AQUEOUS PHARMACEUTICAL COMPOSITION OF AN ANTI-IL17A ANTIBODY AND USE THEREOF

TECHNICAL FIELD

The present disclosure relates to aqueous compositions for anti-IL17a antibodies, and more particularly to aqueous compositions for anti-IL17a antibodies with a V_HHvariable domain and a V_Lvariable domain, and can be used as a medicinal agent for treating IL-17A-mediated diseases.

BACKGROUND

Antibodies, also referred to as immunoglobulins (Ig), are soluble blood or interstitial fluid glycoproteins that play a key role in humoral immunity of the Vertebrata. Antibodies are produced by B-cells in response to the foreign biological and chemical substances (antigens) of various structures. Due to high specificity and high affinity to the antigen, and the ability of producing antibodies against the unlimited antigen repertoire, antibodies and their derivatives are one of the most important reagents to be used in both fundamental and applied medical research.

Classical antibodies are represented by large multimeric proteins (IgG ^˜150 KDa) which comprise two identical heavy H-chains (one variable VH domain, three constant domains CH1, CH2 and CH3, and a hinged domain between CH1 and CH2) and two identical light L-chains (comprising of the variable domain VL and constant domain CL). A four-chain molecule has non-covalent and covalent (disulfide) bonds connecting the chains. Papain protease can be used to break down an antibody molecule into two fragments: Fab (Fragment antigen binding) and Fc (Fragment crystallizable). Therefore, one region of the molecule (Fab) defines its antigen-related specificity, and another region (Fc) exercises the effector functions targeted to antigen elimination. CH1 and CH2 domains of H-chain are spaced by a hinge region that assures the mobility of Fab-region and the interaction of IgG molecule with Ig effector receptors exposed on the cells. CH2 domain contains the regions binding with Fcγ receptors that mediate the cell activation (ADCC and ADCP) and with complement system molecules (CDC). In addition, this domain contains the site that is an attach point for carbohydrates for all immunoglobulin isotypes. CH3-domain pretty much determines the stability of IgG dimer and interacts with FcRn-receptor on the cell surface establishing the pharmacokinetic properties of antibodies as well as their metabolism and distribution in the body. The combination of complementarity determining regions (CDR) of the variable domain of the heavy chain (VH) and the variable domain of the light chain (VL) forms an antigen-binding fragment, while the framework regions of the variable domains and the constant domains are not directly involved in antigen recognition. A minimized Fab-derivative for classical antibodies is a single-chain construct in which variable domains of the heavy and light chains are connected with a linker sequence (scFv).

Finding significant amounts of specific non-classical antibodies of simplified structure in the blood of Camelidae animals (camels, llamas, vicunas) was a valuable discovery. Such antibodies (heavy chain antibody, HCAb) consist of a dimeric single shortened heavy chain (without CH1 domain) with no light chain at all. Antigen-binding fragment of HCAb is formed by only one heavy chain variable domain (VHH), which is connected through the hinged region to the Fc-domain. Rather often VHH is called a single-domain antibody, “nanobody”, “mini-antibody” or “nano-antibody”. It appears that in addition to its small size (12-15 KDa), such isolated mono-domain structure has a number of advantages compared to classical IgG antibodies, namely aggregation, chemical and thermal stability. VHH antibodies can be successfully cloned and expressed in bacterial and yeast cells. Having said properties, these antibodies were developed in therapeutic direction by Ablynx Company and in the direction of laboratory and industrial chromatography (CaptureSelect affinity products).

Heavy chain antibodies comprising a dimer of a single Ig heavy chain were first discovered by electrophoretic analysis of immunoglobulins in the serum obtained from various representatives of Camelidae family [5]. The relative fraction of HCAb varies from about 15-25% (of all IgG) in llamas and vicunas to about 60-80% in camels.

It is assumed that non-classical HCAb, at least in case of Camelidae, resulted from relatively recent evolution of the genes of classical antibodies. Two heavy chain constant domains, CH2 and CH3, in case of HCAb and classical antibodies are highly conserved. In HCAb there is no domain corresponding to the first constant domain CH1 of classical antibodies. Dromedary genome contains a cluster of about fifty VH- and forty VHH-generative genes followed by multiple genes of D-segments, J-segments and genes encoding the constant regions (Cμ, Cγ, Cε and Cα). It is clear that some of Cy-genes serve to form HCAb (mutations result in the loss of CH1-domain), and others-to form classical antibodies (with remained CH1-domain). The same genes of D- and J-segments may randomly connect to either one of VH-genes or one of VHH-genes. This indicates that VH- and VHH-genes are located in the same gene locus.

The organization of variable domains of non-classical antibodies (VHH) and variable domains of classical antibodies (VH) is very similar, as human VH-domains of IgG3 subclass have high homology to VH and VHH of Camelidae. In both cases, V-domains comprise four conservative framework regions FR surrounding three hypervariable complementary-determining regions (CDR). In addition, in both cases a 3-D structure typical for immunoglobulin V-domain is formed of two (3-layers, one of which comprises 4 amino acid sequences and another-of 5 amino acid sequences). All three CDRs in this structure form a cluster on one side of the V-domain, where they participate in antigen recognition and are located in the loops connecting 3-structures. However, there are several important distinctions related to the functioning of single-domain VHH. Thus, CDR1 and CDR3 of VHH are significantly enlarged. Complementary-determining regions of VHH often contain cysteine residues in two fragments at a time (usually in CDR1 and CDR3, less often-in CDR2 and CDR3). The studies of VHH crystal structures have shown that these cysteine residues form disulfide bonds and provide additional stability to the loop structure of these antibodies. The strongest and most reproducible distinguishing feature of VHH is represented by four substitutions of hydrophobic amino acid residues by hydrophilic ones in the second framework region (Val37Phe, Gly44Glu, Leu45Arg, Trp47Gly according to the Kabat numbering). This framework region of the VH-domain is highly conservatively enriched with hydrophobic amino acid residues and is essential for linking to the light chain variable domain VL. VHH-domain differs greatly in this aspect: substitutions of hydrophobic amino acids by hydrophilic makes the association of VHH and VL impossible. These substitutions also explain the high solubility of VHH (nano-antibody) when it is obtained as a recombinant protein.

