATCCTCTCAGA





CCGTCTACCAGCGTGTGGAAGGCCCCCGGAAAGGGCACCTGGAGGAGGAAGA





GGAAGACGGGGAGGAGGGGGCGGAGACATTGGCCCACTTCTGCCCCATGGAG





CTGAGGGGCCCTGAGCCCCTGGGCTCTAGACCCAGGCAGCCAAACCTCATTC





CCTGGGCGGCAGCAGGACGGAGGGCTGCCCCCTACCTGGTCCTGACGGCCCT




GCTGATCTTCACTGGGGCCTTCCTACTGGGCTACGTCGCCTTCCGAGGGTCC



TGCCAGGCGTGCGGAGACTCTGTGTTGGTGGTCAGTGAGGATGTCAACTATG



AGCCTGACCTGGATTTCCACCAGGGCAGACTCTACTGGAGCGACCTCCAGGC



CATGTTCCTGCAGTTCCTGGGGGAGGGGCGCCTGGAGGACACCATCAGGCAA



ACCAGCCTTCGGGAACGGGTGGCAGGCTCGGCCGGGATGGCCGCTCTGACTC



AGGACATTCGCGCGGCGCTCTCCCGCCAGAAGCTGGACCACGTGTGGACCGA



CACGCACTACGTGGGGCTGCAATTCCCGGATCCGGCTCACCCCAACACCCTG



CACTGGGTCGATGAGGCCGGGAAGGTCGGAGAGCAGCTGCCGCTGGAGGACC



CTGACGTCTACTGCCCCTACAGCGCCATCGGCAACGTCACGGGAGAGCTGGT



GTACGCCCACTACGGGCGGCCCGAAGACCTGCAGGACCTGCGGGCCAGGGGC



GTGGATCCAGTGGGCCGCCTGCTGCTGGTGCGCGTGGGGGTGATCAGCTTCG



CCCAGAAGGTGACCAATGCTCAGGACTTCGGGGCTCAAGGAGTGCTCATATA



CCCAGAGCCAGCGGACTTCTCCCAGGACCCACCCAAGCCAAGCCTGTCCAGC



CAGCAGGCAGTGTATGGACATGTGCACCTGGGAACTGGAGACCCCTACACAC



CTGGCTTCCCTTCCTTCAATCAAACCCAGTTCCCTCCAGTTGCATCATCAGG



CCTTCCCAGCATCCCAGCCCAGCCCATCAGTGCAGACATTGCCTCCCGCCTG



CTGAGGAAGCTCAAAGGCCCTGTGGCCCCCCAAGAATGGCAGGGGAGCCTCC



TAGGCTCCCCTTATCACCTGGGCCCCGGGCCACGACTGCGGCTAGTGGTCAA



CAATCACAGGACCTCCACCCCCATCAACAACATCTTCGGCTGCATCGAAGGC



CGCTCAGAGCCAGATCACTACGTTGTCATCGGGGCCCAGAGGGATGCATGGG



GCCCAGGAGCAGCTAAATCCGCTGTGGGGACGGCTATACTCCTGGAGCTGGT



GCGGACCTTTTCCTCCATGGTGAGCAACGGCTTCCGGCCCCGCAGAAGTCTC



CTCTTCATCAGCTGGGACGGTGGTGACTTTGGAAGCGTGGGCTCCACGGAGT



GGCTAGAGGGCTACCTCAGCGTGCTGCACCTCAAAGCCGTAGTGTACGTGAG



CCTGGACAACGCAGTGCTGGGGGATGACAAGTTTCATGCCAAGACCAGCCCC



CTTCTGACAAGTCTCATTGAGAGTGTCCTGAAGCAGGTGGATTCTCCCAACC



ACAGTGGGCAGACTCTCTATGAACAGGTGGTGTTCACCAATCCCAGCTGGGA



TGCTGAGGTGATCCGGCCCCTACCCATGGACAGCAGTGCCTATTCCTTCACG



GCCTTTGTGGGAGTCCCTGCCGTCGAGTTCTCCTTTATGGAGGACGACCAGG



CCTACCCATTCCTGCACACAAAGGAGGACACTTATGAGAACCTGCATAAGGT



GCTGCAAGGCCGCCTGCCCGCCGTGGCCCAGGCCGTGGCCCAGCTCGCAGGG



CAGCTCCTCATCCGGCTCAGCCACGATCGCCTGCTGCCCCTCGACTTCGGCC



GCTACGGGGACGTCGTCCTCAGGCACATCGGGAACCTCAACGAGTTCTCTGG



GGACCTCAAGGCCCGCGGGCTGACCCTGCAGTGGGTGTACTCGGCGCGGGGG



GACTACATCCGGGCGGCGGAAAAGCTGCGGCAGGAGATCTACAGCTCGGAGG



AGAGAGACGAGCGACTGACACGCATGTACAACGTGCGCATAATGCGGGTGGA



GTTCTACTTCCTTTCCCAGTACGTGTCGCCAGCCGACTCCCCGTTCCGCCAC



ATCTTCATGGGCCGTGGAGACCACACGCTGGGCGCCCTGCTGGACCACCTGC



GGCTGCTGCGCTCCAACAGCTCCGGGACCCCCGGGGCCACCTCCTCCACTGG



CTTCCAGGAGAGCCGTTTCCGGCGTCAGCTAGCCCTGCTCACCTGGACGCTG



CAAGGGGCAGCCAATGCGCTTAGCGGGGATGTCTGGAACATTGATAACAACT



TCTGAGGCCCTGGGGATCCTCACATCCCCGTCCCCCAGTCAAGAGCTCCTCT



GCTCCTCGCTTGAATGATTCAGGGTCAGGGAGGTGGCTCAGAGTCCACCTCT



CATTGCTGATCAATTTCTCATTACCCCTACACATCTCTCCACGGAGCCCAGA



CCCCAGCACAGATATCCACACACCCCAGCCCTGCAGTGTAGCTGACCCTAAT



GTGACGGTCATACTGTCGGTTAATCAGAGAGTAGCATCCCTTCAATCACAGC



CCCTTCCCCTTTCTGGGGTCCTCCATACCTAGAGACCACTCTGGGAGGTTTG



CTAGGCCCTGGGACCTGGCCAGCTCTGTTAGTGGGAGAGATCGCTGGCACCA



TAGCCTTATGGCCAACAGGTGGTCTGTGGTGAAAGGGGCGTGGAGTTTCAAT



ATCAATAAACCACCTGATATCAATAA (SEQ ID NO: 203)



>NP_003218.2 transferrin receptor protein 2 isoform



1 [Homo sapiens]




MERLWGLFQRAQQLSPRSSQTVYQRVEGPRKGHLEEEEEDGEEGAETLAHFC





PMELRGPEPLGSRPRQPNLIPWAAAGRRAAPYLVLTALLIFTGAFLLGYVAF





RGSCQACGDSVLVVSEDVNYEPDLDFHQGRLYWSDLQAMFLQFLGEGRLEDT




IRQTSLRERVAGSAGMAALTQDIRAALSRQKLDHVWTDTHYVGLQFPDPAHP



NTLHWVDEAGKVGEQLPLEDPDVYCPYSAIGNVTGELVYAHYGRPEDLQDLR



ARGVDPVGRLLLVRVGVISFAQKVTNAQDFGAQGVLIYPEPADFSQDPPKPS



LSSQQAVYGHVHLGTGDPYTPGFPSFNQTQFPPVASSGLPSIPAQPISADIA



SRLLRKLKGPVAPQEWQGSLLGSPYHLGPGPRLRLVVNNHRTSTPINNIFGC



IEGRSEPDHYVVIGAQRDAWGPGAAKSAVGTAILLELVRTFSSMVSNGFRPR



RSLLFISWDGGDFGSVGSTEWLEGYLSVLHLKAVVYVSLDNAVLGDDKFHAK



TSPLLTSLIESVLKQVDSPNHSGQTLYEQVVFTNPSWDAEVIRPLPMDSSAY



SFTAFVGVPAVEFSFMEDDQAYPFLHTKEDTYENLHKVLQGRLPAVAQAVAQ



LAGQLLIRLSHDRLLPLDFGRYGDVVLRHIGNLNEFSGDLKARGLTLQWVYS



ARGDYIRAAEKLRQEIYSSEERDERLTRMYNVRIMRVEFYFLSQYVSPADSP



FRHIFMGRGDHTLGALLDHLRLLRSNSSGTPGATSSTGFQESRFRRQLALLT



WTLQGAANALSGDVWNIDNNF



(SEQ ID NO: 204)





Human ADAM10
>NM_001110.4 Homo sapiens ADAM metallopeptidase



domain 10 (ADAM10), transcript variant 1, mRNA



GTTGCCGGCCCCTGAAGTGGAGCGAGAGGGAGGTGCTTCGCCGTTTCTCCTG



CCAGGGGAGGTCCCGGCTTCCCGTGGAGGCTCCGGACCAAGCCCCTTCAGCT



TCTCCCTCCGGATCGATGTGCTGCTGTTAACCCGTGAGGAGGCGGCGGCGGC



GGCAGCGGCAGCGGAAGATGGTGTTGCTGAGAGTGTTAATTCTGCTCCTCTC



CTGGGCGGCGGGGATGGGAGGTCAGTATGGGAATCCTTTAAATAAATATATC



AGACATTATGAAGGATTATCTTACAATGTGGATTCATTACACCAAAAACACC



AGCGTGCCAAAAGAGCAGTCTCACATGAAGACCAATTTTTACGTCTAGATTT



CCATGCCCATGGAAGACATTTCAACCTACGAATGAAGAGGGACACTTCCCTT



TTCAGTGATGAATTTAAAGTAGAAACATCAAATAAAGTACTTGATTATGATA



CCTCTCATATTTACACTGGACATATTTATGGTGAAGAAGGAAGTTTTAGCCA



TGGGTCTGTTATTGATGGAAGATTTGAAGGATTCATCCAGACTCGTGGTGGC



ACATTTTATGTTGAGCCAGCAGAGAGATATATTAAAGACCGAACTCTGCCAT



TTCACTCTGTCATTTATCATGAAGATGATATTAACTATCCCCATAAATACGG



TCCTCAGGGGGGCTGTGCAGATCATTCAGTATTTGAAAGAATGAGGAAATAC



CAGATGACTGGTGTAGAGGAAGTAACACAGATACCTCAAGAAGAACATGCTG



CTAATGGTCCAGAACTTCTGAGGAAAAAACGTACAACTTCAGCTGAAAAAAA



TACTTGTCAGCTTTATATTCAGACTGATCATTTGTTCTTTAAATATTACGGA



ACACGAGAAGCTGTGATTGCCCAGATATCCAGTCATGTTAAAGCGATTGATA



CAATTTACCAGACCACAGACTTCTCCGGAATCCGTAACATCAGTTTCATGGT



GAAACGCATAAGAATCAATACAACTGCTGATGAGAAGGACCCTACAAATCCT



TTCCGTTTCCCAAATATTGGTGTGGAGAAGTTTCTGGAATTGAATTCTGAGC



AGAATCATGATGACTACTGTTTGGCCTATGTCTTCACAGACCGAGATTTTGA



TGATGGCGTACTTGGTCTGGCTTGGGTTGGAGCACCTTCAGGAAGCTCTGGA



GGAATATGTGAAAAAAGTAAACTCTATTCAGATGGTAAGAAGAAGTCCTTAA



ACACTGGAATTATTACTGTTCAGAACTATGGGTCTCATGTACCTCCCAAAGT



CTCTCACATTACTTTTGCTCACGAAGTTGGACATAACTTTGGATCCCCACAT



GATTCTGGAACAGAGTGCACACCAGGAGAATCTAAGAATTTGGGTCAAAAAG



AAAATGGCAATTACATCATGTATGCAAGAGCAACATCTGGGGACAAACTTAA



CAACAATAAATTCTCACTCTGTAGTATTAGAAATATAAGCCAAGTTCTTGAG



AAGAAGAGAAACAACTGTTTTGTTGAATCTGGCCAACCTATTTGTGGAAATG




GAATGGTAGAACAAGGTGAAGAATGTGATTGTGGCTATAGTGACCAGTGTAA





AGATGAATGCTGCTTCGATGCAAATCAACCAGAGGGAAGAAAATGCAAACTG





AAACCTGGGAAACAGTGCAGTCCAAGTCAAGGTCCTTGTTGTACAGCACAGT





GTGCATTCAAGTCAAAGTCTGAGAAGTGTCGGGATGATTCAGACTGTGCAAG





GGAAGGAATATGTAATGGCTTCACAGCTCTCTGCCCAGCATCTGACCCTAAA





CCAAACTTCACAGACTGTAATAGGCATACACAAGTGTGCATTAATGGGCAAT





GTGCAGGTTCTATCTGTGAGAAATATGGCTTAGAGGAGTGTACGTGTGCCAG





TTCTGATGGCAAAGATGATAAAGAATTATGCCATGTATGCTGTATGAAGAAA





ATGGACCCATCAACTTGTGCCAGTACAGGGTCTGTGCAGTGGAGTAGGCACT





TCAGTGGTCGAACCATCACCCTGCAACCTGGATCCCCTTGCAACGATTTTAG





AGGTTACTGTGATGTTTTCATGCGGTGCAGATTAGTAGATGCTGATGGTCCT





CTAGCTAGGCTTAAAAAAGCAATTTTTAGTCCAGAGCTCTATGAAAACATTG





CTGAATGGATTGTGGCTCATTGGTGGGCAGTATTACTTATGGGAATTGCTCT





GATCATGCTAATGGCTGGATTTATTAAGATATGCAGTGTTCATACTCCAAGT





AGTAATCCAAAGTTGCCTCCTCCTAAACCACTTCCAGGCACTTTAAAGAGGA





GGAGACCTCCACAGCCCATTCAGCAACCCCAGCGTCAGCGGCCCCGAGAGAG





TTATCAAATGGGACACATGAGACGCTAACTGCAGCTTTTGCCTTGGTTCTTC




CTAGTGCCTACAATGGGAAAACTTCACTCCAAAGAGAAACCTATTAAGTCAT



CATCTCCAAACTAAACCCTCACAAGTAACAGTTGAAGAAAAAATGGCAAGAG



ATCATATCCTCAGACCAGGTGGAATTACTTAAATTTTAAAGCCTGAAAATTC



CAATTTGGGGGTGGGAGGTGGAAAAGGAACCCAATTTTCTTATGAACAGATA



TTTTTAACTTAATGGCACAAAGTCTTAGAATATTATTATGTGCCCCGTGTTC



CCTGTTCTTCGTTGCTGCATTTTCTTCACTTGCAGGCAAACTTGGCTCTCAA



TAAACTTTTACCACAAATTGAAATAAATATATTTTTTTCAACTGCCAATCAA



GGCTAGGAGGCTCGACCACCTCAACATTGGAGACATCACTTGCCAATGTACA



TACCTTGTTATATGCAGACATGTATTTCTTACGTACACTGTACTTCTGTGTG



CAATTGTAAACAGAAATTGCAATATGGATGTTTCTTTGTATTATAAAATTTT



TCCGCTCTTAATTAAAAATTACTGTTTAATTGACATACTCAGGATAACAGAG



AATGGTGGTATTCAGTGGTCCAGGATTCTGTAATGCTTTACACAGGCAGTTT



TGAAATGAAAATCAATTTACCTTTCTGTTACGATGGAGTTGGTTTTGATACT



CATTTTTTCTTTATCACATGGCTGCTACGGGCACAAGTGACTATACTGAAGA



ACACAGTTAAGTGTTGTGCAAACTGGACATAGCAGCACATACTACTTCAGAG



TTCATGATGTAGATGTCTGGTTTCTGCTTACGTCTTTTAAACTTTCTAATTC



AATTCCATTTTTCAATTAATAGGTGAAATTTTATTCATGCTTTGATAGAAAT



TATGTCAATGAAATGATTCTTTTTATTTGTAGCCTACTTATTTGTGTTTTTC



ATATATCTGAAATATGCTAATTATGTTTTCTGTCTGATATGGAAAAGAAAAG



CTGTGTCTTTATCAAAATATTTAAACGGTTTTTTCAGCATATCATCACTGAT



CATTGGTAACCACTAAAGATGAGTAATTTGCTTAAGTAGTAGTTAAAATTGT



AGATAGGCCTTCTGACATTTTTTTTCCTAAAATTTTTAACAGCATTGAAGGT



GAAACAGCACAATGTCCCATTCCAAATTTATTTTTGAAACAGATGTAAATAA



TTGGCATTTTAAAGAGAAAGCAAAAACATTTAATGTATTAACAGGCTTATTG



CTATGCAGGAAATAGAAGGGGCATTACAAAAATTGAAGCTTGTGACATATTT



ATTGCTTCTGTTTTCCAACTACATCACTTCAACTAGAAGTAAAGCTATGATT



TTCCTGACTTCACATAGGAGGCAAATTTAGAGAAAGTTGTAAAGATTTCTAT



GTTTTGGGTTTTTTTTTTTCCTTTTTTTTTTTAAGAGTATAAGGTTTACACA



ATCATTCTCATAATGTGACGCAAGCCAGCAAGGCCAAAAATGCTAGAGAAAA



TAACGGGATCTCTTCCTTGTAAACTTGTACAGTATGTGGTGACTTTTTCAAA



ATACAGCTTTTTGTACATGATTTAGAGACAAATTTTGTACATGAAACCCCAG



ATAGACTATAAATAATTCTAAACAAACAAGTAGGTAGATATGTATGTAATTG



CTTTTAAATCATTTAAATGCCTTTGTTTTTGGACTGTGCAAAGGTTGGAAGT



GGGTTTGCATTTCTAAAATGGTGACTTTTATTCTGCAAGAGTTCTTAGTAAC



TTCTTGAGTGTGGTAGACTTTGGAACATGTAAATTTTTTGCTTGTAATGTTA



TCCTGTGGTAGGATTTTGGCAGGTACACACACTGCCCTATTTTATTTTGAGT



CTAAGTTAAATGTTTTCTGAAAAGAGATACATGCACTGAACTCTTTCCACTG



CGAATCAAGATGTGGTAATATAAAAGGATCAAGACAAATGAGATCTAATACT



ACTGTCAGTTTTAATGTCCACTGTGTTTTATACAGTATCTTTTTTTGTTCAC



TTTGGAAATTTTTACTAAAAATTGCAAAAAATAAAGTATTGTGCAAAGATGT



AAGGTTTTTTGAAACTTGAAATGCATTAATAAATAGACGATTAAATCAACTT



GAAGGTTCTATACTCTTTGAACTCTGAGAACTATCACAAGAAGCTTCCCACA



AGGCAGTGTTTTCTTACAGTTGTCTCTTCCTACAAAAGTATAGATTATCTTT



ATTCTTAATACTTTGGAATCCATGTAGAAAATTTCCAGTTAGATACTCTGCG



TACACACAATAAACCTTTTTAAAACACCCAACTAATCTCAACTGCATTACAT



TGTTTCTAATCAATATTCAGTGCTTGTCTTGGTGGAAGAGGTGAGTCATTTT



GAAAACTTATGGTCTTGTTTTTATGTGTTTTTCAAAGTTTTGAATGCTAAGT



ACCTCATTTATTTTAAAAAGCCTAGTTTAATGATAAGTTTGTTTAAAATTTT



GAGCCATCATTTTTCTCTTCATAGCAAATAAGGAGAGAATTGACATTTCAGT



GTTACCTAGAAAAGGAATTGTAAGCCCAGAATAATTCCCTGCATGAGGTAAT



CTGCTTCAAATTCTTTTTTTAGTCAAGGTTAGCTATAAGTAATACTTGTTAA



ATGAGTAAATATGTAATACTTTGTGAATTACTTTGTTAATTTAGGAGCATCA



AATGTATATTATGTTTAGTTATTTATGAAACTCTCAATATTGATTGATTTGG



GTAATTATAAATTAGTTATTTTTACTTGTAATTGAATGCTTAAATTCTGTTT



ACAGTCCGTCCTCTCTCCCTCCATCCCTCCCTCCCCAGTTTTATAAATTCAG



GTACCAATTCACAAACAAAATCAGAAATAAAATAAATTTATTGACTGCTTCT



GGATTTAGCATTCCCTGTAGTGTCAAGCAATGTCATGCAGTTTGGGGAAGCA



TTTATTTAAGGAAATGACAACTTTCTCTGATCAGTCTTGTTTTGTGAGGTGT



CTTCAACACTTTATGCTTTGGGTACTTCGTGTTTGTCACAGTCTTAGGATAG



TGAAATCTGATTTGTCCAAGCGGAGCAAACTACTCGACCCTCAGTCCTTGTA



TTTGTCCCTGTAGTAAGACCTAATTATTATTATTTCTTAAAGATGGGATTGG



TGTCCTTGGCAACTATGAAATTTCGGGGCTTGTGCATGAGAAGGCATTTCTT



ATTAAGTATTTCTAATTGAAGGTATCAGAGTGTCAAGCATTACAAACCTGGA



CAGTTCACCTGGAGGAGTACAAGAAGAGATATTCATTATCCATATTTAAAGG



GTCAAGGTTTCCCAAAACCAGGGTGCAAGCCAGATGTAGTTTTAAAGCAGCT



GCCAGGGACAGTTCATCTTTAGAGAAGTCACTAAAGTTGTAAGAAATTTTAG



TTTCCCCAAAACCACTTTCAACTTCTTAGAAACTAGAAAGACAATTGGTTTG



CCCCACAGAGGACAACTTCAGTTTCAGCATCTCTCATGTTGTGTTCTTGATT



AAAAACAACTTCCATTTGATATACTTTTCCGTTTATTACCAGTTTAGTTTTT



TCACTATTGTTTCTGTATTCAACTCTTTATATGATTAGGATAGAAATTTAGC



CCTTCTGTTTTATATTACTATATTGTTTGTGTGTCTTAGATATATACATGTA



TGTACTATTTTCAGTAGAAATTCATGTATTTTATAATTGGTAAGTTCTTCAG



AGCATCTCTTCTATAAAAAGCAACAGGATGCTAGGTAAAACGGAGCATTGAG



CAAAATACTGATTAGTTTTTGCTTTTTCCTGAAATCTACACTAAAGTGATAG



GGTGTGGGGTAATCCAACAAGGACAAGGTGAATTGAACAAGAACGAAATCTG



GAAGCAGATGAAGGAGTACTATTGATTGGGCAGACCCAGGGAAGTCAAATCC



TAAACCAGCAGTGGGAACACAACAGAATGGTGTAGTTTGCACTGGTAAGATT



TGGGTACCTGGCAGGGCTGGGTGCGGTGGCTCACACCTGTAATCCCAGCACT



TTGGGAGGCCAAGGCGGGTGGATCACTTGAGGTCAGGAGTTCGAGACCACCC



TGGCCAACATGGTGAAACCCCGTCTCTACTAAAAATACAGCTGGGCGTGGTG



GCACATGCTTGTAATCCCAGCTACTCGGGAGGCAGAGGCAGGAGATTTGCTT



GAACCCGGGAGGCAGAGGCAGGAGATTTGCTTGAACCCAGGAGGCAGAGGCT



GCAGTGAGCCGCGATTGCGCCATTGCACTCCAGCCTGGGTGACAGAGCGAGA



CTCTGTCTCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA



AAAAATTTGAGTACCTGGCCTTTGTTACTTTTTTTCTATGTGTGTGACAAAA



ACATAATATGCACACTTTTGTAACCCACCTTTCTCATTTAATGGTACATTGA



TAATGTATATCACATTAACTACTCTAAATATTTCTGTGGATGTATGTTTTTT



TTTTTCTTAACCAATTTCCCATTGTTTGGACATGTAGGTTCCACATTGTTTA



TTATTTTAAACAATTCTAAAGAATTTTAAACAATTCTTAGGAAAATCCTCAG



CCTAATAATGAAATTAATTCCTAAAAGTGGAATTGTTGGGGTAAAGGTTTTT



TGAGGGACATTGATAAAAATTATGGTACTGTCTCCCAGATAGATGTACCAAG



TTATACTACCACGATTTAATATATATATATATATATATTAAATCAGAGTCCC



ATCCTTAGAAATCCACATATATGCAGCCACATGAATGTATTAGAAACAATAA



TAGAAGACTCATGCTTAATTCAGTTGATTAGCTTTAGACATAATTCAAATGC



AAGTCAAATTGAGTGCCCTAATTGTGGTCTCTTAAGTACCATTTTTCTTCAA



GGGAACCAGACTCCTTTGGATAAATCACTAATTCCACCTGTAAGAAAGAAAT



GTACAAGAAGAACCTAGGAAACATTGTTTTGTACCAGATCAGAAAGATTCAG



GAGGCACCTTAGAAGTTACCACTGGCCAAGGCTGAGATAACTTTAGCATCAG



CAAGGATAATATCTGCAAGAGATTGAAACTCATAGTATTGTATTTAACTCTG



TGAGTTAATGATGGTAGTGGACAGAATTATAGTTACCTTTGGGATACGCTTT



TAAAGAAATTCCAGGTAATAAGAGAAATGATAGAATTAGGATATCACCATTT



TACCCCCCCAACAATTTATGGATCTAGACAATAATCGCCAGTGACTGCTAAC



CTCACAAAGTGAGAGCAATCAGATTTTGTGCCTCCTAATGGAAGTACATATA



CCACCTATGAAGCAGTTCTGCCAAAAGTCACATCTCATCATGATGAAGCCTC



CTGATCTAACTACCCCTTCATTAGAAATACAGGGGACAGAGGGACAAATAAT



ATACAAGGGACTCAATCAGCAAAATCCAGACTCTGGAAAACTACAAGACATA



TGGTCCTGCTTCAACAACAGAAATGCAAAGAGAAAAGACAACGATGGGTTAA



AGGAGACTTAAGAGCTACATCTATCAAGACAATTTATGGACTTATTTGGATA



CTGATTTGAACAAACTGTTGAGACCATTGGAAAAATGTGAAAAGTGGATATT



TGATATTAAGGTTTTTAATTATTTTTAGGTGTGATAATGGTATTGTTACATT



TTTTAAAGGACCCCTTTTAGAGATGCAAATTGAAACACTTAAAAAATGAAAT



GATACGATGTATAAGTTTTTGCTTAAAAATAAGGATTGAAGTTGGCTGGTGT



GTGTGGATATAGTTGAAACAAGATTGGCTGTGAGTTGATAATTATTGAAGCT



GGGTGATGGGCACTTGGGGATTTATTATACTATTTTCTCTACCTGTGTTTAT



ATTTGAAATTTTTCATAGAAGTTTTAAAATGTGGCCAGTTGTGATGGCTCAT



ACCTGTAATCCCAACACTTTGGGAGGCCAAGGTGGGAGGATCACTTGAGCTC



AGGAGTTAGAGACCAGCCTGGGCAAAATAGTGAGACTCCATCTCAAAGAAAA



AAAAAAAGTGTTTTAAATGTGAATCAAATTCCTATAGAAGCTGATTCATTAC



TGTTTTTATTTTAGCAGTAATTCATGATAATGACCTGTATTCATAATGATTT



TCATAATGATTGTTTTAGTGGAATTAAACTTGAACCAGTCAAGCTAACATAA



TTATATTCTGCTCCAGTTACAATGAATAATTAATTGATTTCAACTGCTAGGG



TGAACTCTTGAAGCTATCAGTCATCCAGCAATCTTAGCAAGCAGGCCATTGG



GTCCCTGTTTGCTCTGTCTCTCTCTCTCTCTCTCACTGTTGAAGGGCTTAGC



TAACTACTTAAGTAAAATATTTGTTCTCTGTTAAACATGTCAAGGAGTATGG



TCAGCTTATCCACATTAAGCCTGTGTGTCCCACGTTGGAGTAAATGTTAAGT



AGCTCACTACAATAAACTAGATTCTTCTGCCCTCTCTTGTTTAAATGATCAT



GTTCCCTGGAGGTGGAAATAGATCTTTAAAAAGATATTCTGTAGTTGTTTGT



TCTCAGTGTAAAAAAATGAGAATAATTTGATAAGAGTGTAGGTTGTCTTATA



TAAAAAGTGGTTCCATTTGCATGAATTTTAGAAAAATCATTTTGGAAAAATG



AAGGCTATGTGGTTATACTGAACACATTAAGCAATTTTATTCTTTATTTTAA



ATGAATATTTTATTATCGTTTTCTTCCCTTGCCCTTTGGGTATGGGAGTTAG



CCTTTGTGTTTCTAAATACAACAGGCCGGTTTTTATAAATTAAGGTGTCAAT



ATATTCTTCATTATTTAGTTTTGTGATTGTGGTTAGTTTTCATTTTTCTTAA



GTATCTGCTAGTAGCATCTGTAATTAAGTGAAGTGACCTGTTAACCATTTTC



CTCTTTCTCCTCCTTTCCTCCTCCTTGAAACATATCAGAGCATGTTTGAAAT



TCTTTGGCTTTTATGGTATGCATTTGCTGATATGCATTGACCAGTTACCTTA



CTCACAGATACTTCTTAGGCACTTGATTGTGCCAGGGCCTTGGCTAGATGAT



AAGAATACAGTAGTGAACTTAACAGTTTCCCTGCCCTGGTGAAGCGTATGGT



CTTGTAGGTGAGATAGATATCAGATAATCATGTGAATAAATGTACAATTCCA



GCTGTGATACATGCTGAGGAGGAGGTTTTTGGTGATCCAAGAGCTGATCATG



CAGAGATAGGACTGAGAAAGGAGGGTGGGACGTTGTCACAGCTGATAATGCA



GAGATAGGACTGAGAAAGGAGGGTGGGACATCAGGAAGGTCAGAGAATTCCT



TATGAAAGTGATGCTTGAGTCAAAATATGATGGATGAAGAGAGTTTAAATAG



ATTACATAGAATTTTTAATAATGTCGATTGGTTATATACTGGGCACTGATAG



CTGATTTTTCTTTGGGGAAAGGTATGTCAGCCTAGTCATTCAGATTCCTTTA



TTTTTTTAAATGTTTTTTCATTTTTTGCTTTGCATTGCATTCATTTGCTGAA



GAGCTGGCTTGTACTTTGGCAGGTGTCATACTTGGTTATTCTCCTTAGGATA



TTGGCCCAACAATCTGGGAGTTGTGAAAGGCGCTTCGCTTTTCAGACCTGGG



CGTCTGTATCATGACTATCATAAATTTAGGATTAAGACACCTAGCCTCCTAC



CAGGATGAATGAGGTGTCCATGTGACCTGCTGTGCCCTGGAATTTTATACAT



CTTTCTCTCATAGCACACACCATATTACAATATAATCCTGCCTCATCTAAGC



CAAACTTTCGAGAGAATCATTTACACTCAGTGGCTACTTCAGCTCCCATTCA



CTTATCAACCTGCTGCAATTTTTCACAGCCCCCAAAGGACTGCAGTCTGTGC



CTTCAGGGAGCTGAGGGTCTAGCGGAAGGAAAGAAACCAGCAGTTACAGTAC



AGAGGGGTTTGTGTTGGAAACTCTACAAACACAGGATGCCCTGGTAGCTCAG



AGGAAGTGCATATCGAGCATGGTAGGTAGGTAGTGGGAAGAGCCAAGATGAC



TTCCCAGAGGAGAAAAGCTGGACCTGAGTTTTGGAGTTTCGGTAAAAGTTTG



CTCTAACTAGTCCAAGCTGCTGTCACAAGCTTTTAGAAATGATGTAACCATG



GGGCAGTTGACTGTCGTCATGTTCTTTGCTATTTTCATGACTCTGGATGTGC



TTTTCCTATTCCCTGGATTGCCCTTTCCCTCGATTCCTCTGCAGGACTGGGC



TTTATTAATCTCCATTTCCTTGAGCTTGGCTATAGTAGGTGTTCAATAAACA



TTTGTTTTGTTGTGTGCTTTGTAAATAGGCAATGAAGCTGATTTCACAAGAT



AGGCACAAAAGTTAGTTTCATTACAACACATTACCAACAGCTGTATTTTTAA



CTTTTAACATATCTCATTCTAAATCCTGTGGCAGCACAACCTCCTTCCGTCA



TACCTGGAGATAAATTTTCTTTCAAAATCTAATATGCACTGTATTTATAGAA



TATGAAACATACCGACCATGTTTTGCAAAAATGGGAAAGGCATAACTTAGCT



TTGGGGCATGTAAGTAACAACTCCTGATAGGAGAAGAAATGTATTCAGAAAG



CTCAAATTAGAAATAAAATGGGAGACTCTA (SEQ ID NO: 205)



>NP_001101.1 disintegrin and metalloproteinase



domain-containing protein 10 isoform 1 preproprotein



[Homo sapiens]



MVLLRVLILLLSWAAGMGGQYGNPLNKYIRHYEGLSYNVDSLHQKHQRAKRA



VSHEDQFLRLDFHAHGRHFNLRMKRDTSLFSDEFKVETSNKVLDYDTSHIYT



GHIYGEEGSFSHGSVIDGRFEGFIQTRGGTFYVEPAERYIKDRTLPFHSVIY



HEDDINYPHKYGPQGGCADHSVFERMRKYQMTGVEEVTQIPQEEHAANGPEL



LRKKRTTSAEKNTCQLYIQTDHLFFKYYGTREAVIAQISSHVKAIDTIYQTT



DFSGIRNISFMVKRIRINTTADEKDPTNPFRFPNIGVEKFLELNSEQNHDDY



CLAYVFTDRDFDDGVLGLAWVGAPSGSSGGICEKSKLYSDGKKKSLNTGIIT



VQNYGSHVPPKVSHITFAHEVGHNFGSPHDSGTECTPGESKNLGQKENGNYI



MYARATSGDKLNNNKFSLCSIRNISQVLEKKRNNCFVESGQPICGNGMVEQG




EECDCGYSDQCKDECCFDANQPEGRKCKLKPGKQCSPSQGPCCTAQCAFKSK





SEKCRDDSDCAREGICNGFTALCPASDPKPNFTDCNRHTQVCINGQCAGSIC





EKYGLEECTCASSDGKDDKELCHVCCMKKMDPSTCASTGSVQWSRHFSGRTI





TLQPGSPCNDFRGYCDVFMRCRLVDADGPLARLKKAIFSPELYENIAEWIVA





HWWAVLLMGIALIMLMAGFIKICSVHTPSSNPKLPPPKPLPGTLKRRRPPQP





IQQPQRQRPRESYQMGHMRR (SEQ ID NO: 206)






Transmembrane
>NM_001769.4 Homo sapiens CD9 molecule (CD9),


domain 2 or
transcript variant 1, mRNA


transmembrane
AGCCGCCTGCATCTGTATCCAGCGCCAGGTCCCGCCAGTCCCAGCTGCGCGC


domain 3 from
GCCCCCCAGTCCCGCACCCGTTCGGCCCAGGCTAAGTTAGCCCTCACCATGC


Human CD9
CGGTCAAAGGAGGCACCAAGTGCATCAAATACCTGCTGTTCGGATTTAACTT



CATCTTCTGGCTTGCCGGGATTGCTGTCCTTGCCATTGGACTATGGCTCCGA



TTCGACTCTCAGACCAAGAGCATCTTCGAGCAAGAAACTAATAATAATAATT



CCAGCTTCTACACAGGAGTCTATATTCTGATCGGAGCCGGCGCCCTCATGAT




GCTGGTGGGCTTCCTG

GGCTGCTGCGGGGCTGTGCAGGAGTCCCAGTGCATG






CTGGGACTGTTCTTCGGCTTCCTCTTGGTGATATTCGCCATTGAAATAGCTG





CGGCCATCTGGGGATATTCCCACAAGGATGAGGTGATTAAGGAAGTCCAGGA




GTTTTACAAGGACACCTACAACAAGCTGAAAACCAAGGATGAGCCCCAGCGG



GAAACGCTGAAAGCCATCCACTATGCGTTGAACTGCTGTGGTTTGGCTGGGG



GCGTGGAACAGTTTATCTCAGACATCTGCCCCAAGAAGGACGTACTCGAAAC



CTTCACCGTGAAGTCCTGTCCTGATGCCATCAAAGAGGTCTTCGACAATAAA



TTCCACATCATCGGCGCAGTGGGCATCGGCATTGCCGTGGTCATGATATTTG



GCATGATCTTCAGTATGATCTTGTGCTGTGCTATCCGCAGGAACCGCGAGAT



GGTCTAGAGTCAGCTTACATCCCTGAGCAGGAAAGTTTACCCATGAAGATTG



GTGGGATTTTTTGTTTGTTTGTTTTGTTTTGTTTGTTGTTTGTTGTTTGTTT



TTTTGCCACTAATTTTAGTATTCATTCTGCATTGCTAGATAAAAGCTGAAGT



TACTTTATGTTTGTCTTTTAATGCTTCATTCAATATTGACATTTGTAGTTGA



GCGGGGGGTTTGGTTTGCTTTGGTTTATATTTTTTCAGTTGTTTGTTTTTGC



TTGTTATATTAAGCAGAAATCCTGCAATGAAAGGTACTATATTTGCTAGACT



CTAGACAAGATATTGTACATAAAAGAATTTTTTTGTCTTTAAATAGATACAA



ATGTCTATCAACTTTAATCAAGTTGTAACTTATATTGAAGACAATTTGATAC



ATAATAAAAAATTATGACAATGTCCTGGA (SEQ ID NO: 207)



>NP_001760.1 CD9 antigen isoform 1 [Homo sapiens]



MPVKGGTKCIKYLLFGFNFIFWLAGIAVLAIGLWLRFDSQTKSIFEQETNNN



NSSFYTGVYILIGAGALMMLVGFLGCCGAVQESQCMLGLFFGFLLVIFAIEI




AAAIWGYSHKDEVIKEVQEFYKDTYNKLKTKDEPQRETLKAIHYALNCCGLA




GGVEQFISDICPKKDVLETFTVKSCPDAIKEVFDNKFHIIGAVGIGIAVVMI



FGMIFSMILCCAIRRNREMV (SEQ ID NO: 208)





Human CD298
>NM_001679.4 Homo sapiens ATPase Na+/K+ transporting



subunit beta 3 (ATP1B3), mRNA



AGTCGGCTCGAGTACTCCCCGTAACGAGGAGGTGTTCTCGGCCGTCCCACCC



TTCACTGCCGTCTCCGGGCTGCGCCGCCGGAGCCGGGACGCGCCTCCGCAGC



CCTCGCCGCCTCCATCCCCGCGGCCGCAGCTCCTCTCGCCGTCCGCGCGCAC



ACCATGACGAAGAACGAGAAGAAGTCCCTCAACCAGAGCCTGGCCGAGTGGA



AGCTCTTCATCTACAACCCGACCACCGGAGAATTCCTGGGGCGCACCGCCAA



GAGCTGGGGTTTGATCTTGCTCTTCTACCTAGTTTTTTATGGGTTCCTGGCT



GCACTCTTCTCATTCACGATGTGGGTTATGCTTCAGACTCTCAACGATGAGG



TTCCAAAATACCGTGACCAGATTCCTAGCCCAGGACTCATGGTTTTTCCAAA



ACCAGTGACCGCATTGGAATATACATTCAGTAGGTCTGATCCAACTTCGTAT



GCAGGGTACATTGAAGACCTTAAGAAGTTTCTAAAACCATATACTTTAGAAG



AACAGAAGAACCTCACAGTCTGTCCTGATGGAGCACTTTTTGAACAGAAGGG



TCCAGTTTATGTTGCATGTCAGTTTCCTATTTCATTACTTCAAGCATGCAGT



GGTATGAATGATCCTGATTTTGGCTATTCTCAAGGAAACCCTTGTATTCTTG



TGAAAATGAACAGAATAATTGGATTAAAGCCTGAAGGAGTGCCAAGGATAGA



TTGTGTTTCAAAGAATGAAGATATACCAAATGTAGCAGTTTATCCTCATAAT



GGAATGATAGACTTAAAATATTTCCCATATTATGGGAAAAAACTGCATGTTG



GGTATCTACAGCCATTGGTTGCTGTTCAGGTCAGCTTTGCTCCTAACAACAC



TGGGAAAGAAGTAACAGTTGAGTGCAAGATTGATGGATCAGCCAACCTAAAA



AGTCAGGATGATCGTGACAAGTTTTTGGGACGAGTTATGTTCAAAATCACAG



CACGTGCATAGTATGAGTAGGATATCTCCACAGAGTAAATGTTGTGTTGTCT



GTCTTCATTTTGTAACAGCTGGACCTTCCATTCTAGAATTATGAGACCACCT



TGGAGAAAGGTGTGTGGTACATGACATTGGGTTACATCATAACGTGCTTCCA



GATCATAGTGTTCAGTGTCCTCTGAAGTAACTGCCTGTTGCCTCTGCTGCCC



TTTGAACCAGTGTACAGTCGCCAGATAGGGACCGGTGAACACCTGATTCCAA



ACATGTAGGATGGGGGTCTTGTCCTCTTTTTATGTGGTTTAATTGCCAAGTG



TCTAAAGCTTAATATGCCGTGCTATGTAAATATTTTATGGATATAACAACTG



TCATATTTTGATGTCAACAGAGTTTTAGGGATAAAATGGTACCCGGCCAACA



TCAAGTGACTTTATAGCTGCAAGAAATGTGGTATGTGGAGAAGTTCTGTATG



TGAGGAAGGAAAAAAAGAAAATAAAAGTGTGTTTGAAAAATATTATCTTGGG



TTCTTTGTAAAATTTATTTTTTACATGCTGAATTAGCCTCGATCTTTTTGAT



TAAGAGCACAAACTTTTTTTTGTAAAACATGTAAAAAAAAAAACTGGGATTA



ATTTTTAGTGTTGGAACTGCCTCTTATTTTAGGCTGTAGATAAAATAGCATT



TTTAGGTTAGCCAGTGTGACTATGCACCTAATTTTTTATGAGATTAAATTCA



TAAGACTTAATTTGTACAATAGTTTGTGAAATATCTTGTTACTGCTTTTATT



TAGCAGACTGTGGACTGTAATAAAGTATATAAATTGTGAAATATAAAAACTT



GGAACTTATTCAAAGCTTCAAAGCAAA (SEQ ID NO: 209)



>NP_001670.1 sodium/potassium-transporting ATPase



subunit beta-3 [Homo sapiens]



MTKNEKKSLNQSLAEWKLFIYNPTTGEFLGRTAKSWGLILLFYLVFYGFLAA



LFSFTMWVMLQTLNDEVPKYRDQIPSPGLMVFPKPVTALEYTFSRSDPTSYA



GYIEDLKKFLKPYTLEEQKNLTVCPDGALFEQKGPVYVACQFPISLLQACSG



MNDPDFGYSQGNPCILVKMNRIIGLKPEGVPRIDCVSKNEDIPNVAVYPHNG



MIDLKYFPYYGKKLHVGYLQPLVAVQVSFAPNNTGKEVTVECKIDGSANLKS



QDDRDKFLGRVMFKITARA (SEQ ID NO: 210)





