WO2025153079A1

WO2025153079A1 - Method of treatment

Info

Publication number: WO2025153079A1
Application number: PCT/CN2025/073093
Authority: WO
Inventors: Jianfeng Pan; Dubeiqi HONG; Hui CHAI; Yingying XU; Yanni CONG; Dicong ZHU; Hang YANG; Zhehao XIONG
Original assignee: Biomap Suzhou Intelligent Technology Ltd
Current assignee: Biomap Suzhou Intelligent Technology Ltd
Priority date: 2024-01-19
Filing date: 2025-01-17
Publication date: 2025-07-24
Anticipated expiration: 2026-07-19

Abstract

The disclosure provides novel anti-OSMR antibodies, combination therapy targeting both OSMR and TNF-α, and uses thereof.

Description

METHOD OF TREATMENT

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to PCT Application No. PCT/CN2024/073268, filed on January19, 2024. The disclosure of the prior application is considered part of the disclosure of this application andis incorporated herein in its entirety.

REFERENCE TO THE SEOUENCE LISTING

The Sequence Listing titled DCF231833WO-Sequence Listing. xml, which was created on January18, 2024 and is 44, 594bytes in size, is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

The present disclosure relates to the immune therapy field, particularly relates to the treatment of inflammatory disorders with a combination of OSMR antagonistandTNF-αantagonist, especially the combination of anti-OSMR antibody and anti-TNF-α antibody.

BACKGROUND

Inflammatory bowel diseases (IBDs) are chronic illnesses that involveinflammation of tissues in the digestive tract and areusually divided into Crohn’s disease and ulcerative colitis. In IBD patients, an increase in turnover and activation of monocytes occurs, which are a source of intestinal macrophages. The chemokine MCP-1 (CCL2) is a potent chemotactic and activator of monocytes and macrophages. Several studies havedocumented elevated CCL2 mRNA and protein expression in the mucosa of IBD patients. Further, experimental studies performed in rodents support a role for CCL2 inexperimental colitis. For example, mice deficient in CCL2 show a significantreduction in the severity of colitis both macroscopically and histologically along with adecrease in mortality compared with wild-type control mice.

Neutralizing tumor necrosis factor (TNF) antibodies have been widely used to treat inflammatory bowel disease (IBD) in the clinical practice. However, anti-TNF-αtreatment has recently been implicated in the process of molecular resistance, requiring alternative therapeutic targets, particularly of patients that do not respond to therapies based on an anti-TNF-α antibody alone.

Oncostatin-M specific receptor subunit beta also known as the Oncostatin M receptor (OSMR) , is one of the receptor proteins for oncostatin M (OSM) . The OSMR is expressed in nonepithelial, nonhematopoietic intestinal stromal cells, and these cells produce a range of proinflammatory chemicals in response to OSM.

SUMMARY OF INVENTION

In one aspect, the present disclosure provides synergistic combination therapies employing inhibitors or antagonistsof OSMR and TNF-α. In some embodiments, the synergistic combination therapies are targeted towards the treatment or prevention of inflammatory diseases or autoimmune diseases. In a preferable embodiment, the inflammatory or autoimmune disease is selected from diseases where OSMR activation plays a role, such as pruritus, hypersensitivity, lupus, graft-versus-host disease (GvHD) , vasculitis, Type I diabetes, multiple sclerosis, rheumatoid arthritis, alopecia areata, atherosclerosis, psoriasis, organ transplant rejection, Sjogren's Syndrome, Behcet's disease, atopic dermatitis, asthma, and inflammatory bowel disease (IBD) . In some preferred embodiments, IBD includesTNF-αresistant IBD.

In some embodiments, theinhibitors or antagonists of OSMR is selected fromanti-OSMR antibodies or antigen binding fragments thereof. Theanti-OSMR antibodies or antigen binding fragments thereof could be any anti-OSMR antibodies or antigen binding fragments thereof well-known in the art, or the antibody or antigen binding fragment thereof that binds specifically to OSMR disclosed herein. In some preferred embodiments, the anti-OSMR antibodies are blocking antibodies. In some preferred embodiments, the anti-OSMR antibody or antigen binding fragment thereof comprises the 6 CDRs ofVixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212. In some preferred embodiments, theanti-OSMR antibody or antigen binding fragments thereof is selected fromVixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212.

In some embodiments, the inhibitors or antagonists of TNF-αis selected from anti-TNF-αantibodies or antigen binding fragments thereof. In some preferred embodiments, the anti-TNF-α antibodies are blocking antibodies. In some preferred embodiments, the anti-TNF-α antibody or antigen binding fragment thereof comprises the 6 CDRs ofInfliximab, Adalimumab, Afelimomab, CDP-571, CDP-870, Golimumab, orNerelimomab. In some preferred embodiments, theanti-TNF-α antibody or antigen binding fragment thereof is selected from Infliximab, Adalimumab, Afelimomab, CDP-571, CDP-870, Golimumab, orNerelimomab.

In one aspect, the present disclosure provides an antibody or antigen binding fragment thereof that binds specifically to OSMR, wherein the antibody or antigen binding fragment thereof is selected from any one of the following (a) to (k) :

(a) the antibody or antigen binding fragment thereof comprising a HCDR1 comprisingDNYX₁H as set forth in SEQ ID NO: 38, a HCDR2 comprising RIDPEX₂GDX₃TYX₄X₅KFQX₆as set forth in SEQ ID NO: 39, a HCDR3 comprising DYYX₇X₈X₉YVWYFDV as set forth in SEQ ID NO: 40, a LCDR1 comprising RASSSVSSSYLH as set forth in SEQ ID NO: 14, a LCDR2 comprising STSNLAS as set forth in SEQ ID NO: 15, and a LCDR3 comprising QX₁₀YSGYPLIFT as set forth in SEQ ID NO: 41, where X₁is any one of I, M, and their conservative substitutions, X₂is any one of N, S, and their conservative substitutions, X₃ is any one of I, T, and their conservative substitutions, X₄ is any one of D, A, and their conservative substitutions, X₅ is any one of P, Q, and their conservative substitutions, X₆ is any one of D, G, and their conservative substitutions, X₇ is any one of G, Q, A, and their conservative substitutions, X₈ is any one of S, G, and their conservative substitutions, X₉ is any one of N, D, and their conservative substitutions, X₁₀ is any one of Q, T, and their conservative substitutions;

(b) the antibody or antigen binding fragment thereof comprising a HCDR1 comprisingYYDIN as set forth in SEQ ID NO: 5, a HCDR2 comprisingWIX₁₁PRDX₁₂STKYX₁₃X₁₄X₁₅FX₁₆G as set forth in SEQ ID NO: 42, a HCDR3 comprising EDSDYFDY as set forth inSEQ ID NO: 7, a LCDR1 comprising RASESVDRYGX₁₇SFMY as set forth inSEQ ID NO: 43, a LCDR2 comprising RASNLES as set forth inSEQ ID NO: 9, and a LCDR3 comprising QQSX₁₈EX₁₉PWT as set forth inSEQ ID NO: 44, where X₁₁is any one of F, L, and their conservative substitutions, X₁₂is any one of G, E, and their conservative substitutions, X₁₃ is any one of N, A, and their conservative substitutions, X₁₄ is any one of E, Q, and their conservative substitutions, X₁₅ is any one of R, K, and their conservative substitutions, X₁₆ is any one of K, Q, and their conservative substitutions, X₁₇ is any one of N, S, and their conservative substitutions, X₁₈ is any one of Y, A, and their conservative substitutions, X₁₉ is any one of D, Y, and their conservative substitutions;

(c) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 11 or SEQ ID NO: 11 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 30 or SEQ ID NO: 30 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 12 or SEQ ID NO: 12 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 27 or SEQ ID NO: 27 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 31 or SEQ ID NO: 31 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 13 or SEQ ID NO: 13 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 28 or SEQ ID NO: 28 with 1, 2, or 3 conservative substitutions, SEQ ID NO: 32 or SEQ ID NO: 32 with 1, 2, or 3 conservative substitutions, orSEQ ID NO: 33 or SEQ ID NO: 33 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 14 or SEQ ID NO: 14 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 15 or SEQ ID NO: 15 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 16 or SEQ ID NO: 16 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 29 or SEQ ID NO: 29 with 1, 2, or 3 conservative substitutions;

(d) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 5 or SEQ ID NO: 5 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 6 or SEQ ID NO: 6 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 34 or SEQ ID NO: 34 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 36 or SEQ ID NO: 36 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 7 or SEQ ID NO: 7 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 8 or SEQ ID NO: 8 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 22 or SEQ ID NO: 22 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 9 or SEQ ID NO: 9 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 10 or SEQ ID NO: 10 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 35 or SEQ ID NO: 35 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 37 or SEQ ID NO: 37 with 1, 2, or 3 conservative substitutions;

(e) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 11 or SEQ ID NO: 11 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 12 or SEQ ID NO: 12 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 13 or SEQ ID NO: 13 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 14 or SEQ ID NO: 14 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 15 or SEQ ID NO: 15 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 16 or SEQ ID NO: 16 with 1, 2, or 3 conservative substitutions;

(f) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 11 or SEQ ID NO: 11 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 27 or SEQ ID NO: 27 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 28 or SEQ ID NO: 28 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 14 or SEQ ID NO: 14 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 15 or SEQ ID NO: 15 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 29 or SEQ ID NO: 29 with 1, 2, or 3 conservative substitutions;

(g) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 30 or SEQ ID NO: 30 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 31 or SEQ ID NO: 31 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 32 or SEQ ID NO: 32 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 14 or SEQ ID NO: 14 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 15 or SEQ ID NO: 15 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 29 or SEQ ID NO: 29 with 1, 2, or 3 conservative substitutions;

(h) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 30 or SEQ ID NO: 30 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 31 or SEQ ID NO: 31 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 33 or SEQ ID NO: 33 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 14 or SEQ ID NO: 14 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 15 or SEQ ID NO: 15 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 29 or SEQ ID NO: 29 with 1, 2, or 3 conservative substitutions;

(i) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 5 or SEQ ID NO: 5 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 6 or SEQ ID NO: 6 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 7 or SEQ ID NO: 7 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 8 or SEQ ID NO: 8 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 9 or SEQ ID NO: 9 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 10 or SEQ ID NO: 10 with 1, 2, or 3 conservative substitutions;

(j) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 5 or SEQ ID NO: 5 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 34 or SEQ ID NO: 34 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 7 or SEQ ID NO: 7 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 8 or SEQ ID NO: 8 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 9 or SEQ ID NO: 9 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 35 or SEQ ID NO: 35 with 1, 2, or 3 conservative substitutions;

(k) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 5 or SEQ ID NO: 5 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 36 or SEQ ID NO: 36 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 7 or SEQ ID NO: 7 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 22 or SEQ ID NO: 22 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 9 or SEQ ID NO: 9 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 37 or SEQ ID NO: 37 with 1, 2, or 3 conservative substitutions.

In another aspect, the present disclosure provides an antibody or antigen binding fragment thereof that binds specifically to OSMR, comprising a VH and/or VL of any one of the following (a) to (g) :

(a) a VH comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 1 and/or a VL comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 2;

(b) a VH comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 3 and/or a VL comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 4;

(c) a VH comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 17 and/or a VL comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 18;

(d) a VH comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 19 and/or a VL comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 20;

(e) a VH comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 21 and/or a VL comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 20;

(f) a VH comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 23 and/or a VL comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 24;

(g) a VH comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 25 and/or a VL comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 26.