It appears that the repertoires of paratopes (antigen-binding parts of an antibody) possible for HCAb and classical antibodies may be significantly different. Since these two antibody types co-exist in the same organism, it can be assumed that they do not compete but are complementary to each other. For example, it was repeatedly noted that both antibody types could occur in parallel, exclusively or in different ratios with regard to various epitopes of the antigen material upon immunization of the very same animal. Despite the suspected lower variety of paratopes possible for single-domain antibodies compared to the classical two-domain antibodies, many publications have clearly demonstrated that HCAb can be obtained against the most diverse epitopes of a rather wide range of antigens. Apparently, this is due to enlarged CDR1 and CDR3 regions. We also should note the surprisingly large (compared to V-domains of classical antibodies) number of somatic hypermutations in VHH that are likely to accumulate during the affine maturation of the antibody during the immunization. X-ray diffraction analysis revealed that antigen-binding loop regions of VHH are able to form structures unusual for classical V-domains. In case of VH- and VL-domains of classical antibodies, all six CDRs contribute almost the same to antigen binding; while in the case of VHH, CDR3 is usually the most important for the formation of a paratope. It has been shown that CDR3 in VHH (but not in VH or VL) is capable of forming uncommonly long finger-structures that can deepen into the antigen structure and, in particular, detect the active sites of enzymes. The small size of the antigen-binding region of VHH and its ability to form unusual emerging paratopes explain how HCAb can be obtained able to recognize epitopes inaccessible for the classical antibodies (for example, production of antibodies that effectively inhibit enzymes).

For all the high potential of the specificity unique compared to the classical IgG antibodies, the therapeutic use of a single-domain VHH is sometimes limited due to its rapid elimination form the organism. There are several solutions designed to improve the pharmacokinetics of VHH structures, including the chemical conjugation with PEG and covalent binding to polypeptides mediating the reduced clearance (such as HSA or Fc-fusion proteins that possess the half-life of up to three weeks). Small peptides attached to VHH by the recombinant technology and capable of high-affinity non-covalent interaction with said components (HSA and IgG) in human blood have been successfully used. However, the technological effectiveness and immunogenicity of these approaches remain questionable, and the feasibility of using thereof in either clinical or earlier study phases is now under investigation.

In addition, the largest limitations of using antibodies as medicinal agents are due to their aggregation and chemical stability affinity and immunogenicity. Since the majority of monoclonal antibodies are obtained on the basis of murine ones, the regular use of such antibodies in humans causes the development of immune response to antibody therapy (for example, allergic reactions). These types of immune response finally result in the lack of efficacy at least, and in potential anaphylactic reactions at worst. From the other hand, aggregation- or chemically unstable therapeutic antibodies reduce the therapeutic properties of the drug product over time and may increase its immunogenicity upon administration to human patients.

According to aforesaid, it is important to develop VHH-based antibodies with improved (in comparison to previously known antibodies) functional and therapeutic features, particularly increased aggregation, chemical and thermal stability and improved affinity, which would at the same time be easily obtained on industrial scale.

The background of the disclosure provides the information on various antibody constructs containing the VHH domain.

PCT/EP2008/066368 publication describes antibodies that comprise separate variable domains linked with Fc-fragment. Nano-bodies can be used as variable domains with Fc obtained from IgE type antibodies. Said domain and Fc fragments can be connected through a linker located in the hinge domain.

Patent application US 2009/0202979 disclosed antibodies comprising complete VHH antibodies or parts thereof directly connected to the constant regions of human antibodies.

In addition, amino acid substitutions are known that affect the physical-chemical and biological properties of antibodies.

For example, application US 2011/0028348 describes the heavy chain variable domains wherein amino acid substitutions were introduced in positions 35, 45, 47, 93-100 and 100a to improve the hydrophilic properties of the antibody obtained.

Now, methods have been developed to optimize the structure of isolated VHH and VH mono-domains in order to reduce the immunogenicity and improve the aggregation stability thereof.

Thus, Vincke at al. have found that Glu-49→Gly and Arg-50→Leu substitutions in characteristic amino acids result in the obtainment of a new domain that is more stable yet less soluble. Other substitutions in the framework region FR-2 Phe-42→Val and Gly/Ala-52→Trp are crucial for antibody affinity to the antigen due to re-orientation of H3-loop, so that the dissociation constant increases 6-10-fold (6.85·10-3 l/sec). Phe-42→Val substitution caused the reduced stability of antibodies obtained. The substitution of Gly-49 and Leu-50 in VH-sequence resulted in the lower stability of the domain, while Glu-49 and Arg-50 humanization in VHH allows obtaining the stable variable domains.

It is known from the literature, that in the presence of short HCDR3 regions neutralizing the shading effect of the conformation of classical VHH, and upon introduction of VH-characteristic Trp-47→Gly-47 substitution as well as Tyr-37→Val-37, Glu-4→Gly-44 and Arg-45→Leu-45, the isolated VHH domains can regenerate the ability to bind with VJ domain.

The relationship between the increased aggregation stability of therapeutic antibodies of classical IgG structure and the reduced immunogenicity thereof was demonstrated in multiple studies and summarized in the review by Hermeling et al., 2004. Yet there were no antibodies revealed that comprise VHH domains but were linked to the variable domains of the light chains within the full-size human IgG.

Therefore, there is a need for development of a new format of antibodies that would have improved stability and affinity, good expression and low immunogenicity.

Besides, no approaches were earlier described with regard to the development of such molecules that would be easy to obtain, have improved aggregation stability, increased affinity and high expression level in the mammal cell culture, and aqueous compositions for these antibodies.

SUMMARY

The present disclosure describes aqueous pharmaceutical antibody compositions comprising VHH-derivatives that are joined to variable domains of the light chains of the full-size human IgG, which results in the formation of a construct that (and, hence, having low immunogenicity) has improved aggregation stability, increased affinity over a traditional human antibody with both a heavy chain with a variable V_Hdomain (instead of a variable V_HHdomain) and light chain with a variable V_Ldomain, and a structure of a therapeutic monoclonal antibody. More particularly, the present disclosure relates to such antibodies that are specific to IL17a.

The present disclosure describes an aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting IL17a protein activity comprising a pharmaceutically effective amount of an anti-IL17a antibody comprising a VHH-derivative domain and a variable V_Ldomain.