Lipid affinity tag
>NM_004985.5 Homo sapiens KRAS proto-oncogene,


modified from
GTPase (KRAS), transcript variant b, mRNA


Human KRAS
CTAGGCGGCGGCCGCGGCGGCGGAGGCAGCAGCGGCGGCGGCAGTGGCGGCG



GCGAAGGTGGCGGCGGCTCGGCCAGTACTCCCGGCCCCCGCCATTTCGGACT



GGGAGCGAGCGCGGCGCAGGCACTGAAGGCGGCGGCGGGGCCAGAGGCTCAG



CGGCTCCCAGGTGCGGGAGAGAGGCCTGCTGAAAATGACTGAATATAAACTT



GTGGTAGTTGGAGCTGGTGGCGTAGGCAAGAGTGCCTTGACGATACAGCTAA



TTCAGAATCATTTTGTGGACGAATATGATCCAACAATAGAGGATTCCTACAG



GAAGCAAGTAGTAATTGATGGAGAAACCTGTCTCTTGGATATTCTCGACACA



GCAGGTCAAGAGGAGTACAGTGCAATGAGGGACCAGTACATGAGGACTGGGG



AGGGCTTTCTTTGTGTATTTGCCATAAATAATACTAAATCATTTGAAGATAT



TCACCATTATAGAGAACAAATTAAAAGAGTTAAGGACTCTGAAGATGTACCT



ATGGTCCTAGTAGGAAATAAATGTGATTTGCCTTCTAGAACAGTAGACACAA



AACAGGCTCAGGACTTAGCAAGAAGTTATGGAATTCCTTTTATTGAAACATC



AGCAAAGACAAGACAGGGTGTTGATGATGCCTTCTATACATTAGTTCGAGAA



ATTCGAAAACATAAAGAAAAGATGAGCAAAGATGGTAAAAAGAAGAAAAAGA




AGTCAAAGACAAAGTGTGTAATTATGTAAATACAATTTGTACTTTTTTCTTA




AGGCATACTAGTACAAGTGGTAATTTTTGTACATTACACTAAATTATTAGCA



TTTGTTTTAGCATTACCTAATTTTTTTCCTGCTCCATGCAGACTGTTAGCTT



TTACCTTAAATGCTTATTTTAAAATGACAGTGGAAGTTTTTTTTTCCTCTAA



GTGCCAGTATTCCCAGAGTTTTGGTTTTTGAACTAGCAATGCCTGTGAAAAA



GAAACTGAATACCTAAGATTTCTGTCTTGGGGCTTTTGGTGCATGCAGTTGA



TTACTTCTTATTTTTCTTACCAATTGTGAATGTTGGTGTGAAACAAATTAAT



GAAGCTTTTGAATCATCCCTATTCTGTGTTTTATCTAGTCACATAAATGGAT



TAATTACTAATTTCAGTTGAGACCTTCTAATTGGTTTTTACTGAAACATTGA



GGGAACACAAATTTATGGGCTTCCTGATGATGATTCTTCTAGGCATCATGTC



CTATAGTTTGTCATCCCTGATGAATGTAAAGTTACACTGTTCACAAAGGTTT



TGTCTCCTTTCCACTGCTATTAGTCATGGTCACTCTCCCCAAAATATTATAT



TTTTTCTATAAAAAGAAAAAAATGGAAAAAAATTACAAGGCAATGGAAACTA



TTATAAGGCCATTTCCTTTTCACATTAGATAAATTACTATAAAGACTCCTAA



TAGCTTTTCCTGTTAAGGCAGACCCAGTATGAAATGGGGATTATTATAGCAA



CCATTTTGGGGCTATATTTACATGCTACTAAATTTTTATAATAATTGAAAAG



ATTTTAACAAGTATAAAAAATTCTCATAGGAATTAAATGTAGTCTCCCTGTG



TCAGACTGCTCTTTCATAGTATAACTTTAAATCTTTTCTTCAACTTGAGTCT



TTGAAGATAGTTTTAATTCTGCTTGTGACATTAAAAGATTATTTGGGCCAGT



TATAGCTTATTAGGTGTTGAAGAGACCAAGGTTGCAAGGCCAGGCCCTGTGT



GAACCTTTGAGCTTTCATAGAGAGTTTCACAGCATGGACTGTGTCCCCACGG



TCATCCAGTGTTGTCATGCATTGGTTAGTCAAAATGGGGAGGGACTAGGGCA



GTTTGGATAGCTCAACAAGATACAATCTCACTCTGTGGTGGTCCTGCTGACA



AATCAAGAGCATTGCTTTTGTTTCTTAAGAAAACAAACTCTTTTTTAAAAAT



TACTTTTAAATATTAACTCAAAAGTTGAGATTTTGGGGTGGTGGTGTGCCAA



GACATTAATTTTTTTTTTAAACAATGAAGTGAAAAAGTTTTACAATCTCTAG



GTTTGGCTAGTTCTCTTAACACTGGTTAAATTAACATTGCATAAACACTTTT



CAAGTCTGATCCATATTTAATAATGCTTTAAAATAAAAATAAAAACAATCCT



TTTGATAAATTTAAAATGTTACTTATTTTAAAATAAATGAAGTGAGATGGCA



TGGTGAGGTGAAAGTATCACTGGACTAGGAAGAAGGTGACTTAGGTTCTAGA



TAGGTGTCTTTTAGGACTCTGATTTTGAGGACATCACTTACTATCCATTTCT



TCATGTTAAAAGAAGTCATCTCAAACTCTTAGTTTTTTTTTTTTACAACTAT



GTAATTTATATTCCATTTACATAAGGATACACTTATTTGTCAAGCTCAGCAC



AATCTGTAAATTTTTAACCTATGTTACACCATCTTCAGTGCCAGTCTTGGGC



AAAATTGTGCAAGAGGTGAAGTTTATATTTGAATATCCATTCTCGTTTTAGG



ACTCTTCTTCCATATTAGTGTCATCTTGCCTCCCTACCTTCCACATGCCCCA



TGACTTGATGCAGTTTTAATACTTGTAATTCCCCTAACCATAAGATTTACTG



CTGCTGTGGATATCTCCATGAAGTTTTCCCACTGAGTCACATCAGAAATGCC



CTACATCTTATTTCCTCAGGGCTCAAGAGAATCTGACAGATACCATAAAGGG



ATTTGACCTAATCACTAATTTTCAGGTGGTGGCTGATGCTTTGAACATCTCT



TTGCTGCCCAATCCATTAGCGACAGTAGGATTTTTCAAACCTGGTATGAATA



GACAGAACCCTATCCAGTGGAAGGAGAATTTAATAAAGATAGTGCTGAAAGA



ATTCCTTAGGTAATCTATAACTAGGACTACTCCTGGTAACAGTAATACATTC



CATTGTTTTAGTAACCAGAAATCTTCATGCAATGAAAAATACTTTAATTCAT



GAAGCTTACTTTTTTTTTTTGGTGTCAGAGTCTCGCTCTTGTCACCCAGGCT



GGAATGCAGTGGCGCCATCTCAGCTCACTGCAACCTCCATCTCCCAGGTTCA



AGCGATTCTCGTGCCTCGGCCTCCTGAGTAGCTGGGATTACAGGCGTGTGCC



ACTACACTCAACTAATTTTTGTATTTTTAGGAGAGACGGGGTTTCACCCTGT



TGGCCAGGCTGGTCTCGAACTCCTGACCTCAAGTGATTCACCCACCTTGGCC



TCATAAACCTGTTTTGCAGAACTCATTTATTCAGCAAATATTTATTGAGTGC



CTACCAGATGCCAGTCACCACACAAGGCACTGGGTATATGGTATCCCCAAAC



AAGAGACATAATCCCGGTCCTTAGGTAGTGCTAGTGTGGTCTGTAATATCTT



ACTAAGGCCTTTGGTATACGACCCAGAGATAACACGATGCGTATTTTAGTTT



TGCAAAGAAGGGGTTTGGTCTCTGTGCCAGCTCTATAATTGTTTTGCTACGA



TTCCACTGAAACTCTTCGATCAAGCTACTTTATGTAAATCACTTCATTGTTT



TAAAGGAATAAACTTGATTATATTGTTTTTTTATTTGGCATAACTGTGATTC



TTTTAGGACAATTACTGTACACATTAAGGTGTATGTCAGATATTCATATTGA



CCCAAATGTGTAATATTCCAGTTTTCTCTGCATAAGTAATTAAAATATACTT



AAAAATTAATAGTTTTATCTGGGTACAAATAAACAGGTGCCTGAACTAGTTC



ACAGACAAGGAAACTTCTATGTAAAAATCACTATGATTTCTGAATTGCTATG



TGAAACTACAGATCTTTGGAACACTGTTTAGGTAGGGTGTTAAGACTTACAC



AGTACCTCGTTTCTACACAGAGAAAGAAATGGCCATACTTCAGGAACTGCAG



TGCTTATGAGGGGATATTTAGGCCTCTTGAATTTTTGATGTAGATGGGCATT



TTTTTAAGGTAGTGGTTAATTACCTTTATGTGAACTTTGAATGGTTTAACAA



AAGATTTGTTTTTGTAGAGATTTTAAAGGGGGAGAATTCTAGAAATAAATGT



TACCTAATTATTACAGCCTTAAAGACAAAAATCCTTGTTGAAGTTTTTTTAA



AAAAAGCTAAATTACATAGACTTAGGCATTAACATGTTTGTGGAAGAATATA



GCAGACGTATATTGTATCATTTGAGTGAATGTTCCCAAGTAGGCATTCTAGG



CTCTATTTAACTGAGTCACACTGCATAGGAATTTAGAACCTAACTTTTATAG



GTTATCAAAACTGTTGTCACCATTGCACAATTTTGTCCTAATATATACATAG



AAACTTTGTGGGGCATGTTAAGTTACAGTTTGCACAAGTTCATCTCATTTGT



ATTCCATTGATTTTTTTTTTCTTCTAAACATTTTTTCTTCAAACAGTATATA



ACTTTTTTTAGGGGATTTTTTTTTAGACAGCAAAAACTATCTGAAGATTTCC



ATTTGTCAAAAAGTAATGATTTCTTGATAATTGTGTAGTAATGTTTTTTAGA



ACCCAGCAGTTACCTTAAAGCTGAATTTATATTTAGTAACTTCTGTGTTAAT



ACTGGATAGCATGAATTCTGCATTGAGAAACTGAATAGCTGTCATAAAATGA



AACTTTCTTTCTAAAGAAAGATACTCACATGAGTTCTTGAAGAATAGTCATA



ACTAGATTAAGATCTGTGTTTTAGTTTAATAGTTTGAAGTGCCTGTTTGGGA



TAATGATAGGTAATTTAGATGAATTTAGGGGAAAAAAAAGTTATCTGCAGAT



ATGTTGAGGGCCCATCTCTCCCCCCACACCCCCACAGAGCTAACTGGGTTAC



AGTGTTTTATCCGAAAGTTTCCAATTCCACTGTCTTGTGTTTTCATGTTGAA



AATACTTTTGCATTTTTCCTTTGAGTGCCAATTTCTTACTAGTACTATTTCT



TAATGTAACATGTTTACCTGGAATGTATTTTAACTATTTTTGTATAGTGTAA



ACTGAAACATGCACATTTTGTACATTGTGCTTTCTTTTGTGGGACATATGCA



GTGTGATCCAGTTGTTTTCCATCATTTGGTTGCGCTGACCTAGGAATGTTGG



TCATATCAAACATTAAAAATGACCACTCTTTTAATTGAAATTAACTTTTAAA



TGTTTATAGGAGTATGTGCTGTGAAGTGATCTAAAATTTGTAATATTTTTGT



CATGAACTGTACTACTCCTAATTATTGTAATGTAATAAAAATAGTTACAGTG



AC (SEQ ID NO: 211)



>NP_004976.2 GTPase KRas isoform b [Homo sapiens]



MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCL



LDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVK



DSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQGVDDAF



YTLVREIRKHKEKMSKDGKKKKKKSKTKCVIM (SEQ ID NO: 212)



>Lipid affinity tag nucleotide sequence



AAAAAGAAGAAAAAGAAGAAGAAGACAAAGTGTGTAATTATG 



(SEQ ID NO: 213)



>Lipid affinity tag peptide sequence



KKKKKKKKTKCVIM (SEQ ID NO: 214)





Myr/Palm tag
>NM_002356.7 Homo sapiens myristoylated alanine rich


modified from
protein kinase C substrate (MARCKS), mRNA


Human MARCKS
GCACTTGGGCGTTGGACCCCGCATCTTATTAGCAACCAGGGAGATTTCTCCA



TTTTCCTCTTGTCTACAGTGCGGCTACAAATCTGGGATTTTTTTATTACTTC



TTTTTTTTTCGAACTACACTTGGGCTCCTTTTTTTGTGCTCGACTTTTCCAC



CCTTTTTCCCTCCCTCCTGTGCTGCTGCTTTTTGATCTCTTCGACTAAAATT



TTTTTATCCGGAGTGTATTTAATCGGTTCTGTTCTGTCCTCTCCACCACCCC



CACCCCCCTCCCTCCGGTGTGTGTGCCGCTGCCGCTGTTGCCGCCGCCGCTG



CTGCTGCTGCTCGCCCCGTCGTTACACCAACCCGAGGCTCTTTGTTTCCCCT



CTTGGATCTGTTGAGTTTCTTTGTTGAAGAAGCCAGCATGGGTGCCCAGTTC




TCCAAGACCGCAGCGAAGGGAGAAGCCGCCGCGGAGAGGCCTGGGGAGGCGG




CTGTGGCCTCGTCGCCTTCCAAAGCGAACGGACAGGAGAATGGCCACGTGAA



GGTAAACGGCGACGCTTCGCCCGCGGCCGCCGAGTCGGGCGCCAAGGAGGAG



CTGCAGGCCAACGGCAGCGCCCCGGCCGCCGACAAGGAGGAGCCCGCGGCCG



CCGGGAGCGGGGCGGCGTCGCCCTCCGCGGCCGAGAAAGGTGAGCCGGCCGC



CGCCGCTGCCCCCGAGGCCGGGGCCAGCCCGGTAGAGAAGGAGGCCCCCGCG



GAAGGCGAGGCTGCCGAGCCCGGCTCGCCCACGGCCGCGGAGGGAGAGGCCG



CGTCGGCCGCCTCCTCGACTTCTTCGCCCAAGGCCGAGGACGGGGCCACGCC



CTCGCCCAGCAACGAGACCCCGAAAAAAAAAAAGAAGCGCTTTTCCTTCAAG



AAGTCTTTCAAGCTGAGCGGCTTCTCCTTCAAGAAGAACAAGAAGGAGGCTG



GAGAAGGCGGTGAGGCTGAGGCGCCCGCTGCCGAAGGCGGCAAGGACGAGGC



CGCCGGGGGCGCAGCTGCGGCCGCCGCCGAGGCGGGCGCGGCCTCCGGGGAG



CAGGCAGCGGCGCCGGGCGAGGAGGCGGCAGCGGGCGAGGAGGGGGCGGCGG



GTGGCGACCCGCAGGAGGCCAAGCCCCAGGAGGCCGCTGTCGCGCCAGAGAA



GCCGCCCGCCAGCGACGAGACCAAGGCCGCCGAGGAGCCCAGCAAGGTGGAG



GAGAAAAAGGCCGAGGAGGCCGGGGCCAGCGCCGCCGCCTGCGAGGCCCCCT



CCGCCGCCGGGCCCGGCGCGCCCCCGGAGCAGGAGGCAGCCCCCGCGGAGGA



GCCCGCGGCCGCCGCAGCCTCGTCAGCCTGCGCAGCCCCCTCACAGGAGGCC



CAGCCCGAGTGCAGTCCAGAAGCCCCCCCAGCGGAGGCGGCAGAGTAAAAGA



GCAAGCTTTTGTGAGATAATCGAAGAACTTTTCTCCCCCGTTTGTTTGTTGG



AGTGGTGCCAGGTACTGGTTTTGGAGAACTTGTCTACAACCAGGGATTGATT



TTAAAGATGTCTTTTTTTATTTTACTTTTTTTTAAGCACCAAATTTTGTTGT



TTTTTTTTTTTCTCCCCTCCCCACAGATCCCATCTCAAATCATTCTGTTAAC



CACCATTCCAACAGGTCGAGGAGAGCTTAAACACCTTCTTCCTCTGCCTTGT



TTCTCTTTTATTTTTTATTTTTTCGCATCAGTATTAATGTTTTTGCATACTT



TGCATCTTTATTCAAAAGTGTAAACTTTCTTTGTCAATCTATGGACATGCCC



ATATATGAAGGAGATGGGTGGGTCAAAAAGGGATATCAAATGAAGTGATGGG



GTCACAATGGGGAAATTGAAGTGGTGCATAACATTGCCAAAATAGTGTGCCA



CTAGAAATGGTGTAAAGGCTGTCTTTTTTTTTTTTTTAAAAGAAAAGTTATT



ACCATGTATTTTGTGAGGCAGGTTTACAACACTACAAGTCTTGAGTTAAGAA



GGAAAGAGGAAAAAAGAAAAAACACCAATACCCAGATTTAAAAAAAAAAAAA



CGATCATAGTCTTAGGAGTTCATTTAAACCATAGGAACTTTTCACTTATCTC



ATGTTAGCTGTACCAGTCAGTGATTAAGTAGAACTACAAGTTGTATAGGCTT



TATTGTTTATTGCTGGTTTATGACCTTAATAAAGTGTAATTATGTATTACCA



GCAGGGTGTTTTTAACTGTGACTATTGTATAAAAACAAATCTTGATATCCAG



AAGCACATGAAGTTTGCAACTTTCCACCCTGCCCATTTTTGTAAAACTGCAG



TCATCTTGGACCTTTTAAAACACAAATTTTAAACTCAACCAAGCTGTGATAA



GTGGAATGGTTACTGTTTATACTGTGGTATGTTTTTGATTACAGCAGATAAT



GCTTTCTTTTCCAGTCGTCTTTGAGAATAAAGGAAAAAAAATCTTCAGATGC



AATGGTTTTGTGTAGCATCTTGTCTATCATGTTTTGTAAATACTGGAGAAGC



TTTGACCAATTTGACTTAGAGATGGAATGTAACTTTGCTTACAAAAATTGCT



ATTAAACTCCTGCTTAAGGTGTTCTAATTTTCTGTGAGCACACTAAAAGCGA



AAAATAAATGTGAATAAAATGTACAAATTTGTTGTGTTTTTTTATGTTCTAA



TAATACTGAGACTTCTAGGTCTTAGGTTAATTTTTAGGAAGATCTTGCATGC



CATCAGGAGTAAATTTTATTGTGGTTCTTAATCTGAAGTTTTCAAGCTCTGA



AATTCATAATCCGCAGTGTCAGATTACGTAGAGGAAGATCTTACAACATTTC



CATGTCAAATCTGTTACCATTTATTGGCATTTAGTTTTCATTTAAGAATTGA



ACATAATTATTTTTATTGTAGCTATATAGCATGTCAGATTAAATCATTTACA



ACAAAAGGGGTGTGAACCTAAGACTATTTAAATGTCTTATGAGAAAATTTCA



TAAAGCCATTCTCTTGTCATTCAGGTCCAGAAACAAATTTTAAACTGAGTGA



GAGTCTATAGAATCCATACTGCAGATGGGTCATGAAATGTGACCAAATGTGT



TTCAAAAATTGATGGTGTATTACCTGCTATTGTAATTGCTTAGTGCTTGGCT



AATTTCCAAATTATTGCATAATATGTTCTACCTTAAGAAAACAGGTTTATGT



AACAAAGTAATGGTGTTGAATGGATGATGTCAGTTCATGGGCCTTTAGCATA



GTTTTAAGCATCCTTTTTTTTTTTTTTTTTTGAAAGTGTGTTAGCATCTTGT



TACTCAAAGGATAAGACAGACAATAATACTTCACTGAATCTTAATAATCTTT



ACTAGTTTACCTCCTCTGCTCTTTGCCACCCGATAACTGGATATCTTTTCCT



TCAAAGGACCCTAAACTGATTGAAATTTAAGATATGTATCAAAAACATTATT



TCATTTAATGCACATCTGTTTTGCTGTTTTTGAGCAGTGTGCAGTTTAGGGT



TCATGATAAATCATTGAACCACATGTGTAACAACTGAATGCCAAATCTTAAA



CTCATTAGAAAAATAACAAATTAGGTTTTGACACGCATTCTTAATTGGAATA



ATGGATCAAAAATAGTGGTTCATGACCTTACCAAACACCCTTGCTACTAATA



AAATCAAATAACACTTAGAAGGGTATGTATTTTTAGTTAGGGTTTCTTGATC



TTGGAGGATGTTTGAAAGTTAAAAATTGAATTTGGTAACCAAAGGACTGATT



TATGGGTCTTTCCTATCTTAACCAACGTTTTCTTAGTTACCTAGATGGCCAA



GTACAGTGCCTGGTATGTAGTAAGACTCAGTAAAAAAGTGGATTTTTAAAAA



TAACTCCCAAAGTGAATAGTCAAAAATCCTGTTAGCAAACTGTTATATATTG



CTAAGTTTGTTCTTTTAACAGCTGGAATTTATTAAGATGCATTATTTTGATT



TTATTCACTGCCTAAAACACTTTGGGTGGTATTGATGGAGTTGGTGGATTTT



CCTCCAAGTGATTAAATGAAATTTGACGTATCTTTTCATCCAAAGTTTTGTA



CATCATGTTTTCTAACGGAAAAAAATGTTAATATGGCTTTTTTGTATTACTA



AAAATAGCTTTGAGATTAAGGAAAAATAAATAACTCTTGTACAGTTCAGTAT



TGTCTATTAAATCTGTATTGGCAGTATGTATAATGGCATTTGCTGTGGTTAC



AAAATACTTCCTCTGGGTTATAATAATCATTTGATCCAATTCCTATTGCTTG



TAAAATAAAGTTTTACCAGTTGATATAATCAA (SEQ ID NO: 215)



>NP_002347.5 myristoylated alanine-rich C-kinase



substrate [Homo sapiens]




MGAQFSKTAAKGEAAAERPGEAAVASSPSKANGQENGHVKVNGDASPAAAES




GAKEELQANGSAPAADKEEPAAAGSGAASPSAAEKGEPAAAAAPEAGASPVE



KEAPAEGEAAEPGSPTAAEGEAASAASSTSSPKAEDGATPSPSNETPKKKKK



RFSFKKSFKLSGFSFKKNKKEAGEGGEAEAPAAEGGKDEAAGGAAAAAAEAG



AASGEQAAAPGEEAAAGEEGAAGGDPQEAKPQEAAVAPEKPPASDETKAAEE



PSKVEEKKAEEAGASAAACEAPSAAGPGAPPEQEAAPAEEPAAAAASSACAA



PSQEAQPECSPEAPPAEAAE (SEQ ID NO: 216)



>Myr/Palm tag modified from Human MARCKS, nucleotide



sequence



ATGGGTTGCTGTTTCTCCAAGACC (SEQ ID NO: 217)



>Myr/Palm tag modified from Human MARCKS, peptide



sequence



MGCCFSKT (SEQ ID NO: 218)









In some embodiments of any of the aspects provided herein, the fusion polypeptide further comprises a peptide linker. The linker may be flexible, rigid, or cleavable. Further, the linker can be linked directly or via another linker (e.g., a peptide of one, two, three, four, five, six, seven, eight, nine, ten or more amino acids) to the fusion polypeptides described herein. Linkers can be configured according to a specific need, e.g., based on at least one of the following characteristics. In some embodiments of any of the aspects, linkers can be configured to have a sufficient length and flexibility such that it can allow for a cleavage at a target site. In some embodiments of any of the aspects, linkers can be configured to allow multimerization of the fusion polypeptides provided herein. In some embodiments of any of the aspects, linkers can be configured to facilitate expression and purification of the fusion proteins or engineered extracellular vesicles provided herein.


In some embodiments of any of the aspects, a linker can be configured to have any length in a form of a peptide, peptidomimetic, an aptamer, a protein, a nucleic acid (e.g., DNA or RNA), or any combinations thereof. For example, in one embodiment, the linker may be a polypeptide linker such as Gly-Ser-Ser-Gly (SEQ ID NO: 319) or a variation thereof as known by one of ordinary skill in the art. In another embodiment the linker may be a protein sequence for a self-cleavable peptide. For example, 2A sequences such as P2A, E2A, F2A, and T2A code for self-cleavable peptides by inducing ribosomal slippage on the mRNA at the 2A site which prevents peptide bond formation. The slippage will result in two separate peptides after translation. This allows the expression of two separate proteins from one promoter region. Any combination of the proteins described herein may be expressed with a self-cleavable peptide as known by one of ordinary skill in the art.


In some embodiments of any of the aspects, the polypeptide linker is a non-cleavable linker. In some embodiments of any of the aspects, a linker can be a chemical linker of any length.


In some embodiments of any of the aspects, the linker is an Fc linker. An exemplary nucleic acid sequence encoding an Fc polypeptide is:









>KY053479.1 Synthetic construct Fc-adiponectin


gene, complete cds


(SEQ ID NO: 219)


ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC





ACGAACTCGATATCGGCCATGGTTAGATCTGACAAAACTCACACATGCCCA





CCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCC





CCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC





GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTAC





GTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAG





TACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGAC





TGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCA





GCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCA





CAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTC





AGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG





TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTG





CTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAG





AGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCACGAGGCT





CTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAGCC





AGCGGAAGTGGCGGAGGAGGCGGTCCTGGAGAAGGTGCCTATGTATACCGC





TCAGCATTCAGTGTGGGATTGGAGACTTACGTTACTATCCCCAACATGCCC





ATTCGCTTTACCAAGATCTTCTACAATCAGCAAAACCACTATGATGGCTCC





ACTGGTAAATTCCACTGCAACATTCCTGGGCTGTACTACTTTGCCTACCAC





ATCACAGTCTATATGAAGGATGTGAAGGTCAGCCTCTTCAAGAAGGACAAG





GCTATGCTCTTCACCTATGATCAGTACCAGGAAAATAATGTGGACCAGGCC





TCCGGCTCTGTGCTCCTGCATCTGGAGGTGGGCGACCAAGTCTGGCTCCAG





GTGTATGGGGAAGGAGAGCGTAATGGACTCTATGCTGATAATGACAATGAC





TCCACCTTCACAGGCTTTCTTCTCTACCATGACACCAACTCTAGAAAGCTT





CCTGGAGAAGGTGCCTATGTATACCGCTCAGCATTCAGTGTGGGATTGGAG





ACTTACGTTACTATCCCCAACATGCCCATTCGCTTTACCAAGATCTTCTAC





AATCAGCAAAACCACTATGATGGCTCCACTGGTAAATTCCACTGCAACATT





CCTGGGCTGTACTACTTTGCCTACCACATCACAGTCTATATGAAGGATGTG





AAGGTCAGCCTCTTCAAGAAGGACAAGGCTATGCTCTTCACCTATGATCAG





TACCAGGAAAATAATGTGGACCAGGCCTCCGGCTCTGTGCTCCTGCATCTG





GAGGTGGGCGACCAAGTCTGGCTCCAGGTGTATGGGGAAGGAGAGCGTAAT





GGACTCTATGCTGATAATGACAATGACTCCACCTTCACAGGCTTTCTTCTC





TACCATGACACCAACACTAGTCCTGGAGAAGGTGCCTATGTATACCGCTCA





GCATTCAGTGTGGGATTGGAGACTTACGTTACTATCCCCAACATGCCCATT





CGCTTTACCAAGATCTTCTACAATCAGCAAAACCACTATGATGGCTCCACT





GGTAAATTCCACTGCAACATTCCTGGGCTGTACTACTTTGCCTACCACATC





ACAGTCTATATGAAGGATGTGAAGGTCAGCCTCTTCAAGAAGGACAAGGCT





ATGCTCTTCACCTATGATCAGTACCAGGAAAATAATGTGGACCAGGCCTCC





GGCTCTGTGCTCCTGCATCTGGAGGTGGGCGACCAAGTCTGGCTCCAGGTG





TATGGGGAAGGAGAGCGTAATGGACTCTATGCTGATAATGACAATGACTCC





ACCTTCACAGGCTTTCTTCTCTACCATGACACCAACTAA.







The amino acid sequence of the Fc linker is:









>Fc Translation


(SEQ ID NO: 220)


DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP





EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK





VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY





PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS





CSVMHEALHNHYTQKSLSLSPGK.






In some embodiments of any of the aspects, the linker is a P2A peptide linker. P2A is a self-cleaving peptide sequence allowing for expression of two proteins from one promoter. In some embodiments, the P2A linker is encoded by the nucleic acid sequence: GCTACTAACTTCAGCCTGCTGAAGCAG (SEQ ID NO: 221). The amino acid sequence of P2A is ATNFSLKQAGDVENPGP (SEQ ID NO: 222).


In some embodiments of any of the aspects, the linker is provides a multimerization (e.g., dimerization) domain wherein one fusion polypeptide may connect with another fusion polypeptide at each fusion polypeptide's respective multimerization domain. Multimerization of multiple fusion polypeptides will provide multiple fusion polypeptides within close proximity to one another to one or more a target receptor on the target cell, wherein the multiple fusion peptides will enhance receptor clustering on the target cell. Clustering receptors on a target cell will result in enhanced signal transduction. Without receptor clustering a signal may be weaker or not occur all together. For example, Fc domain sequences presented herein dimerize resulting in two fusion polypeptides connected by a covalent bond via the two Fc domains on their respective fusion polypeptide. One preferred embodiment of an Fc domain is from IgG4, herein labeled 4Fc. In other embodiments Fc may be from IgG1, herein labeled Fc. In certain embodiments Fc from other immunoglobulin, (e.g., IgG2, IgG3, etc.) may be used.


Additional non-limiting examples of linkers that can be used and their properties are further described in detail, e.g., in Chen X, Zaro J L, Shen W C. Fusion protein linkers: property, design and functionality. Adv Drug Deliv Rev. 2013; 65(10): 1357-1369. doi: 10.1016/j.addr.2012.09.039; O'Shea E K, Lumb K J, Kim P S. Peptide ‘Velcro’: design of a heterodimeric coiled coil. Curr Biol. 1993 Oct. 1; 3(10):658-67. doi: 10.1016/0960-9822(93)90063-t. PMID: 15335856; and Müller K M, Arndt K M, Alber T. Protein fusions to coiled-coil domains. Methods Enzymol. 2000; 328:261-82. doi: 10.1016/s0076-6879(00)28402-4. PMID: 11075350, the contents of which are incorporated herein by reference in their entireties.


The engineered extracellular vesicle compositions provided herein can comprise variations in the configuration of the POI domain, linkers, and/or vesicle targeting domain. The specific combination and localization of these domains can enhance fusion polypeptide anchoring, function, or therapeutic effect, e.g., modulating inflammation.


Thus, in one aspect, provided herein is an engineered extracellular vesicle comprising: at least one fusion polypeptide comprising: (i) at least one protein of interest (POI) domain or a fragment thereof; and (ii) at least one vesicle targeting domain, wherein the POI domain is in an extracellular position relative to a lipid membrane of the extracellular vesicle.


In some embodiments, the POI domain or a fragment thereof is a N-terminal domain of the fusion polypeptide. In some embodiments, the vesicle targeting domain or a fragment thereof is a C-terminal domain of the fusion polypeptide.


In another aspect, provided herein is an engineered extracellular vesicle comprising: at least one fusion polypeptide comprising: (i) at least one protein of interest (POI) domain or a fragment thereof; and (ii) at least one vesicle targeting domain, wherein the POI domain is in an extracellular position relative to a lipid membrane of the extracellular vesicle, and wherein the vesicle targeting domain is a transmembrane domain relative to a lipid membrane of the extracellular vesicle.


In some embodiments, the POI domain or a fragment thereof is a C-terminal domain of the fusion polypeptide. In some embodiments, the vesicle targeting domain or a fragment thereof is a N-terminal domain of the fusion polypeptide. In some embodiments, the vesicle targeting domain is in a luminal position relative to the lipid membrane of the extracellular vesicle.


In some embodiments, the linker is in an exterior position relative to the lipid membrane of the extracellular vesicle. In some embodiments, the linker is a transmembrane linker. In some embodiments, the linker is in a luminal position relative to the lipid membrane of the extracellular vesicle.


The engineered extracellular vesicle compositions provided herein can comprise one or more of the following fusion polypeptide sequences in Table 4.









TABLE 4







Full Length Constructs









Nucleic Acid Sequence (SEQ ID NO:)


Fusion Polypeptide
Amino Acid Sequence (SEQ ID NO:)





hCTLA4-Fc-GPI
>Artificial sequence; hCTLA4-Fc-GPI, DNA




ATGGCTTGCCTTGGATTTCAGCGGCACAAGGCTCAGCTGAACCTGGCTACCAGGACC





TGGCCCTGCACTCTCCTGTTTTTTCTTCTCTTCATCCCTGTCTTCTGCAAAGCAATG





CACGTGGCCCAGCCTGCTGTGGTACTGGCCAGCAGCCGAGGCATCGCCAGCTTTGTG





TGTGAGTATGCATCTCCAGGCAAAGCCACTGAGGTCCGGGTGACAGTGCTTCGGCAG





GCTGACAGCCAGGTGACTGAAGTCTGTGCGGCAACCTACATGATGGGGAATGAGTTG





ACCTTCCTAGATGATTCCATCTGCACGGGCACCTCCAGTGGAAATCAAGTGAACCTC





ACTATCCAAGGACTGAGGGCCATGGACACGGGACTCTACATCTGCAAGGTGGAGCTC





ATGTACCCACCGCCATACTACCTGGGCATAGGCAACGGAACCCAGATTTATGTAATT





GATCCAGAACCGTGCCCAGATTCTGACATCGATGACAAAACTCACACATGCCCACCG





TGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCC





AAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTG





AGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCAT





AATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGC





GTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTC





TCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAG





CCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAAC





CAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG





TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC





TCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG





CAGGGGAACGTCTTCTCATGCTCCGTGATGCACGAGGCTCTGCACAACCACTACACG





CAGAAGAGCCTCTCCCTGTCTCCGGGTAAAATCGATCCAAATAAAGGAAGTGGAACC





ACTTCAGGTACTACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTGACAGGTTTG





CTTGGGACGCTAGTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 223)



> Artificial sequence; hCTLA4-Fc-GPI, Amino Acid




MACLGFQRHKAQLNLATRTWPCTLLFFLLFIPVFCKAMHVAQPAVVLASSRGIASFV





CEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNL





TIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEPCPDSDIDDKTHTCPP





CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH





NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ





PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD





SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIDPNKGSGT





TSGTTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 224)





hPDL1-GPI
> Artificial sequence; hPDL1-GPI, DNA




ATGAGGATATTTGCTGTCTTTATATTCATGACCTACTGGCATTTGCTGAACGCATTT





ACTGTCACGGTTCCCAAGGACCTATATGTGGTAGAGTATGGTAGCAATATGACAATT





GAATGCAAATTCCCAGTAGAAAAACAATTAGACCTGGCTGCACTAATTGTCTATTGG





GAAATGGAGGATAAGAACATTATTCAATTTGTGCATGGAGAGGAAGACCTGAAGGTT





CAGCATAGTAGCTACAGACAGAGGGCCCGGCTGTTGAAGGACCAGCTCTCCCTGGGA





AATGCTGCACTTCAGATCACAGATGTGAAATTGCAGGATGCAGGGGTGTACCGCTGC





ATGATCAGCTATGGTGGTGCCGACTACAAGCGAATTACTGTGAAAGTCAATGCCCCA





TACAACAAAATCAACCAAAGAATTTTGGTTGTGGATCCAGTCACCTCTGAACATGAA





CTGACATGTCAGGCTGAGGGCTACCCCAAGGCCGAAGTCATCTGGACAAGCAGTGAC





CATCAAGTCCTGAGTGGTAAGACCACCACCACCAATTCCAAGAGAGAGGAGAAGCTT





TTCAATGTGACCAGCACACTGAGAATCAACACAACAACTAATGAGATTTTCTACTGC





ACTTTTAGGAGATTAGATCCTGAGGAAAACCATACAGCTGAATTGGTCATCCCAGAA





CTACCTCTGGCACATCCTCCAAATGAAAGG
CCAAATAAAGGAAGTGGAACCACTTCA





GGTACTACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTGACAGGTTTGCTTGGG





ACGCTAGTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 225)



>Amino Acid Sequence; hPDL1-GPI, Amino Acid




MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYW





EMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRC





MISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSD





HQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPE





LPLAHPPNER
PNKGSGTTSGTTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 226)





hPDL1-C1C2
>Artificial Sequence; hPDL1-C1C2, DNA




ATGAGGATATTTGCTGTCTTTATATTCATGACCTACTGGCATTTGCTGAACGCATTT





ACTGTCACGGTTCCCAAGGACCTATATGTGGTAGAGTATGGTAGCAATATGACAATT





GAATGCAAATTCCCAGTAGAAAAACAATTAGACCTGGCTGCACTAATTGTCTATTGG





GAAATGGAGGATAAGAACATTATTCAATTTGTGCATGGAGAGGAAGACCTGAAGGTT





CAGCATAGTAGCTACAGACAGAGGGCCCGGCTGTTGAAGGACCAGCTCTCCCTGGGA





AATGCTGCACTTCAGATCACAGATGTGAAATTGCAGGATGCAGGGGTGTACCGCTGC





ATGATCAGCTATGGTGGTGCCGACTACAAGCGAATTACTGTGAAAGTCAATGCCCCA





TACAACAAAATCAACCAAAGAATTTTGGTTGTGGATCCAGTCACCTCTGAACATGAA





CTGACATGTCAGGCTGAGGGCTACCCCAAGGCCGAAGTCATCTGGACAAGCAGTGAC





CATCAAGTCCTGAGTGGTAAGACCACCACCACCAATTCCAAGAGAGAGGAGAAGCTT





TTCAATGTGACCAGCACACTGAGAATCAACACAACAACTAATGAGATTTTCTACTGC





ACTTTTAGGAGATTAGATCCTGAGGAAAACCATACAGCTGAATTGGTCATCCCAGAA





CTACCTCTGGCACATCCTCCAAATGAAAGGATCGATGTCGAGCCACTGGGCATGGAG





AATGGGAACATTGCCAACTCACAGATCGCCGCCTCATCTGTGCGTGTGACCTTCTTG





GGTTTGCAGCATTGGGTCCCGGAGCTGGCCCGCCTGAACCGCGCAGGCATGGTCAAT





GCCTGGACACCCAGCAGCAATGACGATAACCCCTGGATCCAGGTGAACCTGCTGCGG





AGGATGTGGGTAACAGGTGTGGTGACGCAGGGTGCCAGCCGCTTGGCCAGTCATGAG





TACCTGAAGGCCTTCAAGGTGGCCTACAGCCTTAATGGACACGAATTCGATTTCATC





CATGATGTTAATAAAAAACACAAGGAGTTTGTGGGTAACTGGAACAAAAACGCGGTG





CATGTCAACCTGTTTGAGACCCCTGTGGAGGCTCAGTACGTGAGATTGTACCCCACG





AGCTGCCACACGGCCTGCACTCTGCGCTTTGAGCTACTGGGCTGTGAGCTGAACGGA





TGCGCCAATCCCCTGGGCCTGAAGAATAACAGCATCCCTGACAAGCAGATCACGGCC





TCCAGCAGCTACAAGACCTGGGGCTTGCATCTCTTCAGCTGGAACCCCTCCTATGCA





CGGCTGGACAAGCAGGGCAACTTCAACGCCTGGGTTGCGGGGAGCTACGGTAACGAT





CAGTGGCTGCAGATCTTCCCTGGCAACTGGGACAACCACTCCCACAAGAAGAACTTG





TTTGAGACGCCCATCCTGGCTCGCTATGTGCGCATCCTGCCTGTAGCCTGGCACAAC





CGCATCGCCCTGCGCCTGGAGCTGCTGGGCTGTTAG




(SEQ ID NO: 227)



>Artificial Sequence, hPDL1-C1C2, Amino Acid




MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYW





EMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRC





MISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSD





HQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPE





LPLAHPPNERIDVEPLGMENGNIANSQIAASSVRVTFLGLQHWVPELARLNRAGMVN





AWTPSSNDDNPWIQVNLLRRMWVTGVVTQGASRLASHEYLKAFKVAYSLNGHEFDFI





HDVNKKHKEFVGNWNKNAVHVNLFETPVEAQYVRLYPTSCHTACTLRFELLGCELNG





CANPLGLKNNSIPDKQITASSSYKTWGLHLFSWNPSYARLDKQGNFNAWVAGSYGND





QWLQIFPGNWDNHSHKKNLFETPILARYVRILPVAWHNRIALRLELLGC




(SEQ ID NO: 228)





hPDL1-Fc-GPI
>Artificial Sequence; hPDL1-Fc-GPI, DNA




ATGAGGATATTTGCTGTCTTTATATTCATGACCTACTGGCATTTGCTGAACGCATTT





ACTGTCACGGTTCCCAAGGACCTATATGTGGTAGAGTATGGTAGCAATATGACAATT





GAATGCAAATTCCCAGTAGAAAAACAATTAGACCTGGCTGCACTAATTGTCTATTGG





GAAATGGAGGATAAGAACATTATTCAATTTGTGCATGGAGAGGAAGACCTGAAGGTT





CAGCATAGTAGCTACAGACAGAGGGCCCGGCTGTTGAAGGACCAGCTCTCCCTGGGA





AATGCTGCACTTCAGATCACAGATGTGAAATTGCAGGATGCAGGGGTGTACCGCTGC





ATGATCAGCTATGGTGGTGCCGACTACAAGCGAATTACTGTGAAAGTCAATGCCCCA





TACAACAAAATCAACCAAAGAATTTTGGTTGTGGATCCAGTCACCTCTGAACATGAA





CTGACATGTCAGGCTGAGGGCTACCCCAAGGCCGAAGTCATCTGGACAAGCAGTGAC





CATCAAGTCCTGAGTGGTAAGACCACCACCACCAATTCCAAGAGAGAGGAGAAGCTT





TTCAATGTGACCAGCACACTGAGAATCAACACAACAACTAATGAGATTTTCTACTGC





ACTTTTAGGAGATTAGATCCTGAGGAAAACCATACAGCTGAATTGGTCATCCCAGAA





CTACCTCTGGCACATCCTCCAAATGAAAGGATCGATGACAAAACTCACACATGCCCA





CCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAA





CCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGAC





GTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG





CATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTC





AGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAG





GTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGG





CAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAG





AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG





GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTG





GACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGG





CAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCACGAGGCTCTGCACAACCACTAC





ACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAATCGATCCAAATAAAGGAAGTGGA





ACCACTTCAGGTACTACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTGACAGGT





TTGCTTGGGACGCTAGTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 229)



> Artificial Sequence; hPDL1-Fc-GPI, Amino Acid




MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYW





EMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRC





MISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSD





HQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPE





LPLAHPPNERIDDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD





VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK





VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV





EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY





TQKSLSLSPGKIDPNKGSGTTSGTTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 230)





hPDL2-C1C2
>Artificial Sequence; hPDL2-C1C2, DNA




ATGATCTTCCTCCTGCTAATGTTGAGCCTGGAATTGCAGCTTCACCAGATAGCAGCT





TTATTCACAGTGACAGTCCCTAAGGAACTGTACATAATAGAGCATGGCAGCAATGTG





ACCCTGGAATGCAACTTTGACACTGGAAGTCATGTGAACCTTGGAGCAATAACAGCC





AGTTTGCAAAAGGTGGAAAATGATACATCCCCACACCGTGAAAGAGCCACTTTGCTG





GAGGAGCAGCTGCCCCTAGGGAAGGCCTCGTTCCACATACCTCAAGTCCAAGTGAGG





GACGAAGGACAGTACCAATGCATAATCATCTATGGGGTCGCCTGGGACTACAAGTAC





CTGACTCTGAAAGTCAAAGCTTCCTACAGGAAAATAAACACTCACATCCTAAAGGTT





CCAGAAACAGATGAGGTAGAGCTCACCTGCCAGGCTACAGGTTATCCTCTGGCAGAA





GTATCCTGGCCAAACGTCAGCGTTCCTGCCAACACCAGCCACTCCAGGACCCCTGAA





GGCCTCTACCAGGTCACCAGTGTTCTGCGCCTAAAGCCACCCCCTGGCAGAAACTTC





AGCTGTGTGTTCTGGAATACTCACGTGAGGGAACTTACTTTGGCCAGCATTGACCTT





CAAAGTCAGATGGAACCCAGGACCCATCCAACTATCGATGTCGAGCCACTGGGCATG





GAGAATGGGAACATTGCCAACTCACAGATCGCCGCCTCATCTGTGCGTGTGACCTTC





TTGGGTTTGCAGCATTGGGTCCCGGAGCTGGCCCGCCTGAACCGCGCAGGCATGGTC





AATGCCTGGACACCCAGCAGCAATGACGATAACCCCTGGATCCAGGTGAACCTGCTG





CGGAGGATGTGGGTAACAGGTGTGGTGACGCAGGGTGCCAGCCGCTTGGCCAGTCAT





GAGTACCTGAAGGCCTTCAAGGTGGCCTACAGCCTTAATGGACACGAATTCGATTTC





ATCCATGATGTTAATAAAAAACACAAGGAGTTTGTGGGTAACTGGAACAAAAACGCG





GTGCATGTCAACCTGTTTGAGACCCCTGTGGAGGCTCAGTACGTGAGATTGTACCCC





ACGAGCTGCCACACGGCCTGCACTCTGCGCTTTGAGCTACTGGGCTGTGAGCTGAAC





GGATGCGCCAATCCCCTGGGCCTGAAGAATAACAGCATCCCTGACAAGCAGATCACG





GCCTCCAGCAGCTACAAGACCTGGGGCTTGCATCTCTTCAGCTGGAACCCCTCCTAT





GCACGGCTGGACAAGCAGGGCAACTTCAACGCCTGGGTTGCGGGGAGCTACGGTAAC





GATCAGTGGCTGCAGATCTTCCCTGGCAACTGGGACAACCACTCCCACAAGAAGAAC





TTGTTTGAGACGCCCATCCTGGCTCGCTATGTGCGCATCCTGCCTGTAGCCTGGCAC





AACCGCATCGCCCTGCGCCTGGAGCTGCTGGGCTGTTAG




(SEQ ID NO: 231)



>Artificial Sequence; hPDL2-C1C2, Amino Acid




MIFLLLMLSLELQLHQIAALFTVTVPKELYIIEHGSNVTLECNFDTGSHVNLGAITA





SLQKVENDTSPHRERATLLEEQLPLGKASFHIPQVQVRDEGQYQCIIIYGVAWDYKY





LTLKVKASYRKINTHILKVPETDEVELTCQATGYPLAEVSWPNVSVPANTSHSRTPE





GLYQVTSVLRLKPPPGRNFSCVFWNTHVRELTLASIDLQSQMEPRTHPTIDVEPLGM





ENGNIANSQIAASSVRVTFLGLQHWVPELARLNRAGMVNAWTPSSNDDNPWIQVNLL





RRMWVTGVVTQGASRLASHEYLKAFKVAYSLNGHEFDFIHDVNKKHKEFVGNWNKNA





VHVNLFETPVEAQYVRLYPTSCHTACTLRFELLGCELNGCANPLGLKNNSIPDKQIT





ASSSYKTWGLHLFSWNPSYARLDKQGNFNAWVAGSYGNDQWLQIFPGNWDNHSHKKN





LFETPILARYVRILPVAWHNRIALRLELLGC




(SEQ ID NO: 232)





hPDL2-Fc-GPI
>Artificial Sequence; hPDL2-Fc-GPI, DNA




ATGATCTTCCTCCTGCTAATGTTGAGCCTGGAATTGCAGCTTCACCAGATAGCAGCT





TTATTCACAGTGACAGTCCCTAAGGAACTGTACATAATAGAGCATGGCAGCAATGTG





ACCCTGGAATGCAACTTTGACACTGGAAGTCATGTGAACCTTGGAGCAATAACAGCC





AGTTTGCAAAAGGTGGAAAATGATACATCCCCACACCGTGAAAGAGCCACTTTGCTG





GAGGAGCAGCTGCCCCTAGGGAAGGCCTCGTTCCACATACCTCAAGTCCAAGTGAGG





GACGAAGGACAGTACCAATGCATAATCATCTATGGGGTCGCCTGGGACTACAAGTAC





CTGACTCTGAAAGTCAAAGCTTCCTACAGGAAAATAAACACTCACATCCTAAAGGTT





CCAGAAACAGATGAGGTAGAGCTCACCTGCCAGGCTACAGGTTATCCTCTGGCAGAA





GTATCCTGGCCAAACGTCAGCGTTCCTGCCAACACCAGCCACTCCAGGACCCCTGAA





GGCCTCTACCAGGTCACCAGTGTTCTGCGCCTAAAGCCACCCCCTGGCAGAAACTTC





AGCTGTGTGTTCTGGAATACTCACGTGAGGGAACTTACTTTGGCCAGCATTGACCTT





CAAAGTCAGATGGAACCCAGGACCCATCCAACTATCGATGACAAAACTCACACATGC





CCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCA





AAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTG





GACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAG





GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTG





GTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGC





AAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAA





GGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACC





AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC





GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTG





CTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGG





TGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCACGAGGCTCTGCACAACCAC





TACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAATCGATCCAAATAAAGGAAGT





GGAACCACTTCAGGTACTACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTGACA





GGTTTGCTTGGGACGCTAGTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 233)