In another aspect, the present disclosure provides an antibody or antigen binding fragment thereof that binds specifically to OSMR, wherein the antibody or antigen binding fragment thereof comprises any one of the following (a) to (g) :

(a) three CDRs of a VH comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 1, and three CDRs of a VL comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 2;

(b) three CDRs of a VH comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 3, and three CDRs of a VL comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 4;

(c) three CDRs of a VH comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 17, and three CDRs of a VL comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 18;

(d) three CDRs of a VH comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 19, and three CDRs of a VL comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 20;

(e) three CDRs of a VH comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 21, and three CDRs of a VL comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 20;

(f) three CDRs of a VH comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 23, and three CDRs of a VL comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 24;

(g) three CDRs of a VH comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 25, and three CDRs of a VL comprises an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%sequence identity to SEQ ID NO: 26.

In another aspect, the present disclosure provides a method of diagnosing an OSMR-related disease in a subject, comprising contacting the subject’s sample to the antibody or antigen binding fragment thereof disclosed herein that specifically binds to OSMR, and identifying OSMR.

In yet another aspect, the present disclosure provides a kit, a system, a device, or a product for diagnosing OSMR-related disease in a subject, comprising the antibody or antigen binding fragment thereof disclosed herein that specifically binds to OSMR.

In one aspect, the present disclosure provides a multispecific (such as bispecific) antibody or antigen binding fragment thereof, comprising a first antigen binding region that specifically binds to OSMR, and a second antigen binding region. In some embodiments, the first antigen binding region that specifically binds to OSMR comprises the antibody or antigen binding fragment thereof disclosed herein that specifically binds to OSMR.

In some embodiments, the second antigen binding region of the disclosed multispecific antibody or antigen binding fragment thereof specifically binds to one of the following targets selected from tumor associated antigen (TAA) , immune checkpoint targets and targets for immune cell engager.

In another aspect, the present disclosure provides an antibody drug conjugate (ADC) , comprising the antibody or antigen binding antigen thereof disclosed herein that specifically binds to OSMR, or the multispecific antibody or antigen binding fragment thereof disclosed herein.

In one aspect, the present disclosure provides an isolated nucleic acid encoding the antibody or antigen binding fragment thereof disclosed herein that specifically binds to OSMR, or themultispecific antibody or antigen binding fragment thereof disclosed herein.

In another aspect, the present disclosure provides a vector, comprising the isolated nucleic acid disclosed herein.

In yet another aspect, the present disclosure provides a host cell, comprising the isolated nucleic acid disclosed herein, or the vector disclosed herein.

In one aspect, the present disclosure provides a combination, comprising one or more OSMR inhibitors and one or more TNF-α inhibitors. In some preferred embodiments, the OSMR inhibitor is selected from anti-OSMR antibodies or antigen binding fragments thereof. Theanti-OSMR antibodies or antigen binding fragments thereof could be any anti-OSMR antibodies or antigen binding fragments thereof well-known in the art, or the antibody or antigen binding fragment thereof that binds specifically to OSMR disclosed herein. In some embodiments, the said anti-OSMR antibodies are blocking antibodies. In a preferable embodiment, the anti-OSMR antibody or antigen binding fragment thereof comprises the 6 CDRs of Vixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212. In some preferred embodiments, the anti-OSMR antibody is selected from Vixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212. In some preferred embodiments, the TNF-αinhibitor is selected from anti-TNF-α antibodies or antigen binding fragments thereof. In some embodiments, the said anti-TNF-α antibodies are blocking antibodies. The TNF-α inhibitor could be any anti-TNF-α antibody or antigen binding fragment thereof well-known in the art. In a preferable embodiment, the anti-TNF-α antibody or antigen binding fragment thereof comprises the 6 CDRs ofInfliximab, Adalimumab, Afelimomab, CDP-571, CDP-870, Golimumab, orNerelimomab. In some preferred embodiments, the anti-TNF-α antibody or antigen binding fragment thereof is selected from Infliximab, Adalimumab, Afelimomab, CDP-571, CDP-870, Golimumab, orNerelimomab.

In still yet another aspect, the present disclosure provides a pharmaceutical composition comprising the antibody or antigen binding fragment thereof disclosed herein that specifically binds to OSMR, the combination disclosed herein, the multispecific antibody or antigen binding fragment thereof disclosed herein, the ADC disclosed herein, the isolated nucleic acid disclosed herein, the vector disclosed herein, or the host cell disclosed herein, and a pharmaceutically acceptable excipient or carrier.

In one aspect, the present disclosure provides a method of treating or preventing an inflammatory or autoimmune disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody or antigen binding fragment thereof disclosed herein that specifically binds to OSMR, the combination disclosed herein, the multispecific antibody or antigen binding fragment thereof disclosed herein, the ADC disclosed herein, the isolated nucleic acid disclosed herein, the vector disclosed herein, the host cell disclosed herein, or the pharmaceutical composition disclosed herein.

In still another aspect, the present disclosure provides a method of treatingor preventing inflammatory diseases or autoimmune diseases in a subject in need thereof, comprising administering to the subject a therapeutically effective amount ofone or more OSMR inhibitors, in combination with a therapeutically effective amount of one or more TNF-αinhibitors. In some preferred embodiments, the OSMR inhibitor is selected from anti-OSMR antibodies or antigen binding fragments thereof. In some embodiments, the said anti-OSMR antibodies are blocking antibodies. Theanti-OSMR antibodies or antigen binding fragments thereof could be any anti-OSMR antibodies or antigen binding fragments thereof well-known in the art, or the antibody or antigen binding fragment thereof that binds specifically to OSMR disclosed herein. In a preferable embodiment, the anti-OSMR antibody or antigen binding fragment thereof comprises the 6 CDRs of Vixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212. In some preferred embodiments, the anti-OSMR antibody or antigen binding fragments thereof is selected from Vixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212. In some preferred embodiments, the TNF-α inhibitor is selected from anti-TNF-α antibodies or antigen binding fragments thereof. The TNF-α inhibitor could be any anti-TNF-α antibodies or antigen binding fragments thereof, such as any anti-TNF-α antibody or antigen binding fragment thereof well-known in the art. In some embodiments, the anti-TNF-α antibodiesare blocking antibodies. In a preferable embodiment, the anti-TNF-α antibody or antigen binding fragment thereof comprises the 6 CDRs of Infliximab, Adalimumab, Afelimomab, CDP-571, CDP-870, Golimumab, or Nerelimomab. In a preferable embodiment, the anti-TNF-α antibody orantigen binding fragments thereof is selected from Infliximab, Adalimumab, Afelimomab, CDP-571, CDP-870, Golimumab, or Nerelimomab.

In some preferred embodiments, the inflammatory or autoimmunedisease is selected from diseases where OSMR activation plays a role, such as pruritus, hypersensitivity, lupus, graft-versus-host disease (GvHD) , vasculitis, Type I diabetes, multiple sclerosis, rheumatoid arthritis, alopecia areata, atherosclerosis, psoriasis, organ transplant rejection, Sjogren's Syndrome, Behcet's disease, atopic dermatitis, asthma, and inflammatory bowel disease (IBD) . In some preferred embodiments, IBD includesTNF-α resistant IBD.

BRIEF DESCRIPTION OF DRAWINGS

The following is a brief description of the drawings, which are presented for the purposes of illustrating the exemplary embodiments disclosed herein and not for the purposes of limiting the same.

Figure 1 shows that in Example 1 the MCP-1 secretion level incolonic fibroblast cells induced by OSM and TNF-α, or un-induced in PBS, and treated with a combination of anti-OSMR antibody, anti-TNF-α antibody and/or hIgG1 antibody. The IgG herein refers to hIgG1.

Figure 2A shows that in Example 3 the relative light unit (RLU) of hOSM-induced reporter cell line treated with various concentrations of antibody 8A1, vixarelimab, and hIgG1.

Figure 2B shows that in Example 3 the relative light unit (RLU) of hOSM-induced reporter cell line treated with various concentrations of antibody 14C7, vixarelimab, and hIgG1.

Figure 3 shows that in Example 5, the MFI (mean fluorescence intensity) for HEK293-OSMR reporter cells treated with various anti-OSMR antibodies and hIgG1 antibody.

Figure 4A shows that in Example 6 the RLU of hOSM-induced reporter cell line treated with various concentrations of antibody 8A1-hu6, 8A1-hu11, 8A1-hu13, vixarelimab, and hIgG1.

Figure 4B shows that in Example 6 the RLU of hOSM-induced reporter cell line treated with various concentrations of antibody 14C7-hu3, 14C7-hu16, vixarelimab, and hIgG1.

Figure 5A shows that in Example 7 the MCP-1 level in colonic fibroblasts treated with various concentrations of antibody 8A1-hu6, vixarelimab, and hIgG1.

Figure 5B shows that in Example 7 the MCP-1 level in colonic fibroblasts treated with various concentrations of antibody 8A1-hu11, 8A1-hu13, 14C7-hu3, 14C7-hu16, andvixarelimab.

Figure 6 shows that in Example 8 the percent of endocytosis over time in HEK293-OSMR cell line for antibody 8A1-hu6, 8A1-hu11, 8A1-hu13, 14C7-hu3, 14C7-hu16, hIgG1 andvixarelimab.

Figure 7shows that in Example 9 the MCP-1 secretion level in colonic fibroblasts treated with hIgG1, adalimumab (ADA) , or infliximab (INF) , in combination with candidate antibodies. The candidate antibodies are shown on the x-axis, including hIgG1, vixarelimab (VIX) , 8A1-hu6, 8A1-hu11, 8A1-hu13, 14C7-hu3, 14C7-hu16.

DETAILED DESCRIPTION OF THE INVENTION

The aforementioned features and advantages of the disclosure as well as additional features and advantages thereof will be more clearly understood hereafter as a result of a detailed description of the following embodiments when taken in conjunction with the drawings. The embodiments described herein with reference to drawings are explanatory, illustrative, and shall not be construed to limit the scope of the present disclosure.

The description is not intended to be a detailed catalog of all the different ways in which the disclosure may be implemented or all the features that may be added to the instant disclosure. For example, features illustrated with respect to one embodiment may be incorporated into other embodiments, and features illustrated with respect to a particular embodiment may be deleted from that embodiment. In addition, numerous variations and additions to the various embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure which do not depart from the instant disclosure. Hence, the following description is intended to illustrate some particular embodiments of the disclosure, and not to exhaustively specify all permutations, combinations and variations thereof.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains. Although any methods and materials similar or equivalent to those described herein may be used in the practice for testing of the present disclosure, the preferred materials and methods are described herein. In describing and claiming the present disclosure, the following terminology will be used.

DEFINITIONS

Unless clearly indicated otherwise, the term “comprise” , “include” , “contain” , and their variations such as “comprising” , “comprises” as used herein should be understood to imply the inclusion of a stated element or step or a group of elements or steps, but not the exclusion of any other element or step or a group of elements or steps.

Unless clearly contraindicated in the context herein or indicated otherwise, the expression of “A and/or B” includes three situations: (1) A, (2) B, and (3) A and B; the expression of “A, B and/or C” includes seven situations: (1) A, (2) B, (3) C, (4) A and B, (5) A and C, (6) B and C, and (7) A, B and C. The meaning of similar expressions can be inferred in this manner.

Unless indicated otherwise, a singular form of a referent shall include its plural counterparts, and plural terms shall include the singular counterpart.