As described in Patent Application No. PCT/RU2015/000163, incorporated herein by reference, an anti-IL17a antibody including both a V_HHdomain and a variable V_Ldomain (referred herein as “antibodies of the disclosure”) has shown to have increased affinity and stability to IL17a when compared to recombinant anti-IL17a human antibodies with integrated human immunoglobulin cassettes, such as Sekukinumab. As such, it would be advantageous to administer an aqueous composition with the antibody of the disclosure to a patient having an IL17a-mediated disease. Exemplary three complementary determining regions (CDRs) of the V_HHdomain of the anti-IL17a antibody for binding to IL-17a may be those corresponding to SEQ ID Nos 1, 2, 3.

However, due to the structural differences between human antibodies such as Sekukinumab and the antibodies of the disclosure, aqueous compositions suitable for Sekukinumab and related antibodies are not necessarily suitable for the antibodies of the disclosure. For instance, the antibodies of the present disclosure contain a variable V_HHdomain combined with a variable light chain V_Ldomain, where the human antibodies such as Sekukinumab have a heavy chain with a variable V_Hdomain combined with three constant domains, the heavy domain attached to a light chain. As such, there are significant structural differences in size, weight and configuration between the antibodies of the disclosure and human-based antibodies such as Sekukinumab. These differences may impact upon the appropriate selection of suitable aqueous pharmaceutical compositions for each of the antibodies. An aqueous pharmaceutical composition suitable for Sekukinumab may not necessarily be suitable for an aqueous pharmaceutical composition for an antibody of the disclosure, such as Netakimab. The additional testing, as detailed herein, was required to determine suitable aqueous pharmaceutical compositions for antibodies of the disclosure.

For these reasons, it is advantageous to determine suitable aqueous pharmaceutical compositions for the antibodies of the disclosure that provide sufficient colloidal stability, thermal stability, reduce antibody aggregation and antibody homogeneity in the composition.

As such, the present disclosure relates to determining suitable aqueous pharmaceutical compositions for the antibodies of the disclosure.

An exemplary antibody of the disclosure is Netakimab (also referred to BCD-085 herein). Netakimab is a humanized monoclonal IgG antibody with a weight average molecular weight around 149 kDa that is specific to human IL17a. It is also known under the tradename Aleira. Netakimab has a heavy chain with a mutant humanized variant of a VHH domain. The heavy chain counts 455 amino acids (SEQ ID NO: 5). Netakimab has a human kappa light chain counting 215 amino acids (SEQ ID NO: 6).

Another anti-IL17a antibody of the present disclosure that is suitable for the aqueous pharmaceutical compositions described herein includes a VHH domain with 3 CDRs corresponding respectively to SEQ ID NOs 1, 2, 3, and, in some examples, a variable V_Ldomain corresponding to SEQ ID NO 4.

A broad aspect of the present disclosure is an aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting IL17a protein activity. The aqueous pharmaceutical composition may include a pharmaceutically effective amount of an anti-IL17a antibody comprising a VHH-derivative domain and a variable VL domain; a histidine-based buffering agent; and an effective amount of a sugar-based alcohol as an osmotic agent.

In some embodiments, the anti-IL17a antibody may comprise a VHH-derivative domain and a variable VL domain, wherein VHH-derivative domain may be directly connected to a variable VL domain.

In some embodiments, the VHH-derivative domain of the anti-IL17a antibody may comprise 3 hypervariable regions HCDR1, HCDR2 and HCDR3, wherein:

HCDR1 may comprise the amino acid sequence of SEQ ID NO: 1;

HCDR2 may comprise the amino acid sequence of SEQ ID NO: 2;

HCDR3 may comprise the amino acid sequence of SEQ ID NO: 3; and

wherein the variable V_Ldomain of the anti-IL17a antibody may comprise the amino acid sequence of SEQ ID NO: 4.

In some embodiments, the anti-IL17a antibody may be Netakimab.

In some embodiments, the Netakimab may be of an amount of 5 mg/mL to 150 mg/mL.

In some embodiments, the Netakimab may be of an amount of 10 mg/mL to 100 mg/mL.

In some embodiments, the Netakimab may be of an amount of 10 mg/mL to 70 mg/mL.

In some embodiments, the Netakimab may be of an amount of 40 mg/mL.

In some embodiments, the Netakimab may be of an amount of 60 mg/mL.

In some embodiments, the Netakimab may be of an amount of 70 mg/mL.

In some embodiments, the sugar-based alcohol may be Mannitol.

In some embodiments, the Mannitol may be in an amount of 25-60 mg/mL.

In some embodiments, the Mannitol may be in an amount of 50-60 mg/mL.

In some embodiments, the Mannitol may be in an amount of 54.5 mg/mL.

In some embodiments, a suitable amount of the histidine-based buffering agent may be added to reach a pH of around 5.5 to around 6.5.

In some embodiments, the buffering agent may be composed of an amount of 0.4 mg/mL to 1.6 mg/mL of L-histidine; and an amount of 0.4 mg/mL to 1.6 mg/mL of L-histidine hydrochloride monohydrate.

In some embodiments, the aqueous pharmaceutical composition may further include a suitable solubilizer.

In some embodiments, the solubilizer may be Poloxamer 188.

In some embodiments, the Poloxamer 188 may be in an amount greater than 0 mg/mL but equal or less than 1 mg/mL.

Anti-IL17a antibody comprising a VHH-
10-70
mg/mL

derivative domain and a variable VL

domain

L-Histidine
0.4
mg/mL

L-Histidine hydrochloride monohydrate
0.4
mg/mL

Mannitol
54.5
mg/mL

Poloxamer 188
0-1
mg/mL

pH 6 0 ± 0.5

In some embodiments, said VHH-derivative domain of said anti-IL17a antibody may include 3 hypervariable regions HCDR1, HCDR2 and HCDR3, wherein:

HCDR1 may comprise the amino acid sequence of SEQ ID NO: 1;

HCDR2 may comprise the amino acid sequence of SEQ ID NO: 2;

HCDR3 may comprise the amino acid sequence of SEQ ID NO: 3; and

wherein the variable VL domain of said anti-IL17a antibody may comprise the amino acid sequence of SEQ ID NO: 4.

In some embodiments, the anti-IL17a antibody may be Netakimab.

In some embodiments, the Netakimab may be of an amount of 40 mg/mL.

In some embodiments, the Netakimab may be of an amount of 60 mg/mL.

In some embodiments, the Netakimab may be of an amount of 70 mg/mL.