>Artificial Sequence; hPDL2-Fc-GPI, Amino Acid




MIFLLLMLSLELQLHQIAALFTVTVPKELYIIEHGSNVTLECNFDTGSHVNLGAITA





SLQKVENDTSPHRERATLLEEQLPLGKASFHIPQVQVRDEGQYQCIIIYGVAWDYKY





LTLKVKASYRKINTHILKVPETDEVELTCQATGYPLAEVSWPNVSVPANTSHSRTPE





GLYQVTSVLRLKPPPGRNFSCVFWNTHVRELTLASIDLQSQMEPRTHPTIDDKTHTC





PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE





VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK





GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV





LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIDPNKGS





GTTSGTTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 234)





4F2-h41BBL
>Artificial Sequence; 4F2-41BBL, DNA




ATGAGCCAGGACACCGAGGTGGATATGAAGGAGGTGGAGCTGAATGAGTTAGAGCCC





GAGAAGCAGCCGATGAACGCGGCGTCTGGGGCGGCCATGTCCCTGGCGGGAGCCGAG





AAGAATGGTCTGGTGAAGATCAAGGTGGCGGAAGACGAGGCGGAGGCGGCAGCCGCG





GCTAAGTTCACGGGCCTGTCCAAGGAGGAGCTGCTGAAGGTGGCAGGCAGCCCCGGC





TGGGTACGCACCCGCTGGGCACTGCTGCTGCTCTTCTGGCTCGGCTGGCTCGGCATG





CTTGCTGGTGCCGTGGTCATAATCGTG
GCCTGCCCCTGGGCCGTGTCCGGGGCTCGC





GCCTCGCCCGGCTCCGCGGCCAGCCCGAGACTCCGCGAGGGTCCCGAGCTTTCGCCC





GACGATCCCGCCGGCCTCTTGGACCTGCGGCAGGGCATGTTTGCGCAGCTGGTGGCC





CAAAATGTTCTGCTGATCGATGGGCCCCTGAGCTGGTACAGTGACCCAGGCCTGGCA





GGCGTGTCCCTGACGGGGGGCCTGAGCTACAAAGAGGACACGAAGGAGCTGGTGGTG





GCCAAGGCTGGAGTCTACTATGTCTTCTTTCAACTAGAGCTGCGGCGCGTGGTGGCC





GGCGAGGGCTCAGGCTCCGTTTCACTTGCGCTGCACCTGCAGCCACTGCGCTCTGCT





GCTGGGGCCGCCGCCCTGGCTTTGACCGTGGACCTGCCACCCGCCTCCTCCGAGGCT





CGGAACTCGGCCTTCGGTTTCCAGGGCCGCTTGCTGCACCTGAGTGCCGGCCAGCGC





CTGGGCGTCCATCTTCACACTGAGGCCAGGGCACGCCATGCCTGGCAGCTTACCCAG





GGCGCCACAGTCTTGGGACTCTTCCGGGTGACCCCCGAAATCCCAGCCGGACTCCCT





TCACCGAGGTCGGAATAA




(SEQ ID NO: 235)



>Artificial Sequence; 4F2-h41BBL, Amino Acid




MSQDTEVDMKEVELNELEPEKQPMNAASGAAMSLAGAEKNGLVKIKVAEDEAEAAAA





AKFTGLSKEELLKVAGSPGWVRTRWALLLLFWLGWLGMLAGAVVIIV
ACPWAVSGAR





ASPGSAASPRLREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLA





GVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSA





AGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQ





GATVLGLFRVTPEIPAGLPSPRSE




(SEQ ID NO: 236)





hPDL1-4Fc-GPI
>Artificial Sequence; hPDL1-4Fc-GPI, DNA




ATGAGGATATTTGCTGTCTTTATATTCATGACCTACTGGCATTTGCTGAACGCATTT





ACTGTCACGGTTCCCAAGGACCTATATGTGGTAGAGTATGGTAGCAATATGACAATT





GAATGCAAATTCCCAGTAGAAAAACAATTAGACCTGGCTGCACTAATTGTCTATTGG





GAAATGGAGGATAAGAACATTATTCAATTTGTGCATGGAGAGGAAGACCTGAAGGTT





CAGCATAGTAGCTACAGACAGAGGGCCCGGCTGTTGAAGGACCAGCTCTCCCTGGGA





AATGCTGCACTTCAGATCACAGATGTGAAATTGCAGGATGCAGGGGTGTACCGCTGC





ATGATCAGCTATGGTGGTGCCGACTACAAGCGAATTACTGTGAAAGTCAATGCCCCA





TACAACAAAATCAACCAAAGAATTTTGGTTGTGGATCCAGTCACCTCTGAACATGAA





CTGACATGTCAGGCTGAGGGCTACCCCAAGGCCGAAGTCATCTGGACAAGCAGTGAC





CATCAAGTCCTGAGTGGTAAGACCACCACCACCAATTCCAAGAGAGAGGAGAAGCTT





TTCAATGTGACCAGCACACTGAGAATCAACACAACAACTAATGAGATTTTCTACTGC





ACTTTTAGGAGATTAGATCCTGAGGAAAACCATACAGCTGAATTGGTCATCCCAGAA





CTACCTCTGGCACATCCTCCAAATGAAAGG
GAGTCCAAATATGGTCCCCCATGCCCA





TCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAA





CCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGAC





GTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTG





CATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTC





AGGGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGTAAGGAGTACAAGTGCAAG





GTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGG





CAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAG





AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTG





GAGTGGGAGAGCAATGGGCAGCCGGAGGACAACTACAAGACCACGCCTCCCGTGCTG





GACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGG





CAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTAC





ACACAGAAGAGCCTCTCCCTGTCTCCGGGTAAA
CCAAATAAAGGAAGTGGAACCACT





TCAGGTACTACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTGACAGGTTTGCTT





GGGACGCTAGTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 237)



>Artificial Sequence; hPDL1-4Fc-GPI, Amino Acid




MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYW





EMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRC





MISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSD





HQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPE





LPLAHPPNER
ESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD





VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVRVLTVLHQDWLNGKEYKCK





VSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAV





EWESNGQPEDNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHY





TQKSLSLSPGK
PNKGSGTTSGTTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 238)





hPDL1-GPI-P2A-
>Artificial Sequence; hPDL1-GPI-P2A-hFGL1-GPI, DNA


hFGL1-GPI

ATGAGGATATTTGCTGTCTTTATATTCATGACCTACTGGCATTTGCTGAACGCATTT





ACTGTCACGGTTCCCAAGGACCTATATGTGGTAGAGTATGGTAGCAATATGACAATT





GAATGCAAATTCCCAGTAGAAAAACAATTAGACCTGGCTGCACTAATTGTCTATTGG





GAAATGGAGGATAAGAACATTATTCAATTTGTGCATGGAGAGGAAGACCTGAAGGTT





CAGCATAGTAGCTACAGACAGAGGGCCCGGCTGTTGAAGGACCAGCTCTCCCTGGGA





AATGCTGCACTTCAGATCACAGATGTGAAATTGCAGGATGCAGGGGTGTACCGCTGC





ATGATCAGCTATGGTGGTGCCGACTACAAGCGAATTACTGTGAAAGTCAATGCCCCA





TACAACAAAATCAACCAAAGAATTTTGGTTGTGGATCCAGTCACCTCTGAACATGAA





CTGACATGTCAGGCTGAGGGCTACCCCAAGGCCGAAGTCATCTGGACAAGCAGTGAC





CATCAAGTCCTGAGTGGTAAGACCACCACCACCAATTCCAAGAGAGAGGAGAAGCTT





TTCAATGTGACCAGCACACTGAGAATCAACACAACAACTAATGAGATTTTCTACTGC





ACTTTTAGGAGATTAGATCCTGAGGAAAACCATACAGCTGAATTGGTCATCCCAGAA





CTACCTCTGGCACATCCTCCAAATGAAAGG
CCAAATAAAGGAAGTGGAACCACTTCA





GGTACTACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTGACAGGTTTGCTTGGG





ACGCTAGTAACCATGGGCTTGCTGACTGGAAGCGGAGCTACTAACTTCAGCCTGCTG





AAGCAGGCTGGCGACGTGGAGGAGAACCCTGGACCT
ATGGCAAAGGTGTTCAGTTTC





ATCCTTGTTACCACCGCTCTGACAATGGGCAGGGAAATTTCGGCGCTCGAGGACTGT





GCCCAGGAGCAGATGCGGCTCAGAGCCCAGGTGCGCCTGCTTGAGACCCGGGTCAAA





CAGCAACAGGTCAAGATCAAGCAGCTTTTGCAGGAGAATGAAGTCCAGTTCCTTGAT





AAAGGAGATGAGAATACTGTCATTGATCTTGGAAGCAAGAGGCAGTATGCAGATTGT





TCAGAGATTTTCAATGATGGGTATAAGCTCAGTGGATTTTACAAAATCAAACCTCTC





CAGAGCCCAGCAGAATTTTCTGTTTATTGTGACATGTCCGATGGAGGAGGATGGACT





GTAATTCAGAGACGATCTGATGGCAGTGAAAACTTTAACAGAGGATGGAAAGACTAT





GAAAATGGCTTTGGAAATTTTGTCCAAAAACATGGTGAATATTGGCTGGGCAATAAA





AATCTTCACTTCTTGACCACTCAAGAAGACTACACTTTAAAAATCGACCTTGCAGAT





TTTGAAAAAAATAGCCGTTATGCACAATATAAGAATTTCAAAGTTGGAGATGAAAAG





AATTTCTACGAGTTGAATATTGGGGAATATTCTGGAACAGCTGGAGATTCCCTTGCG





GGGAATTTTCATCCTGAGGTGCAGTGGTGGGCTAGTCACCAAAGAATGAAATTCAGC





ACGTGGGACAGAGATCATGACAACTATGAAGGGAACTGCGCAGAAGAAGATCAGTCT





GGCTGGTGGTTTAACAGGTGTCACTCTGCAAACCTGAATGGTGTATACTACAGCGGC





CCCTACACGGCTAAAACAGACAATGGGATTGTCTGGTACACCTGGCATGGGTGGTGG





TATTCTCTGAAATCTGTGGTTATGAAAATTAGGCCAAATGATTTTATTCCAAATGTA





ATT
CCAAATAAAGGAAGTGGAACCACTTCAGGTACTACCCGTCTTCTATCTGGGCAC





ACGTGTTTCACGTTGACAGGTTTGCTTGGGACGCTAGTAACCATGGGCTTGCTGACT





TAG




(SEQ ID NO: 239)



>Artificial Sequence; hPDL1-GPI-P2A-hFGL1-GPI, Amino Acid




MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYW





EMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRC





MISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSD





HQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPE





LPLAHPPNER
PNKGSGTTSGTTRLLSGHTCFTLTGLLGTLVTMGLLTGSGATNFSLL





KQAGDVEENPGP
MAKVFSFILVTTALTMGREISALEDCAQEQMRLRAQVRLLETRVK





QQQVKIKQLLQENEVQFLDKGDENTVIDLGSKRQYADCSEIFNDGYKLSGFYKIKPL





QSPAEFSVYCDMSDGGGWTVIQRRSDGSENFNRGWKDYENGFGNFVQKHGEYWLGNK





NLHFLTTQEDYTLKIDLADFEKNSRYAQYKNFKVGDEKNFYELNIGEYSGTAGDSLA





GNFHPEVQWWASHQRMKFSTWDRDHDNYEGNCAEEDQSGWWFNRCHSANLNGVYYSG





PYTAKTDNGIVWYTWHGWWYSLKSVVMKIRPNDFIPNVI
PNKGSGTTSGTTRLLSGH





TCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 240)





Myr-mScarlet
>Artificial Sequence; Myr-mScarlet, DNA





ATGGGTTGCTGTTTCTCCAAGACC
GGCTCGAGCGGCGTGAGCAAGGGCGAGGCAGTG





ATCAAGGAGTTCATGCGGTTCAAGGTGCACATGGAGGGCTCCATGAACGGCCACGAG





TTCGAGATCGAGGGCGAGGGCGAGGGCCGCCCCTACGAGGGCACCCAGACCGCCAAG





CTGAAGGTGACCAAGGGTGGCCCCCTGCCCTTCTCCTGGGACATCCTGTCCCCTCAG





TTCATGTACGGCTCCAGGGCCTTCACCAAGCACCCCGCCGACATCCCCGACTACTAT





AAGCAGTCCTTCCCCGAGGGCTTCAAGTGGGAGCGCGTGATGAACTTCGAGGACGGC





GGCGCCGTGACCGTGACCCAGGACACCTCCCTGGAGGACGGCACCCTGATCTACAAG





GTGAAGCTCCGCGGCACCAACTTCCCTCCTGACGGCCCCGTAATGCAGAAGAAGACA





ATGGGCTGGGAAGCGTCCACCGAGCGGTTGTACCCCGAGGACGGCGTGCTGAAGGGC





GACATTAAGATGGCCCTGCGCCTGAAGGACGGCGGCCGCTACCTGGCGGACTTCAAG





ACCACCTACAAGGCCAAGAAGCCCGTGCAGATGCCCGGCGCCTACAACGTCGACCGC





AAGTTGGACATCACCTCCCACAACGAGGACTACACCGTGGTGGAACAGTACGAACGC





TCCGAGGGCCGCCACTCCACCGGCGGCATGGACGAGCTGTACAAG




(SEQ ID NO: 241)



>Artificial Sequence; Myr-mScarlet, Amino Acid





MGCCFSKT
GSSGVSKGEAVIKEFMRFKVHMEGSMNGHEFEIEGEGEGRPYEGTQTAK





LKVTKGGPLPFSWDILSPQFMYGSRAFTKHPADIPDYYKQSFPEGFKWERVMNFEDG





GAVTVTQDTSLEDGTLIYKVKLRGTNFPPDGPVMQKKTMGWEASTERLYPEDGVLKG





DIKMALRLKDGGRYLADFKTTYKAKKPVQMPGAYNVDRKLDITSHNEDYTVVEQYER





SEGRHSTGGMDELYK




(SEQ ID NO: 242)





Myr-NanoLuc
> Artificial Sequence; Myr-NanoLuc, DNA


Luciferase


ATGGGTTGCTGTTTCTCCAAGACC
GGCTCGAGCGGCGTCTTCACACTCGAAGATTTC





GTTGGGGACTGGCGACAGACAGCCGGCTACAACCTGGACCAAGTCCTTGAACAGGGA





GGTGTGTCCAGTTTGTTTCAGAATCTCGGGGTGTCCGTAACTCCGATCCAAAGGATT





GTCCTGAGCGGTGAAAATGGGCTGAAGATCGACATCCATGTCATCATCCCGTATGAA





GGTCTGAGCGGCGACCAAATGGGCCAGATCGAAAAAATTTTTAAGGTGGTGTACCCT





GTGGATGATCATCACTTTAAGGTGATCCTGCACTATGGCACACTGGTAATCGACGGG





GTTACGCCGAACATGATCGACTATTTCGGACGGCCGTATGAAGGCATCGCCGTGTTC





GACGGCAAAAAGATCACTGTAACAGGGACCCTGTGGAACGGCAACAAAATTATCGAC





GAGCGCCTGATCAACCCCGACGGCTCCCTGCTGTTCCGAGTAACCATCAACGGAGTG





ACCGGCTGGCGGCTGTGCGAACGCATTCTGGCGTAA




(SEQ ID NO: 243)



>Artificial Sequence; Myr-NanoLuc, Amino Acid





MGCCFSKT
GSSGVFTLEDFVGDWRQTAGYNLDQVLEQGGVSSLFQNLGVSVTPIQRI




VLSGENGLKIDIHVIIPYEGLSGDQMGQIEKIFKVVYPVDDHHFKVILHYGTLVIDG



VTPNMIDYFGRPYEGIAVFDGKKITVTGTLWNGNKIIDERLINPDGSLLFRVTINGV



TGWRLCERILA



(SEQ ID NO: 244)





hSecPDL1-GPI
>Artificial Sequence; hSecPDL1-GPI, DNA




ATGAGGATATTTGCTGTCTTTATATTCATGACCTACTGGCATTTGCTGAACGCATTT





ACTGTCACGGTTCCCAAGGACCTATATGTGGTAGAGTATGGTAGCAATATGACAATT





GAATGCAAATTCCCAGTAGAAAAACAATTAGACCTGGCTGCACTAATTGTCTATTGG





GAAATGGAGGATAAGAACATTATTCAATTTGTGCATGGAGAGGAAGACCTGAAGGTT





CAGCATAGTAGCTACAGACAGAGGGCCCGGCTGTTGAAGGACCAGCTCTCCCTGGGA





AATGCTGCACTTCAGATCACAGATGTGAAATTGCAGGATGCAGGGGTGTACCGCTGC





ATGATCAGCTATGGTGGTGCCGACTACAAGCGAATTACTGTGAAAGTCAATGCCCCA





TACAACAAAATCAACCAAAGAATTTTGGTTGTGGATCCAGTCACCTCTGAACATGAA





CTGACATGTCAGGCTGAGGGCTACCCCAAGGCCGAAGTCATCTGGACAAGCAGTGAC





CATCAAGTCCTGAGTGGTAAGACCACCACCACCAATTCCAAGAGAGAGGAGAAGCTT





TTCAATGTGACCAGCACACTGAGAATCAACACAACAACTAATGAGATTTTCTACTGC





ACTTTTAGGAGATTAGATCCTGAGGAAAACCATACAGCTGAATTGGTCATCCCAGGT





AATATTCTGAATGTGTCCATTAAAATATGTCTAACACTGTCCCCTAGCACC
CCAAAT





AAAGGAAGTGGAACCACTTCAGGTACTACCCGTCTTCTATCTGGGCACACGTGTTTC





ACGTTGACAGGTTTGCTTGGGACGCTAGTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 245)



>Artificial Sequence; hSecPDL1-GPI, Amino Acid




MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYW





EMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRC





MISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSD





HQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPG





NILNVSIKICLTLSPST
PNKGSGTTSGTTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 246)





Tfr2-h41BBL
>Artificial Sequence; Tfr2-h41BBL, DNA




ATGGAGCGGCTTTGGGGTCTATTCCAGAGAGCGCAACAACTGTCCCCAAGATCCTCT





CAGACCGTCTACCAGCGTGTGGAAGGCCCCCGGAAAGGGCACCTGGAGGAGGAAGAG





GAAGACGGGGAGGAGGGGGCGGAGACATTGGCCCACTTCTGCCCCATGGAGCTGAGG





GGCCCTGAGCCCCTGGGCTCTAGACCCAGGCAGCCAAACCTCATTCCCTGGGCGGCA





GCAGGACGGAGGGCTGCCCCCTACCTGGTCCTGACGGCCCTGCTGATCTTCACTGGG





GCCTTCCTACTGGGCTACGTCGCCTTCCGAGGGTCC
custom-character
custom-character





custom-character
custom-character
custom-character
custom-character
custom-character





custom-character
custom-character
custom-character
custom-character
custom-character





custom-character
custom-character
custom-character
custom-character
custom-character





custom-character
custom-character
custom-character
custom-character
custom-character





custom-character
custom-character
custom-character
custom-character
custom-character





custom-character
custom-character
custom-character
custom-character
custom-character





custom-character
custom-character
custom-character
custom-character
custom-character





custom-character
custom-character
custom-character
custom-character
custom-character





custom-character
custom-character
custom-character
custom-character
custom-character





custom-character
custom-character
custom-character
custom-character
custom-character





custom-character
custom-character




(SEQ ID NO: 247)



>Artificial Sequence; Tfr2-h41BBL, Amino Acid




MERLWGLFQRAQQLSPRSSQTVYQRVEGPRKGHLEEEEEDGEEGAETLAHFCPMELR





GPEPLGSRPRQPNLIPWAAAGRRAAPYLVLTALLIFTGAFLLGYVAFRGS
ACPWAVS





GARASPGSAASPRLRGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPG





LAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLR





SAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQL





TQGATVLGLFRVTPEIPAGLPSPRSE




(SEQ ID NO: 248)





CD9tm3-h41BBL
>Artificial Sequence; CD9tm3-h41BBL, DNA




ATGGGCTGCTGCGGGGCTGTGCAGGAGTCCCAGTGCATGCTGGGACTGTTCTTCGGC





TTCCTCTTGGTGATATTCGCCATTGAAATAGCTGCGGCCATCTGGGGATATTCCCAC





AAGGATGAG
GCCTGCCCCTGGGCCGTGTCCGGGGCTCGCGCCTCGCCCGGCTCCGCG





GCCAGCCCGAGACTCCGCGAGGGTCCCGAGCTTTCGCCCGACGATCCCGCCGGCCTC





TTGGACCTGCGGCAGGGCATGTTTGCGCAGCTGGTGGCCCAAAATGTTCTGCTGATC





GATGGGCCCCTGAGCTGGTACAGTGACCCAGGCCTGGCAGGCGTGTCCCTGACGGGG





GGCCTGAGCTACAAAGAGGACACGAAGGAGCTGGTGGTGGCCAAGGCTGGAGTCTAC





TATGTCTTCTTTCAACTAGAGCTGCGGCGCGTGGTGGCCGGCGAGGGCTCAGGCTCC





GTTTCACTTGCGCTGCACCTGCAGCCACTGCGCTCTGCTGCTGGGGCCGCCGCCCTG





GCTTTGACCGTGGACCTGCCACCCGCCTCCTCCGAGGCTCGGAACTCGGCCTTCGGT





TTCCAGGGCCGCTTGCTGCACCTGAGTGCCGGCCAGCGCCTGGGCGTCCATCTTCAC





ACTGAGGCCAGGGCACGCCATGCCTGGCAGCTTACCCAGGGCGCCACAGTCTTGGGA





CTCTTCCGGGTGACCCCCGAAATCCCAGCCGGACTCCCTTCACCGAGGTCGGAATAA




(SEQ ID NO: 249)



>Artificial Sequence; CD9tm3-h41BBL, Amino Acid




MGCCGAVQESQCMLGLFFGFLLVIFAIEIAAAIWGYSHKDE
ACPWAVSGARASPGSA





ASPRLREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTG





GLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAAL





ALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLG





LFRVTPEIPAGLPSPRSE




(SEQ ID NO: 250)





Myr/Palm-4F2-
>Artificial Sequence; Myr/Palm-4F2-h41BBL, DNA


h41BBL


ATGGGTTGCTGTTTCTCCAAGACC
GGCTCGAGOGGCAGCCAGGACACCGAGGTGGAT





ATGAAGGAGGTGGAGCTGAATGAGTTAGAGCCCGAGAAGCAGCCGATGAACGCGGCG





TCTGGGGCGGCCATGTCCCTGGCGGGAGCCGAGAAGAATGGTCTGGTGAAGATCAAG





GTGGCGGAAGACGAGGCGGAGGCGGCAGCCGCGGCTAAGTTCACGGGCCTGTCCAAG





GAGGAGCTGCTGAAGGTGGCAGGCAGCCCCGGCTGGGTACGCACCCGCTGGGCACTG





CTGCTGCTCTTCTGGCTCGGCTGGCTCGGCATGCTTGCTGGTGCCGTGGTCATAATC





GTG
GCCTGCCCCTGGGCCGTGTCCGGGGCTCGCGCCTCGCCCGGCTCCGCGGCCAGC





CCGAGACTCCGCGAGGGTCCCGAGCTTTCGCCCGACGATCCCGCCGGCCTCTTGGAC





CTGCGGCAGGGCATGTTTGCGCAGCTGGTGGCCCAAAATGTTCTGCTGATCGATGGG





CCCCTGAGCTGGTACAGTGACCCAGGCCTGGCAGGCGTGTCCCTGACGGGGGGCCTG





AGCTACAAAGAGGACACGAAGGAGCTGGTGGTGGCCAAGGCTGGAGTCTACTATGTC





TTCTTTCAACTAGAGCTGCGGCGCGTGGTGGCCGGCGAGGGCTCAGGCTCCGTTTCA





CTTGCGCTGCACCTGCAGCCACTGCGCTCTGCTGCTGGGGCCGCCGCCCTGGCTTTG





ACCGTGGACCTGCCACCCGCCTCCTCCGAGGCTCGGAACTCGGCCTTCGGTTTCCAG





GGCCGCTTGCTGCACCTGAGTGCCGGCCAGCGCCTGGGCGTCCATCTTCACACTGAG





GCCAGGGCACGCCATGCCTGGCAGCTTACCCAGGGCGCCACAGTCTTGGGACTCTTC





CGGGTGACCCCCGAAATCCCAGCCGGACTCCCTTCACCGAGGTCGGAATAA




(SEQ ID NO: 251)



>Artificial Sequence; Myr/Palm-4F2-h41BBL, Amino Acid





MGCCFSKTGSSGSQDTEVDMKEVELNELEPEKQPMNAASGAAMSLAGAEKNGLVKIK






VAEDEAEAAAAAKFTGLSKEELLKVAGSPGWVRTRWALLLLFWLGWLGMLAGAVVII





V
ACPWAVSGARASPGSAASPRLREGPELSPDDPAGLLDLRQGMFAQLVAQNVLLIDG





PLSWYSDPGLAGVSLTGGLSYKEDTKELVVAKAGVYYVFFQLELRRVVAGEGSGSVS





LALHLQPLRSAAGAAALALTVDLPPASSEARNSAFGFQGRLLHLSAGQRLGVHLHTE





ARARHAWQLTQGATVLGLFRVTPEIPAGLPSPRSE




(SEQ ID NO: 252)





Myr/Palm-Link-
>Artificial Sequence; Myr/Palm-Link-41BBL, DNA


41BBL (41BBL


ATGGGTTGCTGTTTCTCCAAGACC
GGCTCGAGCGGCTGGGCCCTGGTCGCGGGGCTG



transmembrane

CTGCTGCTGCTGCTGCTCGCTGCCGCCTGCGCCGTCTTCCTCGCCTGCCCCTGGGCC



domain

GTGTCCGGGGCTCGCGCCTCGCCCGGCTCCGCGGCCAGCCCGAGACTCCGCGAGGGT



included)

CCCGAGCTTTCGCCCGACGATCCCGCCGGCCTCTTGGACCTGCGGCAGGGCATGTTT





GCGCAGCTGGTGGCCCAAAATGTTCTGCTGATCGATGGGCCCCTGAGCTGGTACAGT





GACCCAGGCCTGGCAGGCGTGTCCCTGACGGGGGGCCTGAGCTACAAAGAGGACACG





AAGGAGCTGGTGGTGGCCAAGGCTGGAGTCTACTATGTCTTCTTTCAACTAGAGCTG





CGGCGCGTGGTGGCCGGCGAGGGCTCAGGCTCCGTTTCACTTGCGCTGCACCTGCAG





CCACTGCGCTCTGCTGCTGGGGCCGCCGCCCTGGCTTTGACCGTGGACCTGCCACCC





GCCTCCTCCGAGGCTCGGAACTCGGCCTTCGGTTTCCAGGGCCGCTTGCTGCACCTG





AGTGCCGGCCAGCGCCTGGGCGTCCATCTTCACACTGAGGCCAGGGCACGCCATGCC





TGGCAGCTTACCCAGGGCGCCACAGTCTTGGGACTCTTCCGGGTGACCCCCGAAATC





CCAGCCGGACTCCCTTCACCGAGGTCGGAATAA




(SEQ ID NO: 253)



>Artificial Sequence; Myr/Palm-Link-41BBL, Amino Acid





MGCCFSKT
GSSGWALVAGLLLLLLLAAACAVFLACPWAVSGARASPGSAASPRLREG





PELSPDDPAGLLDLRQGMFAQLVAQNVLLIDGPLSWYSDPGLAGVSLTGGLSYKEDT





KELVVAKAGVYYVFFQLELRRVVAGEGSGSVSLALHLQPLRSAAGAAALALTVDLPP





ASSEARNSAFGFQGRLLHLSAGQRLGVHLHTEARARHAWQLTQGATVLGLFRVTPEI





PAGLPSPRSE




(SEQ ID NO: 254)





hPDL1-Link-GPI
>Artificial Sequence; hPDL1-Link-GPI, DNA




ATGAGGATATTTGCTGTCTTTATATTCATGACCTACTGGCATTTGCTGAACGCATTT





ACTGTCACGGTTCCCAAGGACCTATATGTGGTAGAGTATGGTAGCAATATGACAATT





GAATGCAAATTCCCAGTAGAAAAACAATTAGACCTGGCTGCACTAATTGTCTATTGG





GAAATGGAGGATAAGAACATTATTCAATTTGTGCATGGAGAGGAAGACCTGAAGGTT





CAGCATAGTAGCTACAGACAGAGGGCCCGGCTGTTGAAGGACCAGCTCTCCCTGGGA





AATGCTGCACTTCAGATCACAGATGTGAAATTGCAGGATGCAGGGGTGTACCGCTGC





ATGATCAGCTATGGTGGTGCCGACTACAAGCGAATTACTGTGAAAGTCAATGCCCCA





TACAACAAAATCAACCAAAGAATTTTGGTTGTGGATCCAGTCACCTCTGAACATGAA





CTGACATGTCAGGCTGAGGGCTACCCCAAGGCCGAAGTCATCTGGACAAGCAGTGAC





CATCAAGTCCTGAGTGGTAAGACCACCACCACCAATTCCAAGAGAGAGGAGAAGCTT





TTCAANGTGACCAGCACACTGAGAATCAACACAACAACTAATGAGATTTTCTACTGC





ACTTTTAGGAGATTAGATCCTGAGGAAAACCATACAGCTGAATTG
GGCTCGAGCGGC





CCAAATAAAGGAAGTGGAACCACTTCAGGTACTACCCGTCTTCTATCTGGGCACACG





TGTTTCACGTTGACAGGTTTGCTTGGGACGCTAGTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 255)



>Artificial Sequence; hPDL1-Link-GPI, Amino Acid




MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYW





EMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRC





MISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSD





HQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAEL
GSSG





PNKGSGTTSGTTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 256)





hSecPDL1-
>Artificial Sequence; hSecPDL1-CD9tm2, DNA


CD9tm2

ATGAGGATATTTGCTGTCTTTATATTCATGACCTACTGGCATTTGCTGAACGCATTT





ACTGTCACGGTTCCCAAGGACCTATATGTGGTAGAGTATGGTAGCAATATGACAATT





GAATGCAAATTCCCAGTAGAAAAACAATTAGACCTGGCTGCACTAATTGTCTATTGG





GAAATGGAGGATAAGAACATTATTCAATTTGTGCATGGAGAGGAAGACCTGAAGGTT





CAGCATAGTAGCTACAGACAGAGGGCCCGGCTGTTGAAGGACCAGCTCTCCCTGGGA





AATGCTGCACTTCAGATCACAGATGTGAAATTGCAGGATGCAGGGGTGTACCGCTGC





ATGATCAGCTATGGTGGTGCCGACTACAAGCGAATTACTGTGAAAGTCAATGCCCCA





TACAACAAAATCAACCAAAGAATTTTGGTTGTGGATCCAGTCACCTCTGAACATGAA





CTGACATGTCAGGCTGAGGGCTACCCCAAGGCCGAAGTCATCTGGACAAGCAGTGAC





CATCAAGTCCTGAGTGGTAAGACCACCACCACCAATTCCAAGAGAGAGGAGAAGCTT





TTCAATGTGACCAGCACACTGAGAATCAACACAACAACTAATGAGATTTTCTACTGC





ACTTTTAGGAGATTAGATCCTGAGGAAAACCATACAGCTGAATTGGTCATCCCAGGT





AATATTCTGAATGTGTCCATTAAAATATGTCTAACACTGTCCCCTAGCACC
TTCTAC





ACAGGAGTCTATATTCTGATCGGAGCCGGCGCCCTCATGATGCTGGTGGGCTTCCTG





GGCTGCTGCGGGGCTGTGCAGGAGTCCCAGTGCTAG




(SEQ ID NO: 257)



>Artificial Sequence; hSecPDL1-CD9tm2, Amino Acid




MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYW





EMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRC





MISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSD





HQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPG





NILNVSIKICLTLSPST
FYTGVYILIGAGALMMLVGFLGCCGAVQESQC




(SEQ ID NO: 258)





hSecPDL1-
>Artificial Sequence; hSecPDL1-CD9tm2-KRAS, DNA


CD9tm2-

ATGAGGATATTTGCTGTCTTTATATTCATGACCTACTGGCATTTGCTGAACGCATTT



modified KRAS

ACTGTCACGGTTCCCAAGGACCTATATGTGGTAGAGTATGGTAGCAATATGACAATT





GAATGCAAATTCCCAGTAGAAAAACAATTAGACCTGGCTGCACTAATTGTCTATTGG





GAAATGGAGGATAAGAACATTATTCAATTTGTGCATGGAGAGGAAGACCTGAAGGTT





CAGCATAGTAGCTACAGACAGAGGGCCCGGCTGTTGAAGGACCAGCTCTCCCTGGGA





AATGCTGCACTTCAGATCACAGATGTGAAATTGCAGGATGCAGGGGTGTACCGCTGC





ATGATCAGCTATGGTGGTGCCGACTACAAGCGAATTACTGTGAAAGTCAATGCCCCA





TACAACAAAATCAACCAAAGAATTTTGGTTGTGGATCCAGTCACCTCTGAACATGAA





CTGACATGTCAGGCTGAGGGCTACCCCAAGGCCGAAGTCATCTGGACAAGCAGTGAC





CATCAAGTCCTGAGTGGTAAGACCACCACCACCAATTCCAAGAGAGAGGAGAAGCTT





TTCAATGTGACCAGCACACTGAGAATCAACACAACAACTAATGAGATTTTCTACTGC





ACTTTTAGGAGATTAGATCCTGAGGAAAACCATACAGCTGAATTGGTCATCCCAGGT





AATATTCTGAATGTGTCCATTAAAATATGTCTAACACTGTCCCCTAGCACC
TTCTAC





ACAGGAGTCTATATTCTGATCGGAGCCGGCGCCCTCATGATGCTGGTGGGCTTCCTG





GGCTGCTGCGGGGCTGTGCAGGAGTCCCAGTGC

AAAAAGAAGAAAAAGAAGTCAAAG







ACAAAGTGTGTAATTATGTAA





(SEQ ID NO: 259)



>Artificial Sequence; hSecPDL1-CD9tm2-KRAS, Amino Acid




MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYW





EMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRC





MISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSD





HQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPG





NILNVSIKICLTLSPST
FYTGVYILIGAGALMMLVGFLGCCGAVQESQC

KKKKKKSK







TKCVIM





(SEQ ID NO: 260)





hSecPDL1-
>Artificial Sequence; hSecPDL1-CD9tm4, DNA


CD9tm4

ATGAGGATATTTGCTGTCTTTATATTCATGACCTACTGGCATTTGCTGAACGCATTT





ACTGTCACGGTTCCCAAGGACCTATATGTGGTAGAGTATGGTAGCAATATGACAATT





GAATGCAAATTCCCAGTAGAAAAACAATTAGACCTGGCTGCACTAATTGTCTATTGG





GAAATGGAGGATAAGAACATTATTCAATTTGTGCATGGAGAGGAAGACCTGAAGGTT





CAGCATAGTAGCTACAGACAGAGGGCCCGGCTGTTGAAGGACCAGCTCTCCCTGGGA





AATGCTGCACTTCAGATCACAGATGTGAAATTGCAGGATGCAGGGGTGTACCGCTGC





ATGATCAGCTATGGTGGTGCCGACTACAAGCGAATTACTGTGAAAGTCAATGCCCCA





TACAACAAAATCAACCAAAGAATTTTGGTTGTGGATCCAGTCACCTCTGAACATGAA





CTGACATGTCAGGCTGAGGGCTACCCCAAGGCCGAAGTCATCTGGACAAGCAGTGAC





CATCAAGTCCTGAGTGGTAAGACCACCACCACCAATTCCAAGAGAGAGGAGAAGCTT





TTCAATGTGACCAGCACACTGAGAATCAACACAACAACTAATGAGATTTTCTACTGC





ACTTTTAGGAGATTAGATCCTGAGGAAAACCATACAGCTGAATTGGTCATCCCAGGT





AATATTCTGAATGTGTCCATTAAAATATGTCTAACACTGTCCCCTAGCACC
ATCGGC





GCAGTGGGCATCGGCATTGCCGTGGTCATGATATTTGGCATGATCTTCAGTATGATC





TTGTGCTGTGCTATCCGCAGGAACCGCGAGATGGTCTAG




(SEQ ID NO: 261)



>Artificial Sequence; hSecPDL1-CD9tm4, Amino Acid




MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYW





EMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRC





MISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSD





HQVLSGKTTTTNSKREEKLFNVTSTIAINTTTNEIFYCTFRRLDPEENHTAELVIPG





NILNVSIKICLTLSPST
IGAVGIGIAVVMIFGMIFSMILCCAIRRNREMV




(SEQ ID NO: 262)





hSecPDL1-CD81
>Artificial Sequence; hSecPDL1-CD81, DNA




ATGAGGATATTTGCTGTCTTTATATTCATGACCTACTGGCATTTGCTGAACGCATTT





ACTGTCACGGTTCCCAAGGACCTATATGTGGTAGAGTATGGTAGCAATATGACAATT





GAATGCAAATTCCCAGTAGAAAAACAATTAGACCTGGCTGCACTAATTGTCTATTGG





GAAATGGAGGATAAGAACATTATTCAATTTGTGCATGGAGAGGAAGACCTGAAGGTT





CAGCATAGTAGCTACAGACAGAGGGCCCGGCTGTTGAAGGACCAGCTCTCCCTGGGA





AATGCTGCACTTCAGATCACAGATGTGAAATTGCAGGATGCAGGGGTGTACCGCTGC





ATGATCAGCTATGGTGGTGCCGACTACAAGCGAATTACTGTGAAAGTCAATGCCCCA





TACAACAAAATCAACCAAAGAATTTTGGTTGTGGATCCAGTCACCTCTGAACATGAA





CTGACATGTCAGGCTGAGGGCTACCCCAAGGCCGAAGTCATCTGGACAAGCAGTGAC





CATCAAGTCCTGAGTGGTAAGACCACCACCACCAATTCCAAGAGAGAGGAGAAGCTT





TTCAATGTGACCAGCACACTGAGAATCAACACAACAACTAATGAGATTTTCTACTGC





ACTTTTAGGAGATTAGATCCTGAGGAAAACCATACAGCTGAATTGGTCATCCCAGGT





AATATTCTGAATGTGTCCATTAAAATATGTCTAACACTGTCCCCTAGCACC
CTGTAC





CTCATCGGCATTGCTGCCATCGTGGTCGCTGTGATCATGATCTTCGAGATGATCCTG





AGCATGGTGCTGTGCTGTGGCATCCGGAACAGCTCCGTGTACTGA




(SEQ ID NO: 263)



>Artificial Sequence; hSecPDL1-CD81, Amino Acid




MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYW





EMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRC





MISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSD





HQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPG





NILNVSIKICLTLSPST
LYLIGIAAIVVAVIMIFEMILSMVLCCGIRNSSVY




(SEQ ID NO: 264)





hCD200-Fc-GPI
>Artificial Sequence; hCD200-Fc-GPI, DNA




ATGGAGAGGCTGGTGATCAGGATGCCCTTCTCTCATCTGTCTACCTACAGCCTGGTT





TGGGTCATGGCAGCAGTGGTGCTGTGCACAGCACAAGTGCAAGTGGTGACCCAGGAT





GAAAGAGAGCAGCTGTACACACCTGCTTCCTTAAAATGCTCTCTGCAAAATGCCCAG





GAAGCCCTCATTGTGACATGGCAGAAAAAGAAAGCTGTAAGCCCAGAAAACATGGTC





ACCTTCAGCGAGAACCATGGGGTGGTGATCCAGCCTGCCTATAAGGACAAGATAAAC





ATTACCCAGCTGGGACTCCAAAACTCAACCATCACCTTCTGGAATATCACCCTGGAG





GATGAAGGGTGTTACATGTGTCTCTTCAATACCTTTGGTTTTGGGAAGATCTCAGGA





ACGGCCTGCCTCACCGTCTATGTACAGCCCATAGTATCCCTTCACTACAAATTCTCT





GAAGACCACCTAAATATCACTTGCTCTGCCACTGCCCGCCCAGCCCCCATGGTCTTC





TGGAAGGTCCCTCGGTCAGGGATTGAAAATAGTACAGTGACTCTGTCTCACCCAAAT





GGGACCACGTCTGTTACCAGCATCCTCCATATCAAAGACCCTAAGAATCAGGTGGGG





AAGGAGGTGATCTGCCAGGTGCTGCACCTGGGGACTGTGACCGACTTTAAGCAAACC





GTCAACAAAGGCATCGATGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAA





CTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATG





ATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT





GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAG





CCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTG





CACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTC





CCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAG





GTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACC





TGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGG





CAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTC





TTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC





TCATGCTCCGTGATGCACGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCC





CTGTCTCCGGGTAAAATCGATCCAAATAAAGGAAGTGGAACCACTTCAGGTACTACC





CGTCTTCTATCTGGGCACACGTGTTTCACGTTGACAGGTTTGCTTGGGACGCTAGTA





ACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 265)



>Artificial Sequence; hCD200-Fc-GPI, Amino Acid




MERLVIRMPFSHLSTYSLVWVMAAVVLCTAQVQVVTQDEREQLYTPASLKCSLQNAQ





EALIVTWQKKKAVSPENMVTFSENHGVVIQPAYKDKINITQLGLQNSTITFWNITLE





DEGCYMCLFNTFGFGKISGTACLTVYVQPIVSLHYKFSEDHLNITCSATARPAPMVF





WKVPRSGIENSTVTLSHPNGTTSVTSILHIKDPKNQVGKEVICQVLHLGTVTDFKQT





VNKGIDDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP





EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL





PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG





QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS





LSPGKIDPNKGSGTTSGTTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 266)





hFGL1-GPI
>Artificial Sequence; hFGL1-GPI, DNA




ATGGCAAAGGTGTTCAGTTTCATCCTTGTTACCACCGCTCTGACAATGGGCAGGGAA





ATTTCGGCGCTCGAGGACTGTGCCCAGGAGCAGATGCGGCTCAGAGCCCAGGTGCGC





CTGCTTGAGACCCGGGTCAAACAGCAACAGGTCAAGATCAAGCAGCTTTTGCAGGAG





AATGAAGTCCAGTTCCTTGATAAAGGAGATGAGAATACTGTCATTGATCTTGGAAGC





AAGAGGCAGTATGCAGATTGTTCAGAGATTTTCAATGATGGGTATAAGCTCAGTGGA





TTTTACAAAATCAAACCTCTCCAGAGCCCAGCAGAATTTTCTGTTTATTGTGACATG





TCCGATGGAGGAGGATGGACTGTAATTCAGAGACGATCTGATGGCAGTGAAAACTTT





AACAGAGGATGGAAAGACTATGAAAATGGCTTTGGAAATTTTGTCCAAAAACATGGT





GAATATTGGCTGGGCAATAAAAATCTTCACTTCTTGACCACTCAAGAAGACTACACT





TTAAAAATCGACCTTGCAGATTTTGAAAAAAATAGCCGTTATGCACAATATAAGAAT





TTCAAAGTTGGAGATGAAAAGAATTTCTACGAGTTGAATATTGGGGAATATTCTGGA





ACAGCTGGAGATTCCCTTGCGGGGAATTTTCATCCTGAGGTGCAGTGGTGGGCTAGT





CACCAAAGAATGAAATTCAGCACGTGGGACAGAGATCATGACAACTATGAAGGGAAC





TGCGCAGAAGAAGATCAGTCTGGCTGGTGGTTTAACAGGTGTCACTCTGCAAACCTG





AATGGTGTATACTACAGCGGCCCCTACACGGCTAAAACAGACAATGGGATTGTCTGG





TACACCTGGCATGGGTGGTGGTATTCTCTGAAATCTGTGGTTATGAAAATTAGGCCA





AATGATTTTATTCCAAATGTAATT
CCAAATAAAGGAAGTGGAACCACTTCAGGTACT





ACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTGACAGGTTTGCTTGGGACGCTA





GTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 267)