As used herein, the term “antibody” refers to an immunoglobulin (Ig) molecule that specifically binds an antigen. A basic antibody unit is in a tetramer form consisting of two identical light chains (LC) and two identical heavy chains (HC) . The N-terminal of each chain contains a variable region with highly diverse amino acid sequence, and the rest of each chain contains the constant region. The heavy chain variable region (VH) and light chain variable region (VL) are responsible for antigen binding, while the constant regions may participate in the binding of an immunoglobulin to host cells or factors, including immune cells and components of the complement system.

An immunoglobulin can be categorized into five classes based on heavy chain constant region, that are IgA, IgD, IgE, IgG, and IgM. Further, an immunoglobulin can be further divided into subtypes, such as IgG1, IgG2, IgG3, IgG4, IgA1, IgA2. Whereas, the antibody light chain may be a lambda (λ) chain or a kappa (κ) chain.

An exemplary heavy chain constant region could be the wild-type shown as:

or it could be a mutant shown as:

An exemplary light chain constant region could be shown as:

A full-length antibody includes two heavy chains and two light chains. The variable regions/domains of the light and heavy chains are responsible for antigen binding. The “variable region” or “variable domain” of an antibody refers to the amino-terminal domains of the heavy or light chain of the antibody. The variable domains of the heavy chain and light chain may be referred to as “VH” and “VL” , respectively. These domains are generally the most variable parts of the antibody (relative to other antibodies of the same class) and contain the antigen-binding sites. In some embodiments, from the N-to the C-terminus, the variable domain of heavy chain/domain/region, was followed by three constant heavy domains (CH1, CH2, and CH3) . Similarly, from the N-to the C-terminus, the variable domain of light chain/domain/region, was followed by a constant light (CL) domain.

The light chain variable region (VL) or heavy chain variable region (VH) from N-terminal to C-terminal is in an arrangement of FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, where FR represents framework region, and CDR represents complementarity determining region. CDRs 1, 2, and 3 of VL can also be denoted as LCDR1, LCDR2, and LCDR3 respectively; CDRs 1, 2, and 3 of VH can also be denoted as LCDR1, LCDR2, and LCDR3 respectively. The FRs curl to bring the CDRs close to each other, and the CDRs are in a 3D conformation providing an antigen binding surface complementary to the antigen target.

The assignment of amino acids to each domain is in accordance with any conventional protocols, such as the Kabat definition (Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD, 1987 and 1991) and the Chothia definition (Chothia & Lesk, J. Mol. Biol. 196: 901-917, 1987; Chothia et al., Nature 342: 878-883, 1989) .

The terms “complementarity determining region” or “CDR, ” as used herein, refer to the sequences of amino acids within antibody variable regions which confer antigen specificity and binding affinity. In some embodiments, there are three CDRs in each heavy chain variable region (HCDR1, HCDR2, and HCDR3) and three CDRs in each light chain variable region (LCDR1, LCDR2, and LCDR3) .

A number of hypervariable region or CDR delineations are in use and are encompassed herein. The Kabat Complementarity Determining Regions (Kabat CDRs) are based on sequence variability and are the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991) ) . Chothia refers instead to the location of the structural loops (Chothia and Lesk, J. Mol. Biol. 196: 901 -917 (1987) ) . The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, (Chothia "CDRs" ) and are used by Oxford Molecular's AbM antibody modeling software. The "contact" hypervariable regions are based on an analysis of the available complex crystal structures. Another universal numbering system that has been developed and widely adopted is ImMunoGeneTics (IMGT) Information (Lafranc et al., Dev. Comp. Immunol. 27 (1) : 55-77 (2003) ) . IMGT is an integrated information system specializing in immunoglobulins (IG) , T-cell receptors (TCR) , and major histocompatibility complex (MHC) of human and other vertebrates.

Unless otherwise stated, in the present invention, the term "CDRs" or "CDR sequences" encompasses CDR sequences determined in any of the ways described above.

As used herein, the term “antibody” should be understood in its broadest interpretation, including, but not limited to monoclonal antibodies (mAbs) , polyclonal antibodies, fusion antibodies, multi-specific (such as bispecific) antibodies, diabodies, nanobodies, triabody, multivalent antibodies, chimeric antibodies, humanized antibodies, fully human antibodies, single chain antibodies, antibody fragments that preserve the antigen binding specificity, such as antigen binding fragment. The antibody may contain additional modifications, such as mutations in non-CDR regions, constant regions, glycosylation sites, post-translational modifications and others under the condition that the resulting antibody has the preserved binding specificity to a target antigen.

As used herein, the term “antigen-binding fragment” refers to an antibody fragment including VH, VL, a diabody, a Fab, a Fab’, a F (ab’) ₂, scFab, VHH (sdAb or dAb) , an Fv fragment, a disulfide stabilized Fv fragment (dsFv) , a (dsFv) ₂, a bispecific dsFv (dsFv-dsFv’) , a disulfide stabilized diabody (ds diabody) , a single-chain Fv (scFv) , an scFv dimer (bivalent diabody) , taFv, DART and (bispecific T-cell engager) , a multi-specific antibody formed from a portion of an antibody including one or more CDRs, a camelized single domain antibody, a nanobody, a domain antibody, a bivalent domain antibody, or any other antibody fragment that binds to an antigen but does not include a complete antibody structure. An antigen-binding fragment is capable of binding to the same antigen to which the parent antibody or a parent antibody fragment (e.g., a parent scFv) binds.

As used herein, the term “specifically bind” or “bind” refers to the non-covalent interactions between an immunoglobulin and an antigen for which the immunoglobulin is specific. The strength or affinity of the interaction can be expressed by the equilibrium dissociation constant (KD or Kd) for an antigen and the corresponding antibody: the lesser the value of the KD, the stronger the binding strength between an epitope and the antibody. Equilibrium dissociation constant (KD) is calculated as the ratio of koff/kon, where the “on rate constant (Kon) ” and the “off rate constant (Koff) ” can be determined by calculation of the concentrations and the actual rates of association and dissociation. (See, Nature 361: 186-87 (1993) ) .

In some embodiment of the present disclosure, an antibody is said to specifically bind to an antigen when a dissociation constant (KD) is less than or equal to 1X10^-6M, in some embodiments less than or equal to 1x10^-7M, in some embodiments less than or equal to 1x10^- ⁸M, and in some embodiments less than or equal to 1x10^-9M, and in some embodiments is in a range between 1x10^-8 to 1x10^-12M.

As used herein, the term “multispecific antibody” is to be understood as an antibody having binding specificities for at least two different antigens or epitopes, including bispecific antibodies.

Multispecificity can be provided for by a variety of different formats (see Spiess et al. Molecular Immunology. 2015.67 (2 Pt A) : 95-106 and Brinkmann et al. MAbs. 2017.9 (2) : 182-212, both of which are incorporated by reference herein in their entirety) . Examples of such formats include Fab-scFab, orthogonal Fab, DuetMab, CrossMAb, DVD-Ig^TM (dual variable domain immunoglobulin) , and TriFabs.

As used herein, “blockingantibody” refers to an antibody that limits, prevents, inhibits, blocks, eliminates, or reduces biological or functional activity of the antigen to which it binds. Assays to determine the “blocking” by the antibody of the disclosure are well-known in the art.

As used herein, the term “subject” includes animals such as vertebrate, preferably mammals, such as dogs, cats, pigs, sheep, horses, goats, rodents (e.g., mice, rates, guinea pigs) or primates (e.g., gorillas, chimpanzees, monkeys, and humans) .

The term "monoclonal antibody (mAb) ” as used herein refers to a type of immunoglobulin that has identical CDRs, which specifically binds to an antigen or epitope.

As used herein, the term "humanized antibody" generally refers to an antibody containing a heavy and a light chain variable region sequence from a non-human species (e.g., rabbit, mouse, etc. ) , where at least part of the VH and/or VL sequence has been altered to be more "human-like" , i.e. more similar to a human variable sequence. For a type of humanized antibody, at least one human CDR sequence is introduced into the non-human VH and/or VL sequences to replace the non-human CDR counterpart.

In the polypeptide notation used herein, the left-hand end corresponds to the amino terminal/N-terminal, and the right-hand end corresponds to the carboxy-terminal/C-terminal, in accordance with convention. Likewise, the left-hand end of single-stranded polynucleotide sequence is the 5’ end, the left-hand direction of double-stranded polynucleotide sequences is the 5’ direction, the right-hand end of single-stranded polynucleotide sequence is the 3’ end, and the right-hand direction of double-stranded polynucleotide sequences is the 3’ direction.

As used herein, the term “sequence identity” is usually determined using sequence analysis software. Protein analysis software uses similarity measures assigned to various substitutions, deletions, and other modifications, including conservative amino acid substitutions, to match similar sequences. For example, GCG software includes programs such as Gap and Bestfit that can be used to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from organisms of different species, or wild-type proteins and their mutant protein. See, eg, GCG version 6.1. Polypeptide sequences can also be compared using FASTA with default or recommended parameters, and programs in GCG version 6.1. FASTA (eg, FASTA2 and FASTA3) provide alignments and percent sequence identity (Pearson) of the region of optimal overlap between the query and search sequences. (2000) , op. cit. ) . Another preferred algorithm is the computer program BLAST, especially BLASTP, BLASTN, using default parameters when comparing the sequences of the present disclosure with databases containing a large number of sequences from different organisms. See, eg, Altschul et al. (1990) J. Mol. Biol. 215: 403410 and Altschul et al. (1997) Nucleic Acids Res. 25: 3389402.

In some embodiments, the "sequence identity" is determined by comparing two optimally aligned sequences, wherein the portion of the polynucleotide or polypeptide sequence may comprise additions or deletions (i.e., gaps) of 20 percent or less as compared to the reference sequences (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid bases or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence and multiplying the results by 100 to yield the percentage of sequence identity.

As used herein, the term "conservative substitution" means the substitution of an amino acid that is not essential for the activity of the peptide, or the substitution of an amino acid with another amino acid that has similar properties (e.g., acidic, basic, positively or negatively charged, polar or non-polar, etc. ) , such that even the substitution of an essential amino acid does not reduce the activity of the peptide. Conservative substitution that provides functionally similar amino acids is well-known in the field.

In some embodiments, the conservative substitution could be the one occurs within the same group listed below, (a) small aliphatic, nonpolar or slightly polar residues: Ala, Ser, Thr, Pro and Gly; (b) polar, negatively charged residues and their (uncharged) amides: Asp, Asn, Glu and Gln; (c) polar, positively charged residues: His, Arg and Lys; (d) large aliphatic, nonpolar residues: Met, Leu, He, Val and Cys; and (e) aromatic residues: Phe, Tyr and Trp. For example, Asp is substituted with Glu, Ala is substituted with Gly or Ser.

As used herein, when Component A is administered in combination with Component B, the Component A can be administered concurrently or sequentially with Component B. The administration includes situations that Component A is administered at the same time with Component B; Component A is administered prior to Component B; Component A is administered after Component B.

As used herein, when a combination is administered, each component in the combination can be administered concurrently or sequentially. For example, when a combination comprising Component A and Component B is administered, the administration includes situations that Component A is administered at the same time with Component B; Component A is administered prior to Component B; Component A is administered after Component B.