Another broad aspect is an aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting IL17a protein activity, wherein the aqueous pharmaceutical composition may include:

Netakimab
40
mg/mL

L-Histidine
0.4
mg/mL

L-Histidine hydrochloride monohydrate
0.4
mg/mL

Mannitol
54.5
mg/mL

Poloxamer 188
0-1
mg/mL

pH 6.0 ± 0.5

Another broad aspect of the present disclosure is an aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting IL17a protein activity. The aqueous pharmaceutical composition may include a pharmaceutically effective amount of an anti-IL17a antibody comprising a VHH-derivative domain and a variable VL domain; an acetate-based buffering agent; and a disaccharide as an osmotic agent.

In some embodiments, said VHH-derivative domain of said anti-IL17a antibody may comprise 3 hypervariable regions HCDR1, HCDR2 and HCDR3, wherein:

HCDR1 may comprise the amino acid sequence of SEQ ID NO: 1;

HCDR2 may comprise the amino acid sequence of SEQ ID NO: 2;

HCDR3 may comprise the amino acid sequence of SEQ ID NO: 3; and

wherein the variable VL domain of said anti-IL17a antibody may comprise the amino acid sequence of SEQ ID NO: 4.

In some embodiments, the anti-IL17a antibody may be Netakimab.

In some embodiments, the Netakimab may be of an amount of 5 mg/mL to 150 mg/mL.

In some embodiments, the Netakimab may be of an amount of 10 mg/mL to 120 mg/mL.

In some embodiments, the Netakimab may be of an amount of 60 mg/mL.

In some embodiments, the Netakimab may be of an amount of 100 mg/mL.

In some embodiments, the Netakimab may be of an amount of 120 mg/mL.

In some embodiments, the disaccharide may be trehalose.

In some embodiments, the trehalose may be added to the composition as trehalose dihydrate in an amount of 50 mg/mL to 120 mg/mL.

In some embodiments, the trehalose may be added to the composition as trehalose dihydrate in an amount of 50 mg/mL.

In some embodiments, the trehalose may be added to the composition as trehalose dihydrate in an amount of 80 mg/mL.

In some embodiments, the acetate-based buffering agent may be composed of 0.4 mg/mL to 1.8 mg/mL of sodium acetate trihydrate; and a suitable amount of acetic acid to reach a pH of the composition inclusively between 4.0-6.0.

In some embodiments, the aqueous composition may further include a suitable solubilizer.

In some embodiments, the solubilizer may be Poloxamer 188.

In some embodiments, the Poloxamer 188 may be of an amount over 0 mg/mL and equal to or under 1.0 mg/mL.

Anti-IL17a antibody comprising a VHH-
10-120
mg/mL

derivative domain and a variable VL

domain

Sodium acetate trihydrate
0.44-1.74
mg/mL

Trehalose dihydrate
80-100
mg/mL

Poloxamer 188
0-1
mg/mL

Acetic acid glac.
to pH 5.0

pH 5.0 ± 0.5

In some embodiments, said VHH-derivative domain of said anti-IL17a antibody may comprise 3 hypervariable regions HCDR1, HCDR2 and HCDR3:

HCDR1 may comprise the amino acid sequence of SEQ ID NO: 1;

HCDR2 may comprise the amino acid sequence of SEQ ID NO: 2;

HCDR3 may comprise the amino acid sequence of SEQ ID NO: 3; and

wherein the variable VL domain of said anti-IL17a antibody may comprise the amino acid sequence of SEQ ID NO: 4.

In some embodiments, the anti-IL17a antibody may be Netakimab.

In some embodiments, the Netakimab may be of an amount of 60 mg/mL.

In some embodiments, the Netakimab may be of an amount of 100 mg/mL.

In some embodiments, the Netakimab may be of an amount of 120 mg/mL.

Another broad aspect is an aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting IL17a protein activity, wherein the aqueous composition may include:

Netakimab
60
mg/mL

Sodium acetate trihydrate
1.74
mg/mL

Trehalose dihydrate
80
mg/mL

Acetic acid glac.
to pH 5.0

pH 5.0 ± 0.5

Another broad aspect is an aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting IL17a protein activity, wherein the aqueous composition may include:

Netakimab
60
mg/mL

Sodium acetate trihydrate
1.74
mg/mL

Trehalose dihydrate
80
mg/mL

Poloxamer 188
0.5
mg/mL

Acetic acid glac.
to pH 5.0

pH 5.0 ± 0.5

Another broad aspect is an aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting IL17a protein activity, wherein the aqueous composition may include:

Netakimab
60
mg/mL

Sodium acetate trihydrate
1.74
mg/mL

Trehalose dihydrate
80
mg/mL

Poloxamer 188
1
mg/mL

Acetic acid glac.
to pH 5.0

bH 5.0 ± 0.5

Another broad aspect is an aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting IL17a protein activity, wherein the aqueous composition may include:

Netakimab
120
mg/mL

Sodium acetate trihydrate
1.74
mg/mL

Trehalose dihydrate
80
mg/mL

Poloxamer 188
0-1
mg/mL

Acetic acid glac.
to pH 5.0

pH 5.0 ± 0.5

Another broad aspect is an aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting IL17a protein activity, wherein the aqueous composition may include:

Netakimab
120
mg/mL

Sodium acetate trihydrate
1.74
mg/mL

Trehalose dihydrate
80
mg/mL

Acetic acid glac.
to pH 5.0

pH 5.0 ± 0.5

Another broad aspect is an aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting IL17a protein activity, wherein the aqueous composition may include:

Netakimab
120
mg/mL

Sodium acetate trihydrate
1.74
mg/mL

Trehalose dihydrate
80
mg/mL

Poloxamer 188
0.5
mg/mL

Acetic acid glac.
to pH 5.0

pH 5.0 ± 0.5

Another broad aspect is an aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting IL17a protein activity, wherein the aqueous composition may include:

Netakimab
120
mg/mL

Sodium acetate trihydrate
1.74
mg/mL

Trehalose dihydrate
80
mg/mL

Poloxamer 188
1
mg/mL

Acetic acid glac.
to pH 5.0

pH 5.0 ± 0.5

Another broad aspect is the use of the composition as defined herein for treating an IL17a mediated disease.