>Artificial Sequence; hFGL1-GPI, Amino Acid




MAKVFSFILVTTALTMGREISALEDCAQEQMRLRAQVRLLETRVKQQQVKIKQLLQE





NEVQFLDKGDENTVIDLGSKRQYADCSEIFNDGYKLSGFYKIKPLQSPAEFSVYCDM





SDGGGWTVIQRRSDGSENFNRGWKDYENGFGNFVQKHGEYWLGNKNLHFLTTQEDYT





LKIDLADFEKNSRYAQYKNFKVGDEKNFYELNIGEYSGTAGDSLAGNFHPEVQWWAS





HQRMKFSTWDRDHDNYEGNCAEEDQSGWWFNRCHSANLNGVYYSGPYTAKTDNGIVW





YTWHGWWYSLKSVVMKIRPNDFIPNVI
PNKGSGTTSGTTRLLSGHTCFTLTGLLGTL





VTMGLLT




(SEQ ID NO: 268)





hGa19-Fc-GPI
>Artificial Sequence; hGal9-Fc-GPI, DNA




ATGGCCTTCAGCGGTTCCCAGGCTCCCTACCTGAGTCCAGCTGTCCCCTTTTCTGGG





ACTATTCAAGGAGGTCTCCAGGACGGACTTCAGATCACTGTCAATGGGACCGTTCTC





AGCTCCAGTGGAACCAGGTTTGCTGTGAACTTTCAGACTGGCTTCAGTGGAAATGAC





ATTGCCTTCCACTTCAACCCTCGGTTTGAAGATGGAGGGTACGTGGTGTGCAACACG





AGGCAGAACGGAAGCTGGGGGCCCGAGGAGAGGAAGACACACATGCCTTTCCAGAAG





GGGATGCCCTTTGACCTCTGCTTCCTGGTGCAGAGCTCAGATTTCAAGGTGATGGTG





AACGGGATCCTCTTCGTGCAGTACTTCCACCGCGTGCCCTTCCACCGTGTGGACACC





ATCTCCGTCAATGGCTCTGTGCAGCTGTCCTACATCAGCTTCCAGAACCCCCGCACA





GTCCCTGTTCAGCCTGCCTTCTCCACGGTGCCGTTCTCCCAGCCTGTCTGTTTCCCA





CCCAGGCCCAGGGGGCGCAGACAAAAACCTCCCGGCGTGTGGCCTGCCAACCCGGCT





CCCATTACCCAGACAGTCATCCACACAGTGCAGAGCGCCCCTGGACAGATGTTCTCT





ACTCCCGCCATCCCACCTATGATGTACCCCCACCCCGCCTATCCGATGCCTTTCATC





ACCACCATTCTGGGAGGGCTGTACCCATCCAAGTCCATCCTCCTGTCAGGCACTGTC





CTGCCCAGTGCTCAGAGGTTCCACATCAACCTGTGCTCTGGGAACCACATCGCCTTC





CACCTGAACCCCCGTTTTGATGAGAATGCTGTGGTCCGCAACACCCAGATCGACAAC





TCCTGGGGGTCTGAGGAGCGAAGTCTGCCCCGAAAAATGCCCTTCGTCCGTGGCCAG





AGCTTCTCAGTGTGGATCTTGTGTGAAGCTCACTGCCTCAAGGTGGCCGTGGATGGT





CAGCACCTGTTTGAATACTACCATCGCCTGAGGAACCTGCCCACCATCAACAGACTG





GAAGTGGGGGGCGACATCCAGCTGACCCATGTGCAGACAATCGATGACAAAACTCAC





ACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC





CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG





GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC





GTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTAC





CGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTAC





AAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAA





GCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAG





ATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGAC





ATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT





CCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAG





AGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCACGAGGCTCTGCAC





AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAATCGATCCAAATAAA





GGAAGTGGAACCACTTCAGGTACTACCCGTCTTCTATCTGGGCACACGTGTTTCACG





TTGACAGGTTTGCTTGGGACGCTAGTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 269)



>Artificial Sequence; hGal9-Fc-GPI, Amino Acid




MAFSGSQAPYLSPAVPFSGTIQGGLQDGLQITVNGTVLSSSGTRFAVNFQTGFSGND





IAFHFNPRFEDGGYVVCNTRQNGSWGPEERKTHMPFQKGMPFDLCFLVQSSDFKVMV





NGILFVQYFHRVPFHRVDTISVNGSVQLSYISFQNPRTVPVQPAFSTVPFSQPVCFP





PRPRGRRQKPPGVWPANPAPITQTVIHTVQSAPGQMFSTPAIPPMMYPHPAYPMPFI





TTILGGLYPSKSILLSGTVLPSAQRFHINLCSGNHIAFHLNPRFDENAVVRNTQIDN





SWGSEERSLPRKMPFVRGQSFSVWILCEAHCLKVAVDGQHLFEYYHRLRNLPTINRL





EVGGDIQLTHVQTIDDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV





VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY





KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD





IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH





NHYTQKSLSLSPGKIDPNKGSGTTSGTTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 270)





hCD200-GPI
>Artificial Sequence; hCD200-GPI, DNA




ATGGAGAGGCTGGTGATCAGGATGCCCTTCTCTCATCTGTCTACCTACAGCCTGGTT





TGGGTCATGGCAGCAGTGGTGCTGTGCACAGCACAAGTGCAAGTGGTGACCCAGGAT





GAAAGAGAGCAGCTGTACACACCTGCTTCCTTAAAATGCTCTCTGCAAAATGCCCAG





GAAGCCCTCATTGTGACATGGCAGAAAAAGAAAGCTGTAAGCCCAGAAAACATGGTC





ACCTTCAGCGAGAACCATGGGGTGGTGATCCAGCCTGCCTATAAGGACAAGATAAAC





ATTACCCAGCTGGGACTCCAAAACTCAACCATCACCTTCTGGAATATCACCCTGGAG





GATGAAGGGTGTTACATGTGTCTCTTCAATACCTTTGGTTTTGGGAAGATCTCAGGA





ACGGCCTGCCTCACCGTCTATGTACAGCCCATAGTATCCCTTCACTACAAATTCTCT





GAAGACCACCTAAATATCACTTGCTCTGCCACTGCCCGCCCAGCCCCCATGGTCTTC





TGGAAGGTCCCTCGGTCAGGGATTGAAAATAGTACAGTGACTCTGTCTCACCCAAAT





GGGACCACGTCTGTTACCAGCATCCTCCATATCAAAGACCCTAAGAATCAGGTGGGG





AAGGAGGTGATCTGCCAGGTGCTGCACCTGGGGACTGTGACCGACTTTAAGCAAACC





GTCAACAAAGGC
CCAAATAAAGGAAGTGGAACCACTTCAGGTACTACCCGTCTTCTA





TCTGGGCACACGTGTTTCACGTTGACAGGTTTGCTTGGGACGCTAGTAACCATGGGC





TTGCTGACTTAG




(SEQ ID NO: 271)



>Artificial Sequence; hCD200-GPI, Amino Acid




MERLVIRMPFSHLSTYSLVWVMAAVVLCTAQVQVVTQDEREQLYTPASLKCSLQNAQ





EALIVTWQKKKAVSPENMVTFSENHGVVIQPAYKDKINITQLGLQNSTITFWNITLE





DEGCYMCLFNTFGFGKISGTACLTVYVQPIVSLHYKFSEDHLNITCSATARPAPMVF





WKVPRSGIENSTVTLSHPNGTTSVTSILHIKDPKNQVGKEVICQVLHLGTVTDFKQT





VNKG
PNKGSGTTSGTTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 272)





hGal9-GPI
>Artificial Sequence; hGa19-GPI, DNA




ATGGCCTTCAGCGGTTCCCAGGCTCCCTACCTGAGTCCAGCTGTCCCCTTTTCTGGG





ACTATTCAAGGAGGTCTCCAGGACGGACTTCAGATCACTGTCAATGGGACCGTTCTC





AGCTCCAGTGGAACCAGGTTTGCTGTGAACTTTCAGACTGGCTTCAGTGGAAATGAC





ATTGCCTTCCACTTCAACCCTCGGTTTGAAGATGGAGGGTACGTGGTGTGCAACACG





AGGCAGAACGGAAGCTGGGGGCCCGAGGAGAGGAAGACACACATGCCTTTCCAGAAG





GGGATGCCCTTTGACCTCTGCTTCCTGGTGCAGAGCTCAGATTTCAAGGTGATGGTG





AACGGGATCCTCTTCGTGCAGTACTTCCACCGCGTGCCCTTCCACCGTGTGGACACC





ATCTCCGTCAATGGCTCTGTGCAGCTGTCCTACATCAGCTTCCAGAACCCCCGCACA





GTCCCTGTTCAGCCTGCCTTCTCCACGGTGCCGTTCTCCCAGCCTGTCTGTTTCCCA





CCCAGGCCCAGGGGGCGCAGACAAAAACCTCCCGGCGTGTGGCCTGCCAACCCGGCT





CCCATTACCCAGACAGTCATCCACACAGTGCAGAGCGCCCCTGGACAGATGTTCTCT





ACTCCCGCCATCCCACCTATGATGTACCCCCACCCCGCCTATCCGATGCCTTTCATC





ACCACCATTCTGGGAGGGCTGTACCCATCCAAGTCCATCCTCCTGTCAGGCACTGTC





CTGCCCAGTGCTCAGAGGTTCCACATCAACCTGTGCTCTGGGAACCACATCGCCTTC





CACCTGAACCCCCGTTTTGATGAGAATGCTGTGGTCCGCAACACCCAGATCGACAAC





TCCTGGGGGTCTGAGGAGCGAAGTCTGCCCCGAAAAATGCCCTTCGTCCGTGGCCAG





AGCTTCTCAGTGTGGATCTTGTGTGAAGCTCACTGCCTCAAGGTGGCCGTGGATGGT





CAGCACCTGTTTGAATACTACCATCGCCTGAGGAACCTGCCCACCATCAACAGACTG





GAAGTGGGGGGCGACATCCAGCTGACCCATGTGCAGACA
CCAAATAAAGGAAGTGGA





ACCACTTCAGGTACTACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTGACAGGT





TTGCTTGGGACGCTAGTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 273)



>Artificial Sequence; hGal9-GPI, Amino Acid




MAFSGSQAPYLSPAVPFSGTIQGGLQDGLQITVNGTVLSSSGTRFAVNFQTGFSGND





IAFHFNPRFEDGGYVVCNTRQNGSWGPEERKTHMPFQKGMPFDLCFLVQSSDFKVMV





NGILFVQYFHRVPFHRVDTISVNGSVQLSYISFQNPRTVPVQPAFSTVPFSQPVCFP





PRPRGRRQKPPGVWPANPAPITQTVIHTVQSAPGQMPSTPAIPPMMYPHPAYPMPFI





TTILGGLYPSKSILLSGTVLPSAQRFHINLCSGNHIAFHLNPRFDENAVVRNTQIDN





SWGSEERSLPRKMPFVRGQSFSVWILCEAHCLKVAVDGQHLFEYYHRLRNLPTINRL





EVGGDIQLTHVQT
PNKGSGTTSGTTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 274)





hHVEM-GPI
>Artificial Sequence; hHVEM-GPI, DNA




custom-character
custom-character
custom-character
custom-character





custom-character
custom-character
custom-character
custom-character





custom-character
custom-character
custom-character
custom-character





custom-character
custom-character
custom-character
custom-character
custom-character





custom-character
custom-character
custom-character
custom-character
custom-character





custom-character
custom-character
custom-character
custom-character
custom-character





custom-character
custom-character
custom-character
custom-character
custom-character





custom-character
custom-character
custom-character
custom-character
custom-character





custom-character
custom-character
custom-character
custom-character
custom-character





custom-character
custom-character
custom-character
custom-character
custom-character





custom-character
custom-character
custom-character
CCAAATAAAGGAAGTGGAACC





ACTTCAGGTACTACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTGACAGGTTTG





CTTGGGACGCTAGTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 275)



>Artificial Sequence; hHVEM-GPI, Amino Acid




MEPPGDWGPPPWRSTPKTDVLRLVLYLTFLGAPCYAPALPSCKEDEYPVGSECCPKC





SPGYRVKEACGELTGTVCEPCPPGTYIAHLNGLSKCLQCQMCDPAMGLRASRNCSRT





ENAVCGCSPGHFCIVQDGDHCAACRAYATSSPGQRVQKGGTESQDTLCQNCPPGTFS





PNGTLEECQHQTKCSWLVTKAGAGTSSSHWV
PNKGSGTTSGTTRLLSGHTCFTLTGL





LGTLVTMGLLT




(SEQ ID NO: 276)





hPDL2-GPI
>Artificial Sequence; hPDL2-GPI, DNA




ATGATCTTCCTCCTGCTAATGTTGAGCCTGGAATTGCAGCTTCACCAGATAGCAGCT





TTATTCACAGTGACAGTCCCTAAGGAACTGTACATAATAGAGCATGGCAGCAATGTG





ACCCTGGAATGCAACTTTGACACTGGAAGTCATGTGAACCTTGGAGCAATAACAGCC





AGTTTGCAAAAGGTGGAAAATGATACATCCCCACACCGTGAAAGAGCCACTTTGCTG





GAGGAGCAGCTGCCCCTAGGGAAGGCCTCGTTCCACATACCTCAAGTCCAAGTGAGG





GACGAAGGACAGTACCAATGCATAATCATCTATGGGGTCGCCTGGGACTACAAGTAC





CTGACTCTGAAAGTCAAAGCTTCCTACAGGAAAATAAACACTCACATCCTAAAGGTT





CCAGAAACAGATGAGGTAGAGCTCACCTGCCAGGCTACAGGTTATCCTCTGGCAGAA





GTATCCTGGCCAAACGTCAGCGTTCCTGCCAACACCAGCCACTCCAGGACCCCTGAA





GGCCTCTACCAGGTCACCAGTGTTCTGCGCCTAAAGCCACCCCCTGGCAGAAACTTC





AGCTGTGTGTTCTGGAATACTCACGTGAGGGAACTTACTTTGGCCAGCATTGACCTT





CAAAGTCAGATGGAACCCAGGACCCATCCAACT
CCAAATAAAGGAAGTGGAACCACT





TCAGGTACTACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTGACAGGTTTGCTT





GGGACGCTAGTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 277)



>Artificial Sequence; hPDL2-GPI, Amino Acid




MIFLLLMLSLELQLHQIAALFTVTVPKELYIIEHGSNVTLECNFDTGSHVNLGAITA





SLQKVENDTSPHRERATLLEEQLPLGKASFHIPQVQVRDEGQYQCIIIYGVAWDYKY





LTLKVKASYRKINTHILKVPETDEVELTCQATGYPLAEVSWPNVSVPANTSHSRTPE





GLYQVTSVLRLKPPPGRNFSCVFWNTHVRELTLASIDLQSQMEPRTHPT
PNKGSGTT





SGTTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 278)





hTSG6-GPI
>Artificial Sequence; hTSG6-GPI, DNA




ATGATCATCTTAATTTACTTATTTCTCTTGCTATGGGAAGACACTCAAGGATGGGGA





TTCAAGGATGGAATTTTTCATAACTCCATATGGCTTGAACGAGCAGCCGGTGTGTAC





CACAGAGAAGCACGGTCTGGCAAATACAAGCTCACCTACGCAGAAGCTAAGGCGGTG





TGTGAATTTGAAGGCGGCCATCTCGCAACTTACAAGCAGCTAGAGGCAGCCAGAAAA





ATTGGATTTCATGTCTGTGCTGCTGGATGGATGGCTAAGGGCAGAGTTGGATACCCC





ATTGTGAAGCCAGGGCCCAACTGTGGATTTGGAAAAACTGGCATTATTGATTATGGA





ATCCGTCTCAATAGGAGTGAAAGATGGGATGCCTATTGCTACAACCCACACGCAAAG





GAGTGTGGTGGCGTCTTTACAGATCCAAAGCAAATTTTTAAATCTCCAGGCTTCCCA





AATGAGTACGAAGATAACCAAATCTGCTACTGGCACATTAGACTCAAGTATGGTCAG





CGTATTCACCTGAGTTTTTTAGATTTTGACCTTGAAGATGACCCAGGTTGCTTGGCT





GATTATGTTGAAATATATGACAGTTACGATGATGTCCATGGCTTTGTGGGAAGATAC





TGTGGAGATGAGCTTCCAGATGACATCATCAGTACAGGAAATGTCATGACCTTGAAG





TTTCTAAGTGATGCTTCAGTGACAGCTGGAGGTTTCCAAATCAAATATGTTGCAATG





GATCCTGTATCCAAATCCAGTCAAGGAAAAAATACAAGTACTACTTCTACTGGAAAT





AAAAACTTTTTAGCTGGAAGATTTAGCCACTTAATCGATCCAAATAAAGGAAGTGGA





ACCACTTCAGGTACTACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTGACAGGT





TTGCTTGGGACGCTAGTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 279)



>Artificial Sequence; hTSG6-GPI, Amino Acid




MIILIYLFLLLWEDTQGWGFKDGIFHNSIWLERAAGVYHREARSGKYKLTYAEAKAV





CEFEGGHLATYKQLEAARKIGFHVCAAGWMAKGRVGYPIVKPGPNCGFGKTGIIDYG





IRLNRSERWDAYCYNPHAKECGGVFTDPKQIFKSPGFPNEYEDNQICYWHIRLKYGQ





RIHLSFLDFDLEDDPGCLADYVEIYDSYDDVHGFVGRYCGDELPDDIISTGNVMTLK





FLSDASVTAGGFQIKYVAMDPVSKSSQGKNTSTTSTGNKNFLAGRFSHLIDPNKGSG





TTSGTTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 280)





hHVEM-Fc-GPI
>Artificial Sequence; hHVEM-Fc-GPI, DNA




ATGGAGCCTCCTGGAGACTGGGGGCCTCCTCCCTGGAGATCCACCCCCAAAACCGAC





GTCTTGAGGCTGGTGCTGTATCTCACCTTCCTGGGAGCCCCCTGCTACGCCCCAGCT





CTGCCGTCCTGCAAGGAGGACGAGTACCCAGTGGGCTCCGAGTGCTGCCCCAAGTGC





AGTCCAGGTTATCGTGTGAAGGAGGCCTGCGGGGAGCTGACGGGCACAGTGTGTGAA





CCCTGCCCTCCAGGCACCTACATTGCCCACCTCAATGGCCTAAGCAAGTGTCTGCAG





TGCCAAATGTGTGACCCAGCCATGGGCCTGCGCGCGAGCCGGAACTGCTCCAGGACA





GAGAACGCCGTGTGTGGCTGCAGCCCAGGCCACTTCTGCATCGTCCAGGACGGGGAC





CACTGCGCCGCGTGCCGCGCTTACGCCACCTCCAGCCCGGGCCAGAGGGTGCAGAAG





GGAGGCACCGAGAGTCAGGACACCCTGTGTCAGAACTGCCCCCCGGGGACCTTCTCT





CCCAATGGGACCCTGGAGGAATGTCAGCACCAGACCAAGTGCAGCTGGCTGGTGACG





AAGGCCGGAGCTGGGACCAGCAGCTCCCACTGGGTAATCGATGACAAAACTCACACA





TGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCC





CCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTG





GTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG





GAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGT





GTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAG





TGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC





AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATG





ACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATC





GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCC





GTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGC





AGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCACGAGGCTCTGCACAAC





CACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAATCGATCCAAATAAAGGA





AGTGGAACCACTTCAGGTACTACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTG





ACAGGTTTGCTTGGGACGCTAGTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 281)



>Artificial Sequence; hHVEM-Fc-GPI, Amino Acid




MEPPGDWGPPPWRSTPKTDVLRLVLYLTFLGAPCYAPALPSCKEDEYPVGSECCPKC





SPGYRVKEACGELTGTVCEPCPPGTYIAHLNGLSKCLQCQMCDPAMGLRASRNCSRT





ENAVCGCSPGHFCIVQDGDHCAACRAYATSSPGQRVQKGGTESQDTLCQNCPPGTFS





PNGTLEECQHQTKCSWLVTKAGAGTSSSHWVIDDKTHTCPPCPAPELLGGPSVFLFP





PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR





VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM





TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS





RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIDPNKGSGTTSGTTRLLSGHTCFTL





TGLLGTLVTMGLLT




(SEQ ID NO: 282)





hPDL1-GPI-P2A-
>Artificial Sequence; hPDL1-GPI-P2A-hHVEM-GPI, DNA


hHVEM-GPI

ATGAGGATATTTGCTGTCTTTATATTCATGACCTACTGGCATTTGCTGAACGCATTT





ACTGTCACGGTTCCCAAGGACCTATATGTGGTAGAGTATGGTAGCAATATGACAATT





GAATGCAAATTCCCAGTAGAAAAACAATTAGACCTGGCTGCACTAATTGTCTATTGG





GAAATGGAGGATAAGAACATTATTCAATTTGTGCATGGAGAGGAAGACCTGAAGGTT





CAGCATAGTAGCTACAGACAGAGGGCCCGGCTGTTGAAGGACCAGCTCTCCCTGGGA





AATGCTGCACTTCAGATCACAGATGTGAAATTGCAGGATGCAGGGGTGTACCGCTGC





ATGATCAGCTATGGTGGTGCCGACTACAAGCGAATTACTGTGAAAGTCAATGCCCCA





TACAACAAAATCAACCAAAGAATTTTGGTTGTGGATCCAGTCACCTCTGAACATGAA





CTGACATGTCAGGCTGAGGGCTACCCCAAGGCCGAAGTCATCTGGACAAGCAGTGAC





CATCAAGTCCTGAGTGGTAAGACCACCACCACCAATTCCAAGAGAGAGGAGAAGCTT





TTCAATGTGACCAGCACACTGAGAATCAACACAACAACTAATGAGATTTTCTACTGC





ACTTTTAGGAGATTAGATCCTGAGGAAAACCATACAGCTGAATTGGTCATCCCAGAA





CTACCTCTGGCACATCCTCCAAATGAAAGG
CCAAATAAAGGAAGTGGAACCACTTCA





GGTACTACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTGACAGGTTTGCTTGGG





ACGCTAGTAACCATGGGCTTGCTGACTGGAAGCGGAGCTACTAACTTCAGCCTGCTG





AAGCAGGCTGGCGACGTGGAGGAGAACCCTGGACCT
ATGGAGCCTCCTGGAGACTGG





GGGCCTCCTCCCTGGAGATCCACCCCCAAAACCGACGTCTTGAGGCTGGTGCTGTAT





CTCACCTTCCTGGGAGCCCCCTGCTACGCCCCAGCTCTGCCGTCCTGCAAGGAGGAC





GAGTACCCAGTGGGCTCCGAGTGCTGCCCCAAGTGCAGTCCAGGTTATCGTGTGAAG





GAGGCCTGCGGGGAGCTGACGGGCACAGTGTGTGAACCCTGCCCTCCAGGCACCTAC





ATTGCCCACCTCAATGGCCTAAGCAAGTGTCTGCAGTGCCAAATGTGTGACCCAGCC





ATGGGCCTGCGCGCGAGCCGGAACTGCTCCAGGACAGAGAACGCCGTGTGTGGCTGC





AGCCCAGGCCACTTCTGCATCGTCCAGGACGGGGACCACTGCGCCGCGTGCCGCGCT





TACGCCACCTCCAGCCCGGGCCAGAGGGTGCAGAAGGGAGGCACCGAGAGTCAGGAC





ACCCTGTGTCAGAACTGCCCCCCGGGGACCTTCTCTCCCAATGGGACCCTGGAGGAA





TGTCAGCACCAGACCAAGTGCAGCTGGCTGGTGACGAAGGCCGGAGCTGGGACCAGC





AGCTCCCACTGGGTA
CCAAATAAAGGAAGTGGAACCACTTCAGGTACTACCCGTCTT





CTATCTGGGCACACGTGTTTCACGTTGACAGGTTTGCTTGGGACGCTAGTAACCATG





GGCTTGCTGACTTAG




(SEQ ID NO: 283)



>Artificial Sequence; hPDL1-GPI-P2A-hHVEM-GPI, Amino Acid




MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYW





EMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRC





MISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSD





HQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPE





LPLAHPPNER
PNKGSGTTSGTTRLLSGHTCFTLTGLLGTLVTMGLLTGSGATNFSLL





KQAGDVEENPGP
MEPPGDWGPPPWRSTPKTDVLRLVLYLTFLGAPCYAPALPSCKED





EYPVGSECCPKCSPGYRVKEACGELTGTVCEPCPPGTYIAHLNGLSKCLQCQMCDPA





MGLRASRNCSRTENAVCGCSPGHFCIVQDGDHCAACRAYATSSPGQRVQKGGTESQD





TLCQNCPPGTFSPNGTLEECQHQTKCSWINTKAGAGTSSSHWV
PNKGSGTTSGTTRL





LSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 284)





mCTLA4-Fc-GPI
>Artificial Sequence; mCTLA4-Fc-GPI, DNA




ATGGCTTGTCTTGGACTCCGGAGGTACAAAGCTCAACTGCAGCTGCCTTCTAGGACT





TGGCCTTTTGTAGCCCTGCTCACTCTTCTTTTCATCCCAGTCTTCTCTGAAGCCATA





CAGGTGACCCAACCTTCAGTGGTGTTGGCTAGCAGCCATGGTGTCGCCAGCTTTCCA





TGTGAATATTCACCATCACACAACACTGATGAGGTCCGGGTGACTGTGCTGCGGCAG





ACAAATGACCAAATGACTGAGGTCTGTGCCACGACATTCACAGAGAAGAATACAGTG





GGCTTCCTAGATTACCCCTTCTGCAGTGGTACCTTTAATGAAAGCAGAGTGAACCTC





ACCATCCAAGGACTGAGAGCTGTTGACACGGGACTGTACCTCTGCAAGGTGGAACTC





ATGTACCCACCGCCATACTTTGTGGGCATGGGCAACGGGACGCAGATTTATGTCATT





GATCCAGAACCATGCCCGGATTCTGAATCGATGACAAAACTCACACATGCCCACCGT





GCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCA





AGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGA





GCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATA





ATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCG





TCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT





CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC





CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACC





AGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGT





GGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACT





CCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGC





AGGGGAACGTCTTCTCATGCTCCGTGATGCACGAGGCTCTGCACAACCACTACACGC





AGAAGAGCCTCTCCCTGTCTCCGGGTAAAATCGATCCAAATAAAGGAAGTGGAACCA





CTTCAGGTACTACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTGACAGGTTTGC





TTGGGACGCTAGTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 285)



>Artificial Sequence; mCTLA4-Fc-GPI, Amino Acid




MACLGLRRYKAQLQLPSRTWPFVALLTLLFIPVFSEAIQVTQPSVVLASSHGVASFP





CEYSPSHNTDEVRVTVLRQTNDQMTEVCATTFTEKNTVGFLDYPFCSGTFNESRVNL





TIQGLRAVDTGLYLCKVELMYPPPYFVGMGNGTQIYVIDPEPCPDSD




IDDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF




NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI





EKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN





NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG





KIDPNKGSGTTSGTTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 286)





mPDL1-C1C2
>Artificial Sequence; mPDL1-C1C2, DNA




ATGAGGATATTTGCTGGCATTATATTCACAGCCTGCTGTCACTTGCTACGGGCGTTT





ACTATCACGGCTCCAAAGGACTTGTACGTGGTGGAGTATGGCAGCAACGTCACGATG





GAGTGCAGATTCCCTGTAGAACGGGAGCTGGACCTGCTTGCGTTAGTGGTGTACTGG





GAAAAGGAAGATGAGCAAGTGATTCAGTTTGTGGCAGGAGAGGAGGACCTTAAGCCT





CAGCACAGCAACTTCAGGGGGAGAGCCTCGCTGCCAAAGGACCAGCTTTTGAAGGGA





AATGCTGCCCTTCAGATCACAGACGTCAAGCTGCAGGACGCAGGCGTTTACTGCTGC





ATAATCAGCTACGGTGGTGCGGACTACAAGCGAATCACGCTGAAAGTCAATGCCCCA





TACCGCAAAATCAACCAGAGAATTTCCGTGGATCCAGCCACTTCTGAGCATGAACTA





ATATGTCAGGCCGAGGGTTATCCAGAAGCTGAGGTAATCTGGACAAACAGTGACCAC





CAACCCGTGAGTGGGAAGAGAAGTGTCACCACTTCCCGGACAGAGGGGATGCTTCTC





AATGTGACCAGCAGTCTGAGGGTCAACGCCACAGCGAATGATGTTTTCTACTGTACG





TTTTGGAGATCACAGCCAGGGCAAAACCACACAGCGGAGCTGATCATCCCAGAACTG





CCTGCAACACATCCTCCACAGAACAGGACTATCGATGTCGAGCCACTGGGCATGGAG





AATGGGAACATTGCCAACTCACAGATCGCCGCCTCATCTGTGCGTGTGACCTTCTTG





GGTTTGCAGCATTGGGTCCCGGAGCTGGCCCGCCTGAACCGCGCAGGCATGGTCAAT





GCCTGGACACCCAGCAGCAATGACGATAACCCCTGGATCCAGGTGAACCTGCTGCGG





AGGATGTGGGTAACAGGTGTGGTGACGCAGGGTGCCAGCCGCTTGGCCAGTCATGAG





TACCTGAAGGCCTTCAAGGTGGCCTACAGCCTTAATGGACACGAATTCGATTTCATC





CATGATGTTAATAAAAAACACAAGGAGTTTGTGGGTAACTGGAACAAAAACGCGGTG





CATGTCAACCTGTTTGAGACCCCTGTGGAGGCTCAGTACGTGAGATTGTACCCCACG





AGCTGCCACACGGCCTGCACTCTGCGCTTTGAGCTACTGGGCTGTGAGCTGAACGGA





TGCGCCAATCCCCTGGGCCTGAAGAATAACAGCATCCCTGACAAGCAGATCACGGCC





TCCAGCAGCTACAAGACCTGGGGCTTGCATCTCTTCAGCTGGAACCCCTCCTATGCA





CGGCTGGACAAGCAGGGCAACTTCAACGCCTGGGTTGCGGGGAGCTACGGTAACGAT





CAGTGGCTGCAGATCTTCCCTGGCAACTGGGACAACCACTCCCACAAGAAGAACTTG





TTTGAGACGCCCATCCTGGCTCGCTATGTGCGCATCCTGCCTGTAGCCTGGCACAAC





CGCATCGCCCTGCGCCTGGAGCTGCTGGGCTGTTAG




(SEQ ID NO: 287)



>Artificial Sequence; mPDL1-C1C2, Amino Acid




MRIFAGIIFTACCHLLRAFTITAPKDLYVVEYGSNVTMECRFPVERELDLLALVVYW





EKEDEQVIQFVAGEEDLKPQHSNFSGRASLPKDQLLKGNAALQITDVKLQDAGVYCC





IISYGGADYKRITLKVNAPYRKINQRISVDPATSEHELICQAEGYPEAEVIWTNSDH





QPVSGKRSVTTSRTEGMLLNVTSSLRVNATANDVFYCTFWRSQPGQNHTAELIIPEL





PATHPPQNRTIDVEPLGMENGNIANSQIAASSVRVTFLGLQHWVPELARLNRAGMVN





AWTPSSNDDNPWIQVNLLRRMWVTGVVTQGASRLASHEYLKAFKVAYSLNGHEFDFI





HDVNKKHKEFVGNWNKNAVHVNLFETPVEAQYVRLYPTSCHTACTLRFELLGCELNG





CANPLGLKNNSIPDKQITASSSYKTWGLHLFSWNPSYARLDKQGNFNAWVAGSYGND





QWLQIFPGNWDNHSHKKNLFETPILARYVRILPVAWHNRIALRLELLGC




(SEQ ID NO: 288)





mPDL1-Fc-GPI
>Artificial Sequence; mPDL1-Fc-GPI, DNA




ATGAGGATATTTGCTGGCATTATATTCACAGCCTGCTGTCACTTGCTACGGGCGTTT





ACTATCACGGCTCCAAAGGACTTGTACGTGGTGGAGTATGGCAGCAACGTCACGATG





GAGTGCAGATTCCCTGTAGAACGGGAGCTGGACCTGCTTGCGTTAGTGGTGTACTGG





GAAAAGGAAGATGAGCAAGTGATTCAGTTTGTGGCAGGAGAGGAGGACCTTAAGCCT





CAGCACAGCAACTTCAGGGGGAGAGCCTCGCTGCCAAAGGACCAGCTTTTGAAGGGA





AATGCTGCCCTTCAGATCACAGACGTCAAGCTGCAGGACGCAGGCGTTTACTGCTGC





ATAATCAGCTACGGTGGTGCGGACTACAAGCGAATCACGCTGAAAGTCAATGCCCCA





TACCGCAAAATCAACCAGAGAATTTCCGTGGATCCAGCCACTTCTGAGCATGAACTA





ATATGTCAGGCCGAGGGTTATCCAGAAGCTGAGGTAATCTGGACAAACAGTGACCAC





CAACCCGTGAGTGGGAAGAGAAGTGTCACCACTTCCCGGACAGAGGGGATGCTTCTC





AATGTGACCAGCAGTCTGAGGGTCAACGCCACAGCGAATGATGTTTTCTACTGTACG





TTTTGGAGATCACAGCCAGGGCAAAACCACACAGCGGAGCTGATCATCCCAGAACTG





CCTGCAACACATCCTCCACAGAACAGGACTATCGATGACAAAACTCACACATGCCCA





CCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAA





CCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGAC





GTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG





CATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTC





AGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAG





GTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGG





CAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAG





AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG





GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTG





GACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGG





CAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCACGAGGCTCTGCACAACCACTAC





ACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAATCGATCCAAATAAAGGAAGTGGA





ACCACTTCAGGTACTACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTGACAGGT





TTGCTTGGGACGCTAGTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 289)



>Artificial Sequence; mPDL1-Fc-GPI, Amino Acid




MRIFAGIIFTACCHLLRAFTITAPKDLYVVEYGSNVTMECRFPVERELDLLALVVYW





EKEDEQVIQFVAGEEDLKPQHSNFRGRASLPKDQLLKGNAALQITDVKLQDAGVYCC





IISYGGADYKRITLKVNAPYRKINQRISVDPATSEHELICQAEGYPEAEVIWTNSDH





QPVSGKRSVTTSRTEGMLLNVTSSLRVNATANDVPYCTFWRSQPGQNHTAELIIPEL





PATHPPQNRTIDDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD





VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK





VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV





EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY





TQKSLSLSPGKIDPNKGSGTTSGTTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 290)





mPDL1-GPI
>Artificial Sequence; mPDL1-GPI, DNA




ATGAGGATATTTGCTGGCATTATATTCACAGCCTGCTGTCACTTGCTACGGGCGTTT





ACTATCACGGCTCCAAAGGACTTGTACGTGGTGGAGTATGGCAGCAACGTCACGATG





GAGTGCAGATTCCCTGTAGAACGGGAGCTGGACCTGCTTGCGTTAGTGGTGTACTGG





GAAAAGGAAGATGAGCAAGTGATTCAGTTTGTGGCAGGAGAGGAGGACCTTAAGCCT





CAGCACAGCAACTTCAGGGGGAGAGCCTCGCTGCCAAAGGACCAGCTTTTGAAGGGA





AATGCTGCCCTTCAGATCACAGACGTCAAGCTGCAGGACGCAGGCGTTTACTGCTGC





ATAATCAGCTACGGTGGTGCGGACTACAAGCGAATCACGCTGAAAGTCAATGCCCCA





TACCGCAAAATCAACCAGAGAATTTCCGTGGATCCAGCCACTTCTGAGCATGAACTA





ATATGTCAGGCCGAGGGTTATCCAGAAGCTGAGGTAATCTGGACAAACAGTGACCAC





CAACCCGTGAGTGGGAAGAGAAGTGTCACCACTTCCCGGAZAGAGGGGATGCTTCTC





AATGTGACCAGCAGTCTGAGGGTCAACGCCACAGCGAATGATGTTTTCTACTGTACG





TTTTGGAGATCACAGCCAGGGCAAAACCACACAGCGGAGCTGATCATCCCAGAACTG





CCTGCAACACATCCTCCACAGAACAGGACT
CCAAATAAAGGAAGTGGAACCACTTCA





GGTACTACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTGACAGGTTTGCTTGGG





ACGCTAGTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 291)



>Artificial Sequence; mPDL1-GPI, Amino Acid




MRIFAGIIFTACCHLLRAFTITAPKDLYVVEYGSNVTMECRFPVERELDLLALVVYW





EKEDEQVIQFVAGEEDLKPQHSNFRGRASLPKDQLLKGNAALQITDVKLQDAGVYCC





IISYGGADYKRITLKVNAPYRKINQRISVDPATSEHELICQAEGYPEAEVIWTNSDH





QPVSGKRSVTTSRTEGMLLNVTSSLRVNATANDVFYCTFWRSQPGQNHTAELIIPEL





PATHPPQNRT
PNKGSGTTSGTTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 292)





mPDL2-C1C2
>Artificial Sequence; mPDL2-C1C2, DNA




ATGCTGCTCCTGCTGCCGATACTGAACCTGAGCTTACAACTTCATCCTGTAGCAGCT





TTATTCACCGTGACAGCCCCTAAAGAAGTGTACACCGTAGACGTCGGCAGCAGTGTG





AGCCTGGAGTGCGATTTTGACCGCAGAGAATGCACTGAACTGGAAGGGATAAGAGCC





AGTTTGCAGAAGGTAGAAAATGATACGTCTCTGCAAAGTGAAAGAGCCACCCTGCTG





GAGGAGCAGCTGCCCCTGGGAAAGGCTTTGTTCCACATCCCTAGTGTCCAAGTGAGA





GATTCCGGGCAGTACCGTTGCCTGGTCATCTGCGGGGCCGCCTGGGACTACAAGTAC





CTGACGGTGAAAGTCAAAGCTTCTTACATGAGGATAGACACTAGGATCCTGGAGGTT





CCAGGTACAGGGGAGGTGCAGCTTACCTGCCAGGCTAGAGGTTATCCCCTAGCAGAA





GTGTCCTGGCAAAATGTCAGTGTTCCTGCCAACACCAGCCACATCAGGACCCCCGAA





GGCCTCTACCAGGTCACCAGTGTTCTGCGCCTCAAGCCTCAGCCTAGCAGAAACTTC





AGCTGCATGTTCTGGAATGCTCACATGAAGGAGCTGACTTCAGCCATCATTGACCCT





CTGAGTCGGATGGAACCCAAAGTCCCCAGAACGATCGATGTCGAGCCACTGGGCATG





GAGAATGGGAACATTGCCAACTCACAGATCGCCGCCTCATCTGTGCGTGTGACCTTC





TTGGGTTTGCAGCATTGGGTCCCGGAGCTGGCCCGCCTGAACCGCGCAGGCATGGTC





AATGCCTGGACACCCAGCAGCAATGACGATAACCCCTGGATCCAGGTGAACCTGCTG





CGGAGGATGTGGGTAACAGGTGTGGTGACGCAGGGTGCCAGCCGCTTGGCCAGTCAT





GAGTACCTGAAGGCCTTCAAGGTGGCCTACAGCCTTAATGGACACGAATTCGATTTC





ATCCATGATGTTAATAAAAAACACAAGGAGTTTGTGGGTAACTGGAACAAAAACGCG





GTGCATGTCAACCTGTTTGAGACCCCTGTGGAGGCTCAGTACGTGAGATTGTACCCC





ACGAGCTGCCACACGGCCTGCACTCTGCGCTTTGAGCTACTGGGCTGTGAGCTGAAC





GGATGCGCCAATCCCCTGGGCCTGAAGAATAACAGCATCCCTGACAAGCAGATCACG





GCCTCCAGCAGCTACAAGACCTGGGGCTTGCATCTCTTCAGCTGGAACCCCTCCTAT





GCACGGCTGGACAAGCAGGGCAACTTCAACGCCTGGGTTGCGGGGAGCTACGGTAAC





GATCAGTGGCTGCAGATCTTCCCTGGCAACTGGGACAACCACTCCCACAAGAAGAAC





TTGTTTGAGACGCCCATCCTGGCTCGCTATGTGCGCATCCTGCCTGTAGCCTGGCAC





AACCGCATCGCCCTGCGCCTGGAGCTGCTGGGCTGTTAG




(SEQ ID NO: 293)



>Artificial Sequence; mPDL2-C1C2, Amino Acid




MLLLLPILNLSLQLHPVAALFTVTAPKEVYTVDVGSSVSLECDFDRRECTELEGIRA





SLQKVENDTSLQSERATLLEEQLPLGKALFHIPSVQVRDSGQYRCLVICGAAWDYKY





LTVKVKASYMRIDTRILEVPGTGEVQLTCQARGYPLAEVSWQNVSVPANTSHIRTPE





GLYQVTSVLRLKPQPSRNFSCMFWNAHMKELTSAIIDPLSRMEPKVPRTIDVEPLGM





ENGNIANSQIAASSVRVTFLGLQHWVPELARLNRAGMVNAWTPSSNDDNPWIQVNLL





RRMWVTGVVTQGASRLASHEYLKAFKVAYSLNGHEFDFIHDVNKKHKEFVGNWNKNA





VHVNLFETPVEAQYVRLYPTSCHTACTLRFELLGCELNGCANPLGLKNNSIPDKQIT





ASSSYKTWGLHLFSWNPSYARLDKQGNFNAWVAGSYGNDQWLQIFPGNWDNHSHKKN





LFETPILARYVRILPVAWHNRIALRLELLGC




(SEQ ID NO: 294)





mPDL2-Fc-GPI
>Artificial Sequence; mPDL2-Fc-GPI, DNA




ATGCTGCTCCTGCTGCCGATACTGAACCTGAGCTTACAACTTCATCCTGTAGCAGCT





TTATTCACCGTGACAGCCCCTAAAGAAGTGTACACCGTAGACGTCGGCAGCAGTGTG





AGCCTGGAGTGCGATTTTGACCGCAGAGAATGCACTGAACTGGAAGGGATAAGAGCC





AGTTTGCAGAAGGTAGAAAATGATACGTCTCTGCAAAGTGAAAGAGCCACCCTGCTG





GAGGAGCAGCTGCCCCTGGGAAAGGCTTTGTTCCACATCCCTAGTGTCCAAGTGAGA





GATTCCGGGCAGTACCGTTGCCTGGTCATCTGCGGGGCCGCCTGGGACTACAAGTAC





CTGACGGTGAAAGTCAAAGCTTCTTACATGAGGATAGACACTAGGATCCTGGAGGTT





CCAGGTACAGGGGAGGTGCAGCTTACCTGCCAGGCTAGAGGTTATCCCCTAGCAGAA





GTGTCCTGGCAAAATGTCAGTGTTCCTGCCAACACCAGCCACATCAGGACCCCCGAA





GGCCTCTACCAGGTCACCAGTGTTCTGCGCCTCAAGCCTCAGCCTAGCAGAAACTTC





AGCTGCATGTTCTGGAATGCTCACATGAAGGAGCTGACTTCAGCCATCATTGACCCT





CTGAGTCGGATGGAACCCAAAGTCCCCAGAACGATCGATGACAAAACTCACACATGC





CCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCA





AAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTG





GACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAG





GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTG





GTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGC





AAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAA





GGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACC





AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC





GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTG





CTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGG





TGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCACGAGGCTCTGCACAACCAC





TACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAATCGATCCAAATAAAGGAAGT





GGAACCACTTCAGGTACTACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTGACA





GGTTTGCTTGGGACGCTAGTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 295)



>Artificial Sequence; mPDL2-Fc-GPI, Amino Acid




MLLLLPILNLSLQLHPVAALFTVTAPKEVYTVDVGSSVSLECDFDRRECTELEGIRA





SLQKVENDTSLQSERATLLEEQLPLGKALFHIPSVQVRDSGQYRCLVICGAAWDYKY





LTVKVKASYMRIDTRILEVPGTGEVQLTCQARGYPLAEVSWQNVSVPANTSHIRTPE





GLYQVTSVLRLKPQPSRNFSCMFWNAHNKELTSAIIDPLSRMEPKVPRTIDDKTHTC





PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE





VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK





GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV





LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKIDPNKGS





GTTSGTTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 296)





mPDL1-mFc-GPI
>Artificial Sequence; mPDL1-mFc-GPI, DNA




ATGAGGATATTTGCTGGCATTATATTCACAGCCTGCTGTCACTTGCTACGGGCGTTT





ACTATCACGGCTCCAAAGGACTTGTACGTGGTGGAGTATGGCAGCAACGTCACGATG





GAGTGCAGATTCCCTGTAGAACGGGAGCTGGACCTGCTTGCGTTAGTGGTGTACTGG





GAAAAGGAAGATGAGCAAGTGATTCAGTTTGTGGCAGGAGAGGAGGACCTTAAGCCT





CAGCACAGCAACTTCAGGGGGAGAGCCTCGCTGCCAAAGGACCAGCTTTTGAAGGGA





AATGCTGCCCTTCAGATCACAGACGTCAAGCTGCAGGACGCAGGCGTTTACTGCTGC





ATAATCAGCTACGGTGGTGCGGACTACAAGCGAATCACGCTGAAAGTCAATGCCCCA





TACCGCAAAATCAACCAGAGAATTTCCGTGGATCCAGCCACTTCTGAGCATGAACTA





ATATGTCAGGCCGAGGGTTATCCAGAAGCTGAGGTAATCTGGACAAACAGTGACCAC





CAACCCGTGAGTGGGAAGAGAAGTGTCACCACTTCCCGGACAGAGGGGATGCTTCTC





AATGTGACCAGCAGTCTGAGGGTCAACGCCACAGCGAATGATGTTTTCTACTGTACG





TTTTGGAGATCACAGCCAGGGCAAAACCACACAGCGGAGCTGATCATCCCAGAACTG





CCTGCAACACATCCTCCACAGAACAGGACT
GGTTGTAAGCCTTGCATATGTACAGTC





CCAGAAGTATCATCTGTCTTCATCTTCCCCCCAAAGCCCAAGGATGTGCTCACCATT





ACTCTGACTCCTAAGGTCACGTGTGTTGTGGTAGACATCAGCAAGGATGATCCCGAG





GTCCAGTTCAGCTGGTTTGTAGATGATGTGGAGGTGCACACAGCTCAGACGCAACCC





CGGGAGGAGCAGTTCAACAGCACTTTCCGCTCAGTCAGTGAACTTCCCATCATGCAC





CAGGACTGGCTCAATGGCAAGGAGTTCAAATGCAGGGTCAACAGTGCAGCTTTCCCT





GCCCCCATCGAGAAAACCATCTCCAAAACCAAAGGCAGACCGAAGGCTCCACAGGTG





TACACCATTCCACCTCCCAAGGAGCAGATGGCCAAGGATAAAGTCAGTCTGACCTGC





ATGATAACAGACTTCTTCCCTGAAGACATTACTGTGGAGTGGCAGTGGAATGGGCAG





CCAGCGGAGAACTACAAGAACACTCAGCCCATCATGGACACAGATGGCTCTTACTTC





GTCTACAGCAAGCTCAATGTGCAGAAGAGCAACTGGGAGGCAGGAAATACTTTCACC





TGCTCTGTGTTACATGAGGGCCTGCACAACCACCATACTGAGAAGAGCCTCTCCCAC





TCTCCTGGTAAA
CCAAATAAAGGAAGTGGAACCACTTCAGGTACTACCCGTCTTCTA





TCTGGGCACACGTGTTTCACGTTGACAGGTTTGCTTGGGACGCTAGTAACCATGGGC





TTGCTGACTTAG




(SEQ ID NO: 297)