ANTIBODY OR ANTIGEN BINDING FRAGMENT THEREOF

The present disclosure provides an antibody or antigen binding fragment thereof that binds specifically to OSMR, wherein the antibody or antigen binding fragment thereof is selected from any one of the following (a) to (k) :

(b) the antibody or antigen binding fragment thereof comprising a HCDR1 comprisingYYDIN as set forth in SEQ ID NO: 5, a HCDR2 comprising WIX₁₁PRDX₁₂STKYX₁₃X₁₄X₁₅FX₁₆G as set forth in SEQ ID NO: 42, a HCDR3 comprising EDSDYFDY as set forth inSEQ ID NO: 7, a LCDR1 comprising RASESVDRYGX₁₇SFMY as set forth inSEQ ID NO: 43, a LCDR2 comprising RASNLES as set forth inSEQ ID NO: 9, and a LCDR3 comprising QQSX₁₈EX₁₉PWT as set forth inSEQ ID NO: 44, where X₁₁is any one of F, L, and their conservative substitutions, X₁₂is any one of G, E, and their conservative substitutions, X₁₃ is any one of N, A, and their conservative substitutions, X₁₄ is any one of E, Q, and their conservative substitutions, X₁₅ is any one of R, K, and their conservative substitutions, X₁₆ is any one of K, Q, and their conservative substitutions, X₁₇ is any one of N, S, and their conservative substitutions, X₁₈ is any one of Y, A, and their conservative substitutions, X₁₉ is any one of D, Y, and their conservative substitutions;

(d) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 5 or SEQ ID NO: 5 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 6 or SEQ ID NO: 6 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 34 or SEQ ID NO: 34 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 36 or SEQ ID NO: 36 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 7 or SEQ ID NO: 7with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 8 or SEQ ID NO: 8 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 22 or SEQ ID NO: 22 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 9 or SEQ ID NO: 9 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 10 or SEQ ID NO: 10 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 35 or SEQ ID NO: 35 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 37 or SEQ ID NO: 37 with 1, 2, or 3 conservative substitutions;

The present disclosure provides an antibody or antigen binding fragment thereof, comprising a VH and/or VL of any one of the following (a) to (g) :

The present disclosure provides an antibody or antigen binding fragment thereof that binds specifically to OSMR, wherein the antibody or antigen binding fragment thereof comprises any one of the following (a) to (g) :

The CDRs used herein could be defined according to Kabat, IMGT, Chothia or any conventionally used system. In a particular embodiment, the CDRs are defined based on Kabat system.

In some embodiments, theantibody or antigen binding fragment thereof induces internalization or endocytosis of OSMR. In some embodiments, the internalization or endocytosis activities of the antibody or antigen binding fragment thereof disclosed herein are strong. In some embodiments, the endocytosis efficiency of theantibody or antigen binding fragment thereof disclosed hereinreached 67%in half an hour, and reached to 91%in 2h.

In some embodiments, the antibody or antigen binding fragment thereof disclosed herein that specifically binds to OSMR is selected from the following isotypes: IgG, IgM, IgE, IgA, and IgD. In some embodiments, the antibody or antigen binding fragment thereof disclosed herein that specifically binds to OSMR is selected from the following isotypes: IgG1, IgG2, IgG3, IgG4, IgA1, IgA2.

KIT, SYSTEM, DEVICE, PRODUCT

The present disclosure provides a kit, a system, a device, or a product for diagnosing OSMR-related disease in a subject, comprising the antibody or antigen binding fragment thereof disclosed herein that specifically binds to OSMR. In some embodiments, the kit, system, device, or product additionally comprises other components. In some embodiments, the kit additionally comprises package insert, or manufacture’s description.

The present disclosure providesuse of the antibody or antigen binding fragment thereof disclosed herein that specifically binds to OSMR in the preparation of a kit, a system, a device, or a product for diagnosing OSMR-related disease in a subject.

COMBINATION

The present disclosure provides a combination comprising one or more OSMR inhibitors and one or more TNF-α inhibitors. In some embodiments, the OSMR inhibitor is selected from anti-OSMR antibodies or antigen binding fragments thereof. The anti-OSMR antibodies or antigen binding fragments thereof could be any anti-OSMR antibodies or antigen binding fragments thereof well-known in the art, or the antibody or antigen binding fragment thereof that binds specifically to OSMR disclosed herein. In some embodiments, the anti-OSMR antibodiesareblocking antibodies. In a preferable embodiment, the anti-OSMR antibody or antigen binding fragment thereof comprises the 6 CDRs ofVixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212. In some preferred embodiments, the anti-OSMR antibody or antigen binding fragments thereof is selected from Vixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212. In some preferred embodiments, the TNF-αinhibitor is selected from anti-TNF-αantibodies or antigen binding fragments thereof. The TNF-α inhibitorcould be any anti-TNF-α antibodies or antigen binding fragments thereof, such as any anti-TNF-α antibody or antigen binding fragment thereofwell-known in the art. In some embodiments, the anti-TNF-α antibodiesare blocking antibodies. In a preferable embodiment, the TNF-α antibody or antigen binding fragment thereof comprises the 6 CDRs of Infliximab, Adalimumab, Afelimomab, CDP-571, CDP-870, Golimumab, or Nerelimomab. In a preferable embodiment, the TNF-α antibody or antigen binding fragment thereof is selected from Infliximab, Adalimumab, Afelimomab, CDP-571, CDP-870, Golimumab, orNerelimomab.

In some embodiments, theCombination Index (CI) valueless than 1indicates a synergisticeffect. In some embodiments, the Combination Index (CI) value regarding MCP-1 secretionfor the OSMR inhibitor and the TNF-α inhibitor of the combination disclosed herein is less than 1. The OSMR inhibitor and the TNF-α inhibitor of the combination disclosed herein have a synergistic effect on reducing MCP-1 secretion.

In some embodiments, the anti-OSMR antibody or antigen binding fragment thereof of the combination disclosed herein is selected fromVixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212.

In some embodiments, the anti-OSMR antibody or antigen binding fragment thereof of the combination disclosed herein is selected from any one of the following (a) to (k) :

(a) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising DNYX₁H as set forth in SEQ ID NO: 38, a HCDR2 comprising RIDPEX₂GDX₃TYX₄X₅KFQX₆ as set forth in SEQ ID NO: 39, a HCDR3 comprising DYYX₇X₈X₉YVWYFDV as set forth in SEQ ID NO: 40, a LCDR1 comprising RASSSVSSSYLH as set forth in SEQ ID NO: 14, a LCDR2 comprising STSNLAS as set forth in SEQ ID NO: 15, and a LCDR3 comprisingQX₁₀YSGYPLIFT as set forth in SEQ ID NO: 41, where X₁is any one of I, M, and their conservative substitutions, X₂is any one of N, S, and their conservative substitutions, X₃ is any one of I, T, and their conservative substitutions, X₄ is any one of D, A, and their conservative substitutions, X₅ is any one of P, Q, and their conservative substitutions, X₆ is any one of D, G, and their conservative substitutions, X₇ is any one of G, Q, A, and their conservative substitutions, X₈ is any one of S, G, and their conservative substitutions, X₉ is any one of N, D, and their conservative substitutions, X₁₀ is any one of Q, T, and their conservative substitutions;

(b) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising YYDIN as set forth in SEQ ID NO: 5, a HCDR2 comprising WIX₁₁PRDX₁₂STKYX₁₃X₁₄X₁₅FX₁₆G as set forth in SEQ ID NO: 42, a HCDR3 comprising EDSDYFDY as set forth inSEQ ID NO: 7, a LCDR1 comprising RASESVDRYGX₁₇SFMY as set forth inSEQ ID NO: 43, a LCDR2 comprising RASNLES as set forth inSEQ ID NO: 9, and a LCDR3 comprising QQSX₁₈EX₁₉PWT as set forth inSEQ ID NO: 44, where X₁₁is any one of F, L, and their conservative substitutions, X₁₂is any one of G, E, and their conservative substitutions, X₁₃ is any one of N, A, and their conservative substitutions, X₁₄ is any one of E, Q, and their conservative substitutions, X₁₅ is any one of R, K, and their conservative substitutions, X₁₆ is any one of K, Q, and their conservative substitutions, X₁₇ is any one of N, S, and their conservative substitutions, X₁₈ is any one of Y, A, and their conservative substitutions, X₁₉ is any one of D, Y, and their conservative substitutions;

(c) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 11 or SEQ ID NO: 11 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 30 or SEQ ID NO: 30 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 12 or SEQ ID NO: 12 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 27 or SEQ ID NO: 27 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 31 or SEQ ID NO: 31 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 13 or SEQ ID NO: 13 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 28 or SEQ ID NO: 28 with 1, 2, or 3 conservative substitutions, SEQ ID NO: 32 or SEQ ID NO: 32 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 33 or SEQ ID NO: 33 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 14 or SEQ ID NO: 14 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 15 or SEQ ID NO: 15 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 16 or SEQ ID NO: 16 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 29 or SEQ ID NO: 29 with 1, 2, or 3 conservative substitutions;

The anti-OSMR antibodies or antigen binding fragments thereof could be any anti-OSMR antibodies or antigen binding fragments thereof well-known in the art, or the antibody or antigen binding fragment thereof that binds specifically to OSMR disclosed herein. In some embodiments, the anti-OSMR antibody or antigen binding fragment thereof comprises the 6 CDRs of Vixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212. In some preferred embodiments, the anti-OSMR antibody or antigen binding fragments thereof is selected from Vixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212. In some embodiments, the anti-OSMR antibody or antigen binding fragment thereof of the combination disclosed hereincomprises a VH and/or VL of any one of the following (a) to (g) :

The anti-OSMR antibodies or antigen binding fragments thereof could be any anti-OSMR antibodies or antigen binding fragments thereof well-known in the art, or the antibody or antigen binding fragment thereof that binds specifically to OSMR disclosed herein. In some embodiments, the anti-OSMR antibody or antigen binding fragment thereof comprises the 6 CDRs of Vixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212. In some preferred embodiments, the anti-OSMR antibody or antigen binding fragments thereof is selected from Vixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212. In some embodiments, the anti-OSMR antibody or antigen binding fragment thereof of the combination disclosed herein comprises any one of the following (a) to (g) :

In some embodiments, the anti-OSMR antibody or antigen binding fragment thereof of the disclosed combination is selected from the following isotypes: IgG, IgM, IgE, IgA, and IgD. In some embodiments, the anti-OSMR antibody or antigen binding fragment thereof of the disclosed combination is selected from the following isotypes: IgG1, IgG2, IgG3, IgG4, IgA1, IgA2.

In some embodiments, the TNF-α inhibitorof the combination disclosed herein is selected from TNF-α antibodies or antigen binding fragments thereof. In some embodiments, the TNF-αinhibitor is selected from anti-TNF-α antibodies or antigen binding fragments thereof. In some embodiments, the anti-TNF-α antibodies are blocking antibodies. In a preferable embodiment, the anti-TNF-α antibody or antigen binding fragment thereof comprises the 6 CDRs of Infliximab, Adalimumab, Afelimomab, CDP-571, CDP-870, Golimumab, or Nerelimomab. In a preferable embodiment, the anti-TNF-α antibody or antigen binding fragment thereof is selected from Infliximab, Adalimumab, Afelimomab, CDP-571, CDP-870, Golimumab, or Nerelimomab.

MULTISPECIFIC ANTIBODY

The present disclosure provides a multispecific antibody or antigen binding fragment thereof, comprising a first antigen binding region that specifically binds to OSMR, and a second antigen binding region.

In some embodiments, the first antigen binding region that specifically binds to OSMR of the disclosed multispecific antibody or antigen binding fragment thereofcomprises the antibody or antigen binding fragment thereof disclosed herein that specifically binds to OSMR.