In some embodiments, the IL17a mediated disease may be one of: wherein the IL17A-mediated disease or disorder may be selected from: rheumatoid arthritis, juvenile rheumatoid arthritis, systemic-onset juvenile rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, psoriatic arthritis, reactive arthritis, seronegative arthritis, polyarticular juvenile idiopathic arthritis, enthesitis-related arthritis; enthesitis; spondyloarthropathy, axial spondyloarthritis; Behcet' disease; inflammatory bowel disease, Crohn's disease, ulcerative colitis; asthma, allergic disorders, atopic allergy; ichthyosis; Pityriasis rubra pilaris; papulopustular rosacea; pyoderma gangrenosum; hidradenitis suppurativa; psoriasis, psoriatic arthropathy, type I psoriasis, type II psoriasis, plaque psoriasis; dermatitis, atopic dermatitis, autoimmune dermatitis, dermatological conditions; systemic sclerosis; grafting, graft-versus-host disease, graft rejection, acute or chronic immune disease associated with organ grafting, acute graft-associated immune disease, chronic graft-associated immune disease, small intestinal graft rejection, pancreatic graft rejection, any organ or tissue graft rejection, heart transplant rejection, cartilage graft rejection, renal transplant rejection, liver transplant rejection, allograft rejection, skin allograft rejection, heterograft rejection for any organ or tissue, bone graft rejection, bone marrow transplant (BMT) rejection, parathyroid graft rejection; bone erosion; sarcoidosis, atherosclerosis, Wegener's disease, microscopic polyangiitis with renal involvement, uveitis, phacogenic uveitis, noninfectious uveitis, cachexia, acute transverse myelitis, primary biliary cirrhosis, polyglandular autoimmune syndrome type I and type II, Schmidt's syndrome, acute respiratory distress syndrome; arthropathy, seronegative arthropathy, arthropathy associated with ulcerative colitis, Reiter's syndrome, enteropathic synovitis, atheromatosis disease/coronary sclerosis, autoimmune bullous disease, pemphigus, pemphigus foliaceus, linear IgA diseases, autoimmune hemolytic anemia, cranial giant arteritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, cryptogenic fibrosing alveolitis, systemic scleroderma associated with interstitial lung disease, rheumatoid arthritis associated with interstitial lung disease, systemic lupus erythematosus associated with lung disease, dermatomyositis/polymyositis associated with lung disease, Sjogren disease associated with lung disease, ankylosing spondylitis associated with lung disease, vasculitis, diffuse pulmonary vasculitis, primary vasculitis, fibrosis, lung disease with lymphocyte infiltration, autoimmune hepatitis, autoimmune hepatitis type I (classic autoimmune or lupoid hepatitis), autoimmune hepatitis type II (associated with anti-LKM antibody), autoimmune hypoglycemia, osteoarthrosis, primary sclerosing cholangitis, erythematosus; systemic lupus erythematosus, discoid lupus erythematosus, lupus nephritis; multiple sclerosis (all types), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture syndrome, pulmonary manifestations of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic scleroderma, scleroderma disease, scleroderma, Sjogren's Syndrome, Takayasu disease/arthritis; autoimmune thrombocytopenia, idiopathic thrombocytopenia; autoimmune thyroid disorders, hyperthyroid, autoimmune hypothyroidism (Hashimoto disease), atrophic autoimmune hypothyroidism; vitiligo, acute hepatic disease, chronic hepatic disease, cholestasis, Th1- and Th2-mediated disease; malignancies such as lung cancer, breast cancer, stomach cancer, bladder cancer, colorectal cancer, pancreatic cancer, pancreatic carcinoma, ovarian cancer, prostate cancer and hematopoietic malignancies (leukemia and lymphomas), acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, adenocarcinoma, B-cell lymphoma, Burkitt lymphoma, inflammatory response to bypass, chronic myelocytic leukemia (CML), chronic inflammatory pathologies, chronic lymphatic leukemia (CLL), rectocolic carcinoma, cystic fibrosis, malignant lymphoma, malignant histiocytosis, malignant melanoma, multiple myeloma, non-Hodgkin's lymphomas, nasopharyngeal cancer, solid tumors, hairy-cell leukemia, Hodgkin disease, sarcoma, myelodysplastic syndrome, cytokine therapy-induced disorders, demyelinating disease, inflammatory demyelinating disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, usual interstitial pneumonia, iridocyclitis/uveitis/optic neuritis, lymphoedema, mixed connective-tissue disease, monoclonal gammopathy, neonatal chronic lung disease, nephritis, nephrotic, neurodegenerative disorders, osteoporosis, paraneoplastic disease/tumor-related hypercalcemia, Raynaud's phenomenon and disease, skin changes, a comprehensive systemic inflammatory response syndrome, thrombocytopenia, toxicity, urticaria, acute coronary syndrome, adult-onset Stills disease, aplastic anemia, coronary sclerosis, atopic eczema; autoimmune disorder associated with streptococcus infection, autoimmune enteropathy, autoimmune hearing loss, autoimmune lymphoproliferative syndrome (ALPS), autoimmune myocarditis, autoimmune premature ovarian failure; celiac disease, cervical spondylosis, clinically isolated syndrome (cis) with the risk for multiple sclerosis, erythema multiform, severe erythema multiform, pemphigoid, bullous pemphigoid, cicatrical pemphigoid, mucosal pemphigoid, gestational pemphigoid, iritis, keratitis, motor neuron disease, non-A, non-B hepatitis, optic neuritis, oligoarticular JIA, polyarteritis nodosa, polychondritis, poliosis, polymyositis, relapsing neuromyelitis optica, rheumatic heart disease, SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis), secondary amyloidosis, ankylosing spondylitis, systemic inflammation response syndrome, cranial arteritis, and Yersinia- or Salmonella-associated arthropathy.

Another broad aspect is a method of treating an IL17a mediated disease comprising administering a pharmaceutically effective amount of the aqueous pharmaceutical composition as defined herein.

Another broad aspect of the present disclosure is a method of producing an aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting IL17a protein activity. The method includes combining a pharmaceutically effective amount of an anti-IL17a antibody comprising a VHH-derivative domain and a variable VL domain with: a histidine-based buffering agent; and an effective amount of Mannitol as an osmotic agent.

In some embodiments, the anti-IL17a antibody may be Netakimab.

Another broad aspect is a method of producing an aqueous pharmaceutical composition suitable for parenteral administration to a subject for inhibiting IL17a protein activity comprising: combining a pharmaceutically effective amount of an anti-IL17a antibody comprising a VHH-derivative domain and a variable VL domain with an acetate-based buffering agent; and an effective amount of trehalose as an osmotic agent.