>Artificial Sequence; mPDL1-mFc-GPI, Amino Acid




MRIFAGIIFTACCHLLRAFTITAPKDLYVVEYGSNVTMECRFPVERELDLLALVVYW





EKEDEQVIQFVAGEEDLKPQHSNFRGRASLPKDQLLKGNAALQITDVKLQDAGVYCC





IISYGGADYKRITLKVNAPYRKINQRISVDPATSEHELICQAEGYPEAEVIWTNSDH





QPVSGKRSVTTSRTEGMLLNVTSSLRVNATANDVFYCTFWRSQPGQNHTAELIIPEL





PATHPPQNRT
GCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPE





VQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFP





APIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQ





PAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSH





SPGK
PNKGSGTTSGTTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 298)





mPDL2-GPI
>Artificial Sequence; mPDL2-GPI, DNA




ATGCTGCTCCTGCTGCCGATACTGAACCTGAGCTTACAACTTCATCCTGTAGCAGCT





TTATTCACCGTGACAGCCCCTAAAGAAGTGTACACCGTAGACGTCGGCAGCAGTGTG





AGCCTGGAGTGCGATTTTGACCGCAGAGAATGCACTGAACTGGAAGGGATAAGAGCC





AGTTTGCAGAAGGTAGAAAATGATACGTCTCTGCAAAGTGAAAGAGCCACCCTGCTG





GAGGAGCAGCTGCCCCTGGGAAAGGCTTTGTTCCACATCCCTAGTGTCCAAGTGAGA





GATTCCGGGCAGTACCGTTGCCTGGTCATCTGCGGGGCCGCCTGGGACTACAAGTAC





CTGACGGTGAAAGTCAAAGCTTCTTACATGAGGATAGACACTAGGATCCTGGAGGTT





CCAGGTACAGGGGAGGTGCAGCTTACCTGCCAGGCTAGAGGTTATCCCCTAGCAGAA





GTGTCCTGGCAAAATGTCAGTGTTCCTGCCAACACCAGCCACATCAGGACCCCCGAA





GGCCTCTACCAGGTCACCAGTGTTCTGCGCCTCAAGCCTCAGCCTAGCAGAAACTTC





AGCTGCATGTTCTGGAATGCTCACATGAAGGAGCTGACTTCAGCCATCATTGACCCT





CTGAGTCGGATGGAACCCAAAGTCCCCAGAACG
CCAAATAAAGGAAGTGGAACCACT





TCAGGTACTACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTGACAGGTTTGCTT





GGGACGCTAGTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 299)



>Artificial Sequence; mPDL2-GPI, Amino Acid




MLLLLPILNLSLQLHPVAALFTVTAPKEVYTVDVGSSVSLECDFDRRECTELEGIRA





SLQKVENDTSLQSERATLLEEQLPLGKALFHIPSVQVRDSGQYRCLVICGAAWDYKY





LTVKVKASYMRIDTRILEVPGTGEVQLTCQARGYPLAEVSWQNVSVPANTSHIRTPE





GLYQVTSVLRLKPQPSRNFSCMFWNAHMKELTSAIIDPLSRMEPKVPRT
PNKGSGTT





SGTTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 300)





mPDL1-GPI-P2A-
>Artificial Sequence; mPDL1-GPI-P2A-mHVEM-GPI, DNA


mHVEM-GPI

ATGAGGATATTTGCTGGCATTATATTCACAGCCTGCTGTCACTTGCTACGGGCGTTT





ACTATCACGGCTCCAAAGGACTTGTACGTGGTGGAGTATGGCAGCAACGTCACGATG





GAGTGCAGATTCCCTGTAGAACGGGAGCTGGACCTGCTTGCGTTAGTGGTGTACTGG





GAAAAGGAAGATGAGCAAGTGATTCAGTTTGTGGCAGGAGAGGAGGACCTTAAGCCT





CAGCACAGCAACTTCAGGGGGAGAGCCTCGCTGCCAAAGGACCAGCTTTTGAAGGGA





AATGCTGCCCTTCAGATCACAGACGTCAAGCTGCAGGACGCAGGCGTTTACTGCTGC





ATAATCAGCTACGGTGGTGCGGACTACAAGCGAATCACGCTGAAAGTCAATGCCCCA





TACCGCAAAATCAACCAGAGAATTTCCGTGGATCCAGCCACTTCTGAGCATGAACTA





ATATGTCAGGCCGAGGGTTATCCAGAAGCTGAGGTAATCTGGACAAACAGTGACCAC





CAACCCGTGAGTGGGAAGAGAAGTGTCACCACTTCCCGGACAGAGGGGATGCTTCTC





AATGTGACCAGCAGTCTGAGGGTCAACGCCACAGCGAATGATGTTTTCTACTGTACG





TTTTGGAGATCACAGCCAGGGCAAAACCACACAGCGGAGCTGATCATCCCAGAACTG





CCTGCAACACATCCTCCACAGAACAGGACT
CCAAATAAAGGAAGTGGAACCACTTCA





GGTACTACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTGACAGGTTTGCTTGGG





ACGCTAGTAACCATGGGCTTGCTGACTGGAAGCGGAGCTACTAACTTCAGCCTGCTG





AAGCAGGCTGGCGACGTGGAGGAGAACCCTGGACCT
ATGGAACCTCTCCCAGGATGG





GGGTCGGCACCCTGGAGCCAGGCCCCTACAGACAACACCTTCAGGCTGGTGCCTTGT





GTCTTCCTTTTGAACTTGCTGCAGCGCATCTCTGCCCAGCCCTCATGCAGACAGGAG





GAGTTCCTTGTGGGAGACGAGTGCTGCCCCATGTGCAACCCAGGTTACCATGTGAAG





CAGGTCTGCAGTGAGCATACAGGCACAGTGTGTGCCCCCTGTCCCCCACAGACATAT





ACCGCCCATGCAAATGGCCTGAGCAAGTGTCTGCCCTGCGGAGTCTGTGATCCAGAC





ATGGGCCTGCTGACCTGGCAGGAGTGCTCCAGCTGGAAGGACACTGTGTGCAGATGC





ATCCCAGGCTACTTCTGTGAGAACCAGGATGGGAGCCACTGTTCCACATGCTTGCAG





CACACCACCTGCCCTCCAGGGCAGAGGGTAGAGAAGAGAGGGACTCACGACCAGGAC





ACTGTATGTGCTGACTGCCTAACAGGGACCTTCTCACTTGGAGGGACTCAGGAGGAA





TGCCTGCCCTGGACCAACTGCAGTGCATTTCAACAGGAAGTAAGACGTGGGACCAAC





AGCACAGACACCACCTGCTCCTCCCAG
CCAAATAAAGGAAGTGGAACCACTTCAGGT





ACTACCCGTCTTCTATCTGGGCACACGTGTTTCACGTTGACAGGTTTGCTTGGGACG





CTAGTAACCATGGGCTTGCTGACTTAG




(SEQ ID NO: 301)



>Artificial Sequence; mPDL1-GPI-P2A-mHVEM-GPI, Amino Acid




MRIFAGIIFTACCHLLRAFTITAPKDLYVVEYGSNVTMECRFPVERELDLLALVVYW





EKEDEQVIQFVAGEEDLKPQHSNFRGRASLPKDQLLKGNAALQITDVKLQDAGVYCC





IISYGGADYKRITLKVNAPYRKINQRISVDPATSEHELICQAEGYPEAEVIWTNSDH





QPVSGKRSVTTSRTEGMLLNVTSSLRVNATANDVFYCTFWRSQPGQNHTAELIIPEL





PATHPPQNRT
PNKGSGTTSGTTRLLSGHTCFTLTGLLGTLVTMGLLTGSGATNFSLL





KQAGDVEENPGP
MEPLPGWGSAPWSQAPTDNTFRLVPCVFLLNLLQRISAQPSCRQE





EFLVGDECCPMCNPGYHVKQVCSEHTGTVCAPCPPQTYTAHANGLSKCLPCGVCDPD





MGLLTWQECSSWKDTVCRCIPGYFCENQDGSHCSTCLQHTTCPPGQRVEKRGTHDQD





TVCADCLTGTFSLGGTQEECLPWTNCSAFQQEVRRGTNSTDTTCSSQ
PNKGSGTTSG





TTRLLSGHTCFTLTGLLGTLVTMGLLT




(SEQ ID NO: 302)





hPDL1-ADAM10
>Artificial Sequence; hPDL1-ADAM10, DNA




ATGAGGATATTTGCTGTCTTTATATTCATGACCTACTGGCATTTGCTGAACGCATTT





ACTGTCACGGTTCCCAAGGACCTATATGTGGTAGAGTATGGTAGCAATATGACAATT





GAATGCAAATTCCCAGTAGAAAAACAATTAGACCTGGCTGCACTAATTGTCTATTGG





GAAATGGAGGATAAGAACATTATTCAATTTGTGCATGGAGAGGAAGACCTGAAGGTT





CAGCATAGTAGCTACAGACAGAGGGCCCGGCTGTTGAAGGACCAGCTCTCCCTGGGA





AATGCTGCACTTCAGATCACAGATGTGAAATTGCAGGATGCAGGGGTGTACCGCTGC





ATGATCAGCTATGGTGGTGCCGACTACAAGCGAATTACTGTGAAAGTCAATGCCCCA





TACAACAAAATCAACCAAAGAATTTTGGTTGTGGATCCAGTCACCTCTGAACATGAA





CTGACATGTCAGGCTGAGGGCTACCCCAAGGCCGAAGTCATCTGGACAAGCAGTGAC





CATCAAGTCCTGAGTGGTAAGACCACCACCACCAATTCCAAGAGAGAGGAGAAGCTT





TTCAATGTGACCAGCACACTGAGAATCAACACAACAACTAATGAGATTTTCTACTGC





ACTTTTAGGAGATTAGATCCTGAGGAAAACCATACAGCTGAATTGGTCATCCCAGAA





CTACCTCTGGCACATCCTCCAAATGAAAGG
TGTGGAAATGGAATGGTAGAACAAGGT





GAAGAATGTGATTGTGGCTATAGTGACCAGTGTAAAGATGAATGCTGCTTCGATGCA





AATCAACCAGAGGGAAGAAAATGCAAACTGAAACCTGGGAAACAGTGCAGTCCAAGT





CAAGGTCCTTGTTGTACAGCACAGTGTGCATTCAAGTCAAAGTCTGAGAAGTGTCGG





GATGATTCAGACTGTGCAAGGGAAGGAATATGTAATGGCTTCACAGCTCTCTGCCCA





GCATCTGACCCTAAACCAAACTTCACAGACTGTAATAGGCATACACAAGTGTGCATT





AATGGGCAATGTGCAGGTTCTATCTGTGAGAAATATGGCTTAGAGGAGTGTACGTGT





GCCAGTTCTGATGGCAAAGATGATAAAGAATTATGCCATGTATGCTGTATGAAGAAA





ATGGACCCATCAACTTGTGCCAGTACAGGGTCTGTGCAGTGGAGTAGGCACTTCAGT





GGTCGAACCATCACCCTGCAACCTGGATCCCCTTGCAACGATTTTAGAGGTTACTGT





GATGTTTTCATGCGGTGCAGATTAGTAGATGCTGATGGTCCTCTAGCTAGGCTTAAA





AAAGCAATTTTTAGTCCAGAGCTCTATGAAAACATTGCTGAATGGATTGTGGCTCAT





TGGTGGGCAGTATTACTTATGGGAATTGCTCTGATCATGCTAATGGCTGGATTTATT





AAGATATGCAGTGTTaATACTCCAAGTAGTAATCCAAAGTTGCCTCCTCCTAAACCA





CTTCCAGGCACTTTAAAGAGGAGGAGACCTCCACAGCCCATTCAGCAACCCCAGCGT





CAGCGGCCCCGAGAGAGTTATCAAATGGGACACATGAGACGCTAA




(SEQ ID NO: 303)



>Artificial Sequence; hPDL1-ADAM10, Amino Acid




MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKEPVEKQLDLAALIVYW





EMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRC





MISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSD





HQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPE





LPLAHPPNER
CGNGMVEQGEECDCGYSDQCKDECCFDANQPEGRKCKLKPGKQCSPS





QGPCCTAQCAFKSKSEKCRDDSDCAREGICNGFTALCPASDPKPNFTDCNRHTQVCI





NGQCAGSICEKYGLEECTCASSDGKDDEELCHVCCMKKMDPSTCASTGSVQWSRHFS





GRTITLQPGSPCNDFRGYCDVFMRCRLVDADGPLARLKKAIFSPELYENIAEWIVAH





WWAVLLMGIALIMLMAGFIKICSVHTPSSNPKLPPPKPLPGTLKRRRPPQPIQQPQR





QRPRESYQMGHMRR




(SEQ ID NO: 304)





hPDL1-4Fc-
>Artificial Sequence; hPDL1-4Fc-CD9tm2, DNA


CD9tm2

ATGAGGATATTTGCTGTCTTTATATTCATGACCTACTGGCATTTGCTGAACGCATTT





ACTGTCACGGTTCCCAAGGACCTATATGTGGTAGAGTATGGTAGCAATATGACAATT





GAATGCAAATTCCCAGTAGAAAAACAATTAGACCTGGCTGCACTAATTGTCTATTGG





GAAATGGAGGATAAGAACATTATTCAATTTGTGCATGGAGAGGAAGACCTGAAGGTT





CAGCATAGTAGCTACAGACAGAGGGCCCGGCTGTTGAAGGACCAGCTCTCCCTGGGA





AATGCTGCACTTCAGATCACAGATGTGAAATTGCAGGATGCAGGGGTGTACCGCTGC





ATGATCAGCTATGGTGGTGCCGACTACAAGCGAATTACTGTGAAAGTCAATGCCCCA





TACAACAAAATCAACCAAAGAATTTTGGTTGTGGATCCAGTCACCTCTGAACATGAA





CTGACATGTCAGGCTGAGGGCTACCCCAAGGCCGAAGTCATCTGGACAAGCAGTGAC





CATCAAGTCCTGAGTGGTAAGACCACCACCACCAATTCCAAGAGAGAGGAGAAGCTT





TTCAATGTGACCAGCACACTGAGAATCAACACAACAACTAATGAGATTTTCTACTGC





ACTTTTAGGAGATTAGATCCTGAGGAAAACCATACAGCTGAATTGGTCATCCCAGAA





CTACCTCTGGCACATCCTCCAAATGAAAGG
GAGTCCAAATATGGTCCCCCATGCCCA





TCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAA





CCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGAC





GTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTG





CATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTC





AGGGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGTAAGGAGTACAAGTGCAAG





GTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGG





CAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAG





AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTG





GAGTGGGAGAGCAATGGGCAGCCGGAGGACAACTACAAGACCACGCCTCCCGTGCTG





GACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGG





CAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTAC





ACACAGAAGAGCCTCTCCCTGTCTCCGGGTAAA
TTCTACACAGGAGTCTATATTCTG





ATCGGAGCCGGCGCCCTCATGATGCTGGTGGGCTTCCTGGGCTGCTGCGGGGCTGTG





CAGGAGTCCCAGTGC




(SEQ ID NO: 305)



>Artificial Sequence; hPDL1-4Fc-CD9tm2, Amino Acid




MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYW





EMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRC





MISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSD





HQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPE





LPLAHPPNER
ESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD





VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVRVLTVLHQDWLNGKEYKCK





VSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAV





EWESNGQPEDNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHY





TQKSLSLSPGK
FYTGVYILIGAGALMMLVGFLGCCGAVQESQCVIM




(SEQ ID NO: 306)





hPDL1-4Fc-
>Artificial Sequence; hPDL1-4Fc-CD9tm2-KRAS, DNA


CD9tm2-

ATGAGGATATTTGCTGTCTTTATATTCATGACCTACTGGCATTTGCTGAACGCATTT



modified KRas

ACTGTCACGGTTCCCAAGGACCTATATGTGGTAGAGTATGGTAGCAATATGACAATT





GAATGCAAATTCCCAGTAGAAAAACAATTAGACCTGGCTGCACTAATTGTCTATTGG





GAAATGGAGGATAAGAACATTATTCAATTTGTGCATGGAGAGGAAGACCTGAAGGTT





CAGCATAGTAGCTACAGACAGAGGGCCCGGCTGTTGAAGGACCAGCTCTCCCTGGGA





AATGCTGCACTTCAGATCACAGATGTGAAATTGCAGGATGCAGGGGTGTACCGCTGC





ATGATCAGCTATGGTGGTGCCGACTACAAGCGAATTACTGTGAAAGTCAATGCCCCA





TACAACAAAATCAACCAAAGAATTTTGGTTGTGGATCCAGTCACCTCTGAACATGAA





CTGACATGTCAGGCTGAGGGCTACCCCAAGGCCGAAGTCATCTGGACAAGCAGTGAC





CATCAAGTCCTGAGTGGTAAGACCACCACCACCAATTCCAAGAGAGAGGAGAAGCTT





TTCAATGTGACCAGCACACTGAGAATCAACACAACAACTAATGAGATTTTCTACTGC





ACTTTTAGGAGATTAGATCCTGAGGAAAACCATACAGCTGAATTGGTCATCCCAGAA





CTACCTCTGGCACATCCTCCAAATGAAAGG
GAGTCCAAATATGGTCCCCCATGCCCA





TCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAA





CCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGAC





GTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTG





CATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTC





AGGGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGTAAGGAGTACAAGTGCAAG





GTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGG





CAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAG





AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTG





GAGTGGGAGAGCAATGGGCAGCCGGAGGACAACTACAAGACCACGCCTCCCGTGCTG





GACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGG





CAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTAC





ACACAGAAGAGCCTCTCCCTGTCTCCGGGTAAA
TTCTACACAGGAGTCTATATTCTG





ATCGGAGCCGGCGCCCTCATGATGCTGGTGGGCTTCCTGGGCTGCTGCGGGGCTGTG





CAGGAGTCCCAGTGC

AAAAAGAAGAAAAAGAAGAAGAAGACAAAGTGTGTAATTATG







TAA





(SEQ ID NO: 307)



>Artificial Sequence; hPDL1-4Fc-CD9tm2-KRAS, Amino Acid




MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYW





EMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRC





MISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSD





HQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPE





LPLAHPPNER
ESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD





VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVRVLTVLHQDWLNGKEYKCK





VSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAV





EWESNGQPEDNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHY





TQKSLSLSPGK
FYTGVYILIGAGALMMLVGFLGCCGAVQESQC

KKKKKKKKTKCVIM





(SEQ ID NO: 308)





hPDL1-Fc-
>Artificial Sequence; hPDL1-Fc-CD9tm2, DNA


CD9tm2

ATGAGGATATTTGCTGTCTTTATATTCATGACCTACTGGCATTTGCTGAACGCATTT





ACTGTCACGGTTCCCAAGGACCTATATGTGGTAGAGTATGGTAGCAATATGACAATT





GAATGCAAATTCCCAGTAGAAAAACAATTAGACCTGGCTGCACTAATTGTCTATTGG





GAAATGGAGGATAAGAACATTATTCAATTTGTGCATGGAGAGGAAGACCTGAAGGTT





CAGCATAGTAGCTACAGACAGAGGGCCCGGCTGTTGAAGGACCAGCTCTCCCTGGGA





AATGCTGCACTTCAGATCACAGATGTGAAATTGCAGGATGCAGGGGTGTACCGCTGC





ATGATCAGCTATGGTGGTGCCGACTACAAGCGAATTACTGTGAAAGTCAATGCCCCA





TACAACAAAATCAACCAAAGAATTTTGGTTGTGGATCCAGTCACCTCTGAACATGAA





CTGACATGTCAGGCTGAGGGCTACCCCAAGGCCGAAGTCATCTGGACAAGCAGTGAC





CATCAAGTCCTGAGTGGTAAGACCACCACCACCAATTCCAAGAGAGAGGAGAAGCTT





TTCAATGTGACCAGCACACTGAGAATCAACACAACAACTAATGAGATTTTCTACTGC





ACTTTTAGGAGATTAGATCCTGAGGAAAACCATACAGCTGAATTGGTCATCCCAGAA





CTACCTCTGGCACATCCTCCAAATGAAAGGATCGATGACAAAACTCACACATGCCCA





CCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAA





CCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGAC





GTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG





CATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTC





AGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAG





GTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGG





CAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAG





AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG





GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTG





GACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGG





CAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCACGAGGCTCTGCACAACCACTAC





ACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAATCGATTTCTACACAGGAGTCTAT





ATTCTGATCGGAGCCGGCGCCCTCATGATGCTGGTGGGCTTCCTGGGCTGCTGCGGG





GCTGTGCAGGAGTCCCAGTGCGTAATTATGTAA




(SEQ ID NO: 309)



>Artificial Sequence; hPDL1-Fc-CD9tm2, Amino Acid




MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYW





EMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRC





MISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSD





HQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPE





LPLAHPPNERIDDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD





VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK





VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV





EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY





TQKSLSLSPGKIDFYTGVYILIGAGALMMLVGFLGCCGAVQESQCVIM




(SEQ ID NO: 310)





hPDL1-Fc-
>Artificial Sequence; hPDL1-Fc-CD9tm2-KRAS, DNA


CD9tm2-

ATGAGGATATTTGCTGTCTTTATATTCATGACCTACTGGCATTTGCTGAACGCATTT



modified KRAS

ACTGTCACGGTTCCCAAGGACCTATATGTGGTAGAGTATGGTAGCAATATGACAATT





GAATGCAAATTCCCAGTAGAAAAACAATTAGACCTGGCTGCACTAATTGTCTATTGG





GAAATGGAGGATAAGAACATTATTCAATTTGTGCATGGAGAGGAAGACCTGAAGGTT





CAGCATAGTAGCTACAGACAGAGGGCCCGGCTGTTGAAGGACCAGCTCTCCCTGGGA





AATGCTGCACTTCAGATCACAGATGTGAAATTGCAGGATGCAGGGGTGTACCGCTGC





ATGATCAGCTATGGTGGTGCCGACTACAAGCGAATTACTGTGAAAGTCAATGCCCCA





TACAACAAAATCAACCAAAGAATTTTGGTTGTGGATCCAGTCACCTCTGAACATGAA





CTGACATGTCAGGCTGAGGGCTACCCCAAGGCCGAAGTCATCTCTGGAAGCAGTGAC





CATCAAGTCCTGAGTGGTAAGACCACCACCACCAATTCCAAGAGAGAGGAGAAGCTT





TTCAATGTGACCAGCACACTGAGAATCAACACAACAACTAATGAGATTTTCTACTGC





ACTTTTAGGAGATTAGATCCTGAGGAAAACCATACAGCTGAATTGGTCATCCCAGAA





CTACCTCTGGCACATCCTCCAAATGAAAGGATCGATGACAAAACTCACACATGCCCA





CCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCQCCCCAAAA





CCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGAC





GTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG





CATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTC





AGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAG





GTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGG





CAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAG





AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG





GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTG





GACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGG





CAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCACGAGGCTCTGCACAACCACTAC





ACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAATCGATTTCTACACAGGAGTCTAT





ATTCTGATCGGAGCCGGCGCCCTCATGATGCTGGTGGGCTTCCTGGGCTGCTGCGGG





GCTGTGCAGGAGTCCCAGTGC

AAAAAGAAGAAAAAGAAGAAGAAGACAAAGTGTGTA







ATTATGTAA 
 (SEQ ID NO: 311)




>Artificial Sequence; hPDL1-Fc-CD9tm2-KRAS, Amino Acid




MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYW





EMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRC





MISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSD





HQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPE





LPLAHPPNERIDDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD





VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK





VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV





EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY





TQKSLSLSPGKIDFYTGVYILIGAGALMMLVGFLGCCGAVQESQCKKKKKKKKTKCV






IM





(SEQ ID NO: 312)





mPDL1-mFc-
>Artificial Sequence; mPDL1-mFc-CD9tm2, DNA


CD9tm2

ATGAGGATATTTGCTGGCATTATATTCACAGCCTGCTGTCACTTGCTACGGGCGTTT





ACTATCACGGCTCCAAAGGACTTGTACGTGGTGGAGTATGGCAGCAACGTCACGATG





GAGTGCAGATTCCCTGTAGAACGGGAGCTGGACCTGCTTGCGTTAGTGGTGTACTGG





GAAAAGGAAGATGAGCAAGTGATTCAGTTTGTGGCAGGAGAGGAGGACCTTAAGCCT





CAGCACAGCAACTTCAGGGGGAGAGCCTCGCTGCCAAAGGACCAGCTTTTGAAGGGA





AATGCTGCCCTTCAGATCACAGACGTCAAGCTGCAGGACGCAGGCGTTTACTGCTGC





ATAATCAGCTACGGTGGTGCGGACTACAAGCGAATCACGCTGAAAGTCAATGCCCCA





TACCGCAAAATCAACCAGAGAATTTCCGTGGATCCAGCCACTTCTGAGCATGAACTA





ATATGTCAGGCCGAGGGTTATCCAGAAGCTGAGGTAATCTGGACAAACAGTGACCAC





CAACCCGTGAGTGGGAAGAGAAGTGTCACCACTTCCCGGACAGAGGGGATGCTTCTC





AATGTGACCAGCAGTCTGAGGGTCAACGCCACAGCGAATGATGTTTTCTACTGTACG





TTTTGGAGATCACAGCCAGGGCAAAACCACACAGCGGAGCTGATCATCCCAGAACTG





CCTGCAACACATCCTCCACAGAACAGGACT
GGTTGTAAGCCTTGCATATGTACAGTC





CCAGAAGTATCATCTGTCTTCATCTTCCCCCCAAAGCCCAAGGATGTGCTCACCATT





ACTCTGACTCCTAAGGTCACGTGTGTTGTGGTAGACATCAGCAAGGATGATCCCGAG





GTCCAGTTCAGCTGGTTTGTAGATGATGTGGAGGTGCACACAGCTCAGACGCAACCC





CGGGAGGAGCAGTTCAACAGCACTTTCCGCTCAGTCAGTGAACTTCCCATCATGCAC





CAGGACTGGCTCAATGGCAAGGAGTTCAAATGCAGGGTCAACAGTGCAGCTTTCCCT





GCCCCCATCGAGAAAACCATCTCCAAAACCAAAGGCAGACCGAAGGCTCCACAGGTG





TACACCATTCCACCTCCCAAGGAGCAGATGGCCAAGGATAAAGTCAGTCTGACCTGC





ATGATAACAGACTTCTTCCCTGAAGACATTACTGTGGAGTGGCAGTGGAATGGGCAG





CCAGCGGAGAACTACAAGAACACTCAGCCCATCATGGACACAGATGGCTCTTACTTC





GTCTACAGCAAGCTCAATGTGCAGAAGAGCAACTGGGAGGCAGGAAATACTTTCACC





TGCTCTGTGTTACATGAGGGCCTGCACAACCACCATACTGAGAAGAGCCTCTCCCAC





TCTCCTGGTAAA
TTCTACACAGGAGTCTATATTCTGATCGGAGCCGGCGCCCTCATG





ATGCTGGTGGGCTTCCTGGGCTGCTGCGGGGCTGTGCAGGAGTCCCAGTGCGTAATT





ATGTAA




(SEQ ID NO: 313)



>Artificial Sequence; mPDL1-mFc-CD9tm2, Amino Acid




MRIFAGIIFTACCHLLRAFTITAPKDLYVVEYGSNVTMECRFPVERELDLLALVVYW





EKEDEQVIQFVAGEEDLKPQHSNFRGRASLPKDQLLKGNAALQITDVKLQDAGVYCC





IISYGGADYKRITLKVNAPYRKINQRISVDPATSEHELICQAEGYPEAEVIWTNSDH





QPVSGKRSVTTSRTEGMLLNVTSSLRVNATANDVFYCTFWRSQPGQNHTAELIIPEL





PATHPPQNRT
GCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPE





VQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFP





APIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQ





PAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSH





SPGKP
FYTGVYILIGAGALMMLVGFLGCCGAVQESQCVIM




(SEQ ID NO: 314)





mPDL1-mFc-
>Artificial Sequence; mPDL1-mFc-CD9tm2-KRAS, DNA


CD9tm2-

ATGAGGATATTTGCTGGCATTATATTCACAGCCTGCTGTCACTTGCTACGGGCGTTT



modified KRAS

ACTATCACGGCTCCAAAGGACTTGTACGTGGTGGAGTATGGCAGCAACGTCACGATG





GAGTGCAGATTCCCTGTAGAACGGGAGCTGGACCTGCTTGCGTTAGTGGTGTACTGG





GAAAAGGAAGATGAGCAAGTGATTCAGTTTGTGGCAGGAGAGGAGGACCTTAAGCCT





CAGCACAGCAACTTCAGGGGGAGAGCCTCGCTGCCAAAGGACCAGCTTTTGAAGGGA





AATGCTGCCCTTCAGATCACAGACGTCAAGCTGCAGGACGCAGGCGTTTACTGCTGC





ATAATCAGCTACGGTGGTGCGGACTACAAGCGAATCACGCTGAAAGTCAATGCCCCA





TACCGCAAAATCAACCAGAGAATTTCCGTGGATCCAGCCACTTCTGAGCATGAACTA





ATATGTCAGGCCGAGGGTTATCCAGAAGCTGAGGTAATCTGGACAAACAGTGACCAC





CAACCCGTGAGTGGGAAGAGAAGTGTCACCACTTCCCGGACAGAGGGGATGCTTCTC





AATGTGACCAGCAGTCTGAGGGTCAACGCCACAGCGAATGATGTTTTCTACTGTACG





TTTTGGAGATCACAGCCAGGGCAAAACCACACAGCGGAGCTGATCATCCCAGAACTG





CCTGCAACACATCCTCCACAGAACAGGACT
GGTTGTAAGCCTTGCATATGTACAGTC





CCAGAAGTATCATCTGTCTTCATCTTCCCCCCAAAGCCCAAGGATGTGCTCACCATT





ACTCTGACTCCTAAGGTCACGTGTGTTGTGGTAGACATCAGCAAGGATGATCCCGAG





GTCCAGTTCAGCTGGTTTGTAGATGATGTGGAGGTGCACACAGCTCAGACGCAACCC





CGGGAGGAGCAGTTCAACAGCACTTTCCGCTCAGTCAGTGAACTTCCCATCATGCAC





CAGGACTGGCTCAATGGCAAGGAGTTCAAATGCAGGGTCAACAGTGCAGCTTTCCCT





GCCCCCATCGAGAAAACCATCTCCAAAACCAAAGGCAGACCGAAGGCTCCACAGGTG





TACACCATTCCACCTCCCAAGGAGCAGATGGCCAAGGATAAAGTCAGTCTGACCTGC





ATGATAACAGACTTCTTCCCTGAAGACATTACTGTGGAGTGGCAGTGGAATGGGCAG





CCAGCGGAGAACTACAAGAACACTCAGCCCATCATGGACACAGATGGCTCTTACTTC





GTCTACAGCAAGCTCAATGTGCAGAAGAGCAACTGGGAGGCAGGAAATACTTTCACC





TGCTCTGTGTTACATGAGGGCCTGCACAACCACCATACTGAGAAGAGCCTCTCCCAC





TCTCCTGGTAAA
TTCTACACAGGAGTCTATATTCTGATCGGAGCCGGCGCCCTCATG





ATGCTGGTGGGCTTCCTGGGCTGCTGCGGGGCTGTGCAGGAGTCCCAGTGC

AAAAAG







AAGAAAAAGAAGAAGAAGACAAAGTGTGTAATTATGTAA





(SEQ ID NO: 315)



>Artificial Sequence; mPDL1-mFc-CD9tm2-KRAS, Amino Acid




MRIFAGIIFTACCHLLRAFTITAPEDLYVVEYGSNVTMECRFPVERELDLLALVVYW





EKEDEQVIQFVAGEEDLKPQHSNFRGRASLPKDQLLKGNAALQITDVKLQDAGVYCC





IISYGGADYKRITLKVNAPYRKINQRISVDPATSEHELICQAEGYPEAEVIWTNSDH





QPVSGKRSVTTSRTEGMLLNVTSSLRVNATANDVFYCTFWRSQPGQNHTAELIIPEL





PATHPPQNRT
GCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPE





VQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFP





APIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQ





PAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSH





SPGK
FYTGVYILIGAGALMMLVGFLGCCGAVQESQC

KKKKKKKKTKCVIM





(SEQ ID NO: 316)









In some embodiments of any of the aspects, the fusion polypeptides provided herein comprise two or more POI domains. The specific combinations of POI domains can be used to regulate inflammatory immune responses. Non-limiting examples of additive and synergistic combinations of POIs that can modulate inflammatory signaling pathways are provided in Table 5 (below).









TABLE 5







Exemplary POI combinations and combined targets


for modulating inflammation.










COMBINED
PUTATIVE ADDITIVE or


POIs (LIGANDS)
TARGETS
SYNERGISTIC MOA





PD-L1 or PD-L2
PD-1
Differential use of Shp


HVEM
BTLA
phosphatases. BTLA inhibits




both TCR and CD28




phosphorylation (via Shpl)




while PD-1 inhibits CD28




phosphorylation (via Shp2).


PD-L1 or PD-L2
PD-1
LAG-3 exerts differential


FGL1
LAG-3
inhibitory impacts on various




types of lymphocytes and




shows synergy with PD-1 to




inhibit immune responses.


PD-L1 or PD-L2
PD-1
PD-1 and Tim-3 have non-


CEACAM-1 or GAL9
TIM-3
redundant downstream




signaling mechanisms.


PD-L1 or PD-L2
PD-1
Differential use of Shp


CD155
TIGIT
phosphatases. Non-redundantly




regulate T cell responses.


PD-L1 or PD-L2
PD-1
PD-1 and VISTA non-


VSIG3
VISTA
redundantly regulate T cell




responses. VISTA contains




cytosolic SH3 binding domains




for adapter proteins.


CEACAM-1 or GAL9
TIM-3
TIGIT and TIM-3 have non-


CD155
TIGIT
redundant downstream




signaling mechanisms.


PD-L1 or PD-L2
PD-1
PD-1, LAG-3 and TIM-3 have


FGL1
LAG-3
non-redundant downstream


CEACAM-1 or GAL9
TIM-3
signaling mechanisms.









Methods of Preparing Extracellular Vesicle Compositions

In another aspect, provided herein is a method of preparing an engineered extracellular vesicle provided herein. Generally, the method comprises providing a population of cells expressing a vector construct encoding one or more sticky binder (vesicle targeting domain) and one or more signaling domains (POI domain).


The EVs provided herein can be isolated and purified form any biological source, e.g., cells. The cells that produce the engineered EVs provided herein can be from any viable non-human source or organism. Usually the organism is an animal, vertebrate, or mammal. In some embodiments, the cell described herein is from a human. The cells described herein can be from any tissue isolated from an organism by methods known in the art. The scientific literature provides guidance for one of ordinary skill in the art to isolate, prepare, and culture cells as necessary for use in the compositions and methods described herein. One of skill in the art can appreciate that the cell source of the EVs may alter the cellular protein expression and the native or endogenous cargo within the EV. It is contemplated herein that this can be leveraged for therapeutic effect depending on the disease or disorder being treated.


In some embodiments, the population of cells has been altered by exposure to environmental conditions (e.g., hypoxia), small molecule addition, presence/absence of exogenous factors (e.g., growth factors, cytokines) at the time, or substantially contemporaneous with, isolating the plurality of artificial synapses in a manner altering the regulatory state of the cell. In various embodiments, the cells are HEK 293 cells, MSCs, PER.C, fibrosarcoma HT-1080 or HuH7 cell lines.


The method comprises providing a population of cells and culturing the cells in serum-free or un-concentrated conditioned medium. This includes, for example, artificial synapses secreted into media as conditioned by a population of cells in culture, further including cell lines capable of serial passaging. In certain embodiments, the cells in culture are grown to 10, 20, 30, 40, 50, 60, 70, 80, 90, or 90% or more confluency when artificial synapses (engineered EVs) are isolated.


The methods provided herein further comprise contacting the cells provided herein with a nucleic acid vector encoding the at least one fusion polypeptide provided herein. The vector can be added to the cell culture medium of the cells by methods known in the art and discussed further below.


A vector is a nucleic acid construct designed for delivery to a host cell or for transfer of genetic material between different host cells. As used herein, a vector can be viral or non-viral. The term “vector” encompasses any genetic element that is capable of replication when associated with the proper control elements and that can transfer genetic material to cells. A vector can include, but is not limited to, a cloning vector, an expression vector, a plasmid, phage, transposon, cosmid, artificial chromosome, virus, virion, etc. In some embodiments of any of the aspects, the vector is selected from the group consisting of: a plasmid, a cosmid and a viral vector.


“Expression” refers to the cellular processes involved in producing RNA and proteins and as appropriate, secreting proteins, including where applicable, but not limited to, for example, transcription, transcript processing, translation and protein folding, modification and processing. “Expression products” include RNA transcribed from a gene, and polypeptides obtained by translation of mRNA transcribed from a gene.


In some embodiments, a vector is capable of driving expression of one or more sequences in a mammalian cell; i.e., the vector is a mammalian expression vector. Examples of mammalian expression vectors include pCDM8 (Seed, 1987. Nature 329: 840) and pMT2PC (Kaufman, et al., 1987. EMBO J. 6: 187-195). When used in mammalian cells, the expression vector's control functions are typically provided by one or more regulatory elements. For example, commonly used promoters are derived from polyoma, adenovirus 2, cytomegalovirus, simian virus 40, and others disclosed herein and known in the art. For other suitable expression systems for both prokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 of Sambrook, et al., MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989.


In some embodiments, the recombinant expression vector is capable of directing expression of the exogenous fusion polypeptide nucleic acid sequence preferentially in a particular cell type (e.g., via tissue-specific regulatory elements).


Tissue-specific and inducible regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert, et al., 1987. Genes Dev. 1: 268-277), lymphoid-specific promoters (Calame and Eaton, 1988. Adv. hnmunol. 43: 235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989. EMO J. 8: 729-733) and immunoglobulins (Baneiji, et al., 1983. Cell 33: 729-740; Queen and Baltimore, 1983. Cell 33: 741-748), neuron-specific promoters (e. g., the neurofilament promoter; Byrne and Ruddle, 1989. Proc. Natl. Acad. Sci. USA 86: 5473-5477), pancreas-specific promoters (Edlund, et al., 1985. Science 230: 912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are also encompassed, e.g., the murine hox promoters (Kessel and Gruss, 1990. Science 249: 374-379) and the a-fetoprotein promoter (Campes and Tilghman, 1989. Genes Dev. 3: 537-546).


In some embodiments, the at least one nucleic acid sequence described herein is delivered to the cell described herein via an integrating vector. Integrating vectors have their delivered genetic material (or a copy of it) permanently incorporated into a host cell chromosome. Non-integrating vectors remain episomal which means the nucleic acid contained therein is never integrated into a host cell chromosome. Examples of integrating vectors include retroviral vectors, lentiviral vectors, hybrid adenoviral vectors, and herpes simplex viral vectors.


In some embodiments, the at least one nucleic acid sequence described herein is delivered to the cell described herein via a non-integrative vector. Non-integrative vectors include non-integrative viral vectors. Non-integrative viral vectors eliminate one of the primary risks posed by integrative retroviruses, as they do not incorporate their genome into the host DNA. One example is the Epstein Barr oriP/Nuclear Antigen-1 (“EBNA1”) vector, which is capable of limited self-replication and known to function in mammalian cells. Containing two elements from Epstein-Barr virus, oriP and EBNA1, binding of the EBNA1 protein to the virus replicon region oriP maintains a relatively long-term episomal presence of plasmids in mammalian cells. This particular feature of the oriP/EBNA1 vector makes it ideal for generation of integration-free host cells. Other non-integrative viral vectors include adenoviral vectors and the adeno-associated viral (AAV) vectors.


Another non-integrative viral vector is RNA Sendai viral vector, which can produce protein without entering the nucleus of an infected cell. The F-deficient Sendai virus vector remains in the cytoplasm of infected cells for a few passages, but is diluted out quickly and completely lost after several passages (e.g., 10 passages). This permits a self-limiting transient expression of a chosen heterologous gene or genes in a target cell. This aspect can be helpful, e.g., for the transient introduction of reprogramming factors, among other uses. As noted above, in some embodiments, the nucleic acid sequence described herein is expressed in the cells from a viral vector.


A “viral vector” includes a nucleic acid vector construct that includes at least one element of viral origin and has the capacity to be packaged into a viral vector particle. The viral vector can contain a nucleic acid encoding a polypeptide described herein in place of non-essential viral genes. The vector and/or particle can be utilized for the purpose of transferring nucleic acids into cells either in vitro or in vivo.


The nucleic acids described herein can be delivered using any transfection reagent or other physical means that facilitates entry of nucleic acids into a cell. Methods of non-viral delivery of nucleic acids include lipofection, nucleofection, microinjection, electroporation, biolistics, virosomes, liposomes, immunoliposomes, polycation or lipid:nucleic acid conjugates, naked DNA, artificial virions, and agent-enhanced uptake of DNA. Lipofection is described in e.g. U.S. Pat. Nos. 5,049,386, 4,946,787; and 4,897,355) and lipofection reagents are sold commercially (e.g., Transfectam™ and Lipofectin™). Cationic and neutral lipids that are suitable for efficient receptor-recognition lipofection of polynucleotides include those of Felgner, WO 91/17424; WO 91/16024. Delivery can be to cells (e.g. in vitro or ex vivo administration) or target tissues (e.g. in vivo administration).


The preparation of lipid:nucleic acid complexes, including targeted liposomes such as immunolipid complexes, is well known to one of skill in the art (see, e.g., Crystal, Science 270:404-410 (1995); Blaese et al., Cancer Gene Ther. 2:291-297 (1995); Behr et al., Bioconjugate Chem. 5:382-389 (1994); Remy et al., Bioconjugate Chem. 5:647-654 (1994); Gao et al., Gene Therapy 2:710-722 (1995); Ahmad et al., Cancer Res. 52:4817-4820 (1992); U.S. Pat. Nos. 4,186,183, 4,217,344, 4,235,871, 4,261,975, 4,485,054, 4,501,728, 4,774,085, 4,837,028, and 4,946,787).


An “agent that increases cellular uptake” is a molecule that facilitates transport of a molecule, e.g., nucleic acid, or peptide or polypeptide, or other molecule that does not otherwise efficiently transit the cell membrane across a lipid membrane. For example, a nucleic acid can be conjugated to a lipophilic compound (e.g., cholesterol, tocopherol, etc.), a cell penetrating peptide (CPP) (e.g., penetratin, TAT, Syn1B, etc.), or a polyamine (e.g., spermine). Further examples of agents that increase cellular uptake are disclosed, for example, in Winkler (2013). Oligonucleotide conjugates for therapeutic applications. Ther. Deliv. 4(7); 791-809. The one or more nucleic acid sequences encoding the fusion polypeptides provided herein can be delivered to the cell by any method discussed above or known in the art.


In some embodiments of any of the aspects, the vectors provided herein comprise a nucleic acid modification by methods known in the art. In some embodiments, the cell can be genetically manipulated to express one or more vectors, each encoding one or more vesicle targeting domains and/or one or more signaling domains. In certain embodiments, the population of cells has been genetically manipulated. This includes, for example, knockout (KO) or transgenic (TG) cell lines, wherein an endogenous gene has been removed and/or an exogenous introduced in a stable, persistent manner. In certain embodiments, this further includes transient knockdown of one or more genes and associated coding and non-coding transcripts within the population of cells, via any number of methods known in the art, such as introduction of dsRNA, siRNA, microRNA, etc. This further includes transient expression of one or more genes and associated coding and non-coding transcripts within the population of cells, via any number of methods known in the art, such as introduction of a vector, plasmid, artificial plasmid, replicative and/or non-replicative virus, etc.