In some embodiments, the second antigen binding region of the disclosed multispecific antibody or antigen binding fragment thereofspecifically binds to one of the following targets selected from tumor associated antigen (TAA) , immune checkpoint targets and targets for immune cell engager.

The immune cell engager includes but is not limited to an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager. In some embodiments, the second binding region specifically binds to immune effector cell, antigen specifically expressed in T cell or NK cell. In some embodiments, the second binding region binds to target antigen selected from PD-1, CTLA-4, PD-L1, CD47, LAG-3, TIGIT, TIM-3, VISTA, BTLA, hHVEM, CSF1R, CCR4, CD39, CD40, CD73, CD96, CXCR2, CXCR4, CD200, GARP, SIRPa, CXCL9, CXCL10, CXCL11, CD155, CD137, GITR, OX40, CD40, CXCR3, CD27, CD3, ICOS, HER2, EGFR, CD20, CLAUDIN18.2 and BCMA.

In some embodiments, tumor associated antigens includes but are not limited to GPC, CEA, immature laminin receptor, TAG-72, HPV E6, HPV E7, EGFR, Ep-CAM, EphA3, Her2, Her3, ROR2, PSMA, STEAP1, FGFR2, TROP2, B7-H3, B7-H4, B7-H6, FOLR1, BAGE family, CAGE family, GAGE family, MAGE family, SAGE family, XAGE family, SSX-2, Fibronectin, MART-2, PDL-1, VEGFR, CLAUDIN, and others.

The present disclosure provides a multispecific antibody or antigen binding fragment thereof, comprising a first antigen binding region that specifically binds to OSMR, and a second antigen binding region that specifically binds to TNF-α.

In some embodiments, the second antigen binding region that specifically binds to TNF-αcomprises 6 CDRs ofInfliximab, Adalimumab, Afelimomab, CDP-571, CDP-870, Golimumab, orNerelimomab.

In some embodiments, the first antigen binding region that specifically binds to OSMR of the disclosed multispecific antibody or antigen binding fragment thereof comprises the antibody or antigen binding fragment thereof disclosed herein that specifically binds to OSMR.

ANTIBODY DRUG CONJUGATE

The present disclosure provides an antibody drug conjugate (ADC) , comprising the antibody or antigen binding antigen thereof disclosed herein that specifically binds to OSMR, or the multispecific antibody or antigen binding fragment thereof disclosed herein.

The present disclosure provides an ADC, comprising the antibody or antigen binding antigen thereof disclosed herein that specifically binds to OSMR, or the multispecific antibody or antigen binding fragment thereof disclosed herein, and cytotoxic agent. In some embodiments, the antibody or antigen binding antigen thereof disclosed herein that specifically binds to OSMR, or the multispecific antibody or antigen binding fragment thereof disclosed herein is covalently attached, directly or via a cleavable or non-cleavable linker to the cytotoxic agent.

In some embodiments, the cytotoxic agent may be any compound that results in the death of a cell, or induces cell death, or in some manner decreases cell viability. Preferred cytotoxic agents include, for example, maytansinoids and maytansinoid analogs, taxoids, taxanes such as paclitaxel and docetaxel, CC-1065 and CC-1065 analogs, dolastatin and dolastatin analogs, methotrexate, daunorubicin, doxorubicin, vincristine, vinblastine, melphalan, mitomycin C, chlorambucil, calicheamicin, tubulysin and tubulysin analogs, duocarmycin and duocarmycin analogs, taxanes such as paclitaxel and docetaxel.

ISOLATED NUCLEIC ACID, VECTOR, HOST CELL

The present disclosure provides an isolated nucleic acid encoding the antibody or antigen binding fragment thereof disclosed hereinthat specifically binds to OSMR, or the multispecific antibody or antigen binding fragment thereof disclosed herein.

As used herein, the term "nucleic acid" includes both single-stranded and double-stranded nucleotide polymers. The nucleic acid can be ribonucleotides or deoxyribonucleotides or a modified form of either type of nucleotide. Said modifications include base modifications such as bromouridine and inosine derivatives, ribose modifications such as 2', 3'-dideoxyribose, and internucleotide linkage modifications such as phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phoshoraniladate and phosphoroamidate.

An “isolated” nucleic acid comprising a nucleotide sequence encoding a protein, or portion or fragment thereof described herein is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the environment in which it was produced. In some preferred embodiments, the isolated nucleic acid is free of association with all components associated with the production environment. The isolated nucleic acid encoding the protein, or portion or fragment thereof described herein is in a form other than in the form or setting in which it is found in nature. Isolated nucleic acid, therefore, are distinguished from nucleic acid encoding the protein, or portion or fragment thereof described herein existing naturally in cells.

The present disclosure provides a vector, comprising the isolated nucleic acid disclosed herein.

As used herein, the term “vector” refers to a nucleic acid molecule used as a vehicle to carry genetic material into another cell, where it can be replicated and/or expressed. In some embodiments, the vector is an expression vector. In some embodiments, the vector is a viral vector. In some embodiments, the vector is a retroviral vector, a DNA vector, a murine leukemia virus vector, an SFG vector, a plasmid, an RNA vector, an adenoviral vector, a baculoviral vector, an Epstein Barr viral vector, a papovaviral vector, a vaccinia viral vector, a herpes simplex viral vector, an adenovirus associated vector (AAV) , a lentiviral vector, or any combination thereof.

The present disclosure provides a host cell comprising the isolated nucleic acid disclosed herein, or the vector disclosed herein.

In some embodiments, the cell can be a prokaryotic cell, fungal cell, yeast cell, or eukaryotic cells such as a mammalian cell. Suitable prokaryotic cells include, without limitation, eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobactehaceae such as Escherichia, e.g., E. coli; Enterobacter; Erwinia; Klebsiella; Proteus; Salmonella, e.g., Salmonella typhimurium; Serratia, e.g., Serratia marcescans, and Shigella; Bacilli such as B. subtilis and B. licheniformis; Pseudomonas such as P. aeruginosa; and Streptomyces. In some embodiments, the cell is a human cell. In some embodiments, the cell is an immune cell. In some embodiments, host cells include, for example, CHO cells, such as CHOS cells and CHO-K1 cells, or HEK293 cells, such as HEK293A, HEK293T and HEK293FS.

PHARMACEUTICAL COMPOSITION

The present disclosure provides a pharmaceutical composition comprising theantibody or antigen binding fragment thereof disclosed herein that specifically binds to OSMR, the combination disclosed herein, the multispecific antibody or antigen binding fragment thereof disclosed herein, the ADC disclosed herein, the isolated nucleic acid disclosed herein, the vector disclosed herein, or the host cell disclosed herein, and a pharmaceutically acceptable excipient or carrier.

As used herein, the term “pharmaceutical composition” means a mixture of the elements disclosed herein with other chemical components (such as carriers or excipients) that are compatible with pharmaceutical administration. The pharmaceutical composition facilitates the administration of the disclosed elements (such as the antibody, activable antibody disclosed herein) to the subject in need. Various administration methods are known in the art, including but not limited to subcutaneous, intramuscular, oral, transdermal, parenteral, intravenous, intraperitoneal, intrathecal, transpulmonary, transnasal, ocular, systemic, and topical administration.

The pharmaceutical composition disclosed herein may be configured in a dosage form suitable for administration to a subject by the desired route of administration. Said dosage forms include, but are not limited to, tablets, capsules, caplet, pills, soft gel, troche, powders, syrups, elixir, suspensions, solutions, emulsions, transdermal patches, suppositories, inhalations, creams, pastes, lotions, ointment, sprays, lyophilized preparation, injectables, and gels.

As used herein, the term “pharmaceutically acceptable carrier or excipient” refers to the carrier or excipient compatible with the other ingredients of the composition and not substantially deleterious to the recipient thereof and/or that such carrier or excipient is approved or approvable for inclusion in a pharmaceutical composition for parenteral administration to subject. The term includes all pharmaceutically acceptable materials, solvents, carriers, excipients, stabilizers, diluents, dispersants, suspending agents, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, thickeners and/or excipients. Examples of such carriers or excipients include, but are not limited to, water, saline, ringer's solutions, dextrose solution, and 5%human serum albumin, liposomes and non-aqueous vehicles such as fixed oils.

METHODS, PHARMACEUTICAL USE

The present disclosure provides a method of diagnosing an OSMR-related disease in a subject, comprising contacting the subject’s sample to the antibody or antigen binding fragment thereof disclosed herein that specifically binds to OSMR, and identifying OSMR.

The present disclosure provides use of the antibody or antigen binding fragment thereof disclosed herein that specifically binds to OSMR in the preparation of a kit, system, device, or product for diagnosing an OSMR-related disease in a subject. In some embodiments, the kit, system, device, or productis used in a method comprising contacting the subject’s sample to the antibody or antigen binding fragment thereof disclosed herein that specifically binds to OSMR, and identifying OSMR

The present disclosure provides a method of treating or preventing an inflammatory or autoimmune disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody or antigen binding fragment thereof disclosed herein that specifically binds to OSMR, the combination disclosed herein, the multispecific antibody or antigen binding fragment thereof disclosed herein, the ADC disclosed herein, the isolated nucleic acid disclosed herein, the vector disclosed herein, the host cell disclosed herein, or the pharmaceutical composition disclosed herein. In some embodiments, when administering the combination disclosed herein to treat or prevent an inflammatory or autoimmune disease in a subject in need thereof, each component in the combination disclosed herein can be administeredconcurrently or sequentially. In some embodiments, the one or more OSMR inhibitors and one or more TNF-α inhibitors are administered at the same time. In some embodiments, the one or more OSMR inhibitors are administered prior to the one or more TNF-α inhibitors. In some embodiments, the one or more OSMR inhibitors are administered after the one or more TNF-α inhibitors.

The present disclosure provides use of the antibody or antigen binding fragment thereof disclosed herein that specifically binds to OSMR, the combination disclosed herein, the multispecific antibody or antigen binding fragment thereof disclosed herein, the ADC disclosed herein, the isolated nucleic acid disclosed herein, the vector disclosed herein, the host cell disclosed herein, or the pharmaceutical composition disclosed herein in the preparation of a medicament for treating or preventing a disease, such asinflammatory or autoimmune disease.

In some embodiments, the antibody or antigen binding fragment thereof disclosed herein that specifically binds to OSMR, the combination disclosed herein, the multispecific antibody or antigen binding fragment thereof disclosed herein, the ADC disclosed herein, the isolated nucleic acid disclosed herein, the vector disclosed herein, the host cell disclosed herein, or the pharmaceutical composition disclosed herein is administered in combination with a second therapeutic agent.

For example, the second therapeutic agent includes an antibody or antigen binding fragment thereof, a chemotherapeutic agent and a small molecule drug, including but not limited toPD-1 agonists, CTLA-4 agonists, Bruton’s tyrosine kinase (BTK) inhibitor, tyrosine kinase inhibitor, phosphodiesterase-4 (PDE-4) inhibitor, janus kinase 1 (JAK1) inhibitor, sphingosine-1 phosphate receptor (S1PR) modulator, CD20 inhibitors, antibodies to immune cell specific antigens or self-antigens or inflammatory factor, immune stimulatory antibodies, antibodies to targets for T cell engager, antibodies to virus-infected cell antigens, chemotherapeutic agent, NSAIDs, corticosteroids.