In some embodiments, the anti-IL17a antibody may be Netakimab.

In some embodiments, Poloxamer 188 may be added as a solubilizer.

Another broad aspect is a method of treating psoriasis, comprising administering to a patient in need thereof a dose of 40 mg of Netakimab once a week during week 0, 1, 2, 4, 6, 8, 10.

In some embodiments, the method may include, after the administering the dose of Netakimab on week 10, administering a dose of 40 mg of Netakimab once every four weeks thereafter.

In some embodiments, the method may include, after the administering the dose of Netakimab on week 10, administering a dose of 40 mg of Netakimab once every two weeks thereafter.

Another broad aspect is a method of treating psoriasis, comprising administering to a patient in need thereof a dose of 80 mg of Netakimab once a week during week 0, 1, 2, 4, 6, 8, 10.

Another broad aspect is a method of treating psoriasis, comprising administering to a patient in need thereof a dose of 80 mg of Netakimab once a week during week 0, 1, 2, 6, 10.

In some examples, the method may include, after the administering the dose of Netakimab on week 10, administering a dose of 80 mg of Netakimab once every four weeks thereafter.

In some examples, the method may include, after the administering the dose of Netakimab on week 10, administering a dose of 80 mg of Netakimab once every two weeks thereafter.

Another broad aspect is a method of treating psoriasis, comprising administering to a patient in need thereof a dose of 80 mg of Netakimab once a week during week 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include, after the administering the dose of 80 mg of Netakimab on week 12, administering a dose of 80 mg of Netakimab once every four weeks thereafter.

In some embodiments, the method may include, after the administering the dose of 80 mg of Netakimab on week 12, administering a dose of 80 mg of Netakimab once every two weeks thereafter.

In some embodiments, the method may include, after the administering the dose of 80 mg of Netakimab on week 12, administering a dose of 80 mg of Netakimab once every four weeks during next 12 weeks thereafter.

In some embodiments, the method may include, after the administering the dose of 80 mg of Netakimab on week 12, administering a dose of 80 mg of Netakimab once every two weeks during next 12 weeks thereafter.

In some embodiments, the method may include the administering of Netakimab according to the following regimen:

1) administering the dose of 80 mg of Netakimab once a week during week 0, 1, 2, 4, 6, 8, 10, 12,

2) administering the dose of 80 mg of Netakimab once every two weeks during next 12 weeks thereafter,

3) administering the dose of 80 mg of Netakimab once every four weeks thereafter.

In some embodiments, the method may include the administering of Netakimab according to the following regimen:

1) administering the dose of 80 mg of Netakimab once a week during week 0, 1, 2, 4, 6, 8, 10, 12,

2) administering the dose of 80 mg of Netakimab once every two weeks during next 12 weeks thereafter,

3) administering the dose of 80 mg of Netakimab once every two weeks thereafter.

In some embodiments, the method may include the administering of Netakimab according to the following regimen:

1) administering the dose of 80 mg of Netakimab once a week during week 0, 1, 2, 4, 6, 8, 10, 12,

2) administering the dose of 80 mg of Netakimab once every four weeks during next 12 weeks thereafter,

3) administering the dose of 80 mg of Netakimab once every four weeks thereafter.

In some embodiments, the method may include the administering of Netakimab according to the following regimen:

1) administering the dose of 80 mg of Netakimab once a week during week 0, 1, 2, 4, 6, 8, 10, 12,

2) administering the dose of 80 mg of Netakimab once every four weeks during next 12 weeks thereafter,

3) administering the dose of 80 mg of Netakimab once every two weeks thereafter.

In some embodiments, the dose of 80 mg of Netakimab may be administered by two injections comprising 40 mg of Netakimab.

Another broad aspect is a method of treating psoriasis, comprising administering to a patient in need thereof a dose of 120 mg of Netakimab once a week during week 0, 1, 2, 4, 6, 8, 10.

Another broad aspect is a method of treating psoriasis, comprising administering to a patient in need thereof a dose of 120 mg of Netakimab once a week during week 0, 1, 2, 6, 10.

In some embodiments, after the administering the dose of Netakimab on week 10, the method may include administering a dose of 120 mg of Netakimab once every four weeks thereafter.

In some embodiments, after the administering the dose of Netakimab on week 10, the method may include administering a dose of 120 mg of Netakimab once every two weeks thereafter.

Another broad aspect is a method of treating psoriasis, comprising administering to a patient in need thereof a dose of 120 mg of Netakimab once a week during week 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, after the administering the dose of Netakimab on week 12, the method may include administering a dose of 120 mg of Netakimab once every four weeks thereafter.

In some embodiments, after the administering the dose of Netakimab on week 12, the method may include administering a dose of 120 mg of Netakimab once every two weeks thereafter.

In some embodiments, the method may include, after the administering the dose of 120 mg of Netakimab on week 12, administering a dose of 120 mg of Netakimab once every four weeks during next 12 weeks thereafter.

In some embodiments, the method may include, after the administering the dose of 120 mg of Netakimab on week 12, administering a dose of 120 mg of Netakimab once every two weeks during next 12 weeks thereafter.

In some embodiments, the method may include the administering of Netakimab according to the following regimen:

1) administering the dose of 120 mg of Netakimab once a week during week 0, 1, 2, 4, 6, 8, 10, 12,

2) administering the dose of 120 mg of Netakimab once every two weeks during next 12 weeks thereafter,

3) administering the dose of 120 mg of Netakimab once every four weeks thereafter.

In some embodiments, the method may include the administering of Netakimab according to the following regimen:

1) administering the dose of 120 mg of Netakimab once a week during week 0, 1, 2, 4, 6, 8, 10, 12,

2) administering the dose of 120 mg of Netakimab once every two weeks during next 12 weeks thereafter,

3) administering the dose of 120 mg of Netakimab once every two weeks thereafter.

In some embodiments, the method may include the administering of Netakimab according to the following regimen:

1) administering the dose of 120 mg of Netakimab once a week during week 0, 1, 2, 4, 6, 8, 10, 12,

2) administering the dose of 120 mg of Netakimab once every four weeks during next 12 weeks thereafter,

3) administering the dose of 120 mg of Netakimab once every four weeks thereafter.