In certain embodiments the cell population has been manipulated to knockout the expression of one or more endogenous gene sequences that encode for metalloendopeptidases. In certain embodiments the cell population has been manipulated to knockout the expression of one or more endogenous gene sequences that code for metalloproteinases. In certain embodiments the cell population has been manipulated to knockout the expression of one or more endogenous gene sequences that encode for a disintegrin and metalloproteinase (ADAM). For example, the cell population can be manipulated to knock of the expression of one or more gene sequences that encode for ADAM1, ADAM2, ADAM7, ADAM8, ADAM9, ADAM10, ADAM11, ADAM12, ADAM15, ADAM17, ADAM18, ADAM19, ADAM20, ADAM21, ADAM22, ADAM23, ADAM28, ADAM29, ADAM30, ADAM33, etc.


In certain embodiments the cell population has been manipulated to knockout the expression of one or more endogenous genes that encode for enzymes that hydrolyze the inositol phosphate linkage in proteins anchored by phosphatidylinositol glycans, thereby preventing the release of proteins attached to the plasma membrane via GPI anchors. For example, the cell population can be manipulated to knock of the expression of phosphatidylinositol-glycan-specific phospholipase D (GPLD1).


In certain embodiments, the population of cells has been genetically manipulated. This includes, for example, knock-in of an exogenous genetic sequence, wherein the exogenous genetic sequence is expressed in a stable, persistent manner. In certain embodiments, the cell population has been manipulated to knock-in recombinase recognition sequences (e.g., FRT), transgenic reporters such as antibiotic resistance genes, fluorescent or enzymatic reporter genes, etc. or the like.


In some embodiments, the method comprises a step of isolating the engineered extracellular vesicles provided herein. Particulates within the medium are removed by a series of specific centrifugation steps and the media is filtered. The general method of isolating extracellular vesicles as provided herein is depicted in FIG. 21 of the working examples. Methods of isolating and purifying the extracellular vesicles and exosomes are known in the art and further described, e.g., in Whitford W, Guterstam P. Exosome manufacturing status. Future Med Chem. 2019 May; 11(10):1225-1236. doi: 10.4155/fmc-2018-0417. PMID: 31280675, Patel D B, Santoro M, Born L J, Fisher J P, Jay S M. Towards rationally designed biomanufacturing of therapeutic extracellular vesicles: impact of the bioproduction microenvironment. Biotechnol Adv. 2018 December; 36(8):2051-2059. doi: 10.1016/j.biotechadv.2018.09.001. Epub 2018 Sep. 12. PMID: 30218694; PMCID: PMC6250573, Ng K S, Smith J A, McAteer M P, Mead B E, Ware J, Jackson F O, Carter A, Ferreira L, Bure K, Rowley J A, Reeve B, Brindley D A, Karp J M. Bioprocess decision support tool for scalable manufacture of extracellular vesicles. Biotechnol Bioeng. 2019 February; 116(2):307-319. doi: 10.1002/bit.26809. Epub 2018 Nov. 8. PMID: 30063243; PMCID: PMC6322973, Paganini C, Capasso Palmiero U, Pocsfalvi G, Touzet N, Bongiovanni A, Arosio P. Scalable Production and Isolation of Extracellular Vesicles: Available Sources and Lessons from Current Industrial Bioprocesses. Biotechnol J. 2019 October; 14(10):e1800528. doi: 10.1002/biot.201800528. Epub 2019 Jul. 8. PMID: 31140717, which are incorporated herein by reference in their entireties.


In some embodiments, isolating the plurality of engineered EVs (artificial synapses) includes precipitation, centrifugation, filtration, immuno-separation, tangential flow, liquid chromatography, and/or flow fractionation. For example, differential ultracentrifugation has become a technique wherein secreted exosomes are isolated from the supernatants of cultured cells. This approach allows for separation of exosomes from non-membranous particles, by exploiting their relatively low buoyant density. Size exclusion allows for their separation from biochemically similar, but biophysically different microvesicles, which possess larger diameters of up to 1,000 nm. Differences in floatation velocity further allows for separation of differentially sized exosomes. In general, exosome sizes will possess a diameter ranging from 30-300 nm, including sizes of 30-150 nm. Further purification may rely on specific properties of the particular exosomes of interest. This includes, for example, use of immunoadsorption with a protein of interest to select specific vesicles with exoplasmic or outward orientations.


Among current methods (differential centrifugation, discontinuous density gradients, immunoaffinity, ultrafiltration and liquid chromatography (e.g., fast protein liquid chromatography (FPLC)), differential ultracentrifugation is the most commonly used for exosome isolation. This technique utilizes increasing centrifugal force from 2000×g to 10,000×g to separate the medium- and larger-sized particles and cell debris from the exosome pellet at 100,000×g. Centrifugation alone allows for significant separation/collection of exosomes from a conditioned medium, although it is insufficient to remove various protein aggregates, genetic materials, particulates from media and cell debris that are common contaminants. Enhanced specificity of exosome purification may deploy sequential centrifugation in combination with ultrafiltration, or equilibrium density gradient centrifugation in a sucrose density gradient, to provide for the greater purity of the exosome preparation (flotation density 1.1-1.2 g/ml) or application of a discrete sugar cushion in preparation.


Ultrafiltration can be used to purify exosomes without compromising their biological activity. Membranes with different pore sizes—such as 100 kDa molecular weight cut-off (MWCO) or 300 kDa MWCO and gel filtration to eliminate smaller particles—have been used to avoid the use of a nonneutral pH or non-physiological salt concentration. Currently available tangential flow filtration (TFF) systems are scalable (to >10,000 L), allowing one to not only purify, but concentrate the exosome fractions, and such approaches are less time consuming than differential centrifugation. Liquid Chromatography can also be used to purify exosomes to homogeneously sized particles and preserve their biological activity as the preparation is maintained at a physiological pH and salt concentration.


Other chemical methods have exploit differential solubility of exosomes for precipitation techniques, addition to volume-excluding polymers (e.g., polyethylene glycols (PEGs)), possibly combined additional rounds of centrifugation or filtration. For example, a precipitation reagent, ExoQuick®, can be added to conditioned cell media to quickly and rapidly precipitate a population of exosomes, although re-suspension of pellets prepared via this technique may be difficult. Flow field-flow fractionation (FlFFF) is an elution-based technique that is used to separate and characterize macromolecules (e.g., proteins) and nano- to micro-sized particles (e.g., organelles and cells) and which has been successfully applied to fractionate exosomes from culture media.


Beyond these techniques relying on general biochemical and biophysical features, focused techniques may be applied to isolated specific exosomes of interest. This includes relying on antibody immunoaffinity to recognizing certain exosome-associated antigens. Conjugation to magnetic beads, chromatography matrices, plates or microfluidic devices allows isolating of specific exosome populations of interest as may be related to their production from a parent cell of interest or associated cellular regulatory state. Other affinity-capture methods use lectins which bind to specific saccharide residues on the exosome surface.


In several embodiments, isolating a plurality of artificial synapses from the population of cells includes centrifugation of the cells and/or media conditioned by the cells. In several embodiments, ultracentrifugation is used. In several embodiments, isolating a plurality of artificial synapses from the population of cells is via size-exclusion filtration. In other embodiments, isolating a plurality of artificial synapses from the population of cells includes use of discontinuous density gradients, immunoaffinity, ultrafiltration, tangential flow and/or liquid chromatography.


In certain embodiments, differential ultracentrifugation includes using centrifugal force from 1000-2000×g, 2000-3000×g, 3000-4000×g, 4000-5000×g, 5000×g-6000×g, 6000-7000×g, 7000-8000×g, 8000-9000×g, 9000-10,000×g, to 10,000×g or more to separate larger-sized particles from a plurality of artificial synapses derived from the cells.


In other embodiments, isolating a plurality of artificial synapses from the population of cells includes use of filtration or ultrafiltration. In certain embodiments, a size exclusion membrane with different pore sizes is used. For example, a size exclusion membrane can include use of a filter with a pore size of 0.1-0.5 micron (μm), 0.5-1.0 μm, 1-2.5 μm, 2.5-5 μm, 5 or more μm. In certain embodiments, the pore size is about 0.2 μm. In certain embodiments, filtration or ultrafiltration includes size exclusion ranging from 100-500 daltons (Da), 500-1 kDa, 1-2 kDa, 2-5 kDa, 5-10 kDa, 10-25 kDa, 25-50 kDa, 50-100 kDa, 100-250 kDa, 250-500 kDa, 500 or more kDa. In certain embodiments, the size exclusion is for about 2-5 kDa. In certain embodiments, the size exclusion is for about 3 kDa. In other embodiments, filtration or ultrafiltration includes size exclusion includes use of hollow fiber membranes capable of isolating particles ranging from 100-500 daltons (Da), 500-1 kDa, 1-2 kDa, 2-5 kDa, 5-10 kDa, 10-25 kDa, 25-50 kDa, 50-100 kDa, 100-250 kDa, 250-500 kDa, 500 or more kDa. In certain embodiments, the size exclusion is for about 2-5 kDa. In certain embodiments, the size exclusion is for about 3 kDa. In other embodiments, a molecular weight cut-off (MWCO) gel filtration capable of isolating particles ranging from 100-500 daltons (Da), 500-1 kDa, 1-2 kDa, 2-5 kDa, 5-10 kDa, 10-25 kDa, 25-50 kDa, 50-100 kDa, 100-250 kDa, 250-500 kDa, 500 or more kDa. In certain embodiments, the size exclusion is for about 2-5 kDa. In certain embodiments, the size exclusion is for about 3 kDa. In various embodiments, such systems are used in combination with variable fluid flow systems. In certain embodiments, a size exclusion membrane with different pore sizes is used to purify extracellular vesicles from a solution comprising undesirable proteins or nucleic acids.


In other embodiments, isolating a plurality of artificial synapses from the population of cells includes use of tangential flow filtration (TFF) systems are used purify and/or concentrate the exosome fractions. In other embodiments, isolating a plurality of artificial synapses from the population of cells includes use of liquid chromatography can also be used to purify artificial synapses to homogeneously sized particles. In various embodiments, density gradients as used, such as centrifugation in a sucrose density gradient or application of a discrete sugar cushion in preparation.


In other embodiments, isolating a plurality of artificial synapses from the population of cells includes use of a precipitation reagent. For example, a precipitation reagent, ExoQuick®, can be added to conditioned cell media to quickly and rapidly precipitate a population of artificial synapses. In other embodiments, isolating a plurality of artificial synapses from the population of cells includes use of volume-excluding polymers (e.g., polyethylene glycols (PEGs)) are used. In another embodiment, isolating a plurality of artificial synapses from the population of cells includes use of flow field-flow fractionation (FlFFF), an elution-based technique.


In certain embodiments, isolating a plurality of artificial synapses from the population of cells includes use of one or more capture agents to isolate one or more artificial synapses possessing specific biomarkers or containing particular biological molecules. In one embodiment, one or more capture agents include at least one antibody. For example, antibody immunoaffinity recognizing exosome-associated antigens is used to capture specific artificial synapses. In other embodiments, the at least one antibody are conjugated to a fixed surface, such as magnetic beads, chromatography matrices, plates or microfluidic devices, thereby allowing isolation of the specific exosome populations of interest. In other embodiments, isolating a plurality of artificial synapses from the population of cells includes use of one or more capture agents that is not an antibody. This includes, for example, use of a “bait” molecule presenting an antigenic feature complementary to a corresponding molecule of interest on the exosome surface, such as a receptor or other coupling molecule. In one embodiment, the non-antibody capture agent is a lectin capable of binding to polysaccharide residues on the exosome surface.


In other embodiments, isolating a plurality of artificial synapses from the population of cells includes use of ion exchange chromatography. In other embodiments, isolating a plurality of artificial synapses from the population of cells includes use of anion exchange chromatography. In other embodiments, isolating a plurality of artificial synapses from the population of cells includes use of cation exchange chromatography. In certain embodiments, ion exchange chromatography comprises a chromatography resin with a functional group selected from the group consisting of diethylaminoethyl (DEAE), quaternary aminoethyl (QAE), quaternary ammonium (Q), carboxymethyl (CM), sulfopropyl (SP), or methyl sulfate (S). In certain embodiments, ion exchange chromatography comprises a chromatography resin which may have properties of a weak acid, strong acid, weak base, or strong basic. In certain embodiments, ion exchange chromatography comprises a chromatography selected from the group consisting of DEAE cellulose, DEAE Sephadex, Mono Q, Mini Q, HiTrap Capto, Capto Core 700, HiPrep Q, QAE Sephadex, Q Sepharose, CM Cellulose, SP Sepharose, SOURCE S, EAH-Sepharose, sulfooxyethyl cellulose, CM Sephadex, or CM Sepharose. Isolating a plurality of artificial synapses can be prepared by any of a variety of ion exchange chromatography techniques that are known in the art.


In other embodiments, isolating a plurality of artificial synapses from the population of cells includes use of a nuclease enzyme (e.g., a DNase or RNase). For example, a working concentration of Benzonase® nuclease may be added to an extracellular vesicle sample preparation in the presence of a divalent cation, for example 1-2 mM Mg2+, 2-5 mM Mg2+, 10-20 mM Mg2+, 20-50 mM Mg2+, 50-100 mM Mg2+, or more than 100 mM Mg2+.


Following isolation and purification of the engineered EVs provided herein, EVs can be further evaluated for the desired structural and functional properties by methods known in the art. For example, the engineered exosomes provided herein can be assayed for functional activity on a target cell using a cell-based bioassays (e.g., those commercially available, Promega DiscoverX®), ligand-receptor binding assays, vesicle flow cytometric assays, enzyme-linked immunosorbent assays, tunable resistive pulse sensing (TRPS), nanoparticle tracking analysis (NTA), surface plasmon resonance (SSPR), nucleotide sequencing, lipidomics, proteomics, colorimetric assays, fluorescence assays, luminescence assays, immunoblotting, radioimmunoassays, electron microscopy, or EV automated analysis (e.g., Exoview®). Additional methods of characterizing EVs are found, e.g., in Zhang Y, Bi J, Huang J, Tang Y, Du S, Li P. Exosome: A Review of Its Classification, Isolation Techniques, Storage, Diagnostic and Targeted Therapy Applications. Int J Nanomedicine. 2020 Sep. 22; 15:6917-6934. doi: 10.2147/IJN.S264498. PMID: 33061359; PMCID: PMC7519827, Kluszczyńska K, Czernek L, Cypryk W, Pȩczek Ł, Düchler M. Methods for the Determination of the Purity of Exosomes. Curr Pharm Des. 2019; 25(42):4464-4485. doi: 10.2174/1381612825666191206162712. PMID: 31808383, Nolan J P, Duggan E. Analysis of Individual Extracellular Vesicles by Flow Cytometry. Methods Mol Biol. 2018; 1678:79-92. doi: 10.1007/978-1-4939-7346-0_5. PMID: 29071676; Doyle L M, Wang M Z. Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis. Cells. 2019 Jul. 15; 8(7):727. doi: 10.3390/cells8070727. PMID: 31311206; PMCID: PMC6678302, Pugholm L H, Revenfeld A L, Søndergaard E K, Jorgensen M M. Antibody-Based Assays for Phenotyping of Extracellular Vesicles. Biomed Res Int. 2015; 2015:524817. doi: 10.1155/2015/524817. Epub 2015 Dec. 3. PMID: 26770974; PMCID: PMC4681819, Shao H, Im H, Castro C M, Breakefield X, Weissleder R, Lee H. New Technologies for Analysis of Extracellular Vesicles. Chem Rev. 2018 Feb. 28; 118(4):1917-1950. doi: 10.1021/acs.chemrev.7b00534. Epub 2018 Jan. 31. PMID: 29384376; PMCID: PMC6029891, which are incorporated herein by reference in their entireties.


Pharmaceutical Compositions

Provided herein are compositions comprising the engineered extracellular vesicles (artificial synapses) provided herein.


In one aspect, provided herein is a composition comprising: a plurality of the engineered extracellular vesicles provided herein. In some embodiments of any of the aspects, the compositions and engineered EVs provided herein further comprise a pharmaceutically acceptable carrier.


For clinical use of the methods and compositions described herein, administration of the engineered EVs/artificial synapses provided herein can include formulation into pharmaceutical compositions or pharmaceutical formulations for parenteral administration, e.g., intravenous; mucosal, e.g., intranasal; ocular, or other mode of administration. In some embodiments, the engineered EVs described herein can be administered along with any pharmaceutically acceptable carrier compound, material, or composition which results in an effective treatment in the subject. Thus, a pharmaceutical formulation for use in the methods described herein can contain the engineered EVs described herein in combination with one or more pharmaceutically acceptable ingredients. The phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, media, encapsulating material, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in maintaining the stability, solubility, or activity of, an engineered EV as described herein. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. The terms “excipient,” “carrier,” “pharmaceutically acceptable carrier” or the like are used interchangeably herein.


The engineered EVs provided herein can be formulated for administration of the compound to a subject in solid, liquid, or gel form, including those adapted for the following: (1) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (2) transdermally; (3) transmucosally; (4) via bronchoalveolar lavage.


In some embodiments, the compositions described herein comprise a particle or polymer-based vehicle. Exemplary particle or polymer-based vehicles include, but are not limited to, nanoparticles, microparticles, polymer microspheres, or polymer-drug conjugates.


In one embodiment of any of the aspects, the compositions described herein further comprise a lipid vehicle. Exemplary lipid vehicles include, but are not limited to, liposomes, phospholipids, micelles, lipid emulsions, and lipid-drug complexes.


Formulations can be adapted for delivery to the airway, e.g., to address respiratory inflammation. Such formulations can be adapted for delivery as an aerosol, e.g., for inhalation. In some embodiments, the compositions described herein are formulated for aerosol administration, nebulizer administration, tracheal lavage administration, or for a pulmonary delivery device.


As used herein, the term “pulmonary delivery device” refers to a device used to deliver a therapeutic dose of a composition of the present invention to the respiratory system including, but not limited to, a nebulizer, metered-dose inhaler, or dry powder inhaler.


Examples of nebulizers include, but are not limited to, soft mist inhalers (for example Respimat® Boehringer Ingelheim) jet nebulizers (use compressed gas or air), ultrasonic nebulizers (produce aerosols using a piezoelectric crystal vibrating at high frequencies), and vibrating mesh nebulizers.


As used herein, the term “jet nebulizer” refers to a device that flows compressed air or gas through a composition of the present invention for aerosolization. The aerosolized composition of the present invention may be inhaled by a patient. Jet nebulizer may include, but is not limited to, jet nebulizers with a corrugated tube, jet nebulizers with a collection bag, breath enhanced jet nebulizers, breath actuated jet nebulizers, and metered-dose inhalers. Examples of jet nebulizers include, but are not limited to, Circulaire (Westmed INC, Tucson, AZ), Pari Inhalierboy (PARI, Midlothian, VA), Pari LC Plus (PARI, Midlothian, VA), NebuTech (Salter Labs, Arvin, CA), AeroEclipse (Monoghan/Trudell Medical International, London, Ontario, Canada), and Maxin MA-2 (MA-2; Clinova Medical AB, Malmo, Sweden). Examples of ultrasonic nebulizers include, but are not limited to, DeVilbiss-Pulmosonic (Somerset, PA), Omron-Microair (Omron, Kyoto, Japan), Omron NE-U17 (Omron, Kyoto, Japan), Rhone Poulenc-Rorer-Fisoneb (Sanofi, Paris, France), and Beurer Nebulizer IH30 (Beurer GmbH, Neu-Ulm, Germany).


As used herein, the term “mesh nebulizer” refers to forcing a liquid, gel, fluid, solution, tincture, or the like through apertures in a mesh or aperture plate to generate aerosol. Mesh nebulizer may include, but is not limited to, active mesh nebulizers and passive mesh nebulizers. Examples of active mesh nebulizers include, but is not limited to, Aeroneb® (Aerogen, Galway, Ireland) and eFlow® (PARI, Midlothian, VA). Examples of passive mesh nebulizers are, but not limited to, I-neb (Philips Respironics, Newark, USA), AKITA (Activaero, Gemunden/Wohra, Germany), and Microair NE-U22® (Omron, Kyoto, Japan).


For use as aerosols, the compositions described herein can be prepared in a solution or suspension and may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional excipients.


The engineered EVs provided herein can also be administered in a non-pressurized form such as in a nebulizer or atomizer that reduces a liquid to a fine spray. Preferably, by such nebulization small liquid droplets of uniform size are produced from a larger body of liquid in a controlled manner. Nebulization can be achieved by any suitable means therefor, including by using many nebulizers known and marketed today. For example, an AEROMIST™ pneumatic nebulizer available from Inhalation Plastic, Inc. of Niles, Ill.


When the active ingredients are adapted to be administered, either together or individually, via nebulizer(s) they can be in the form of a nebulized aqueous suspension or solution, with or without a suitable pH or tonicity adjustment, either as a unit dose or multi-dose device.


Furthermore, any suitable gas can be used to apply pressure during the nebulization, with preferred gases to date being those which are chemically inert. Exemplary gases including, but are not limited to, nitrogen, argon, or helium can be used to advantage.


In some embodiments, the compositions described herein can also be administered directly to the airways in the form of a dry powder. Thus, the engineered EVs can be administered via an inhaler. Exemplary inhalers include metered dose inhalers and dry powdered inhalers.


A metered dose inhaler or “MDI” is a pressure resistant canister or container filled with a product such as a pharmaceutical composition dissolved in a liquefied propellant or micronized particles suspended in a liquefied propellant. The propellants which can be used include chlorofluorocarbons, hydrocarbons or hydrofluoroalkanes. Commonly used propellants are P134a (tetrafluoroethane) and P227 (heptafluoropropane) each of which may be used alone or in combination. They are optionally used in combination with one or more other propellants and/or one or more surfactants and/or one or more other excipients, for example ethanol, a lubricant, an anti-oxidant and/or a stabilizing agent.


As used herein, the term “dry powder inhaler” refers to a device that delivers a therapeutic dose of a composition of the present invention in a powdered form without propellants to the respiratory system. A dry powder inhaler (i.e., Turbuhaler™ (Astra AB)) is a system operable with a source of pressurized air to produce dry powder particles of a pharmaceutical composition that is compacted into a very small volume. Examples of dry powder inhalers include, but are not limited to, Spinhaler® (Fisons Pharmaceuticals, Rochester, NY), Rotahaler® (GlaxoSmithKline, NC), Turbuhaler® (AstraZeneca, UK), and Diskhaler® (GlaxoSmithKline, NC).


Dry powder aerosols for inhalation therapy are generally produced with mean diameters primarily in the range of <5 μm. As the diameter of particles exceeds 3 μm, there is increasingly less phagocytosis by macrophages. However, increasing the particle size also has been found to minimize the probability of particles (possessing standard mass density) entering the airways and acini due to excessive deposition in the oropharyngeal or nasal regions.


Suitable powder compositions include, by way of illustration, powdered preparations including the engineered EVs described herein. These can be intermixed with lactose, or other inert powders acceptable for intrabronchial administration. The powder compositions can be administered via an aerosol dispenser or encased in a breakable capsule which may be inserted by the patient or clinician into a device that punctures the capsule and blows the powder out in a steady stream suitable for inhalation. The compositions can include propellants, surfactants, and co-solvents and may be filled into conventional aerosol containers that are closed by a suitable metering valve.


Aerosols for the delivery to the respiratory tract are described, for example, by Adjei, A. and Garren, J. Pharm. Res., 1: 565-569 (1990); Zanen, P. and Lamm, J.-W. J. Int. J. Pharm., 114: 111-115 (1995); Gonda, I. “Aerosols for delivery of therapeutic and diagnostic agents to the respiratory tract,” in Critical Reviews in Therapeutic Drug Carrier Systems, 6:273-313 (1990); Anderson et al., Am. Rev. Respir. Dis., 140: 1317-1324 (1989)) and have potential for the systemic delivery of peptides and proteins as well (Patton and Platz, Advanced Drug Delivery Reviews, 8:179-196 (1992)); Timsina et. al., Int. J. Pharm., 101: 1-13 (1995); and Tansey, I. P., Spray Technol. Market, 4:26-29 (1994); French, D. L., Edwards, D. A. and Niven, R. W., Aerosol Sci., 27: 769-783 (1996); Visser, J., Powder Technology 58: 1-10 (1989)); Rudt, S. and R. H. Muller, J. Controlled Release, 22: 263-272 (1992); Tabata, Y, and Y. Ikada, Biomed. Mater. Res., 22: 837-858 (1988); Wall, D. A., Drug Delivery, 2: 10 1-20 1995); Patton, J. and Platz, R., Adv. Drug Del. Rev., 8: 179-196 (1992); Bryon, P., Adv. Drug. Del. Rev., 5: 107-132 (1990); Patton, J. S., et al., Controlled Release, 28: 15 79-85 (1994); Damms, B. and Bains, W., Nature Biotechnology (1996); Niven, R. W., et al., Pharm. Res., 12(9); 1343-1349 (1995); and Kobayashi, S., et al., Pharm. Res., 13(1): 80-83 (1996), the contents of each of which are incorporated herein by reference in their entirety.


Microemulsification technology can improve bioavailability of some lipophilic (water insoluble) pharmaceutical agents. Examples include Trimetrine (Dordunoo, S. K., et al., Drug Development and Industrial Pharmacy, 17(12), 1685-1713, 1991 and REV 5901 (Sheen, P. C., et al., J Pharm Sci 80(7), 712-714, 1991). Among other things, microemulsification provides enhanced bioavailability by preferentially directing absorption to the lymphatic system instead of the circulatory system, which thereby bypasses the liver, and prevents destruction of the cell-based compositions in the hepatobiliary circulation.


The engineered EVs described herein can be formulated with an amphiphilic carrier. Amphiphilic carriers are saturated and monounsaturated polyethyleneglycolyzed fatty acid glycerides, such as those obtained from fully or partially hydrogenated various vegetable oils. Such oils may advantageously consist of tri-, di-, and mono-fatty acid glycerides and di- and mono-polyethyleneglycol esters of the corresponding fatty acids, with a particularly preferred fatty acid composition including capric acid 4-10, capric acid 3-9, lauric acid 40-50, myristic acid 14-24, palmitic acid 4-14 and stearic acid 5-15%. Another useful class of amphiphilic carriers includes partially esterified sorbitan and/or sorbitol, with saturated or mono-unsaturated fatty acids (SPAN-series) or corresponding ethoxylated analogs (TWEEN-series).


Commercially available amphiphilic carriers are particularly contemplated, including Gelucire-series, Labrafil, Labrasol, or Lauroglycol (all manufactured and distributed by Gattefosse Corporation, Saint Priest, France), PEG-mono-oleate, PEG-di-oleate, PEG-mono-laurate and di-laurate, Lecithin, Polysorbate 80, etc. (produced and distributed by a number of companies in USA and worldwide).


The engineered EV compositions provided herein can be formulated with hydrophilic polymers. Hydrophilic polymers are water-soluble, can be covalently attached to a vesicle-forming lipid, and which are tolerated in vivo without toxic effects (i.e., are biocompatible). Suitable polymers include polyethylene glycol (PEG), polylactic (also termed polylactide), polyglycolic acid (also termed polyglycolide), a polylactic-polyglycolic acid copolymer, and polyvinyl alcohol. Other hydrophilic polymers which may be suitable include polyvinylpyrrolidone, polymethoxazoline, polyethyloxazoline, polyhydroxypropyl methacrylamide, polymethacrylamide, polydimethylacrylamide, and derivatized celluloses such as hydroxymethylcellulose or hydroxyethylcellulose.


In certain embodiments, a pharmaceutical composition as described herein comprises a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polymers of acrylic and methacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and co-polymers thereof, celluloses, polypropylene, polyethylenes, polystyrene, polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, poly(butic acid), poly(valeric acid), poly(lactide-co-caprolactone), polysaccharides, proteins, polyhyaluronic acids, polycyanoacrylates, and blends, mixtures, or copolymers thereof.


In certain embodiments, a pharmaceutical composition described herein is formulated as a liposome. Liposomes can be prepared by any of a variety of techniques that are known in the art. See, e.g., U.S. Pat. No. 4,235,871; Published PCT applications WO 96/14057; New RRC, Liposomes: A practical approach, IRL Press, Oxford (1990), pages 33-104; Lasic D D, Liposomes from physics to applications, Elsevier Science Publishers BV, Amsterdam, 1993.


Therapeutic formulations of the engineered EV compositions as described herein can be prepared for storage by with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations 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 propyl paraben; 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).


Vaccine or other pharmaceutical compositions comprising an engineered EV composition as described herein can contain a pharmaceutically acceptable salt, typically, e.g., sodium chloride, and preferably at about physiological concentrations. The formulations of the vaccine or other pharmaceutical compositions described herein can contain a pharmaceutically acceptable preservative. In some embodiments, the preservative concentration ranges from 0.1 to 2.0%, typically v/v. Suitable preservatives include those known in the pharmaceutical arts. Benzyl alcohol, phenol, m-cresol, methylparaben, and propylparaben are examples of preservatives. The formulations of the vaccine or other pharmaceutical compositions described herein can include a pharmaceutically acceptable surfactant at a concentration of 0.005 to 0.02%.


Therapeutic pharmaceutical compositions described herein can also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other.


In some embodiments in which the engineered EVs are formulated for use in or with a vaccine, the vaccine composition can be formulated with the engineered EVs as an adjuvant. In other embodiments the vaccine composition can be formulated with the engineered EVs and an additional adjuvant, e.g., as known in the art.


As used herein in the context of immunization, immune response and vaccination, the term “adjuvant” refers to any substance than when used in combination with a specific antigen produces a more robust immune response than the antigen alone. When incorporated into a vaccine formulation, an adjuvant acts generally to accelerate, prolong, or enhance the quality of specific immune responses to the vaccine antigen(s). Adjuvants typically promote the accumulation and/or activation of accessory cells or factors to enhance antigen-specific immune responses and thereby enhance the efficacy of vaccines, i.e., antigen-containing or encoding compositions used to induce protective immunity against the antigen.


Adjuvants, in general, include adjuvants that create a depot effect, immune-stimulating adjuvants, and adjuvants that create a depot effect and stimulate the immune system. An adjuvant that creates a depot effect is an adjuvant that causes the antigen to be slowly released in the body, thus prolonging the exposure of immune cells to the antigen. This class of adjuvants includes but is not limited to alum (e.g., aluminum hydroxide, aluminum phosphate); emulsion-based formulations including mineral oil, non-mineral oil, water-in-oil or oil-in-water-in oil emulsion, oil-in-water emulsions such as Seppic ISA series of Montanide adjuvants (e.g., Montanide ISA 720; AirLiquide, Paris, France); MF-59 (a squalene-in-water emulsion stabilized with Span 85 and Tween 80; Chiron Corporation, Emeryville, Calif.); and PROVAX™ (an oil-in-water emulsion containing a stabilizing detergent and a micelle-forming agent; IDEC Pharmaceuticals Corporation, San Diego, Calif.).


An immune-stimulating adjuvant is an adjuvant that causes activation of a cell of the immune system. It may, for instance, cause an immune cell to produce and secrete cytokines and interferons. This class of adjuvants includes but is not limited to saponins purified from the bark of the Q. saponaria tree, such as QS21 (a glycolipid that elutes in the 21st peak with HPLC fractionation; Aquila Biopharmaceuticals, Inc., Worcester, Mass.); poly [di(carboxylatophenoxy)phosphazene (PCPP polymer; Virus Research Institute, USA); derivatives of lipopolysaccharides such as monophosphoryl lipid A (MPL; Ribi ImmunoChem Research, Inc., Hamilton, Mont.), muramyl dipeptide (MDP; Ribi) and threonyl-muramyl dipeptide (t-MDP; Ribi); OM-174 (a glucosamine disaccharide related to lipid A; OM Pharma SA, Meyrin, Switzerland); and Leishmania elongation factor (a purified Leishmania protein; Corixa Corporation, Seattle, Wash.). This class of adjuvants also includes CpG DNA.


Adjuvants that create a depot effect and stimulate the immune system are those compounds which have both of the above-identified functions. This class of adjuvants includes but is not limited to ISCOMS (immunostimulating complexes which contain mixed saponins, lipids and form virus-sized particles with pores that can hold antigen; CSL, Melbourne, Australia); SB-AS2 (SmithKline Beecham adjuvant system #2 which is an oil-in-water emulsion containing MPL and QS21: SmithKline Beecham Biologicals [SBB], Rixensart, Belgium); SB-AS4 (SmithKline Beecham adjuvant system #4 which contains alum and MPL; SBB, Belgium); non-ionic block copolymers that form micelles such as CRL 1005 (these contain a linear chain of hydrophobic polyoxypropylene flanked by chains of polyoxyethylene; Vaxcel, Inc., Norcross, Ga.); and Syntex Adjuvant Formulation (SAF, an oil-in-water emulsion containing Tween 80 and a nonionic block copolymer; Syntex Chemicals, Inc., Boulder, Colo.).


The active ingredients of the pharmaceutical compositions described herein can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).


In some embodiments, sustained-release preparations can be used. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a composition described herein in which the matrices are in the form of shaped articles, e.g., films, or microcapsule. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and y ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated, the composition can remain in the body for a long time (e.g., up to about 1 hour, between 1-12 hours, 12-24 hours, 24 hours to 2 days, 2-3 days, 3-4 days, 4-5 days, 5-6 days, 6-7 days, 1-2 weeks, 3-4 weeks, 4 weeks to 2 months, 2-3 months, 3-4 months, 4-5 months, 5-6 months, or more than 6 months, or a variation thereof), denature, or aggregate as a result of exposure to moisture at 37° C., resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies can be devised for stabilization depending on the mechanism involved. For example, if the aggregation mechanism is discovered to be intermolecular S—S— bond formation through thio-disulfide interchange, stabilization can be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.


Administration, Dosing, Efficacy

The engineered EV compositions, pharmaceutical compositions, or vaccine compositions described herein can be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular subject being treated, the clinical condition of the individual subject, the cause of the disorder, the site of delivery of the vaccine composition, the method of administration, the scheduling of administration, and other factors known to medical practitioners.


Generally, application of artificial synapses as therapy will take into account similar parameters as other therapeutic strategies, including concentration, timing of delivery, and sustained bioavailability at injury/disease site. Extracellular vesicle can be delivered via a number of routes: intravenous, intracoronary, and intramyocardial. Extracellular vesicles (e.g., exosomes), also allow for new delivery routes that were previously infeasible for cell therapy, such as inhalation or injection. These various approaches are described below, including injection, topical application, enteral administration, and pulmonary delivery.


The engineered EV compositions provided herein can be administered to a subject in need thereof by any appropriate route which results in an effective treatment in the subject. As used herein, the terms “administering,” and “introducing” are used interchangeably and refer to the placement of a composition provided herein into a subject by a method or route which results in at least partial localization of such compositions at a desired site, such as a site of inflammation or a tumor, such that a desired effect(s) is produced. The compositions can be administered to a subject by any mode of administration that delivers the composition systemically or to a desired surface or target, and can include, but is not limited to, injection, infusion, instillation, and inhalation administration. To the extent that the composition can be protected from inactivation in the gut, oral administration forms are also contemplated. “Injection” includes, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intraventricular, intracapsular, intraorbital, retro-orbital, intravitreal, intraocular, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intracerebral, intratarsal, and intrasternal, intratumoral injection, and infusion or the like as known in the art.


A therapeutic does of the present invention may be delivered to a patient by means of controlled release, for example but not limited to, implantable pump and implantable cannulas to provide continuous access to the venous or arterial system.


Topical application refers to applying or spreading a composition of the present invention onto surfaces on or in the body, both internally and/or externally, in a therapeutically effective amount for local and/or systemic treatment. Topical application may be epicutaneous wherein a composition of the present invention may be directly applied onto a localized surface of the skin or mucous membranes. Topical application may include transdermal application wherein a composition of the present invention may be absorbed into the body to obtain systemic delivery and systemic distribution. Topical application formulations may include, but are not limited to, creams, foams, gels, lotions, solutions, ointments, dermal patch, transdermal patches, powder, solid, sponge, tape, vapor, paste, film, liposomes, balm, shampoo, spray, or tincture or the like or a combination thereof. A therapeutic dose of a composition of the present invention may be delivered vaginally (for example a vaginal suppository, vaginal ring, douche, intrauterine device, intravesical infusion, and the like) or urethra or the like or a combination thereof.


Enteral administration refers to a composition of the present invention administered via the gastrointestinal tract in a therapeutically effective amount for local or systemic treatment. Enteral administration may include, but is not limited to, delivery of a composition of the present invention via the mouth, sublingual, esophagus, gastric (for example the stomach), small intestines, large intestines or rectum. Oral delivery of the present invention may include, but is not limited to, the use of a capsule, pastille, pill, tablet, solution, gel, suspension, emulsion, syrup, elixir, tincture, mouthwash, lozenges, chewing gum, lollipop, cream, foam, solution, powder, solid, vapor, liposomes, spray, or tincture osmotic-controlled release oral delivery system, or the like. Gastric delivery may involve the use of a tube or nasal passage that leads directly to the stomach, for example, a percutaneous endoscopic gastrostomy tube. Gastric delivery may involve direct injection made through the abdominal wall. Rectal delivery may involve, but is not limited to, the use of a suppository, ointment, enema, murphy drip, or the like. A therapeutic does of the present invention may be delivered to a patient by means of controlled release, for example but not limited to, controlled release drug delivery pellet or pill.


Inhalation (i.e., pulmonary delivery, pulmonary administration refers to delivery to the respiratory system through the respiratory route, including but not limited to, intranasal administration, oral administration, and oral inhalative administration (e.g. intratracheal instillation and intratracheal inhalation) of a therapeutically effective amount for local or systemic treatment. Pulmonary delivery of a therapeutically effective amount of a composition of the present invention may be achieved by dispersion, for example by using a syringe. Pulmonary delivery of a composition of the present invention may be achieved by aerosol administration, wherein aerosol administration may deposit a therapeutically effective amount of the present invention by gravitational sedimentation, inertial impaction, or diffusion.


Intravenous delivery technique can occur through a peripheral or central venous catheter. As the simplest delivery mode, this technique avoids the risk of an invasive procedure. However, intravenous may be regarded as a comparatively inefficient and less localized delivery method, as a high percentage of infused cell exosomes may become sequestered in organs such as the lung, liver, or spleen. Such sequestration may result in few or no cellular exosomes reaching broader circulation or have unintended systemic effects following their distribution.


In certain embodiments, administration can include delivery to a tissue or organ site that is the same as the site of diseased and/or dysfunctional tissue. In certain embodiments, administration can include delivery to a tissue or organ site that is different from the site or diseased and/or dysfunctional tissue. In certain embodiments, the delivery is via inhalation or oral administration. In various embodiments, administration of artificial synapses can include combinations of multiple delivery techniques.


In some embodiments, the compositions described herein are administered by aerosol administration, nebulizer administration, or tracheal lavage administration.


The term “effective amount” as used herein refers to the amount of an engineered EV composition needed to alleviate or prevent at least one or more symptom of a disease or disorder (e.g., autoimmune disease or cancer), and relates to a sufficient amount of pharmacological composition to provide the desired effect, e.g., reduce the pathology, or any symptom associated with or caused by the a disease. The term “therapeutically effective amount” therefore refers to an amount of an engineered EV composition or vaccine composition described herein using the methods as disclosed herein, that is sufficient to affect a particular disease state when administered to a typical subject. An effective amount as used herein would also include an amount sufficient to delay the development of a symptom of the disease, alter the course of a symptom disease (for example, but not limited to, slow the progression of a symptom of the disease), or reverse a symptom of the disease. Thus, it is not possible to specify the exact “effective amount.” However, for any given case, an appropriate “effective amount” can be determined by one of ordinary skill in the art using only routine experimentation.


Effective amounts, toxicity, and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dosage can vary depending upon the dosage form employed and the route of administration utilized. The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50/ED50. Compositions and methods that exhibit large therapeutic indices are preferred. A therapeutically effective dose can be estimated initially from cell culture assays. Also, a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the engineered EVs or fusion polypeptides provided herein), which achieves a half-maximal inhibition of symptoms) as determined in cell culture, or in an appropriate animal model. Levels of therapeutic engineered EVs in plasma can be measured, for example, by high performance liquid chromatography, enzyme linked immunosorbent assay (ELISA), flow cytometry, FACS sorting, western blot, mass spectroscopy, tunable resistive pulse sensing, ExoView®, qRT-PCR, next generation sequencing (NGS), or by any analysis technique known by one of ordinary skill in the art. The effects of any particular dosage can be monitored by a suitable bioassay. The dosage can be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.


The engineered EV compositions, pharmaceutical compositions, or vaccine compositions described herein can be formulated, in some embodiments, with one or more additional therapeutic agents currently used to prevent or treat the infection, for example. The effective amount of such other agents depends on the amount of an engineered EV in the formulation, the type of disorder or treatment, and other factors discussed above. These are generally used in the same dosages and with administration routes as used herein before or about from 1 to 99% of the heretofore employed dosages.


The dosage ranges for the pharmaceutical compositions described herein depend upon the potency and encompass amounts large enough to produce the desired effect. The dosage should not be so large as to cause unacceptable adverse side effects. Generally, the dosage will vary with the age, condition, health, and sex of the patient and can be determined by one of skill in the art. The dosage can also be adjusted by the individual physician in the event of any complication. In some embodiments, the dosage ranges from 0.001 mg/kg body weight to 100 mg/kg body weight. In some embodiments, the dose range is from 5 μg/kg body weight to 100 μg/kg body weight. Alternatively, the dose range can be titrated to maintain serum levels between 0.1 μg/mL and 1000 μg/mL. For systemic administration, subjects can be administered a therapeutic amount, such as, e.g., 0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, or more. These doses can be administered by one or more separate administrations, or by continuous infusion. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until, for example, the infection is treated, as measured by the methods described above or known in the art. However, other dosage regimens can be useful.


In various embodiments, the quantities of artificial synapses that are administered to achieve these effects range from 1×106 to 1×107, 1×107 to 1×108, 1×108 to 1×109, 1×109 to 1×1010, 1×1010 to 1×1011, 1×1011 to 1×1012, 1×1012 to 1×1013, 1×1013 to 1×1014, 1×1014 to 1×1015, 1×1015 or more EVs/artificial synapses. In other embodiments, the numbers of artificial synapses are relative to the number of cells used in a clinically relevant dose for a cell-therapy method. For example, defining an effective dose range, dosing regimen and route of administration, may be guided by studies using fluorescently labeled artificial synapses, and measuring target tissue retention, which can be >10×, >50×, or >100× background, as measured 5, 10, 15, 30, or 30 or more min as a screening criterion. In certain embodiments, >100× background measured at 30 mins is a baseline measurement for a low and high dose that is then assess for safety and bioactivity (e.g., using MRI endpoints: scar size, global and regional function of the target organ being treated). In various embodiments, single doses are compared to two, three, four, four or more sequentially-applied doses. In various embodiments, the repeated or sequentially-applied doses are provided for treatment of an acute disease and/or condition. In various embodiments, the repeated or sequentially-applied doses are provided for treatment of a chronic disease and/or condition. In other embodiments, administration of the plurality of artificial synapses is adjunctive to standard therapy.


In other embodiments, administering a composition includes 1×1010 or more artificial synapses in a single dose. In various embodiments, exosome quantity may be defined by protein quantity, such as dosages including 1-10, 10-25, 25-50, 50-75, 75-100, or 100 or more mg exosome protein. In other embodiments, a single dose is administered multiple times to the subject. In other embodiments, administering a composition consists of one or more of: injection, topical administration, enteral, intravenous, intra-arterial, or inhalation.


In various embodiments, exosome quantity may be defined by protein quantity, such as dosages including 1-10, 10-25, 25-50, 50-75, 75-100, or 100 or more mg exosome protein. In various embodiments, administering a composition includes multiple dosages of the artificial synapses. In various embodiments, the repeated or sequentially-applied doses are provided for treatment of an acute disease and/or condition. In various embodiments, the repeated or sequentially-applied doses are provided for treatment of a chronic disease and/or condition.


In other embodiments, administering a composition including a plurality of artificial synapses to the subject is adjunctive to standard therapy.


The duration of a therapy using the methods described herein will continue for as long as medically indicated or until a desired therapeutic effect (e.g., those described herein) is achieved. In certain embodiments, the administration of the vaccine composition described herein is continued for 1 month, 2 months, 4 months, 6 months, 8 months, 10 months, 1 year, 2 years, 3 years, 4 years, 5 years, 10 years, 20 years, or for a period of years up to the lifetime of the subject.


As will be appreciated by one of skill in the art, appropriate dosing regimens for a given composition can comprise a single administration/immunization or multiple ones. Subsequent doses may be given repeatedly at time periods, for example, about two weeks or greater up through the entirety of a subject's life, e.g., to provide a sustained preventative effect. Subsequent doses can be spaced, for example, about two weeks, about three weeks, about four weeks, about one month, about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months, about ten months, about eleven months, or about one year after a primary immunization.


The precise dose to be employed in the formulation will also depend on the route of administration and should be decided according to the judgment of the practitioner and each patient's circumstances. Ultimately, the practitioner or physician will decide the amount of the engineered EV or composition thereof to administer to particular subjects.


Methods of Modulating Inflammation and Treating Autoimmune Diseases

The artificial synapses/engineered EVs and compositions thereof provided herein can be deployed in a therapeutic strategy against virtually any injury/disease, as providing a platform for altering biological signaling. This includes, for example, inflammation and immune signaling, which plays a role in virtually all injuries and diseases in living organisms.


Thus, described herein is a method of modulating inflammation, including selecting a subject afflicted with an inflammatory related disease and/or condition; and administering to the subject a composition including a plurality of artificial synapses (engineered EVs) to the subject, wherein administration of the composition modulates inflammation.


As used herein, the term “inflammation” or “inflamed” refers to activation or recruitment of the immune system or immune cells (e.g. T cells, B cells, macrophages). A tissue that has inflammation can become reddened, white, swollen, hot, painful, sensitivity, exhibit a loss of function, or have a film or mucus. Methods of identifying inflammation are well known in the art. Inflammation typically occurs following injury, infection by a microorganism, exposure to a substance (e.g., a toxin, chemical, or dust) or autoimmune dysfunction. Onset of inflammation may be rapid (e.g., immediately following injury) or slow (e.g., repeated exposure to an irritant such as a chemical over time) with a duration of minutes, hours, days, months, years, or an individual's life.