In some embodiments, the combination or the pharmaceutical composition disclosed herein is administered in combination with another therapeutic agent. In some preferred embodiments, the another therapeutic agent includes an antibody or antigen binding fragment thereof, a chemotherapeutic agent and a small molecule drug, such as PD-1 agonists, CTLA-4 agonists, Bruton’s tyrosine kinase (BTK) inhibitor, tyrosine kinase inhibitor, phosphodiesterase-4 (PDE-4) inhibitor, janus kinase 1 (JAK1) inhibitor, sphingosine-1 phosphate receptor (S1PR) modulator, CD20 inhibitors, antibodies to immune cell specific antigens or self-antigens or inflammatory factor, immune stimulatory antibodies, antibodies to targets for T cell engager, antibodies to virus-infected cell antigens, chemotherapeutic agent, NSAIDs, corticosteroids. In some embodiments, when administering thecombination or the pharmaceutical composition disclosed herein in combination with another therapeutic agent, the combination or the pharmaceutical composition disclosed herein can be administered concurrently or sequentiallywith the another therapeutic agent. In some embodiments, thecombination or the pharmaceutical composition disclosed herein and theanother therapeutic agent are administered at the same time. In some embodiments, the combination or the pharmaceutical composition disclosed hereinis administered prior totheanother therapeutic agent. In some embodiments, the combination or the pharmaceutical composition disclosed hereinis administered aftertheanother therapeutic agent.

The present disclosure provides a method of treating or preventing inflammatory diseases or autoimmune diseases in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more OSMR inhibitors, in combination with a therapeutically effective amount of one or more TNF-α inhibitors.

In some embodiments, theone or more of OSMR inhibitors can be administered concurrently or sequentially with the one or more TNF-α inhibitors. In some embodiments, the one or more OSMR inhibitors and one or more TNF-α inhibitors are administered at the same time. In some embodiments, the one or more OSMR inhibitors are administered prior tothe one or more TNF-α inhibitors. In some embodiments, the one or more OSMR inhibitors are administered after the one or more TNF-α inhibitors.

In some embodiments, the OSMR inhibitor and the TNF-αinhibitor are administered concurrently or sequentially, and optionally the OSMR inhibitor and the TNF-αinhibitor are administered in combination with another therapeutic agent. In some embodiments, the another therapeutic agent is administeredconcurrently or sequentially with the OSMR inhibitor and the TNF-αinhibitor. In some embodiments, the another therapeutic agent is administered at the same time with the OSMR inhibitor and the TNF-αinhibitor. In some embodiments, the another therapeutic agent is administered prior to the OSMR inhibitor and the TNF-αinhibitor. In some embodiments, the another therapeutic agent is administered after the OSMR inhibitor and the TNF-αinhibitor.

The present disclosure provides use of one or more of OSMR inhibitors and one or more TNF-α inhibitors in the preparation of a medicament for a disease, such as inflammatory or autoimmune disease.

In some embodiments, the OSMR inhibitor is selected from anti-OSMR antibodies or antigen binding fragments thereof. In some embodiments, the said anti-OSMR antibodiesare blocking antibodies. The anti-OSMR antibodies or antigen binding fragments thereof could be any anti-OSMR antibodies or antigen binding fragments thereof well-known in the art, or the antibody or antigen binding fragment thereof that binds specifically to OSMR disclosed herein.

In some embodiments, the anti-OSMR antibody or antigen binding fragment thereof comprises the 6 CDRs of Vixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212. In a preferable embodiment, the anti-OSMR antibody or antigen binding fragments thereof is selected from Vixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212. In some embodiments, the anti-OSMR antibody or antigen binding fragment thereofis selected from any one of the following (a) to (k) :

In some embodiments, the anti-OSMR antibody or antigen binding fragment thereof comprises the 6 CDRs of Vixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212. In a preferable embodiment, the anti-OSMR antibody or antigen binding fragments thereof is selected from Vixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212. In some embodiments, the anti-OSMR antibody or antigen binding fragment thereof comprises a VH and/or VL of any one of the following (a) to (g) :

In some embodiments, the TNF-α inhibitor is selected from TNF-α antibodies or antigen binding fragments thereof. In some embodiments, the TNF-α inhibitor is selected from TNF-αantibodies or antigen binding fragments thereofwell-known in the art. In preferable embodiments, TNF-α antibodies are blocking antibodies. In some preferred embodiments, the TNF-αantibody or antigen binding fragment thereof comprises the 6 CDRs of Infliximab, Adalimumab, Afelimomab, CDP-571, CDP-870, Golimumab, or Nerelimomab. In some more preferred embodiments, the TNF-α antibody or antigen binding fragment thereof is selected from Infliximab, Adalimumab, Afelimomab, CDP-571, CDP-870, Golimumab, orNerelimomab.

In some embodiments, the OSMR inhibitor and the TNF-αinhibitor are administered concurrently or sequentially. In some embodiments, the OSMR inhibitor and the TNF-αinhibitor are administered concurrently or sequentially, and optionally the OSMR inhibitor and the TNF-αinhibitor are administered in combination with another therapeutic agent. In some embodiments, the another therapeutic agent is administeredconcurrently or sequentially with the OSMR inhibitor and the TNF-αinhibitor. In some embodiments, the another therapeutic agent is administered at the same time with the OSMR inhibitor and the TNF-αinhibitor. In some embodiments, the another therapeutic agent is administered prior to the OSMR inhibitor and the TNF-αinhibitor. In some embodiments, the another therapeutic agent is administered after the OSMR inhibitor and the TNF-αinhibitor. The another therapeutic agent includes an antibody or antigen binding fragment thereof, a chemotherapeutic agent and a small molecule drug, such as PD-1 agonists, CTLA-4 agonists, Bruton’s tyrosine kinase (BTK) inhibitor, tyrosine kinase inhibitor, phosphodiesterase-4 (PDE-4) inhibitor, janus kinase 1 (JAK1) inhibitor, sphingosine-1 phosphate receptor (S1PR) modulator, CD20 inhibitors, antibodies to immune cell specific antigens or self-antigens or inflammatory factor, immune stimulatory antibodies, antibodies to targets for T cell engager, antibodies to virus-infected cell antigens, chemotherapeutic agent, NSAIDs, corticosteroids.

In some embodiments, when treating or preventing a disease (such as inflammation or autoimmune disease) , one or more doses of the OSMR inhibitor are administered prior to administering one or more doses of the TNF-α inhibitor.

In some embodiments, the inflammatory or autoimmunedisease is selected from diseases where OSMR activation plays a role, including but not limited topruritus, hypersensitivity, lupus, graft-versus-host disease (GvHD) , vasculitis, Type I diabetes, multiple sclerosis, rheumatoid arthritis, alopecia areata, atherosclerosis, psoriasis, organ transplant rejection, Sjogren's Syndrome, Behcet's disease, atopic dermatitis, asthma, and inflammatory bowel disease (IBD) . In some preferred embodiments, IBD includes TNF-α resistant IBD.

As used herein, the term “treat” , “treatment” , or “treating” refers to the alleviation or amelioration of a disease or disorder (i.e., slowing or stopping the progression of a disease or at least one clinical symptom) ; or the alleviation or amelioration of at least one physical parameter or biomarker associated with the disease or disorder.

As used herein, the term “prevent” or “preventing” includes providing prophylaxis with respect to the occurrence or recurrence of a disease in an individual that may be predisposed to the disease but has not yet been diagnosed with the disease.

As used herein, the term “disease” refers to any alteration in the state of the body or some organs that interrupts or interferes with the performance of a function and/or causes symptoms (e.g., discomfort, dysfunction, distress, or even death) in the subject who is ill or in contact with the patient.

As used herein, the term “therapeutically effective amount” indicates that when comparing to a subject without receiving any treatment, the subject administered with such amount of the therapeutics shows a beneficial effect or therapeutic effect towards a disease, but the amount is sufficiently low in the range of sound medical judgment to avoid serious side effects. The therapeutically effective amount of the antibody, activable antibody and others disclosed herein will vary at least based on the following factors, the route of administration; the severity of the disease being treated; the age, height, weight and physical condition of the patient; the medical history of the patient; the duration of the treatment; the desired therapeutic effect. However, the therapeutically effective amount can still be determined in a conventional manner by those skilled in the art.

EXAMPLES

The following examples, both actual and prophetic, are provided in conjunction with the accompanying drawings for the purpose of illustrating specific embodiments or features of the present invention and are not intended to limit its scope.

The skilled in the art should recognize that various alterations and modifications can be made to the embodiments described herein without departing from the spirit and scope of the present disclosure. Description of well-known functions, structures and the like in the art are omitted from the following description for conciseness.

The experimental methods in the following embodiments, if not otherwise specified, are conventional methods, performed in accordance with the techniques or conditions described in the literature in the field or in accordance with the product protocols. The materials, reagents, and the like used in the following embodiments are commercially available, if not otherwise specified.

Example 1. The synergisticinhibitioneffect of anti-OSMR and anti-TNF-α on MCP-1 secretion

The effect of anti-OSMR antibody (Vixarelimab (VIX, US10822406B2) ) and/or anti-TNF-α antibody (infliximab (INF) or oradalimumab (ADA) or ) on MCP-1 secretion was evaluated in Ccd18-Co colonic fibroblasts (ATCC, no. CRL-1459) . Briefly, Ccd18-Co colonic fibroblasts were plated at 5,000 cells per well in a 96-well plate. For blockade experiments, 5ng/ml of recombinant human TNF-α and 2.5ng/ml of recombinant human OSM were applied to stimulate the cells which were preincubated with different concentrations of sampleantibodies (Vixarelimab: 100nM, Adalimumab: 50nM, Infliximab: 50nM, Negative control/hIgG1 (Bio intron B11790) : 150 nM) for 1h at room temperature. PBS control group was also set up, where PBS instead of TNF-α and OSM was applied to the cells after pre-incubating with different concentrations of antibodies. After 24h, supernatants were collected, and theconcentrations of MCP-1 were determined with ELISA.

The CI-Index (combination inhibition index) ofantibodies was calculated with the following formula:

Conc (Ab1) refers to the concentrations of MCP-1 treatedwithanti-OSMR antibody and hIgG1; Conc (Ab2) refers to the concentrations of MCP-1 treated with anti-TNF-α antibody and hIgG1; Conc (Ab1+Ab2) refers to the concentrations of MCP-1 treated with anti-OSMR andanti-TNF-α, and Conc (Ab0) refers to the concentrations of MCP-1 with only negative control hIgG1.

CI-index values indicate synergistic (<1) , additive (=1) or antagonistic (>1) relationships. Results are shown in Table 1-2 and Figure 1. From the results, it can be seen that the CI-Index of Vixarelimab and adalimumab was 0.50639, and the CI-Index of Vixarelimab and Infliximab was 0.47817. It suggests that there is a synergistic inhibition effect of anti-OSMR and anti-TNF-α antibodies on MCP-1 secretion.

Table 1. MCP-1 secretion under various treatments of antibodies

Table 2. CI-index of antibodies

Example 2. Immunogen preparation, immunization and single B cell sorting for antibody generation

To further demonstrate the synergistic effect of OSMR antagonist and TNF-α antagonist, a panel of anti-OSMR antibodies were generated and assessed.

Recombinant antigens, human OSMR extracellular domain (Uniprot: Q99650) fused with mouse IgG2a Fc domain (PRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK, SEQ ID NO: 47) was constructed. BALB/c mice were immunized with recombinant antigens for four rounds over a course of 42 days. For the first immunization 50ug antigens were mixed with an equal volume of adjuvant (CFA) (Sigma, Cat#F5881) . Then the mixed antigens were injectedsubcutaneously to multiple sites of the mice. Booster immunizations were given in a similar fashion. Mice serum was collected and tested for OSMR binding by ELISA.