In some embodiments, the method may include the administering of Netakimab according to the following regimen:

1) administering the dose of 120 mg of Netakimab once a week during week 0, 1, 2, 4, 6, 8, 10, 12,

2) administering the dose of 120 mg of Netakimab once every four weeks during next 12 weeks thereafter,

3) administering the dose of 120 mg of Netakimab once every two weeks thereafter.

In some embodiments, the dose of 120 mg of Netakimab may be administered by three injections comprising 40 mg of Netakimab.

In some embodiments, a dose of 120 mg of Netakimab may be administered by two injections comprising 60 mg of Netakimab.

In some embodiments, Netakimab may be administered by subcutaneous injection.

In some embodiments, Netakimab may be administered by intravenous injection.

In some embodiments, psoriasis may be plaque psoriasis.

Another broad aspect is a method of treating psoriatic arthritis, comprising administering to a patient in need thereof a dose of 120 mg of Netakimab once a week during week 0, 1, 2, 4, 6, 8, 10.

Another broad aspect is a method of treating psoriatic arthritis, comprising administering to a patient in need thereof a dose of 120 mg of Netakimab once a week during week 0, 1, 2, 6, 10.

In some embodiments, the method may include, after the administering the dose of Netakimab on week 10, administering a dose of 120 mg of Netakimab once every four weeks thereafter.

In some embodiments, the method may include, after the administering the dose of Netakimab on week 10, administering a dose of 120 mg of Netakimab once every two weeks thereafter.

Another broad aspect is a method of treating psoriatic arthritis, comprising administering to a patient in need thereof a dose of 120 mg of Netakimab once a week during week 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include, after the administering the dose of Netakimab on week 12, administering a dose of 120 mg of Netakimab once every four weeks thereafter.

In some embodiments, the method may include, after the administering the dose of Netakimab on week 12, administering a dose of 120 mg of Netakimab once every two weeks thereafter.

In some embodiments, the dose of 120 mg of Netakimab may be administered by three injections comprising 40 mg of Netakimab.

In some embodiments, the dose of 120 mg of Netakimab may be administered by two injections comprising 60 mg of Netakimab.

In some embodiments, Netakimab may be administered by subcutaneous injection.

In some embodiments, Netakimab may be administered by intravenous injection.

Another broad aspect is a method of treating ankylosing spondylitis, comprising administering to a patient in need thereof a dose of 40 mg of Netakimab once a week during week 0, 1, 2.

In some embodiments, the method may include, after the administering the dose of Netakimab on week 2, administering a dose of 40 mg of Netakimab once every two weeks thereafter.

Another broad aspect is a method of treating ankylosing spondylitis, comprising administering to a patient in need thereof a dose of 40 mg of Netakimab once a week during week 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include, after the administering the dose of Netakimab on week 12, administering a dose of 40 mg of Netakimab once every two weeks thereafter.

Another broad aspect is a method of treating ankylosing spondylitis, comprising administering to a patient in need thereof a dose of 80 mg of Netakimab once a week during week 0, 1, 2.

In some embodiments, after the administering the dose of Netakimab on week 2, the method may include administering a dose of 80 mg of Netakimab once every two weeks thereafter.

Another broad aspect is a method of treating ankylosing spondylitis, comprising administering to a patient in need thereof a dose of 80 mg of Netakimab once a week during week 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, after the administering the dose of 80 mg of Netakimab on week 12, the method may include administering a dose of 80 mg of Netakimab once every two weeks thereafter.

In some embodiments, after administration of a dose of 80 mg of netakimab on week 12, starting on week 16 the method may include administering a dose of 80 mg of netakimab once every two weeks thereafter.

In some embodiments, after administration of a dose of 80 mg of netakimab on week 12, starting on week 16 the method may include administering a dose of 120 mg of Netakimab once every two weeks thereafter.

In some embodiments, the dose of 80 mg of Netakimab may be administered by two injections comprising 40 mg of Netakimab.

Another broad aspect is a method of treating ankylosing spondylitis, comprising administering to a patient in need thereof a dose of 120 mg of Netakimab once a week during week 0, 1, 2.

In some embodiments, after the administering the dose of Netakimab on week 2, the method may include administering a dose of 120 mg of Netakimab once every two weeks thereafter.

Another broad aspect is a method of treating ankylosing spondylitis, comprising administering to a patient in need thereof a dose of 120 mg of Netakimab once a week during week 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, after the administering the dose of Netakimab on week 12, the method may include administering a dose of 120 mg of Netakimab once every two weeks thereafter.

In some embodiments, after administration of a dose of 120 mg of Netakimab on week 12, starting on week 16 the method may include administering a dose of 80 mg of Netakimab once every two weeks thereafter.

In some embodiments, after administration of a dose of 120 mg of Netakimab on week 12, starting on week 16 the method may include administering a dose of 120 mg of Netakimab once every two weeks thereafter.

In some embodiments, a dose of 120 mg of Netakimab may be administered by three injections comprising 40 mg of Netakimab.

In some embodiments, a dose of 120 mg of Netakimab may be administered by two injections comprising 60 mg of Netakimab.

In some embodiments, Netakimab may be administered by subcutaneous injection.

In some embodiments, Netakimab may be administered by intravenous injection.

Another broad aspect is a pharmaceutical composition suitable for administration to a subject for inhibiting IL17a protein activity wherein, for each 1 mL of the pharmaceutical composition, the pharmaceutical composition comprises:

Netakimab
40.0
mg,

histidine hydrochloride monohydrate
0.4
mg,

L-histidine
0.4
mg,

mannitol
54.5
mg,

water for injection ad
1.0
mL.

Another broad aspect is a method of treating psoriasis comprising administering to a patient a pharmacologically effective volume of the pharmaceutical composition described herein.

In some embodiments, 1 mL of the pharmaceutical composition may be administered.

In some embodiments, 1 mL of the pharmaceutical composition may be administered once a week during week 0, 1, 2, 4, 6, 8, 10.

In some embodiments, the method may include, after the administering the dose of Netakimab on week 10, administering 1 mL doses of Netakimab on each of every four weeks thereafter.

In some embodiments, the method may include, after the administering the dose of Netakimab on week 10, administering 1 mL doses of Netakimab on each of every two weeks thereafter.

In some embodiments, 2 mL of the pharmaceutical composition may be administered.

In some embodiments, 2 mL of the pharmaceutical composition may be administered once a week during week 0, 1, 2, 4, 6, 8, 10.