Inflammation plays a vital role in alerting the immune system of potential danger and damage within a body. Inflammation is necessary to control and repair injury. For example, acute inflammation is a response to physical trauma, infection, and stress. Acute inflammation helps prevent further injury and triggers healing and recovery. Unfortunately, inflammation can become excessive and inappropriately active, lasting beyond the typical recovery time from an injury or infection. Wherein healthy inflammation helps a body respond to injury, chronic inflammation perpetuates injury and may lead to negative consequences to one's health. In particular, autoimmune diseases are chronic diseases from a host's immune system attacking itself, often due to aberrant biological signaling in the host. Restoring normal homeostatic signaling via application of artificial synapses, particularly targeting immune checkpoints, represents a highly promising avenue. For example, surface bound immune-checkpoint proteins or fragments thereof may modulate immune cell stimulation and affect suppression of immune cell function when delivered via artificial synapses. Injection, inhalation, ingestion or topical application of artificial synapses with surface bound immune-checkpoint proteins or fragments thereof may be used to treat immune, auto-immune, inflammatory, and auto-inflammatory conditions. Examples include chronic obstructive pulmonary disease (COPD) which is an inflammatory, progressive, life-threatening lung disease, psoriasis, a common chronic noncommunicable inflammatory skin disease, arthritis, a debilitating and painful degeneration of joints, among others well-understood to one of skill in the art.


In other embodiments, the inflammatory related disease and/or condition is acute, for example septicemia. In other embodiments, the inflammatory related disease and/or condition is chronic, for example chronic obstructive pulmonary disease. In other embodiments, the inflammatory condition is an autoimmune disease wherein the autoimmune disease and/or condition is one or more of: polymyositis, dermatomyositis, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, vasculitis, multiple sclerosis, psoriasis, rheumatoid arthritis, psoriatic arthritis, scleroderma, systemic lupus erythematosus, inflammatory bowel disease, Crohn's disease, hyperthyroidism, autoimmune adrenal insufficiency, Sjogren syndrome, type I diabetes mellitus, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, myasthenia gravis, ulcerative colitis, uveitis, polyarteritis nodosa, relapsing polychondritis, Behcet's disease, reactive arthritis, ankylosing spondylitis, Guillain-Barre syndrome, or optic neuropathy. In other embodiments, the disease and/or condition is chronic obstructive pulmonary disease, rheumatoid arthritis, uveoretinitis, psoriasis, and eczema. In other embodiments, the disease and/or condition is irritable bowel disease, multiple sclerosis or lupus


In other embodiments, the inflammatory related disease and/or condition is an ocular disease. As used herein, the terms “ocular disease”, “eye disorder” and “eye disease” are used interchangeably and refer to a disease or disorder that affects the health and/or vision of either one or both eyes or the general area of the eye(s), eye lid(s), or area surrounding or in near proximity to the eye(s). Eye disease may include, but are not limited to, macular degeneration (e.g., age-related macular degeneration), cataracts, diabetic retinopathy, diabetic macular edema, eye floaters, eye flashes, glaucoma, amblyopia, strabismus, retinitis (e.g., CMV retinitis), color blindness, keratoconus, retinal detachment, eyelid twitching, ocular hypertension, blepharitis, uveitis, Bietti's crystalline dystrophy, blepharospasm, cornea and corneal diseases, dry eye, histoplasmosis, macular hole, macular pucker, conjunctivitis, presbyopia, retinoblastoma, retinitis pigmentosa, retinopathy, Stargardt disease, Usher syndrome, uveal Coloma, and vitreous detachment, or the like.


Described herein is a method for treatment including, selecting a subject in need of treatment, administering a composition including a plurality of artificial synapses to the individual, wherein administration of the composition treats the subject. In certain embodiments, the subject is in need to treatment for a disease and/or condition involving tissue damage or dysfunction.


Described herein is a method of treating an autoimmune disease, inflammation, inflammatory disease or condition, or cancer in a subject, the method comprising: administering to a subject the an engineered EV or composition thereof as provided herein to the subject.


Measured or measurable parameters include clinically detectable markers of disease, for example, elevated or depressed levels of a clinical or biological marker, as well as parameters related to a clinically accepted scale of symptoms or markers for a disease or disorder. It will be understood, however, that the total usage of the compositions and formulations as disclosed herein will be decided by the attending physician within the scope of sound medical judgment. The exact amount required will vary depending on factors such as the type of disease being treated.


Non-limiting examples of clinical tests that can be used to assess autoimmune diseases, inflammatory conditions, or inflammation parameters include blood tests, skin biopsy, MRI, eye examination, ocular pressure tests, etc. Where necessary or desired, animal models of injury or disease can be used to gauge the effectiveness of a particular composition as described herein. For example, an EAU animal model, as demonstrated in the working examples can be used.


In various embodiments, administration of the plurality of artificial synapses alters gene expression in the damaged or dysfunctional tissue, improves viability of the damaged tissue, and/or enhances regeneration or production of new tissue in the individual. In various embodiments, administration of the plurality of artificial synapses alters gene expression in the damaged or dysfunctional tissue, improves viability of the damaged tissue, and/or enhances regeneration or production of new tissue in the individual.


In various embodiments, the damaged or dysfunctional tissue is in need of repair, regeneration, or improved function due to an acute event. Acute events include, but are not limited to, trauma such as laceration, crush or impact injury, shock, loss of blood or oxygen flow, infection, chemical or heat exposure, poison or venom exposure, drug overuse or overexposure, and the like. Other sources of damage also include, but are not limited to, injury, age-related degeneration, cancer, and infection. In several embodiments, the regenerative cells used to prepare the engineered EVs provided herein are from the same tissue type as is in need of repair or regeneration. In several other embodiments, the regenerative cells are from a tissue type other than the tissue in need of repair or regeneration. In some embodiments, the engineered EVs provided herein are derived from the subject being treated. In some embodiments, the engineered EVs are derived from a donor subject.


In other embodiments, the damaged or dysfunctional tissue is in need of repair, regeneration, or improved function due to damage from chronic disease.


Some Selected Definitions

All references cited herein are incorporated by reference in their entirety as though fully set forth. Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Allen et al., Remington: The Science and Practice of Pharmacy 22nd ed., Pharmaceutical Press (Sep. 15, 2012); Hornyak et al., Introduction to Nanoscience and Nanotechnology, CRC Press (2008); Singleton and Sainsbury, Dictionary of Microbiology and Molecular Biology 3rd ed., revised ed., J. Wiley & Sons (New York, NY 2006); Smith, March's Advanced Organic Chemistry Reactions, Mechanisms and Structure 7th ed., J. Wiley & Sons (New York, NY 2013); Singleton, Dictionary of DNA and Genome Technology 3rd ed., Wiley-Blackwell (Nov. 28, 2012); and Green and Sambrook, Molecular Cloning: A Laboratory Manual 4th ed., Cold Spring Harbor Laboratory Press (Cold Spring Harbor, N Y 2012), provide one skilled in the art with a general guide to many of the terms used in the present application. For references on the preparation and structure of antibodies and fusion polypeptides, see, e.g., Greenfield, Antibodies A Laboratory Manual 2nd ed., Cold Spring Harbor Press (Cold Spring Harbor NY, 2013); Köhler and Milstein, Derivation of specific antibody-producing tissue culture and tumor lines by cell fusion, Eur. J. Immunol. 1976 July, 6(7):511-9; Queen and Selick, Humanized immunoglobulins, U.S. Pat. No. 5,585,089 (1996 December); and Riechmann et al., Reshaping human antibodies for therapy, Nature 1988 Mar. 24, 332(6162):323-7. See also, Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991), Lanzavecchia et al., Eur. J. Immunol. 17, 105 (1987)), Huston et al., Proc. Natl. Acad. Sci. U.S.A., 85, 5879-5883 (1988), Bird et al., Science 242, 423-426 (1988), Brinkman et al. mAbs Vol 9, No. 2, 182-212 (2017), Chothia & Lesk, J. Mol. Biol, 196:901-917 (1987), Chothia et al., Nature 342:877-883 (1989)), Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90: 6444-6448; Poljak (1994) Structure 2: 1121-1123); Kontermann and Dubel eds., Antibody Engineering, Springer-Verlag, N.Y. (2001), p. 790 (ISBN 3-540-41354-5, Zapata et al. (1995) Protein Eng. 8(10): 1057-1062; Morrison, et al., Proc. Natl. Acad. Sci. USA, 81:6851 (1984), U.S. Pat. Nos. 4,816,567, 5,693,780, which are incorporated herein by reference in their entireties.


One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. Indeed, the present invention is in no way limited to the methods and materials described. For purposes of the present invention, the following terms are defined below.


As used herein, the term “extracellular vesicle” and “vesicle” are used interchangeably and refer to a particle, wherein the particle comprises a phospholipid bilayer that encloses an internal space and an exterior surface and may or may not be derived from a cell. The size of extracellular vesicles can range between 20 nm to 3 μm in diameter but may be smaller than 20 nm or larger than 3 μm. Examples of extracellular vesicles include, but is not limited to, exosomes (for example small exosomes and large exosomes), ectosomes, macrovesicles, microparticles, apoptotic bodies, vesicular organelles, oncosomes (for examples large oncosomes), exospheres, exomeres, cell derived nanovesicles (CDN) (e.g., by genesis via grating or shearing cells), liposomes or the like known by one of ordinary skill in the art. Extracellular vesicles may originate naturally via known or unknown biosynthetic pathways. Extracellular vesicles may be promoted to originate by using mechanical methods such as cell grating or cell shearing wherein a cell is grated or sheared causing portions or parts of the cell membrane to from vesicles. For example, CDNs may be formed by using mechanical methods such as cell grating or cell shearing wherein a cell is grated or sheared causing portions or parts of the cell membrane to from vesicles. Additional non-limiting examples of mechanical methods that can be used to form cell derived nanovesicles are further described in detail, e.g., Goh, Zou, S., Ong, W. Y. et al. Bioinspired Cell-Derived Nanovesicles versus Exosomes as Drug Delivery Systems: a Cost-Effective Alternative. Sci Rep 7, 14322 (2017). https://doi.org/10.1038/s41598-017-14725-x, the contents of which are incorporated herein by reference in their entireties.


Extracellular vesicles comprise cargo, wherein the term “cargo” refers to peptides, proteins, nucleic acids, lipids, metabolites, carbohydrates, biomolecules, small molecules, large molecules, vesicles, organelles, or fragments thereof. In some embodiments, cargo may refer to existing drugs or therapeutics known in the art. Extracellular vesicle cargo may be located within the internal space of the extracellular vesicle. Extracellular vesicle cargo may be membrane bound and span one or both layers of the extracellular vesicle phospholipid bilayer (for example a transmembrane protein). Extracellular vesicle cargo may be in contact with the external or internal surface of the extracellular vesicle, for example through a covalent bond or a non-covalent bond. The phospholipid bilayer of the extracellular vesicle may comprise one or more transmembrane proteins, wherein a portion of the one or more transmembrane membrane proteins is located within the internal space of the extracellular vesicle. The phospholipid bilayer of the extracellular vesicle may comprise one or more transmembrane proteins, wherein the one or more transmembrane membrane proteins comprises a domain on the exterior of the extracellular vesicle. The phospholipid bilayer of the extracellular vesicle may comprise one or more transmembrane proteins, wherein the one or more transmembrane membrane proteins comprises a domain on the interior of the extracellular vesicle. Cargo may refer to a protein on the luminal side (e.g., in the internal space) of the extracellular vesicle wherein said protein encodes a vesicle targeting domain that may be in contact with the interior phospholipid layer of the extracellular vesicle. Cargo may refer to a protein on the luminal side (e.g., in the internal space) of the extracellular vesicle wherein said protein encodes a vesicle targeting domain that may be in contact with the interior phospholipid layer of the extracellular vesicle and wherein said protein may be presented into the internal space of the extracellular vesicle.


As used herein, the terms “sticky binder” and “vesicle targeting domain” and “anchor protein” are used interchangeably and refer to a protein that is covalently or non-covalently attached to at least one lipid wherein the one or more lipid is embedded within a membrane (e.g. a cell membrane), and the lipid serves to anchor the protein to the membrane. The terms “sticky binder” and “vesicle targeting domain” and “anchor protein” can also mean a protein sequence that encodes for one or more transmembrane domains wherein the one or more transmembrane domains spans at least partly through a phospholipid bilayer, for example the phospholipid bilayer of an extracellular vesicle. The transmembrane domain can be of a Type I or Type II membrane protein. Transmembrane domains can be structurally identified using methods known to those of skill in the art, such as sequence analysis programs that identify hydrophobic and hydrophilic domains (for example TMHMM Server, v. 2.0—DTU, Erik L. L. Sonnhammer, Gunnar von Heijne, and Anders Krogh: A hidden Markov model for predicting transmembrane helices in protein sequences. In Proc. of Sixth Int. Conf. on Intelligent Systems for Molecular Biology, p 175-182 Ed J. Glasgow, T. Littlejohn, F. Major, R. Lathrop, D. Sankoff, and C. Sensen Menlo Park, CA: AAAI Press, 1998, which is incorporated herein by reference in its entirety.)


A vesicle targeting domain may include, but is not limited to, one or more prenylation site, fatty acylation site, and/or glycosylphosphatidylinositol (GPI) linked protein. One preferred embodiment of a vesicle targeting domain is the GPI sequence from CD55. Another preferred embodiment of a vesicle targeting domain is the GPI sequence from CD59. Another embodiment of a vesicle targeting domain is the C1C2 domain from MFGE8. Other embodiments of sequences for vesicle targeting domains include transmembrane regions of CD9 (for example transmembrane 2 or 3 of CD9, CD9tm2 or CD9tm3, respectively), K-Ras (for example K-Ras4A and K-Ras4B), transmembrane domain from A Disintegrin and Metalloproteinase Domain-containing protein 10 (ADAM10, also known as CDw156 or CD156c) or other ADAM proteins. Vesicle targeting domains may include one or more sequences from 4F2 (for example 4F2 encoded by the solute carrier family 3 member 2 (SLC3A2) gene which makes up the heavy subunit of CD98). Vesicle targeting domains can include a sequence for one or more myristoylation sites. For example, the protein sequence for a myristoylation site from myristoylated alanine-rich C-kinase substrate (MARCKS) protein. Vesicle targeting domains can include a sequence for one or more palmitoylation sites. For example, the myristoylation sequence from the MARCKS protein may be modified to encode for a palmitoylation site. All variants, isoforms, or fragments or the like known by one of ordinary skill in the art are encompassed by the present invention.


Vesicle targeting domains may include transmembrane sequences from Homo sapiens transferrin receptor 2 (TFR2), transcript variant 1 (transferrin receptor protein 2 isoform 1) or versions therefore. In a preferred embodiment, the vesicle targeting domain may be a transmembrane domain from CD298.


As used herein, the terms “proteins” and “peptides” and “polypeptides” are used interchangeably herein to designate a series of amino acid residues connected to the other by peptide bonds between the alpha-amino and carboxy groups of adjacent residues. Although “protein” is often used in reference to relatively large polypeptides, and “peptide” is often used in reference to small polypeptides, usage of these terms in the art overlaps and varies. The term “peptide” as used herein refers to peptides, polypeptides, proteins and fragments of proteins, unless otherwise noted. The terms “protein” and “peptide” are used interchangeably herein when referring to a gene product and fragments thereof. Thus, exemplary peptides or proteins include gene products, naturally occurring proteins, homologs, orthologs, paralogs, fragments and other equivalents, variants, fragments, and analogs of the foregoing.


“As used herein, the term “linker” refers to a synthetic protein sequence of amino acids that is used to connect two polypeptide domains via peptide bonds.


As used herein, the term “fusion protein” refers to a single chimeric protein comprising a protein of interest (e.g. checkpoint protein) joined to an exogenous protein or protein fragment (e.g. an anchor protein), wherein the components of the fusion protein are linked to each other by peptide-bonds, either directly or through a peptide linker. The anchor protein of the fusion protein may enhance incorporation of the fusion protein onto and/or into the membrane of a vesicle, for example the internal and/or external leaflet of the phospholipid bilayer of an exosome membrane. The fusion protein may have at least a part of an amino acid sequence of an immune checkpoint protein or proteins involved in immune synapses. The fusion protein may have at least a part of an amino acid sequence of A2AR, VTCN1, Galectin 9, FGL-1, PECAM-1, TSG-6, STAB-1, NRP1, NRP2, SEMA3A, SEMA3F, RGMB, TIM-3, TIGIT, HLA class I, HLA class II, VISTA, HMGB1, phosphatidylserine, T-cell receptor (TCR), SHP-1, SHP-2, FBXO38, SH2D1A, B7RP1, IDO, NOX2, TNFRSF18, B7-H4, B7-H5, SISP1, B7-H6, B7-H7, APLNR, IFN y, PD-1, WNT5A, IL-6, IL-10, NKG2 family of C-type lectin receptors, ligands of NKG2 family, killer cell immunoglobulin-like receptors, CD2, CD4, CD8, CD27, CD27 ligand (CD70), CD28, CD28H, CD39, CD40, CD44, CD47, CD63, CD66a, CD80, B7-2, CD86, CD73, CD94, CD96, CD101, CD112, CD112R, CD122, CD134, CD137 (4-1BB), CD137 ligand (4-1BBL), CD152, CD154, CD155, CD158, CD158a, CD158g, CD158h, KIR2DL1, KIR2DS1, KIRDS3, KIR2DS5, CD160, CD172a, CD200, CD200R, CD223, CD226, CD252, CD270, CD272, CD273, CD274, CD275, CD276, CD278, CD279 (PD-1), CD279 ligand (PD-L1/PDL-2), CD328, CD329, and/or CD337. The fusion protein may have a polypeptide linker sequence (e.g., an Fc domain and/or a GSSG linker), followed by an amino acid sequence coding for an anchor protein sequence (e.g., a prenylation site, fatty acylation site, or a GPI sequence) or any isoform, fragment, variation thereof, or a ligand to the aforementioned proteins thereof, or the like known by one of ordinary skill in the art. All variants are encompassed by the present invention.


As used herein, the term “immune synapse” and “cell synapse” are used interchangeably and refer to cell-to-cell interaction wherein said interaction results in activation, suppression, and/or adhesion of either one or more cells. Immune synapse or cell synapse are mediated by proteins that may be cytoplasmic, membrane bound, membrane associated, and/or secreted. Immune or cell synapses may be mediated by one or more “immune checkpoint proteins” which herein refers to any protein that is involved in maintaining immune homeostasis or plays a role in regulating immune activation or suppression. Immune checkpoint proteins may be cytoplasmic, membrane bound, membrane associated, and/or secreted.


As used herein, the term “fragment” or “active fragment” refers to a portion of a nucleic acid or polypeptide provided herein that retains the ability to be expressed by the engineered EVs provided herein. In some embodiments, the active fragment retains the ability to activate a target polypeptide, thereby increasing the activity of said target polypeptide (e.g., suppressing an immune response).


As used herein, the terms “specifically bind” and/or “specifically recognize” or “substantially binds” refers to the affinity of a binding molecule for a target molecule compared to the binding molecule's affinity for non-target molecules. A binding molecule (e.g., a POI domain) that specifically binds a target molecule (e.g., a target polypeptide provided herein) does not substantially recognize or bind non-target molecules. e.g., an antibody “specifically binds” and/or “specifically recognize” another molecule, meaning that this interaction is dependent on the presence of the binding specificity of the molecule structure, e.g., an antigenic epitope. As used herein, “non-specific binding” and “background binding” refers to the interaction that does not depend on the presence of specific structure (e.g., a specific antigenic epitopes). Methods of measuring binding of a polypeptide to a target are known in the art (e.g., differential scanning calorimetry, isothermal titration calorimetry, spectroscopy, crystallography, surface plasmon resonance, co-immunoprecipitation, pulldown assays, crosslinking, yeast two-hybrid system, tandem affinity purification-mass spectroscopy, protein microarrays, bio-layer interferometry, far-Western blots, computational prediction, analytical ultracentrifugation, light scattering, fluorescence spectroscopy, resonance energy transfer, ELISA or ELISPOT assays, or any other assays known in the art).


As used herein, the terms “treat,” “treatment,” “treating,” or “amelioration” refer to therapeutic treatments, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a condition associated with, a disease or disorder. The term “treating” includes reducing or alleviating at least one adverse effect or symptom of a condition, disease or disorder associated with an infection or a cancer. Treatment is generally “effective” if one or more symptoms or clinical markers are reduced. Alternatively, treatment is “effective” if the progression of a disease is reduced or halted. That is, “treatment” includes not just the improvement of symptoms or markers, but also a cessation or at least slowing of progress or worsening of symptoms that would be expected in absence of treatment. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s), diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. The term “treatment” of a disease also includes providing relief from the symptoms or side-effects of the disease (including palliative treatment).


As used herein “preventing” or “prevention” refers to any methodology where the disease state does not occur due to the actions of the methodology (such as, for example, administration of a composition or construct as described herein). In one aspect, it is understood that prevention can also mean that the disease is not established to the extent that occurs in untreated controls. Accordingly, prevention of a disease encompasses a reduction in the likelihood that a subject can develop the disease, relative to an untreated subject (e.g., a subject who is not treated with the methods or compositions described herein).


As used herein, the terms “autoimmune condition” and “autoimmune disease” are used interchangeably and refer to any disease characterized by abnormal functioning of the immune system and may include, but is not limited to, achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM/Anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal & neuronal neuropathy (AMAN), Baló disease, Behcet's disease, benign mucosal pemphigoid, bullous pemphigoid, Castleman disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS), eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), hidradenitis suppurativa (HS) (acne inversa), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, type 1 diabetes, juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus, lyme disease chronic, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal Lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism (PR), PANDA, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndromes type I, II, III, polymyalgia rheumatica, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm & testicular autoimmunity, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), takayasu's arteritis, temporal arteritis/Giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease. An autoimmune condition or autoimmune diseases may be caused by, but not limited to, a natural predisposition, a infection (e.g., bacteria or virus), drugs, vaccination, environmental triggers (e.g., toxins or chemicals such as dust, silica, oil, benzene, tri- or per-chloroethylene etc.), stress, cancer, blood or tissue or organ transplantation, or unknown etiology. Autoimmune disorders may result in but not limited to the destruction of body tissue, abnormal growth of an organ or tissue, changes in organ or tissue function (e.g., changes in blood vessels, connective tissue, function of endocrine glands, joints, muscles, blood cells, skin, etc.).


As used herein, the term “cancer” refers to a hyperproliferation of cells that exhibit a loss of normal cellular control that results in unregulated growth, lack of differentiation, local tissue invasion, and metastasis. The methods and compositions described herein can be used for the treatment of solid tumors (e.g., cancer) or non-solid tumors, such as leukemia, blood cell cancers, and the like. Solid tumors can be found in bones, muscles, the brain, or organs, and can be sarcomas or carcinomas. Where the methods and compositions described herein can overcome barriers of tumor treatment, including, but not limited to barriers to treatment or inhibition of metastases, it is contemplated that aspects of the technology described herein can be used to treat all types of solid and non-solid tumor cancers, including cancers not listed in the instant specification. The compositions and methods described herein, without limitation, include methods of treating cancer, methods of inhibiting metastases, and methods of inducing an anti-tumor immune response.


As used herein, the terms “subject”, “individual”, “host”, and “patient” are used interchangeably and may refer to any animal, mammal, bird, fish, reptile, and amphibian, for example, human, monkey, dog, cat, horse, pig, cattle, ox, donkey, rabbit, sheep, goat, mouse, rat, guinea pig, llama, chicken, goose, duck, turkey, or the like receiving or registered to receive a therapeutic amount of a composition of the present invention for medical care or treatment.


As used herein, the term “injection” refers to any process or method which allows the person skilled in the art to administer any therapeutic to a target site by penetration. Examples of injection are, but not limited to, subcutaneous, subcuticular, subcapsular, subarachnoid, intradermal, intramuscular, intravenous, intra-arterial, intraventricular, intracapsular, intraorbital, intraocular, intrathoracic, intraperitoneal, intravitreal, retro-orbital, intranasal, intracerebral, intrathymic, intraspinal, intrasternal, intra-articular, intracavernous, intracardiac, intraosseous, intrathecal, transtracheal, epidural, or the like as known in the art. A therapeutic does of the present invention may be delivered to a patient by means of controlled release, for example but not limited to, implantable pump and implantable cannulas to provide continuous access to the venous or arterial system.


As used herein, the term “topical application” refers to applying or spreading a composition of the present invention onto surfaces on or in the body, both internally and/or externally, in a therapeutically effective amount for local and/or systemic treatment. Topical application may be epicutaneous wherein a composition of the present invention may be directly applied onto a localized surface of the skin or mucous membranes. Topical application may include transdermal application wherein a composition of the present invention may be absorbed into the body to obtain systemic delivery and systemic distribution. For example, a transdermal patch may be applied onto the body to deliver a therapeutic dose of a composition of the invention presented herein. Topical application formulations may include, but are not limited to, creams, foams, gels, lotions, solutions, ointments, dermal patch, transdermal patches, powder, solid, sponge, tape, vapor, paste, film, liposomes, balm, shampoo, spray, or tincture. A therapeutic dose of a composition of the present invention may be delivered vaginally (for example a vaginal suppository, vaginal ring, douche, intrauterine device, intravesical infusion, and the like) or urethra.


As used herein, the term “enteral administration” refers to a composition of the present invention administered via the gastrointestinal tract in a therapeutically effective amount for local or systemic treatment. Enteral administration may include, but is not limited to, delivery of a composition of the present invention via the mouth, sublingual, esophagus, gastric (for example the stomach), small intestines, large intestines or rectum. Oral delivery of the present invention may include, but is not limited to, the use of a capsule, pastille, pill, tablet, solution, gel, suspension, emulsion, syrup, elixir, tincture, mouthwash, lozenges, chewing gum, lollipop, osmotic-controlled release oral delivery system, or the like. Gastric delivery may involve the use of a tube or nasal passage that leads directly to the stomach, for example, a percutaneous endoscopic gastrostomy tube. Gastric delivery may involve direct injection made through the abdominal wall. Rectal delivery may involve, but is not limited to, the use of a suppository, ointment, enema, murphy drip, or the like. A therapeutic does of the present invention may be delivered to a patient by means of controlled release, for example but not limited to, controlled release drug delivery pellet or pill.


As used herein, the terms “pulmonary system” or “respiratory system” are used interchangeably and refer, but are not limited, to the respiratory region, conducting airways, nasal cavity, sinuses, nasopharynx, oropharynx, larynx, trachea, bronchi, bronchioles, respiratory bronchioles, alveolar ducts, alveolar sacs, respiratory epithelium (e.g., alveolar epithelial cells), endothelial cells, or the like.


As used herein, the terms “pulmonary delivery” and “pulmonary administration” are used interchangeably and refer to delivering a composition of the present invention to the respiratory system through the respiratory route, including but not limited to, intranasal administration, oral administration, and oral inhalative administration (e.g., intratracheal instillation and intratracheal inhalation) of a therapeutically effective amount for local or systemic treatment. Pulmonary delivery of a therapeutically effective amount of a composition of the present invention may be achieved by dispersion, for example by using a syringe. Pulmonary delivery of a composition of the present invention may be achieved by aerosol administration, wherein aerosol administration may deposit a therapeutically effective amount of the present invention by gravitational sedimentation, inertial impaction, or diffusion.


Pulmonary delivery of a therapeutically effective amount of a composition of the present invention may be deposited on any mucus layer of the respiratory system, for example, but not limited to, the mucus layer which coats the walls of conducting airways, the smaller airway, and/or alveolar space.


As used herein, an “appropriate control” refers to an untreated, otherwise identical cell or population (e.g., a subject who was not administered the composition described herein, or was administered by only a subset of agents provided herein, as compared to a non-control cell).


As used herein, a “reference level” can refer to one or more parameters or markers as measured for a normal, otherwise unaffected cell population or tissue (e.g., a biological sample obtained from a healthy subject, or a biological sample obtained from the subject at a prior time point, or a biological sample that has not yet been contacted with a pathogen as described herein). For measuring or monitoring therapeutic efficacy, a level determined prior to treatment or earlier in treatment can also provide a reference level for a given parameter or value.


As used herein, the term “modulates” refers to an effect including increasing or decreasing a given parameter as those terms are defined herein.


The terms “increased,” “increase,” “increases,” or “enhance” or “activate” are all used herein to generally mean an increase of a property, level, or other parameter by a statistically significant amount; for the avoidance of any doubt, the terms “increased”, “increase” or “enhance” or “activate” means an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, at least about a 20-fold increase, at least about a 50-fold increase, at least about a 100-fold increase, at least about a 1000-fold increase or more as compared to a reference level. For example, increasing activity can refer to activating a receptor or a signaling pathway (e.g., antibody production or inflammation).


The terms “decrease”, “reduced”, “reduction”, or “inhibit” are all used herein to mean a decrease or lessening of a property, level, or other parameter by a statistically significant amount. In some embodiments of any of the aspects, “reduce,” “reduction” or “decrease” or “inhibit” typically means a decrease by at least 10% as compared to a reference level (e.g., the absence of a given treatment) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or more. As used herein, “reduction” or “inhibition” does not encompass a complete inhibition or reduction as compared to a reference level. “Complete inhibition” is a 100% inhibition as compared to a reference level. A decrease can be preferably down to a level accepted as within the range of normal for an individual without a given disorder.


As used herein the term “comprising” or “comprises” is used in reference to compositions, methods, and respective component(s) thereof, that are essential to the method or composition, yet open to the inclusion of unspecified elements, whether essential or not.


As used herein the term “consisting essentially of” refers to those elements required for a given embodiment. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment.


The term “consisting of” refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the embodiment.


As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus for example, references to “the method” includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth. Similarly, the word “or” is intended to include “and” unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The abbreviation, “e.g.” is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation “e.g.” is synonymous with the term “for example.”


The abbreviation, “etc.” is derived from the Latin et cetera, and is used herein to indicate a non-limiting list. Thus, the abbreviation “etc.” is synonymous with the term “and other similar things”, or “and so forth”.


Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.” The term “about” when used in connection with percentages can mean±1%.


The term “statistically significant” or “significantly” refers to statistical significance and generally means a two-standard deviation (2SD) difference, above or below a reference value. Additional definitions are provided in the text of individual sections below.


It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such may vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims.


As used herein and in the claims, the singular forms include the plural reference and vice versa unless the context clearly indicates otherwise. The term “or” is inclusive unless modified, for example, by “either.” Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.”


Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.


It is to be understood that the foregoing description and the following examples are illustrative only and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments, which will be apparent to those of skill in the art, may be made without departing from the spirit and scope of the present invention. Further, all patents, patent applications, and publications identified are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that might be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents are based on the information available to the applicants and do not constitute any admission as to the correctness of the dates or contents of these documents.


All patents and other publications identified are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that could be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.


Some embodiments of the technology described herein can be defined according to any of the following numbered paragraphs:

    • 1. An engineered extracellular vesicle comprising:
      • at least one fusion polypeptide comprising:
        • (i) at least one protein of interest (POI) domain or a fragment thereof; and
        • (ii) at least one vesicle targeting domain,
      • wherein the POI domain is in an extracellular position relative to a lipid membrane of the extracellular vesicle.
    • 2. The engineered extracellular vesicle of paragraph 1, wherein the extracellular vesicle is an exosome.
    • 3. The engineered extracellular vesicle of paragraph 1 or paragraph 2, wherein the protein of interest (POI) domain or a fragment thereof is a N-terminal domain of the fusion polypeptide.
    • 4. The engineered extracellular vesicle of any one of paragraphs 1-3, wherein the vesicle targeting domain is a C-terminal domain of the fusion polypeptide.
    • 5. The engineered extracellular vesicle of any one of paragraphs 1-4, wherein the fusion polypeptide comprises at least two POI domains and/or at least two exosome targeting domains.
    • 6. The engineered extracellular vesicle of any one of paragraphs 1-5, wherein the fusion polypeptide further comprises a peptide linker.
    • 7. The engineered extracellular vesicle of any one of paragraphs 1-6, wherein the fusion polypeptide further comprises a fragment crystallizable region (Fc) domain.
    • 8. The engineered extracellular vesicle of any one of paragraphs 1-7, wherein the vesicle targeting domain is in a luminal position relative to the lipid membrane of the extracellular vesicle.
    • 9. The engineered extracellular vesicle of any one of paragraphs 1-7, wherein the vesicle targeting domain in an exterior position relative to the lipid membrane of the extracellular vesicle.
    • 10. The engineered extracellular vesicle of any one of paragraphs 1-9, wherein the POI domain is selected from the group consisting of: Table 1.
    • 11. The engineered extracellular vesicle of any one of paragraphs 1-10, wherein the POI domain is PD-L1 or a fragment thereof.
    • 12. The engineered extracellular vesicle of any one of paragraphs 1-11, wherein the POI domain is PD-L2 or a fragment thereof.
    • 13. The engineered extracellular vesicle of any one of paragraphs 1-12, wherein the POI domain is FGL1 or a fragment thereof.
    • 14. The engineered extracellular vesicle of any one of paragraphs 1-13, wherein the POI domain is 4-1BBL or a fragment thereof.
    • 15. The engineered extracellular vesicle of any one of paragraphs 1-14, wherein the POI domain is CTLA-4 or a fragment thereof.
    • 16. The engineered extracellular vesicle of any one of paragraphs 1-15, wherein the POI domain substantially binds to one or more of a target polypeptide.
    • 17. The engineered extracellular vesicle of paragraph 16, wherein the target polypeptide is selected from the group consisting of: Table 2.
    • 18. The engineered extracellular vesicle of any one of paragraphs 1-17, wherein the vesicle targeting domain is selected from the group consisting of: Table 3.
    • 19. The engineered extracellular vesicle of any one of paragraphs 1-18, wherein the linker is in an exterior position relative to the lipid membrane of the extracellular vesicle.
    • 20. The engineered extracellular vesicle of any one of paragraphs 1-18, wherein the linker is a transmembrane linker.
    • 21. The engineered extracellular vesicle of any one of paragraphs 1-18, wherein the linker is in a luminal position relative to the lipid membrane of the extracellular vesicle.
    • 22. The engineered extracellular vesicle of any one of paragraphs 1-21, wherein the extracellular vesicle does not comprise an endogenous POI polypeptide.
    • 23. A composition comprising a plurality of the engineered extracellular vesicles of any one of paragraphs 1-22.
    • 24. The composition of paragraph 23, further comprising a pharmaceutically acceptable carrier.
    • 25. An engineered extracellular vesicle comprising:
      • (a) a first fusion polypeptide comprising:
        • (i) at least one protein of interest (POI) domain or a fragment thereof; and
        • (ii) at least one vesicle targeting domain,
      • wherein the at least one POI domain is in an extracellular position relative to a lipid membrane of the extracellular vesicle,
      • (b) a second fusion polypeptide comprising:
        • (i) at least one protein of interest (POI) domain or a fragment thereof; and
        • (ii) at least one vesicle targeting domain,
      • wherein the POI domain is in an extracellular position relative to a lipid membrane of the extracellular vesicle,
      • and wherein the at least one vesicle targeting domain is within a lipid membrane of the extracellular vesicle.
    • 26. A composition comprising two or more of the engineered extracellular vesicles selected from any one of paragraphs 1-25.
    • 27. An extracellular vesicle composition comprising:
      • a plurality of artificial synapses,
      • wherein each artificial synapse comprises (i) an extracellular vesicle; (ii) one or more sticky binders; and (iii) one or more signaling domains.
      • The composition of paragraph 27, wherein the extracellular vesicle comprises an exosome.
    • 28. The composition of paragraph 27, wherein the one or more sticky binders is selected from the group consisting of: a GPI anchor, a fatty acylation site, and a prenylation site.
    • 30. The composition of paragraph 27, wherein the signaling domain comprises one or more of: PD-L1, PD-L2, CTLA-4 (CD152), 4-1BBL (CD137L), HVEM (CD270), FGL1, OX-2 (CD200), Galectin-9, PVR (CD155), Nectin-2 (CD112) isoform alpha, Nectin-2 (CD112) isoform beta, Nectin-2 (CD112) isoform delta, IL-10, TSG-6, B7-H3 (CD276), B7-H4 (VTCN1), B7-H5 (VISTA), B7-H7 (HHLA2), BTNL1, VSIG8, VSIG3 (IGSF11), VSIG4, TIM-3 (HAVCR2), TIM-4 (TIMD4), CEACAM1, BTN3A1, BTN3A2, BTN2A1, BTNL8, BTN2A2, BTN1A1, TIGIT, CD27L (CD70), CD30L (CD153), GITRL, CD40L (CD154), LIGHT (CD258), TL1, CD80, CD86, LFA-3 (CD58), SLAM (CD150), CD40, CD28, CD28H, CD2, LFA-3 (CD58), CD48, CD226, DR3, DcR3, FasL, TIM-1 (CD365), PD-1, or active fragment thereof
    • 29. A method of producing the engineered extracellular vesicle or the composition of any one of paragraphs 1-30, comprising:
      • (a) providing a population of cells expressing a vector construct encoding one or more sticky binder and one or more signaling domains; and
      • (b) isolating a plurality of artificial synapses from the population of cells.
    • 30. A method of producing the engineered extracellular vesicle or the composition of any one of paragraphs 1-30, comprising:
      • (a) providing a population of cells expressing a vector construct encoding one or more sticky binder and one or more signaling domains; and
      • (b) isolating a plurality of artificial synapses from the population of cells; and
      • (c) purifying the plurality of artificial synapses from the population of cells.
    • 33. The method of paragraph 31 or paragraph 32, the isolating is via size exclusion chromatography.
    • 34. The method of paragraph 32, wherein the purifying is via multimodal chromatography.
    • 35. The method of any of paragraphs 31-34, further comprising performing an assay for POI binding to a target polypeptide.
    • 36. The method of paragraph 35, wherein the vector construct further encodes a promoter.
    • 37. The method of paragraph 36, wherein the promoter is a tissue-specific promoter or an inducible promotor.
    • 38. A method of modulating inflammation in a subject, the method comprising:
      • administering a composition comprising a plurality of engineered extracellular vesicles to a subject in need thereof,
      • wherein the engineered extracellular vesicles comprise at least one fusion polypeptide comprising:
        • (i) at least one protein of interest (POI) domain or a fragment thereof; and
        • (ii) at least one vesicle targeting domain.
    • 39. The method of paragraph 38, wherein the extracellular vesicle comprises an exosome.
    • 40. The method of any one of paragraphs 38-39, further comprising selecting a subject that has or is suspected of having an autoimmune disease or an inflammatory disease or condition.
    • 41. The method of any one of paragraphs 38-40, wherein the vesicle targeting domain is selected from the group consisting of: a Glycosylphosphatidylinositol (GPI) anchor, a fatty acylation site, and a prenylation site.
    • 42. The method of any one of paragraphs 38-41, wherein the vesicle targeting domain is a GPI anchor.
    • 43. The method of any one of paragraphs 38-41, wherein the vesicle targeting domain is C1C2.
    • 44. The method of any one of paragraphs 38-43, wherein the protein of interest (POI) domain comprises one or more of: PD-L1, PD-L2, CTLA-4 (CD152), 4-1BBL (CD137L), HVEM (CD270), FGL1, OX-2 (CD200), Galectin-9, PVR (CD155), Nectin-2 (CD112) isoform alpha, Nectin-2 (CD112) isoform beta, Nectin-2 (CD112) isoform delta, IL-10, TSG-6, B7-H3 (CD276), B7-H4 (VTCN1), B7-H5 (VISTA), B7-H7 (HHLA2), BTNL1, VSIG8, VSIG3 (IGSF11), VSIG4, TIM-3 (HAVCR2), TIM-4 (TIMD4), CEACAM1, BTN3A1, BTN3A2, BTN2A1, BTNL8, BTN2A2, BTN1A1, TIGIT, CD27L (CD70), CD30L (CD153), GITRL, CD40L (CD154), LIGHT (CD258), TL1, CD80, CD86, LFA-3 (CD58), SLAM (CD150), CD40, CD28, CD28H, CD2, LFA-3 (CD58), CD48, CD226, DR3, DcR3, FasL, TIM-1 (CD365), PD-1, or active fragment thereof.
    • 45. The method of any one of paragraphs 38-44, wherein the protein of interest (POI) domain is PD-L1 or a fragment thereof
    • 46. The method of any one of paragraphs 38-44, wherein the protein of interest (POI) domain is PD-L2 or a fragment thereof
    • 47. The method of any one of paragraphs 38-44, wherein the protein of interest (POI) domain is CTLA-4 or a fragment thereof.
    • 48. The method of any one of paragraphs 38-44, wherein the protein of interest (POI) domain is HVEM or a fragment thereof.
    • 49. The method of paragraph 40, wherein the inflammatory disease and/or condition is acute.
    • 50. The method of paragraph 40, wherein the inflammatory related disease and/or condition is chronic.
    • 51. The method of paragraph 38, wherein administering the composition comprises injection, topical administration, or inhalation.
    • 52. Use of a composition comprising a plurality of engineered extracellular vesicles, the engineered extracellular vesicles each comprising:
      • at least one fusion polypeptide comprising:
        • (i) at least one protein of interest (POI) domain or a fragment thereof; and
        • (ii) at least one vesicle targeting domain
    • for the treatment of an inflammatory disease or condition.
    • 53. Use of a composition comprising a plurality of engineered extracellular vesicles, the engineered extracellular vesicles each comprising:
      • at least one fusion polypeptide comprising:
        • (i) at least one protein of interest (POI) domain or a fragment thereof; and
        • (ii) at least one vesicle targeting domain
    • for the treatment of an autoimmune disease or condition.
    • 54. Use of a composition comprising a plurality of engineered extracellular vesicles, the engineered extracellular vesicles each comprising:
      • at least one fusion polypeptide comprising:
        • (i) at least one protein of interest (POI) domain or a fragment thereof; and
        • (ii) at least one vesicle targeting domain
      • for the treatment of cancer.


EXAMPLES

The following examples are provided by way of illustration, not limitation.


Example 1
Design of Artificial Synapse

As described, artificial synapses are engineered to induce and propagate biological signaling, including for example, antagonist and agonist signaling. Artificial synapses are designed to include hallmark biophysical and biochemical features of extracellular vesicles, further including vesicle targeting domains and signaling domains. Vesicle targeting domains capable of attaching to extracellular vesicles such as exosomes, signaling domains, optionally including a linker (e.g., Fc linker), can be organized in genetic vector constructs. Designs are shown in FIG. 1.


Sticky binders are extracellular vesicle targeting sequences. Preliminary extracellular vesicle targeting sequences of interest are from, but not limited to, 4F2 (CD98), ADAM10, CD298, TFR2, transmembrane domains of CD9, MARCKS, KRAS, etc. or the like as appreciate by one of ordinary skill in the art. The Inventors discovered high efficiency when proteins are engineered with a GPI domain. Optionally, linker regions such as an Fc linker between the vesicle targeting domains and signaling domains can be added.


A variety of signaling domains are of interest with proof-of-concept examples including PD-L1, PD-L2 and CTLA-4 (CD152). Artificial synapses including these three signaling domains are shown in FIGS. 2-5.


Each of these elements are described in the following non-limiting examples.


Example 2
Genetic Constructs

Examples of constructs including these variable elements (e.g., sticky binders GPI or C1C2, or signaling domains including PD-L1, PD-L2 and CTLA-4 (CD152) were engineered into vectors shown in FIGS. 2-5.


Example 3
Purification of hPD-L1 Tagged Artificial Synapses by a Multimodal Resin Marketed for Exosome Purification

Upon expression of hPD-L1-Fc-GPI in mammalian cells, artificial synapses were further purified using a size exclusion resin marketed for exosome purification. Large MW artificial synapses elute in the first fraction as shown by the high hPD-L1 concentration and exosome quantity (2.26E9 artificial synapses/ml) in elution 1. Clean in place (CIP) fractions show bound and eliminated proteins from the Inventors' exosome elution. Results are shown in FIG. 6.


Example 4
hPDL1-Fc-GPI Exosome Purification—Size Exclusion Chromatography Column

Artificial synapses engineered from exosomes such as hPDL1-Fc-GPI after elution from size exclusion resin marketed for exosome purification can be further purified via a size exclusion column as shown here. Using a size exclusion chromatography (SEC), artificial synapses elute in fractions 7-9. Total protein (determined by qBit) and hPD-L1 ng/ml (determined by ELISA) of each fraction is shown in the graph. Bars show exosome number per ml (i.e. 1E10 artificial synapses/ml etc.). Fractions 7-9 contain >99% purified artificial synapses. Fractions 7-9 are pooled and may be concentrated using a filtration device, for example a 10K MWCO Amicon Centrifugal Filter. Final purified product is filtered through a low protein binding 0.2 μm or 0.45 μm filter, for example a PES filter. Results are shown in FIG. 7.


Example 5
hPD-L1 Expression on Artificial Synapses

Exosome quantity and hPD-L1 concentration was determined in SEC fractions 7-9. Knowing the molecular weight of engineered hPD-L1, the Inventors can determine the number of hPD-L1 molecules per exosome to be approximately between 12 to 40 PD-L1/exosome. This value is consistent between different purification runs and constructs. Results are shown in FIG. 8.


Example 6
Purification of hPD-L2-Fc-GPI Artificial Synapses Via Multimodal Resin Chromatography Marketed for Exosome Purification

This graph shows Abs 280 of multimodal resin chromatography fractions and quantity of hPDL2 in indicated fractions. Artificial synapses eluted in Elution 1.