Four days after the final immunization, mice were euthanized. Spleens and lymph nodes were isolated and prepared for B cell isolation. Mice spleen and lymph nodes cells were combined and washed with PBS. B cells were enriched with mouse pan-B cell isolation kit (Stemcell, Cat#19844) following the manufacturer's instruction.

FACS sorting was carried out on a Sony FACS sorter MA900. All antigen-specific single B cells were sorted at single-cell per well into reverse transcription mix chilled to 4℃ in 96-well PCR plates.

DNA sequences encoding heavy chains and light chains of antibodies were obtained by standard PCR and sequencing techniques. The amino acid sequences of the heavy chain variable region (VH) and the light chain variable region (VL) of the identified antibodies are listed in Table 3 The amino acid sequences of the CDRs of the identified antibodies are listed in Table 4.

Table 3. VH and VL of anti-OSMR antibodies

Table 4. CDRs of anti-OSMR antibodies

Antibodies were reformatted to the human IgG1 backbone and recombinantly expressed in ExpiCHO cells. The amino acid sequence of the heavy chain constant region is as shown in SEQ ID NO: 45 (ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK) and the amino acid sequence of the light chain constant region is as shown in SEQ ID NO: 46 (RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC) . ExpiCHO-S^TM was used for transient expression with commercially available transfection kit and culture medium (Thermo Fisher Scientific) . The antibody purification was performed on a protein purification system (Cytiva, AKTA Avant 25) , using MabSelect PrismA Preloaded Column (Cytiva) . Protein concentration was quantified by UV-Vis absorbance measurement at 280 nm.

Example 3. Screen of candidate clones

OSMR and gp130 form the heterodimeric receptor through OSM signals. The major downstream signaling pathways that are activated in OSM signaling are JAK/STAT, Ras/Raf/MAPK, and PI3K pathways. The interaction of the OSM and OSMR-gp130 receptor leads to activation of STAT3. To assess the blockingactivity of the anti-OSMR antibodies, OSMR reporter cell line, HEK293-OSMR (Cobioer, CBP74157) was engineered to express OSMR and STAT3 signaling response element. The binding of blocking antibody to OSMR leads to reduction of theluciferase signalinginduced by STAT3.

HEK293-OSMR cells of 4x10⁴ cells/well in 50ul DMEM medium (ThermoFisher Scientific, 11965092) were seeded to a 96 well flat bottom plate (Corning, 3599) with OSM protein (Sino, 10452-H08H) of a final concentration of 2ng/ml in 50ul DMEM medium, and incubatedat 37℃ in 5%CO₂ for 30min. Then OSMR blocking antibodies were added with indicated concentrations (100, 25, 6.25, 1.5625, 0.390625, 0.097656, 0.024414, 0.006104, 0.001526, 0.000381 nM) in 50ul DMEM medium. The plate was incubated at 37℃ in 5%CO₂ for 6h. 100ul of Bright-Lite Luciferase Assay Buffer (Vazyme, DD1204-03) were added and shaken for 3mins. HEK293-OSMR cells activation was analyzed with a Perkin Elmer Envision plate reader, and data was processed with Prism Graphpad software. The luminescence readings are expressed as RLU (relative light unit) and IC50 was calculated. hIgG1 was used as a negative control. Vixarelimab (US10822406B2) was used as a positive control. The activation of HEK293-OSMR cell is shown in Figure 2 A-B. As shown in Figure 2 A-B, the binding of OSMR with OSM could be blocked by 8A1 and 14C7.

Example 4. Generation of Humanized Antibodies

Humanization of murine monoclonal antibodies (mAbs) wascarried out by a CDR grafting approach (Proc. Nal. Acad. Sci. USA 86, 10029-10033 (1989) ) . Briefly, the frameworks (FRs) of the parental (murine antibody) variable regions (VH and VL) were replaced with those of the selected human germline V and J genes for VH and VL respectively. The germline genes were selected on the basis of the homology between the parental antibody and the germline V and J genes. The VH and VL amino acid sequences of antibody were separately subjected to IgBlast or IMGT/DomainGapAlign against the entire human antibody germline V genes. The human IGVH and IGVL with high homology to the parental antibody were selected as the template for humanization.

The CDRs of each murine antibody were then grafted into the selected human germline to generate humanized antibodies. Then the key framework residues, including Vernier zone residues, supporting CDR confirmation and interchain packing residues located VH-VL interface were selectively back-mutated to their parental murine counterparts to generate a series of humanized antibodies. In order to further humanize the entire variable region, some amino acids within the CDRs were also mutated to match those of the corresponding human germline sequences. Site-directed mutagenesis was utilized to eliminate potential instability motifs in the CDR regions.

A series of humanized 8A1-hu6, 8A1-hu11, 8A1-hu13 were generated for humanization and optimization of murine antibody 8A1, and a series of humanized 14C7-hu3 and 14C7-hu16 were generated for humanization and optimization of murine antibody 14C7. All recombinant mAbs were expressed and purified as described previouslyin Example2.

The VH and VL sequences of humanized antibodies are shown in Table 5. The CDR sequences of them are listed in Table 6.

Table 5. VH and VL sequences of humanized antibodies

Table 6. CDR sequences of humanized antibodies

Example 5. Binding activities of Humanized Antibodies

i. BLI-test

The affinity between an antibody and an antigen can be represented by an equilibrium dissociation constant (KD) , which is the ratio of the dissociation rate constant (k_off) to the association rate (k_on) . In this assay, the antibodies (8A1-hu6, 8A1-hu11, 8A1-hu13, 14C7-hu3, and 14C7-hu16) were captured by AHC2.0 biosensor at the concentration of 10μg/ml under kinetics buffer for 300 seconds. The antigen Human OSMR (Kactus, Catalog: OSM-HM101) at a concentration of 100 nm was bound to the antibodies shown in Table 7as analytes for 240 seconds and dissociated for 600 seconds. The entire procedure was performed using Octet BLI Discovery 12.2 and the data was analyzed by Octet Analysis 12.2. The results are shown in Table 7. It can be seen that 8A1-hu6, 8A1-hu11, 8A1-hu13, 14C7-hu3, and 14C7-hu16 have sub nanomolaraffinity to OSMR antigen.

Table 7. Affinity of antibodies

ii. FACS binding

HEK293-OSMR cells (Cobioer, CBP74157) were collected and adjusted to a density of 1x10⁵ per well. Antibodies (8A1-hu6, 8A1-hu11, 8A1-hu13, 14C7-hu3, and 14C7-hu16) were diluted to a series of concentrations with FACS buffer (DPBS+2%FBS) . The cells were incubated with above diluted antibodies for 30min at 4℃. After washing, the diluted secondary antibody (Jackson ImmunoResearch, 109-605-098) (1: 1000) in FACS buffer was added. Cells were resuspended with 200ul FACS buffer for flow meter detection (Thermo-Attune) . The EC50 values were calculated from MFI (mean fluorescence intensity) . As shown in Figure 3, 8A1-hu6, 8A1-hu11, 8A1-hu13, 14C7-hu3, and 14C7-hu16 show high binding activity with HEK293-OSMR cell.

Example 6. Inhibitory effect on the activation of STAT3

HEK293-OSMR cells (Cobioer, CBP74157) of 4x104 cells/well in 50ul DMEM medium (ThermoFisher Scientific, 11965092) were seeded to a 96 well flat bottom plate (Corning, 3599) with OSM protein (Sino, 10452-H08H) of a final concentration of 2ng/ml in 50ul DMEM medium, and incubatedat 37℃ in 5%CO2 for 30min. Then OSMR blocking antibodies (8A1-hu6, 8A1-hu11, 8A1-hu13, 14C7-hu3, and 14C7-hu16) were added with indicated concentrations (100, 25, 6.25, 1.5625, 0.390625, 0.097656, 0.024414, 0.006104nM) in 50ul DMEM medium. The plate was incubated at 37℃ in 5%CO2 for 6h. 100 ul of Bright-Lite Luciferase Assay Buffer (Vazyme, DD1204-03) were added and shaken for 3mins. HEK293-OSMR cells activation was analyzed with a Perkin Elmer Envision plate reader and data was processed with Prism Graphpad software. The activation of STAT3 inHEK293-OSMR cell is shown in Figure 4 A-B. It can be seen that the OSMR blocking antibodies 8A1-hu6, 8A1-hu11, 8A1-hu13, 14C7-hu3, and 14C7-hu16 have significantinhibitory effect on theactivationof STAT3inOSMR reporter cells (HEK293-OSMR) .

Example 7. MCP-1 secretion assay

The binding of OSM to OSMR initiates the secretion of OSM-induced MCP-1 (CLL2, Uniprot Q8NEM0) . The decrease of MCP-1 secretion reflects the blocking effect of the antibodies to OSMR, and was evaluated in Ccd18-Co colonic fibroblasts (ATCC, no. CRL-1459) which express OSMR naturally. Briefly, Ccd18-Co colonic fibroblasts were plated at 5,000 cells per well in a 96-well plate. After 24h incubation, cells were preincubated with different concentrations of OSMR-targeted antibodies (8A1-hu6, 8A1-hu11, 8A1-hu13, 14C7-hu3, and 14C7-hu16) for 1 h at room temperature. Recombinant human OSM at the concentration of 5ng/ml was applied to stimulate MCP-1 secretion. Supernatants were collected after 24h and the concentrations of MCP-1 were determined with ELISA. The results areshown in Figure 5 A-B. It can be seen that 8A1-hu6, 8A1-hu11, 8A1-hu13, 14C7-hu3, and 14C7-hu16 block the secretion of MCP-1, which refers that the antibodies may be able to effectively block the binding of OSM to OSMR.

Example 8. Endocytosis

HEK293-OSMR cells (Cobioer, CBP74157) were harvestedand resuspended in 50 μl of cold FACS Buffer. Add 50 μl of the 5μg/ml of anti-OSMR antibodies (8A1-hu6, 8A1-hu11, 8A1-hu13, 14C7-hu3, and 14C7-hu16) orhIgG1 (hIgG1 as a negative control) in FACS Buffer (DPBS+2%FBS) to the cell suspension. The mixture wasdivided into two groups. One incubated at 37 ℃ to trigger endocytosis for desired time points while another group was incubated on ice as a control. After completing the incubation at a specific time point, two washes were performed with FACS buffer. The second antibody (Jackson ImmunoResearch, 109-605-098) was incubated at 4℃ for 30min. After washing with PBS twice. Resuspend the cell pellet in 200 μl of FACS Buffer and transfer the cell suspension to FACS tubes. Keep samples on ice and in the dark before measurement of MFI by flow cytometry. Analyze samples via flow cytometry (Thermo-Attune) . The percentage of endocytosis was calculated by the formula below:

Endocytosis (%) refers tothe percentage of endocytosisat a certain time point; “MFI37℃” refers to MFI value of the group incubate at 37℃at a certain time point; “MFI 4℃” refers to the MFI value of the group incubate at 4 ℃ (on ice) .

The result is shown in Figure 6 and Table 8. It can be seen that the endocytosis efficiency ofall the antibodies reached 67%in half an hour, and reached to 91%in 2h, which refers that the endocytosis activitiesof all the antibodies are strong.