In some embodiments, 2 mL of the pharmaceutical composition may be administered once a week during week 0, 1, 2, 6, 10.

In some embodiments, the method may include, after the administering the dose of Netakimab on week 10, administering 2 mL doses of Netakimab once every four weeks thereafter.

In some embodiments, the method may include, after the administering the dose of Netakimab on week 10, administering 2 mL doses of Netakimab once every two weeks thereafter.

In some embodiments, 2 mL of the pharmaceutical composition may be administered once a week during week 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include after the administering the dose of Netakimab on week 12, administering 2 mL doses of Netakimab once every four weeks thereafter.

In some embodiments, the method may include after the administering the dose of Netakimab on week 12, administering 2 mL doses of Netakimab once every two weeks thereafter.

In some embodiments, the method may include, after the administering 2 mL doses of Netakimab on week 12, administering 2 mL doses of Netakimab once every four weeks during next 12 weeks thereafter.

In some embodiments, the method may include after the administering 2 mL doses of Netakimab on week 12, administering 2 mL doses of Netakimab once every two weeks during next 12 weeks thereafter.

In some embodiments, the method may include the administering of the pharmaceutical composition according to the following regimen:

1) administering 2 mL of the pharmaceutical composition once a week during week 0, 1, 2, 4, 6, 8, 10, 12,

2) administering 2 mL of the pharmaceutical composition once every two weeks during next 12 weeks thereafter,

3) administering 2 mL of the pharmaceutical composition once every four weeks thereafter.

In some embodiments, the method may include the administering of the pharmaceutical composition according to the following regimen:

1) administering 2 mL of the pharmaceutical composition once a week during week 0, 1, 2, 4, 6, 8, 10, 12,

2) administering 2 mL of the pharmaceutical composition once every two weeks during next 12 weeks thereafter,

3) administering 2 mL of the pharmaceutical composition once every two weeks thereafter.

In some embodiments, the method may include the administering of the pharmaceutical composition according to the following regimen:

1) administering 2 mL of the pharmaceutical composition once a week during week 0, 1, 2, 4, 6, 8, 10, 12,

2) administering 2 mL of the pharmaceutical composition once every four weeks during next 12 weeks thereafter,

3) administering 2 mL of the pharmaceutical composition once every four weeks thereafter.

In some embodiments, the method may include the administering of the pharmaceutical composition according to the following regimen:

1) administering 2 mL of the pharmaceutical composition once a week during week 0, 1, 2, 4, 6, 8, 10, 12,

2) administering 2 mL of the pharmaceutical composition once every four weeks during next 12 weeks thereafter,

3) administering 2 mL of the pharmaceutical composition once every two weeks thereafter.

In some embodiments, the 2 mL may be delivered via syringe in two separate 1 mL doses.

In some embodiments, the syringe may be a pre-filled syringe.

In some embodiments, 3 mL of the pharmaceutical composition may be administered.

In some embodiments, 3 mL of the pharmaceutical composition may be administered once a week during week 0, 1, 2, 4, 6, 8, 10.

In some embodiments, 3 mL of the pharmaceutical composition may be administered once a week during week 0, 1, 2, 6, 10.

In some embodiments, the method may include, after the administering the dose of Netakimab on week 10, administering 3 mL doses of Netakimab once every four weeks thereafter.

In some embodiments, the method may include, after the administering the dose of Netakimab on week 10, administering 3 mL doses of Netakimab once every two weeks thereafter.

In some embodiments, 3 mL of the pharmaceutical composition may be administered once a week during week 0, 1, 2, 4, 6, 8, 10, 12.

In some embodiments, the method may include, after the administering the dose of Netakimab on week 12, administering 3 mL doses of Netakimab once every four weeks thereafter.

In some embodiments, the method may include, after the administering the dose of Netakimab on week 12, administering 3 mL doses of Netakimab once every two weeks thereafter.

In some embodiments, the method may include, after the administering 3 mL doses of Netakimab on week 12, administering 3 mL doses of Netakimab once every four weeks during next 12 weeks thereafter.

In some embodiments, the method may include after the administering 3 mL doses of Netakimab on week 12, administering 3 mL doses of Netakimab once every two weeks during next 12 weeks thereafter.

In some embodiments, the method may include the administering of the pharmaceutical composition according to the following regimen:

1) administering 3 mL of the pharmaceutical composition once a week during week 0, 1, 2, 4, 6, 8, 10, 12,

2) administering 3 mL of the pharmaceutical composition once every two weeks during next 12 weeks thereafter,

3) administering 3 mL of the pharmaceutical composition once every four weeks thereafter.

In some embodiments, the method may include the administering of the pharmaceutical composition according to the following regimen:

1) administering 3 mL of the pharmaceutical composition once a week during week 0, 1, 2, 4, 6, 8, 10, 12,

2) administering 3 mL of the pharmaceutical composition once every two weeks during next 12 weeks thereafter,

3) administering 3 mL of the pharmaceutical composition once every two weeks thereafter.

In some embodiments, the method may include the administering of the pharmaceutical composition according to the following regimen:

1) administering 3 mL of the pharmaceutical composition once a week during week 0, 1, 2, 4, 6, 8, 10, 12,

2) administering 3 mL of the pharmaceutical composition once every four weeks during next 12 weeks thereafter,

3) administering 3 mL of the pharmaceutical composition once every four weeks thereafter.

In some embodiments, the method may include the administering of the pharmaceutical composition according to the following regimen:

1) administering 3 mL of the pharmaceutical composition once a week during week 0, 1, 2, 4, 6, 8, 10, 12,

2) administering 3 mL of the pharmaceutical composition once every four weeks during next 12 weeks thereafter,

3) administering 3 mL of the pharmaceutical composition once every two weeks thereafter.

In some embodiments, the 3 mL may be delivered via syringe in three separate 1 mL doses.

In some embodiments, the syringe may be a pre-filled syringe.

In some embodiments, the pharmaceutical composition may be administered intramuscularly.

In some embodiments, the pharmaceutical composition may be administered subcutaneously.

In some embodiments, the pharmaceutical composition may be administered intravenously.

In some embodiments, psoriasis may be plaque psoriasis.

Another broad aspect is a method of treating psoriatic arthritis comprising administering to a patient a pharmacologically effective volume of the pharmaceutical composition as described herein.