Clean in place (CIP) fractions show bound and eliminated proteins from the Inventors' exosome elution. Results are shown in FIG. 9.


Example 7
PD-L2 Purification Via Size Exclusion Chromatography

Artificial synapses engineered from artificial synapses such as hPDL2-GPI after elution from size exclusion resin size exclusion resin marketed for exosome purification are further purified via size exclusion chromatography as shown. Results are shown in FIG. 10.


Example 8
hCTLA4-Fc-GPI Exosome Purification Via Size Exclusion Chromatography

Using size exclusion chromatography marketed for exosome purification, artificial synapses elute in fractions 7-9. Total protein (determined by qBit) and hPD-L1 ng/ml (determined by ELISA) of each fraction is shown in the graph. Fractions 7-9 are pooled and contain >99% purified artificial synapses. Pooled artificial synapses engineered from artificial synapses fractions may then be concentrated using a filtration device, for example a 10K MWCO Amicon. Final purified product is filtered through a low protein binding filter, for example a 0.2 μm or 0.45 um PES filter. Results are shown in FIG. 11.


Example 9
PD-L1 and PD-L2 In Vitro Assay from DiscoverX

To perform this validation method, the Inventors modified the PathHunter PD-1 Signaling Bioassay from DiscoverX Briefly, the PathHunter PD-1 Signaling Bioassay relies on the well-established PathHunter Enzyme Fragment Complementation (EFC) technology to interrogate receptor activity. EFC consists of a split β-galactosidase (β-gal) enzyme: the Enzyme Donor (ED) and Enzyme Acceptor (EA) fragments which independently have no β-gal activity. However, when forced to complement they form an active β-gal enzyme that will hydrolyze substrate to produce a chemiluminescent signal. The PathHunter PD-1 Signaling Bioassay consists of human cells engineered to stably express an ED-tagged PD-1 receptor, while EA is fused to the phosphotyrosine-binding SH2 domain of the intracellular signaling protein, SHP1. Ligand or antibody-induced activation of the receptor results in phosphorylation of the receptor's cytosolic tail. The SH2-domain fused to EA binds the phosphorylated receptor, forcing complementation of ED and EA, resulting in formation of an active β-gal enzyme, which hydrolyzes the substrate to produce a chemiluminescent signal. Full-length PD-1 receptor was engineered with a small β-gal fragment (ED in red) fused to its C-terminus, and the SH2-domain of SHP1 was engineered with the complementing β-gal fragment (EA). These constructs were stably expressed in Jurkat cells (produced by DiscoverX), while PD-L1 and PD-L2 was stably expressed on artificial synapses produced by Diadem Biotherapeutics. Artificial synapses were engineered to have surface expressed human PD-L1 or PD-L2. Briefly, the gene sequence coding for the extracellular domain of human PD-L1 or PD-L2 was linked to the exosome via a glycosylphosphatidylinositol (GPI) linker with an Fc domain between the linker and PD-L1 or PD-L2 (PD-L1-Fc-GPI and PD-L2-Fc-GPI). Additional variations of the Inventors' PD-L1 and PD-L2 artificial synapses include cloning a C1C2 linker (from MFGE8) in place of the GPI linker, and with or without the Fc domain. The Inventors also cloned murine versions of PD-L1 and PD-L2 extracellular domains in place of the human PD-L1 and PD-L2 all variations. Ligand engagement, through addition of ligand-presenting artificial synapses, results in phosphorylation of PD-1, leading to the recruitment of SHP1-EA


The Inventors obtained approximately 1000× higher increase in Relative Light Units (RLU) in Jurkat signaling cells treated with PD-L1 or PD-L2 labeled artificial synapses when compared to soluble PD-L1-Fc or PD-L2-Fc ligand, respectively. Meaning, it took 1000× less ug/ml of PD-L1 or PD-L2 on artificial synapses than solubilized PD-L1-Fc or PD-L2 ligand to achieve the same RLU signaling. Results are shown in FIG. 12.


Example 10
PD-L1 In Vivo Assay—Experimental Autoimmune Uveoretinitis (EAU) in Lewis Rats Bioassay

Experimental autoimmune uveoretinitis (EAU) is an organ-specific, T lymphocyte-mediated autoimmune disease, which serves as a model for several human ocular inflammations of an apparently autoimmune nature. There is a statistically significant initial reduction in EAU in mPDL1 artificial synapse treated rats via either the intravitreal and intravenous delivery modes. 2nd intravitreal and 3rd intravenous injections are performed on Day 12. There appears to be a more rapid rate of resolution in the 1× intravitreal and intravenous groups. (C) Simplified view of aforementioned results. (D) Weight of rats was monitored throughout the study. 3rd intravitreal and 4th intravenous injections are performed on Day 16. There does not appear to be any significant change in EAU in any of the test groups. The aforementioned results provide proof of principle of successfully immunizing the rats with human cell derived artificial synapses with mouse PDL1 injected into rats. Results are shown in FIG. 13.


Example 11
Engineered Exosome Multivalent Display

The inventors have developed the following 3 types of protein display on or within exosomes:

    • Type I membrane proteins wherein the N-Terminus is on the luminal (interior) side of the exosome membrane and the C-Terminus is on the exterior of the exosome.
    • Type II membrane proteins wherein the N-Terminus is on the exterior while the C-Terminus is on the interior.
    • Luminal internally loaded proteins which are linked to the exosome by a Myristoylation/Palmitoylation site which attaches proteins to the interior of the exosome membrane.



FIGS. 14-21 demonstrate the various embodiments of the engineered extracellular vesicles.


Additional embodiments or ligands displayed on the exosome surface (Type I and Type II membrane proteins) and internal luminal display can include the following:

    • Type I: PD-L1, PD-L2, FGL1, OX40L
    • Type II: 4-1BBL, GITRL, CD27L, CD30L
    • Luminal: NanoLuc® luciferase; Green fluorescent protein (GFP) (e.g., eGFP, etc.); Red fluorescent protein (RFP) (e.g., mScarlet, mCherry, mRuby, tdTomato, etc.); Cyan fluorescent protein (CFP); Yellow fluorescent protein (YFP); A therapeutic protein; and CRISPR/CAS-9



FIG. 20 shows an exemplary multiple protein display construct. Sequences such as P2A, E2A, F2A, and T2A induce ribosomal slippage which prevent peptide bond formation, meaning that a single mRNA transcript with a 2A sequence will result in two separate peptides after translation. This allows the expression of two separate proteins from one promoter region and thus loading of two proteins on an exosome. Any combination of the proteins of interest domains provided herein can be engineered. Furthermore, a cell line with multiple transgene inserts under separate promoter control. Either method can be used to label Type I, Type II, and luminal display proteins.


Example 12a
Designed and Engineered Human Fusion Polypeptide Constructs

The inventors have designed, engineered, and purified the following human fusion polypeptide constructs for therapeutic use (FIG. 5A-FIG. 5WW):

    • pEF5-FRT-hPDL1-C1C2 (FIG. 5I)
    • pEF5-FRT-hPDL2-C1C2 (FIG. 5J)
    • pEF5-FRT-hPDL1-GPI-P2A-hFGL1-GPI (FIG. 5E)
    • pEF5-FRT-hCTLA4-Fc-GPI (FIG. 5C)
    • pEF5-FRT-hPDL2-Fc-GPI (FIG. 5H)
    • pEF5-FRT-hPD-L1-GPI-P2A-hHVEM-GPI (FIG. 5D)
    • pEF5-FRT-hPDL1-GPI (FIG. 5F)
    • pcDNA5-FRT-hSecPDL1-GPI (FIG. 5C)
    • pcDNA5-FRT-hPDL1-GPI (FIG. 5F)
    • pcDNA5-FRT-hPDL1-Link-GPI (FIG. 5T)
    • pcDNA5-FRT-4F2-h41BBL (FIG. 5K)
    • pcDNA5-FRT-Tfr2-h41BBL (FIG. 5P)
    • pEF5-FRT-hPDL1-Fc-GPI (FIG. 5G)
    • pcDNA5-FRT-CD9tm3-h41BBL (FIG. 5Q)
    • pcDNA5-FRT-hPDL1-Fc-GPI (FIG. 5G)
    • pcDNA5-FRT-hPDL1-4Fc-CD9tm2 (FIG. 5RR)
    • pcDNA5-FRT-hPDL1-Fc-CD9tm2KRAS (FIG. 5UU)
    • pcDNA5-FRT-hPDL1-4Fc-CD9tm2KRAS (FIG. 5SS)
    • pcDNA5-FRT-hPDL1-4Fc-GPI (FIG. 5L)
    • pcDNA5-FRT-hPDL1-ADAM10 (FIG. 5QQ)
    • pcDNA5-FRT-MyrPalm-4F2-h41BBL (FIG. 5R)
    • pcDNA5-FRT-MyrPalm-h41BBL (FIG. 5S)
    • pcDNA5-FRT-hPDL1-Fc-CD9tm2 (FIG. 5TT)
    • pcDNA5-FRT-hSecPDL1-CD9tm4 (FIG. 5W)
    • pcDNA5-FRT-hSecPDL1-CD9tm2KRas (FIG. 5V)
    • pcDNA5-FRT-hSecPDL1-CD9tm2 (FIG. 5U)
    • pcDNA5-FRT-hSecPDL1-CD81 (FIG. 5X)
    • pEF5-FRT-hCD200-Fc-GPI (FIG. 5Y)
    • pEF5-FRT-hCD200-GPI (FIG. 5BB)
    • pEF5-FRT-hTSG6-GPI (FIG. 5FF)
    • pEF5-FRT-hPDL2-GPI (FIG. 5EE)
    • pEF5-FRT-hFGL-1-GPI (FIG. 5Z)
    • pEF5-FRT-hHVEM-GPI (FIG. 5DD)
    • pEF5-FRT-hGa19-GPI (FIG. 5CC)
    • pEF5-FRT-hHVEM-Fc-GPI (FIG. 5GG), and
    • pEF5-FRT-hGa19-Fc-GPI (FIG. 5AA)


Example 12b
Designed and Engineered Fusion Polypeptide Constructs

The inventors have designed, engineered, and purified the following mouse fusion polypeptide constructs for therapeutic use (FIG. 5A-FIG. 5WW):

    • pcDNA5-FRT-mPDL1-mFc-CD9tm2KRAS (FIG. 5WW)
    • pcDNA5-FRT-mPDL1-mFc-CD9tm2 (FIG. 5VV)
    • pcDNA5-FRT-mPDL1-mFc-GPI (FIG. 5NN)
    • pcDNA5-FRT-mPDL1-GPI (FIG. 5KK)
    • pEF5-FRT-mPDL2-GPI (FIG. 5. OO)
    • pEF5-FRT-mPDL1-GPI-P2A-mHVEM-GPI (FIG. 5PP)
    • pEF5-FRT-mPDL1-GPI (FIG. 5KK)
    • pEF5-FRT-mPDL2-Fc-GPI (FIG. 5MM)
    • pEF5-FRT-mPDL1-Fc-GPI (FIG. 5JJ)
    • pEF5-FRT-mCTLA4-Fc-GPI (FIG. 5HH)
    • pEF5-FRT-mPDL1-C1C2 (FIG. 5II); and
    • pEF5-FRT-mPDL2-C1C2 (FIG. 5LL).


Example 12c
Designed and Engineered Luminal Loaded Fusion Polypeptide Constructs

The inventors have designed, engineered, and purified the following fusion polypeptide constructs for internal luminal loading of the fusion polypeptide:

    • pcDNA5-FRT-Myr-NanoLuc (FIG. 5M)
    • pcDNA5-FRT-Myr-mScarlet (FIG. 5N)


Example 13
Purification of Exosomes Labeled with Type I Membrane Fusion Polypeptides

The inventors have purified engineered EVs, including hPD-L1-GPI; hPDL1-Fc-GPI; hPDL2-Fc-GPI; hCTLA4-Fc-GPI; mPDL1-GPI; and mPD-L1-Fc-GPI. The process for purification and analytical processing of the engineered EVs are shown in the flow chart provided in FIG. 21.


Size exclusion chromatography was performed to purify hPD-L1-GPI (no Fc) exosomes (FIG. 24). Protein, RNA and DNA measurements in SEC fractions. Invitrogen Qubit fluorometric assays were used to measure biomolecules from unmodified concentrated cell media SEC fractions or hPD-L1-Exo-Tag concentrated cell media SEC fractions. PD-L1 was measured using an R&D systems PD-L1 ELISA kit. Dot-blot immunoblot analysis of SEC fractions. A 96-well dot blot apparatus was used to immobilize 50 ul of each SEC fraction onto PVDF. Exosome size and concentration was measured in fraction 7 by tunable resistive pulse sensing (TRPS). It was confirmed that GPI anchors the hPD-L1 fusion protein onto the exosomes (FIG. 25).


Furthermore, a commercially available multimodal exosome purification resin was also used to purify and isolate PD-L1-GPI exosomes and PD-L1-Fc-GPI exosomes. Fraction 7 was further analyzed by dot blots (FIG. 28A-28B). In particular, FIG. 28B shows SEC purification results of various embodiments of human PD-L1 displayed on the surface of extracellular vesicles. One embodiment is the hPD-L1-4Fc-GPI (CMV) construct as seen in the top dot blot (stained with rabbit monoclonal anti-PD-L1 antibody). Another embodiment is the hPD-L1-4Fc-GPI (EF1a) as seen in the top dot blot (stained with rabbit monoclonal anti-PD-L1 antibody).


Large MW exosomes elute in the first fraction as shown by the high hPD-L1 concentration and exosome quantity (2.26E9 exosomes/ml) in elution 1. Clean in place (CIP) fractions show bound and eliminated proteins from our exosome elution. Exosome quantity and hPD-L1 concentration was determined in SEC fractions 7-9. Knowing the molecular weight of engineered hPD-L1, we can determine the number of hPD-L1 molecules per exosome to be approximately 12 PD-L1/exosome. This value is consistent between different purification runs and constructs (FIG. 8).


Human hPD-L2 and hCTLA-4-Fc-GPI SEC fractions were purified. In addition, purification of the mouse PD-L1-FcGPI exosomes was performed (FIG. 29). The mouse Fc-PD-L1 expressing exosomes have a higher valency than those that do not comprise the Fc linker.


Example 14
Comparative Proteomics Analysis of the Engineered EVs

Fc-GPI enables high density display and has a higher abundance than endogenous PTGFRN or CD81. Therefore, comparison proteomics of transprotein expression and surface labeling on the engineered exosomes, hPD-L1-Fc-GPI; hPD-L2-Fc-GPI; and hCTLA-Fc-GPI, was performed to determine the effects on endogenous protein expression in engineered exosomes. It was confirmed that the fusion polypeptide expression does not affect the relative expression of native and associated exosome proteins. However, the trans protein may crowd out abundant proteins like CD81 (data not shown).


Example 15
Scale-Up Production and Purification of mPD-L1-Fc-GPI Exosomes Using Microcarriers in a Stirred Tank Single-Use Bioreactor (STR)

1E7 HEK 293 cells were utilized for the production of mPDL1-Fc-GPI exosomes. Cells were passaged on SoloHill® Microcarriers up to Passage 4, at which point cells were expanded in a 2.5 L Stirred Tank Single-Use Bioreactor. Passage 4 cells were cultured for an additional 5 days and media was harvested on Day 5 and used for exosome purification. The general aim and process is provided below


AIM: Utilize SoloHill's Xeno-free microcarrier technology to scale up cells for engineering EVs and evaluate Microcarrier—stir tank bioreactor technology for production of therapeutic exosomes in the Xeno-free medium conditions.


Passage 1:

Thaw vial (1.00E+07) of cells and seed Corning T-150 & CellSTACK2 tissue culture treated flask at 1.00E+04 cells per cm2 seed density.


Perform 100% medium exchange from both flasks on day 3.


Harvest Corning T-150 & CellSTACK2 flasks on day 4 post seeding and seed spinner microcarrier culture.


Passage 2:

Expand cells in 2×200 mL spinner flasks at 10 cm2/mL microcarrier density using SoloHill's Xeno-free prototype microcarrier.


Seed microcarrier cultures at 1.00E+04 cells per cm2 seed density and T-25 as flatware control flask.


Perform 80% batch volume medium exchange from spinners and T-25 flasks on day 3.


Harvest both microcarrier and T-25 flasks on day 4 post seeding and seed spinner microcarrier culture.


Passage 3:

Expand cells in 3×300 mL spinner flasks at 10 cm2/mL microcarrier density using SoloHill's Xeno-free prototype microcarrier.


Seed microcarrier cultures at 1.00E+04 cells per cm2 seed density and T-25 as flatware control flask.


Perform 80% batch volume medium exchange from spinners and T-25 flasks on day 3.


Harvest both microcarrier and T-25 flasks on day 4 post seeding.


Seed microcarrier—stir tank bioreactor for exosome production.


Passage 4:

Expand cells into a 2.5 L microcarrier-stir tank at 10 cm2/mL surface area to medium ratio.


Seed cultures at 1.00E+04 cells per cm2 seed density and T-25 as flatware control flask.


Perform 80% batch volume medium exchange on day 2.


On day 3 rinse all cultures with 2× cell culture volumes of DPBS containing Ca and Mg.


Add exosome production medium (DMEM-1% Glutamax) to all cultures at 10 cm2/mL surface area to medium volume ratio.


On day 5 collect harvest spent medium from all cultures, filter using 0.45 μm Nalgene rapid flow system and freeze at −20° C.


Procedures:
Medium Composition
DMEM 1× (Corning ref #10-013-CV)
1% Glutamax (Thermo ref #35050061)

3% Human platelet lysate (Stemulate from Cook Reagentec PG-NH-500)


Cell Harvest Protocol for Planar Culture

Settle microcarriers and remove maximum volume of spent medium without removing microcarriers.


Wash microcarrier culture with DPBS 2× time at 0.1 mL/cm2 volume to surface area ratio.


Add 37° C. warmed TrypLE 5× enzyme at 0.012 mL/cm2 and incubate flask at room temperature for ˜15 minutes.


Add complete medium at 0.024 mL/cm2 to quench TrypLE 5x activity.


Perform viable cell count using NC200 cell count instrument.


Nuclei Count Protocol for Microcarrier Culture

Obtain 4-5 mL of microcarrier culture from bioreactor or spinner flask


Settle microcarriers and remove maximum volume of spent medium without removing microcarriers.


Add 1.5 mL Nucleocounter Reagent A to macrocarrier sample tube and vortex at high speed for a minute.


Add 1.5 mL Nucleocounter Reagent B to macrocarrier sample tube and vortex at high speed for a minute.


Perform nuclei count using NC200 nuclei count instrument.


Medium Collection from STR Bioreactor


Stop all controls and settle microcarriers in the bioreactor vessel.


Pump out medium through screen bag into collection bottle at 200 mL/minute flowrate using peristaltic pump.


Inside BSC pour medium into 0.45 μm Nalgene rapid flow filter system and remove free floating cells.


Freeze medium bottles in minus 20° C. freezer.


Medium Collection from Spinner Flasks


Inside BSC pour microcarrier culture into 0.45 nm Nalgene rapid flow filter system and remove free floating cells as well as microcarriers.


Freeze medium bottles in minus 20° C. freezer.












Cell culture set points













Tem-

Dis-

Incubator



perature
Agitation
solved
Oxygen
CO2



° C.
rpm
(DO) %
pH
setting %





T-Flask
37
n/a
n/a
n/a
5 ± 1


CellSTACK 2
37
n/a
n/a
n/a
5 ± 1


Spinner flask
37
35
n/a
n/a
5 ± 1


STR bioreactor
37
35
50
7.35
n/a










FIG. 31 shows mPDL1-Fc-GPI production, growth parameters, and analyte concentrations from a 2.6 L culture in a Stirred Tank Single-Use (STR) bioreactor. Day 2: 80% batch volume medium was exchanged (1st increase in glucose and decreased in lactate) Day 3: rinse culture with 2× cell culture volumes of DPBS containing Ca and Mg. (2nd increase in glucose and decreased in lactate). Add exosome production medium (DMEM-1% Glutamax) to culture at 10 cm2/mL surface area to medium volume ratio.


mPDL1 was purified using the purification process outlined above (FIGS. 32-33).


Example 16
PD-L1-Fc-GPI and PDL2-Fc-GPI Exosomes Increase PD-1 Signaling

The purified exosomes were tested using the modified DiscoverX Assay in FIG. 12A. Approximately a 1000× increase in Relative Light Units (RLU) was achieved for Jurkat signaling cells treated with PD-L1 or PD-L2 labeled exosomes when compared to soluble PD-L1-Fc or PD-L2-Fc ligands alone, respectively. Therefore, it takes 1000× less μg/ml of PD-L1 or PD-L2 on the engineered exosomes to activate PD-1 over solubilized ligands, PD-L1-Fc or PD-L2, achieve the same RLU signaling. FIG. 12B show a dose-response curves for the PD-L1 and PD-L2 exosomes vs soluble PD-L1 and PD-L2 signaling bioassay. FIG. 12B shows dose-response curves for the PD-L1 and PD-L2 exosomes comprising an Fc linker and GPI sticky binder vs. soluble ligands with an Fc domain linker. These results show that the PD-L1 and PD-L2 polypeptides fused with the Fc and GPI domains on EVs have a more potent effect on PD-1 signaling than the soluble ligands alone.


Example 17
In Vivo Assay—Therapeutic Effect of mPD-L1 Exosomes in an Experimental Autoimmune Uveoretinitis (EAU) Model in Lewis Rats

Lewis rats were challenged with retinal antigen interphotoreceptor retinoid-binding protein (IRBP) peptide. This model can be used to study anterior and posterior chamber dependent EAU. Rats were immunized on Day 1 with EAU presenting typically at Day 6. Clinical scores in the rat were determined. The EAU dosing schedule is shown in FIG. 13A. EAU dosing test article are shown in the following table.












EAU dosing test articles












Unmodified
mPD-Ll-Fc-GPI
mPD-L1-Fc-GPI
mPD-L1



Exosomes (IVT)
Exosomes 1X (IVT)
Exosomes 10X (IVT)
Exosomes (IV)


















Dose
2
ul
2
ul
2
ul
5
ml/kg


Total protein
40
ug/ml
40
ug/ml
400
ug/ml
40
ug/ml


concentration










Total protein
80
ng/eye
80
ng/eye
800
ng/eye
50
ug/animal


administered



















Exosome
5.7 × 1010/ml
2.34 × 1010/ml
2.34 × 1011/ml
2.34 × 1010/ml


concentration






Total exosomes
4.7 × 107     
 4.7 × 107    
4.7 × 108   
2.93 × 1010   


administered





*IVT-intravitreal, IV-intravenous







The study design is outlined below:


















Group
Test Article
N
Route
Concentration
Dosage
Regimen







1
Cyclosporine
8
p.o.
1 mg/mL
 10 mg/kg
BID from day








0 to Day 20


2
Negative control (PBS
8
Intravitreal both

2-3 μL
Day 6, Day 12,



vehicle)

eyes


and Day 16


3
Unmodified exosomes
8
Intravitreal both
1× (~40 ug/ml)
2-3 μL
Day 6 and Day



(Control exosomes)

eyes


12


4
mPD-L1-Fc-GPI (40
8
Intravitreal both
1× (~40 ug/ml)
2-3 μL
Day 6, Day 12,



ug/ml)

eyes


and Day 16


5
mPD-Ll-Fc-GPI (40
4
Intravenous
1× (~40 ug/ml)
  5 mL/kg
Day 1, Day 6,



ug/ml)

Injection


Day 12, and








Day 16


6
No IRBP peptide but
4
Intravitreal both
1× (~40 ug/ml)
2-3 μL
Day 6, Day 12,



treated with Test Agent

eyes


and Day 16



B (for tolerability)







7
mPD-L1-Fc-GPI (400
8
Intravitreal both
1× (400 ug/ml)
2-3 μL
Day 6, Day 12,



ug/ml)

eyes


and Day 16










Clinical Scores were determined as follows:












EAU Clinical Scores in Rats








Score
Clinical Criteria





0
No disease; eye is translucent and reflects light(red reflex)


0.5
Dilated blood vessels in the iris


(trace)



1
Engorged blood vessels in the iris; abnormal pupil contraction


2
Hazy anterior chamber;decreased red reflex


3
Moderately opaque anterior chamber,but pupil still visible;



dull red reflex


4
Opaque anterior chamber and obscured pupil;



red reflex absent; proptosis










Each higher grade includes the criteria of the preceding one.


It was discovered that there is a statistically significant initial reduction in EAU in mPDL1 exosome treated rats via either the intravitreal and intravenous delivery modes as compared with untreated animals (FIG. 13A). Rat weight did not change post immunization (FIG. 13C).


Example 18
Purification of Exosomes Labeled with Type II Membrane Proteins

The inventors designed, engineered, and purified pcDNA5-FRT-4F2-4-1BBL exosomes by the methods provided herein (FIG. 34). Several embodiments of the 4-1BBL labeled exosomes are shown in FIG. 35. Cell expression of the 4F2-4-1BBL was confirmed (data not shown). FIGS. 36A-36B shows the purification of 4F2-4-1BBL exosomes.


Example 19
Purification of Luminal Labeled Exosomes (Internal Loading)

In addition to Type I and Type II display fusion proteins on the surface of an EV, exosomes can be loaded with fusion proteins that are localized to the lumen of the phospholipid bilayer of the exosome (FIG. 37). The Myr/Palm sequence used herein when fused to mScarlet the fusion protein into the luminal interior of extracellular vesicles. Fluorescence at an excitation wavelength 470 nm and emission wavelength of 665-720 nm peaks in SEC fractions 7, 8, and 9. SEC fractions 7, 8, and 9 contain exosomes as demonstrated by the dot blot. Fraction 8 was further analyzed for exosome quantification using an ExoView system (FIG. 38). Unmodified exosomes do not show fluorescence. Exosomes show near 80% loading with Myr/Palm-mScarlet. The remaining 20% were out of the detection limit. Thus, nearly 100% internal loading was achieved using the specific Myr/Palm sequence.


NanoLuc luciferase expressing exosomes were also purified with the Myr/Palm sequence incorporated into the vector encoding the fusion polypeptide. A Qubit fluorometer was used to measure total protein and Promega Nano-Glo substrate and plate luminometer to measure luminescence (FIG. 39A). Tetraspanin characterization of exosomes was performed and determined that the NanoLuc luciferase exosomes were internally loaded and purified in fraction 8 (FIG. 39B).

Claims
  • 1. An engineered extracellular vesicle comprising a fusion protein, the protein comprising: at least two signaling domains, each of the at least two signaling domains being a same signaling domain and selected from the group consisting of either full length or active fragments of 4-1BBL (CD137L), mNectin-2 beta, BTN3A2, BTNL8, mBTN2A2, CD27L (CD70), CD30L (CD153), mCD30L, GITRL, CD40L (CD154), mCD140L, LIGHT (CD258), TL1, mTL1, B7-1 (CD80), B7-2 (CD86), LFA-3 (CD58), SLAM (CD150), mSLAM, CD40, CD28, mCD28, CD28H/TMIGD2/IGPR1, CD2, CD48, CD226, DR3, DcR3, FasL, Tim-1 (CD365), PD-1 (CD279), mScarlet, Nanoluciferase, A2AR, PECAM-1, STAB-1, Clever-1, NRP1, NRP2, SEMA3A, SEMA3F, RGMB/DRG11, HLA I/II, HMGB1, CEACAM-1 (CD66a), TCR, SHP-1, SHP-2, FBOX38, SH2D1A, B7RP1, IDO, NOX2, TNFRSF18/GITR/CD357, SISP1, B7-H6/NCR3LG1, APLNR, IFNg receptor, WNT5A, PAK4, IL-6, IL-10, NKG2 family, NKG2 family ligands, Killer cell Ig-like receptors CD4, CD8, CD27, CD39, CD44, CD47, CD73, CD94, CD96, CD98, IGSF2/CD101, NECTIN2/CD112, PVIRG/CD112R, IL5RB/CD122, OX40L (CD252), 4-1BB/TNFRSF4/CD137, CTLA-4/CD152, PVR/CD155, KIRs/CD158 family, CD160, SIRP alpha/CD172a, OX-2/CD200, CD200R, LAG-3/CD223, CD244, HVEM/TNFRSF14/CD270, BTLA/CD272, PD-L2/CD273, PD-L1/B7-H1/CD274, B7H2/ICOSLG/B7RP1/CD275, ICOS/CD278, LIAR-1/CD305, Collagen family members, SIGLEC7/CD328, SIGLEC9/CD329, NKp30/CD337, TNFR superfamily, Nectin-like binding receptors, Nectin, IL10RA, IL10RB, TNFRSF25, TNFRSF6B, CD113, CD30, TRAF family members, and TIM family members other than Tim-3 and Tim-4; andat least one vesicle targeting domain linked to the at least two signaling domains;wherein the at least two signaling domains are in an extracellular position relative to a lipid membrane of the extracellular vesicle.
  • 2. The engineered extracellular vesicle of claim 1, wherein the at least one vesicle targeting domain comprises a fatty acetylation site or a prenylation site, whereby the at least one vesicle targeting domain is embedded in a phospholipid bilayer of the engineered extracellular vesicle through covalent lipid attachment to the fatty acetylation site or the prenylation site.
  • 3. The engineered extracellular vesicle of claim 1, wherein the at least one vesicle targeting domain is selected from the group consisting of sequences from ADAM10, sequences from TFR2, modified myristoylation and palmitoylation tags from MARCKS, prenylation sites, fatty acylation sites, lipid affinity tags from KRAS, CD81, CD63, ALIX, TSG101, CD98, CD298, GPI, CD9, CD9 transmembrane domain 2 (CD9tm2), CD9 transmembrane domain 3 (CD9tm3), and CD105.
  • 4. The engineered extracellular vesicle of claim 1, wherein the at least one vesicle targeting domain comprises at least two exosome targeting domains.
  • 5. The engineered extracellular vesicle of claim 1, further comprising a tetraspanin selected from the group consisting of CD9, CD63, CD81, CD82, CD53, and CD37.
  • 6. The engineered extracellular vesicle of claim 5, wherein the at least two signaling domains comprise three identical signaling domains.
  • 7. The engineered extracellular vesicle of claim 1, comprising a plurality of the fusion protein, and wherein the density of the plurality of fusion protein is configured to support receptor clustering on a target cell.
  • 8. The engineered extracellular vesicle of claim 1, wherein the at least two signaling domains substantially bind to one or more of a target polypeptide.
  • 9. The engineered extracellular vesicle of claim 1, further comprising one or more secondary fusion proteins, each comprising a secondary signaling domain different from the at least two signaling domains of the fusion protein.
  • 10. The engineered extracellular vesicle of claim 9, wherein the secondary signaling domains are each independently selected from the group consisting of either full length or active fragments of PD-L1 (CD274), PD-L2 (CD273), CTLA-4 (CD152), 4-1BBL (CD137L), HVEM (CD270), FGL1, OX-2 (CD200), Galectin-9, PVR (CD155), Nectin-2 (CD112) isophorm alpha, Nectin-2 (CD112) isophorm delta, mNectin-2 beta, IL-10, TSG-6, B7-H3 (CD276), B7-H4 (VTCN1), B7-H5 (VISTA), B7-H7 (HHLA2), VSIG8, VSIG3 (IGSF11), VSIG4, Tim-3 (HAVCR2), Tim-4, CEACAM1 (CD66a), BTN3A1, BTN3A2, BTN2A1, BTNL8, BTN2A2, mBTN2A2, BTN1A1, TIGIT, CD27L (CD70), CD30L (CD153), mCD30L, GITRL, CD40L (CD154), mCD140L, LIGHT (CD258), TL1, mTL1, B7-1, (CD80), B7-2 (CD86), LFA-3 (CD58), SLAM (CD150), mSLAM, CD40, CD28, mCD28, CD28H/TMIGD2/IGPR1, CD2, CD48, CD226, DR3, DcR3, FasL, Tim-1 (CD365), PD-1 (CD279), mScarlet, Nanoluciferase, A2AR, PECAM-1, STAB-1, Clever-1, NRP1, NRP2, SEMA3A, SEMA3F, RGMB/DRG11, HLA I/II, HMGB1, TCR, SHP-1, SHP-2, FBOX38, SH2D1A, B7RP1, IDO, NOX2, TNFRSF18/GITR/CD357, SISP1, B7-H6/NCR3LG1, APLNR, IFNg receptor, WNT5A, PAK4, IL-6, NKG2 family, NKG2 family ligands, Killer cell Ig-like receptors, CD4, CD8, CD27, CD39, CD44, CD47, CD73, CD94, CD96, CD98, IGSF2/CD101, PVIRG/CD112R, IL5RB/CD122, OX40L (CD252), 4-1BB/TNFRSF4/CD137, PVR/CD155, KIRs/CD158 family, CD160, SIRP alpha/CD172a, CD200R, LAG-3/CD223, CD244, BTLA/CD272, B7H2/ICOSLG/B7RP1/CD275, ICOS/CD278, LIAR-1/CD305, Collagen family members, SIGLEC7/CD328, SIGLEC9/CD329, NKp30/CD337, TNFR superfamily, Nectin-like binding receptors, Nectin, IL10RA, IL10RB, TNFRSF25, TNFRSF6B, CD113, CD30, TRAF family members, and TIM family members.
  • 11. The engineered extracellular vesicle of claim 9, wherein the one or more secondary fusion proteins each comprises a secondary vesicle targeting domain linked to its secondary signaling domain.
  • 12. The engineered extracellular vesicle of claim 11, wherein the one or more secondary vesicle targeting domains are each independently selected from the group consisting of sequences from ADAM10, sequences from TFR2, modified myristoylation and palmitoylation tags from MARCKS, prenylation sites, fatty acylation sites, lipid affinity tags from KRAS, CD81, CD63, ALIX, TSG101, CD98, CD298, GPI, GPI from CD55/DAF, GPI from CD59, CD9, CD9 transmembrane domain 2 (CD9tm2), CD9 transmembrane domain 3 (CD9tm3), and CD105.
  • 13. A method of manufacturing a population of engineered extracellular vesicles of claim 1, comprising the steps of: genetically engineering a cell line selected from the group consisting of HEK293, PER.C, fibrosarcoma HT-1080, HuH7, and mesenchymal stem cells, with a vector or vectors comprising a gene or genes encoding the at least two signaling domains and a gene encoding the at least one vesicle targeting domain or genes encoding at least two exosome targeting domains, to produce a genetically engineered cell line; andgenerating, separating and purifying the population of engineered extracellular vesicles from the genetically engineered cell line.
  • 14. A method of treating a human subject having a disease or condition, comprising administering to the subject a composition comprising a therapeutically effective amount of the engineered extracellular vesicle of claim 1 and a pharmaceutically acceptable carrier.
  • 15. The method of claim 14, wherein the disease or condition is selected from the group consisting of an inflammatory related disease, septicemia, a chronic inflammatory related disease, polymyositis, dermatomyositis, Hashimoto's thyroiditis, myasthenia gravis, vasculitis, multiple sclerosis, psoriatic arthritis, hyperthyroidism, autoimmune adrenal insufficiency, Sjogren syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, polyarteritis nodosa, relapsing polychondritis, Behcet's disease, reactive arthritis, ankylosing spondylitis, Guillain-Barre syndrome, uveoretinitis, eczema, trauma, loss of blood or oxygen flow, infection, chemical or heat exposure, poison or venom exposure, drug overuse or overexposure, injury, age related degeneration, cancer, eye diseases, acute events, laceration, crush or impact injury, shock, and organ transplantation.
  • 16. An engineered extracellular vesicle comprising a fusion protein, the fusion protein comprising: at least two, signaling domains, each the at least two signaling domains being a same signaling domain and selected from the group consisting of either full length or active fragments of 4-1BBL (CD137L), mNectin-2 beta, BTN3A2, BTNL8, mBTN2A2, CD27L (CD70), CD30L (CD153), mCD30L, GITRL, CD40L (CD154), mCD140L, LIGHT (CD258), TL1, mTL1, B7-1 (CD80), B7-2 (CD86), LFA-3 (CD58), SLAM (CD150),mSLAM, CD40, CD28, mCD28, CD28H/TMIGD1/IGPR1, CD2, CD48, CD226, DR3, DcR3, FasL, Tim-1 (CD365), PD-1 (CD279), mScarlet, Nanoluciferase, A2AR, PECAM-1, STAB-1, Clever-1, NRP1, NRP2, SEMA3A, SEMA3F, RGMB/DRG11, HLA I/II, HMGB1, CEACAM-1 (CD66a), TCR, SHP-1, SHP-2, FBOX38, SH2D1A, B7RP1, IDO, NOX2, TNFRSF18/GITR/CD357, SISP1, B7-H6/NCR3LG1, APLNR, IFNg receptor, WNT5A, PAK4, IL-6, IL-10, NKG2 family, NKG2 family ligands, Killer cell Ig-like receptors, CD4, CD8, CD27, CD39, CD44, CD47, CD73, CD94, CD96, CD98, IGSF2/CD101, NECTIN2/CD112, PVIRG/CD112R, IL5RB/CD122, OX40L (CD252), 4-1BB/TNFRSF4/CD137, CTLA-4/CD152, PVR/CD155, KIRs/CD158 family, CD160, SIRP alpha/CD172a, OX-2/CD200, CD200R, LAG-3/CD223, CD244, HVEM/TNFRSF14/CD270, BTLA/CD272, PD-L2/CD273, PD-L1/B7-H1/CD274, B7H2/ICOSLG/B7RP1/CD275, ICOS/CD278, LIAR-1/CD305, Collagen family members, SIGLEC7/CD328, SIGLEC9/CD329, NKp30/CD337, TNFR superfamily, Nectin-like binding receptors, Nectin, IL10RA, IL10RB, TNFRSF25, TNFRSF6B, CD113, CD30, TRAF family members, and TIM family members other than Tim-3 and Tim-4;at least one vesicle targeting domain linked to the at least two signaling domains; anda linker between the at least two signaling domains and the at least one vesicle targeting domain,wherein the at least two signaling domains are in an extracellular position relative to a lipid membrane of the extracellular vesicle.
  • 17. The engineered extracellular vesicle of claim 16, wherein the linker is selected from the group consisting of Fc domains, Gly-Ser-Ser-Gly (SEQ ID NO: 319), cleavable 2A sequences, P2A, E2A, F2A, T2A, Fc, Fc from IgG1, Fc from IgG2, Fc from IgG3, Fc from IgG4 (4Fc), (GGGGS (SEQ ID NO: 320))n, and sequences with at least 70%, 80%, or 90% homology with any of the foregoing.
  • 18. The engineered extracellular vesicle of claim 16, wherein the linker is an Fc domain.
  • 19. The engineered extracellular vesicle of claim 16, wherein the at least one vesicle targeting domain comprises a fatty acetylation site or a prenylation site, whereby the at least one vesicle targeting domain is embedded in a phospholipid bilayer of the engineered extracellular vesicle through covalent lipid attachment to the fatty acetylation site or the prenylation site.
  • 20. The engineered extracellular vesicle of claim 16, wherein the at least one vesicle targeting domain is selected from the group consisting of sequences from ADAM10, sequences from TFR2, modified myristoylation and palmitoylation tags from MARCKS, prenylation sites, fatty acylation sites, lipid affinity tags from KRAS, CD81, CD63, ALIX, TSG101, CD98, CD298, GPI, GPI from CD55/DAF, GPI from CD59, CD9 transmembrane domain 2 (CD9tm2), CD9 transmembrane domain 3 (CD9tm3), and CD105.
  • 21. The engineered extracellular vesicle of claim 16, further comprising a tetraspanin selected from the group consisting of CD9, CD63, CD81, CD82, CD53, and CD37.
  • 22. The engineered extracellular vesicle of claim 21, wherein the at least two signaling domains comprise three identical signaling domains.
  • 23. The engineered extracellular vesicle of claim 16, comprising a plurality of the fusion protein, and wherein the density of the plurality of fusion protein is configured to support receptor clustering on a target cell.
  • 24. The engineered extracellular vesicle of claim 16, further comprising one or more secondary fusion proteins, each comprising a secondary signaling domain different from the signaling domain of the protein.
  • 25. The engineered extracellular vesicle of claim 24, wherein the secondary signaling domains are each independently selected from the group consisting of either full length or active fragments of PD-L1, PD-L2, CTLA-4 (CD152), 4-1BBL (CD137L), HVEM (CD270), FGL1, OX-2 (CD200), Galectin-9, PVR (CD155), Nectin-2 (CD112) isophorm alpha, Nectin-2 (CD112) isophorm delta, mNectin-2 beta, IL-10, TSG-6, B7-H3 (CD276), B7-H4 (VTCN1), B7-H5 (VISTA), B7-H7 (HHLA2), VSIG8, VSIG3 (IGSF11), VSIG4, Tim-3 (HAVCR2), Tim-4, CEACAM1 (CD66a), BTN3A1, BTN3A2, BTN2A1, BTNL8, BTN2A2, mBTN2A2, BTN1A1, TIGIT, CD27L (CD70), CD30L (CD153), mCD30L, GITRL, CD40L (CD154), mCD140L, LIGHT (CD258), TL1, mTL1, B7-1 (CD80), B7-2 (CD86), LFA-3 (CD58), SLAM (CD150), mSLAM, CD40, CD28, mCD28, CD28H/TMIGD2/IGPR1, CD2, CD48, CD226, DR3, DcR3, FasL, Tim-1 (CD365), PD-1 (CD279), mScarlet, Nanoluciferase, A2AR, PECAM-1, STAB-1, Clever-1, NRP1, NRP2, SEMA3A, SEMA3F, RGMB/DRG11, HLA I/II, HMGB1, TCR, SHP-1, SHP-2, FBOX38, SH2D1A, B7RP1, IDO, NOX2, TNFRSF18/GITR/CD357, SISP1, B7-H6/NCR3LG1, APLNR, IFNg receptor, WNT5A, PAK4, IL-6, IL-10, NKG2 family, NKG2 family ligands, Killer cell Ig-like receptors, CD4, CD8, CD27, CD39, CD44, CD47, CD73, CD94, CD96, CD98, IGSF2/CD101, NECTIN2/CD112, PVIRG/CD112R, IL5RB/CD122, OX40L (CD252), 4-1BB/TNFRSF4/CD137, CTLA-4/CD152, PVR/CD155, KIRs/CD158 family, CD160, SIRP alpha/CD172a, OX-2/CD200, CD200R, LAG-3/CD223, CD244, HVEM/TNFRSF14/CD270, BTLA/CD272, PD-L2/CD273, PD-L1/B7-H1/CD274, B7H2/ICOSLG/B7RP1/CD275, ICOS/CD278, LIAR-1/CD305, Collagen family members, SIGLEC7/CD328, SIGLEC9/CD329, NKp30/CD337, TNFR superfamily, Nectin-like binding receptors, Nectin, IL10RA, IL10RB, TNFRSF25, TNFRSF6B, CD113, CD30, TRAF family members, and TIM family members.
  • 26. The engineered extracellular vesicle of claim 24, wherein the one or more secondary fusion proteins each comprises a secondary vesicle targeting domain linked to its secondary signaling domain.
  • 27. The engineered extracellular vesicle of claim 26, wherein the one or more secondary vesicle targeting domains are each independently selected from the group consisting of sequences from ADAM10, sequences from TFR2, modified myristoylation and palmitoylation tags from MARCKS, prenylation sites, fatty acylation sites, lipid affinity tags from KRAS, CD81, CD63, ALIX, TSG101, CD98, CD298, GPI, GPI from CD55/DAF, GPI from CD59, CD9 transmembrane domain 2 (CD9tm2), CD9 transmembrane domain 3 (CD9tm3), and CD105.
  • 28. A method of manufacturing a population of the engineered extracellular vesicle of claim 16, comprising the steps of: genetically engineering a cell line selected from the group consisting of HEK293, PER.C, fibrosarcoma HT-1080, HuH7, and mesenchymal stem cells, with a vector or vectors comprising a gene or genes encoding the at least two signaling domains and a gene encoding the at least one vesicle targeting domain or genes encoding at least two exosome targeting domains, to produce a genetically engineered cell line; andgenerating, separating and purifying the population of engineered extracellular vesicles from the genetically engineered cell line.
  • 29. A method of treating a human subject having a disease or condition, comprising administering to the subject a composition comprising a therapeutically effective amount of the engineered extracellular vesicle of claim 16 and a pharmaceutically acceptable carrier.
  • 30. The method of claim 29, wherein the disease or condition is selected from the group consisting of an inflammatory related disease, septicemia, a chronic inflammatory related disease, polymyositis, dermatomyositis, Hashimoto's thyroiditis, myasthenia gravis, vasculitis, multiple sclerosis, psoriatic arthritis, hyperthyroidism, autoimmune adrenal insufficiency, Sjogren syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, polyarteritis nodosa, relapsing polychondritis, Behcet's disease, reactive arthritis, ankylosing spondylitis, Guillain-Barre syndrome, uveoretinitis, eczema, trauma, loss of blood or oxygen flow, infection, chemical or heat exposure, poison or venom exposure, drug overuse or overexposure, injury, age related degeneration, cancer, eye diseases, acute events, laceration, crush or impact injury, shock, and organ transplantation.
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 17/377,550, filed Jul. 16, 2021, which is a continuation of International Application No. PCT/US2021/016949, filed Feb. 5, 2021, which designated the U.S., and also claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 62/970,374, filed Feb. 5, 2020, the contents all of which are incorporated herein by reference in their entirety.

Provisional Applications (1)
Number Date Country
62970374 Feb 2020 US
Divisions (1)
Number Date Country
Parent 17377550 Jul 2021 US
Child 18056029 US
Continuations (1)
Number Date Country
Parent PCT/US2021/016949 Feb 2021 US
Child 17377550 US