Table 8. Endocytosis (%) over time for various antibodies

Example 9. The synergistic effect of anti-OSMR and anti-TNF-α

Anti-OSMR blockingantibodies (8A1-hu6, 8A1-hu11, 8A1-hu13, 14C7-hu3, and 14C7-hu16) and/or anti-TNF-α antibodies (adalimumab or Infliximab) were used to demonstrate the synergistic inhibitory effect on theOSM and/or TNF-α-induced MCP-1 secretion. Theprotocolis the same as that in Example 1. For blockade experiments, 5ng/ml of recombinant human TNF-α and 2.5ng/ml of recombinant human OSM were applied to stimulate the cells which were preincubated with different concentrations of antibodies (Anti-OSMR: 100mM, Anti-TNF-α: 50nM, Negative control, hIgG1: 150 nM) for 1h at room temperature.

CI-index values indicate synergistic (<1) , additive (=1) or antagonistic (>1) relationships. Results are shown in Table 9-10, and Figure 7. From the results, it can be seen that there is a synergistic effect of OSMR inhibitorand TNF-αinhibitor.

Table9. MCP-1 secretion under various treatments of antibodies

Table 10. CI-index of antibodies

Claims

A method oftreatingor preventing inflammatory diseases or autoimmune diseases in a subjectin need thereof, comprisingadministering to the subject a therapeutically effective amount of one or more OSMR inhibitors, in combination with a therapeutically effective amount of one or more TNF-αinhibitors,

preferably the inflammatory or autoimmune disease is selected from diseases where OSMR activation plays a role, such as pruritus, hypersensitivity, lupus, graft-versus-host disease (GvHD) , vasculitis, Type I diabetes, multiple sclerosis, rheumatoid arthritis, alopecia areata, atherosclerosis, psoriasis, organ transplant rejection, Sjogren's Syndrome, Behcet's disease, atopic dermatitis, asthma, and inflammatory bowel disease (IBD) , preferably IBD including TNF-α resistant IBD.
The method of claim 1, wherein the OSMR inhibitor is selected from anti-OSMR antibodies or antigen binding fragments thereof, preferably the anti-OSMR antibodiesareblockingantibodies.
The method of claim 2, wherein the anti-OSMR antibody or antigen binding fragment thereof comprises the 6 CDRs of Vixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212,

preferably the anti-OSMR antibody is selected from Vixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212.
The method ofclaim 2 or 3, wherein the anti-OSMR antibody or antigen binding fragment thereof is selected from any one of the following (a) to (k) :

(a) the antibody or antigen binding fragment thereof comprising a HCDR1 comprisingDNYX₁H as set forth in SEQ ID NO: 38, a HCDR2 comprising RIDPEX₂GDX₃TYX₄X₅KFQX₆as set forth in SEQ ID NO: 39, a HCDR3 comprising DYYX₇X₈X₉YVWYFDV as set forth in SEQ ID NO: 40, a LCDR1 comprising RASSSVSSSYLH as set forth in SEQ ID NO: 14, a LCDR2 comprising STSNLAS as set forth in SEQ ID NO: 15, and a LCDR3 comprising QX₁₀YSGYPLIFT as set forth in SEQ ID NO: 41, where X₁is any one of I, M, and their conservative substitutions, X₂is any one of N, S, and their conservative substitutions, X₃ is any one of I, T, and their conservative substitutions, X₄ is any one of D, A, and their conservative substitutions, X₅ is any one of P, Q, and their conservative substitutions, X₆ is any one of D, G, and their conservative substitutions, X₇ is any one of G, Q, A, and their conservative substitutions, X₈ is any one of S, G, and their conservative substitutions, X₉ is any one of N, D, and their conservative substitutions, X₁₀ is any one of Q, T, and their conservative substitutions;

(b) the antibody or antigen binding fragment thereof comprising a HCDR1 comprisingYYDIN as set forth in SEQ ID NO: 5, a HCDR2 comprising WIX₁₁PRDX₁₂STKYX₁₃X₁₄X₁₅FX₁₆G as set forth in SEQ ID NO: 42, a HCDR3 comprising EDSDYFDY as set forth inSEQ ID NO: 7, a LCDR1 comprising RASESVDRYGX₁₇SFMY as set forth inSEQ ID NO: 43, a LCDR2 comprising RASNLES as set forth inSEQ ID NO: 9, and a LCDR3 comprising QQSX₁₈EX₁₉PWT as set forth inSEQ ID NO: 44, where X₁₁is any one of F, L, and their conservative substitutions, X₁₂is any one of G, E, and their conservative substitutions, X₁₃ is any one of N, A, and their conservative substitutions, X₁₄ is any one of E, Q, and their conservative substitutions, X₁₅ is any one of R, K, and their conservative substitutions, X₁₆ is any one of K, Q, and their conservative substitutions, X₁₇ is any one of N, S, and their conservative substitutions, X₁₈ is any one of Y, A, and their conservative substitutions, X₁₉ is any one of D, Y, and their conservative substitutions;

(c) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 11 or SEQ ID NO: 11 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 30 or SEQ ID NO: 30 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 12 or SEQ ID NO: 12 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 27 or SEQ ID NO: 27 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 31 or SEQ ID NO: 31 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 13 or SEQ ID NO: 13 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 28 or SEQ ID NO: 28 with 1, 2, or 3 conservative substitutions, SEQ ID NO: 32 or SEQ ID NO: 32 with 1, 2, or 3 conservative substitutions, orSEQ ID NO: 33 or SEQ ID NO: 33 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 14 or SEQ ID NO: 14 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 15 or SEQ ID NO: 15 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 16 or SEQ ID NO: 16 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 29 or SEQ ID NO: 29 with 1, 2, or 3 conservative substitutions;

(d) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 5 or SEQ ID NO: 5 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 6 or SEQ ID NO: 6 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 34 or SEQ ID NO: 34 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 36 or SEQ ID NO: 36 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 7 or SEQ ID NO: 7 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 8 or SEQ ID NO: 8 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 22 or SEQ ID NO: 22 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 9 or SEQ ID NO: 9 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 10 or SEQ ID NO: 10 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 35 or SEQ ID NO: 35 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 37 or SEQ ID NO: 37 with 1, 2, or 3 conservative substitutions;

(e) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 11 or SEQ ID NO: 11 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 12 or SEQ ID NO: 12 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 13 or SEQ ID NO: 13 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 14 or SEQ ID NO: 14 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 15 or SEQ ID NO: 15 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 16 or SEQ ID NO: 16 with 1, 2, or 3 conservative substitutions;

(f) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 11 or SEQ ID NO: 11 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 27 or SEQ ID NO: 27 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 28 or SEQ ID NO: 28 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 14 or SEQ ID NO: 14 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 15 or SEQ ID NO: 15 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 29 or SEQ ID NO: 29 with 1, 2, or 3 conservative substitutions;

(g) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 30 or SEQ ID NO: 30 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 31 or SEQ ID NO: 31 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 32 or SEQ ID NO: 32 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 14 or SEQ ID NO: 14 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 15 or SEQ ID NO: 15 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 29 or SEQ ID NO: 29 with 1, 2, or 3 conservative substitutions;

(h) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 30 or SEQ ID NO: 30 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 31 or SEQ ID NO: 31 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 33 or SEQ ID NO: 33 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 14 or SEQ ID NO: 14 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 15 or SEQ ID NO: 15 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 29 or SEQ ID NO: 29 with 1, 2, or 3 conservative substitutions;

(i) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 5 or SEQ ID NO: 5 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 6 or SEQ ID NO: 6 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 7 or SEQ ID NO: 7 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 8 or SEQ ID NO: 8 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 9 or SEQ ID NO: 9 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 10 or SEQ ID NO: 10 with 1, 2, or 3 conservative substitutions;

(j) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 5 or SEQ ID NO: 5 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 34 or SEQ ID NO: 34 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 7 or SEQ ID NO: 7 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 8 or SEQ ID NO: 8 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 9 or SEQ ID NO: 9 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 35 or SEQ ID NO: 35 with 1, 2, or 3 conservative substitutions;

(k) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 5 or SEQ ID NO: 5 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 36 or SEQ ID NO: 36 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 7 or SEQ ID NO: 7 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 22 or SEQ ID NO: 22 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 9 or SEQ ID NO: 9 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 37 or SEQ ID NO: 37 with 1, 2, or 3 conservative substitutions.
The method of any one of claims 1-4, wherein the TNF-α inhibitor is selected from TNF-α antibodies or antigen binding fragments thereof,

preferably, the TNF-α antibody or antigen binding fragment thereof comprises the 6 CDRs of Infliximab, Adalimumab, Afelimomab, CDP-571, CDP-870, Golimumab, or Nerelimomab,

more preferably the TNF-α antibody or antigen binding fragment thereof is selected from Infliximab, Adalimumab, Afelimomab, CDP-571, CDP-870, Golimumab, or Nerelimomab.
The method of any one of claims1-5, wherein the OSMR inhibitor and theTNF-αinhibitor are administered concurrently or sequentially, optionally the OSMR inhibitor and the TNF-αinhibitor are administered in combination with another therapeutic agent,

preferably, the another therapeutic agent includes an antibody or antigen binding fragment thereof, a chemotherapeutic agent and a small molecule drug, such as PD-1 agonists, CTLA-4 agonists, Bruton’s tyrosine kinase (BTK) inhibitor, tyrosine kinase inhibitor, phosphodiesterase-4 (PDE-4) inhibitor, janus kinase 1 (JAK1) inhibitor, sphingosine-1 phosphate receptor (S1PR) modulator, CD20 inhibitors, antibodies to immune cell specific antigens or self-antigens or inflammatory factor, immune stimulatory antibodies, antibodies to targets for T cell engager, antibodies to virus-infected cell antigens, chemotherapeutic agent, NSAIDs, corticosteroids.
The method of any one ofclaims1-6, whereinone or more doses of the OSMR inhibitorare administered prior to administering one or more doses of the TNF-α inhibitor.
Acombination, comprising one or more OSMR inhibitors and one or more TNF-α inhibitors,

preferably, the OSMR inhibitor is selected from anti-OSMR antibodies or antigen binding fragments thereof, preferably the anti-OSMR antibodies are blocking antibodies.
The combination of claim 8, wherein the anti-OSMR antibody or antigen binding fragment thereof comprises the 6 CDRs of Vixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212,

preferably the anti-OSMR antibody is selected from Vixarelimab, GSK315234, GSK2330811, CNTO 1119 or CNTO 8212.
The combination of claim 8 or 9, wherein the anti-OSMR antibody or antigen binding fragment thereof is selected from any one of the following (a) to (k) :

(a) the antibody or antigen binding fragment thereof comprising a HCDR1 comprisingDNYX₁H as set forth in SEQ ID NO: 38, a HCDR2 comprising RIDPEX₂GDX₃TYX₄X₅KFQX₆as set forth in SEQ ID NO: 39, a HCDR3 comprising DYYX₇X₈X₉YVWYFDV as set forth in SEQ ID NO: 40, a LCDR1 comprising RASSSVSSSYLH as set forth in SEQ ID NO: 14, a LCDR2 comprising STSNLAS as set forth in SEQ ID NO: 15, and a LCDR3 comprising QX₁₀YSGYPLIFT as set forth in SEQ ID NO: 41, where X₁is any one of I, M, and their conservative substitutions, X₂is any one of N, S, and their conservative substitutions, X₃ is any one of I, T, and their conservative substitutions, X₄ is any one of D, A, and their conservative substitutions, X₅ is any one of P, Q, and their conservative substitutions, X₆ is any one of D, G, and their conservative substitutions, X₇ is any one of G, Q, A, and their conservative substitutions, X₈ is any one of S, G, and their conservative substitutions, X₉ is any one of N, D, and their conservative substitutions, X₁₀ is any one of Q, T, and their conservative substitutions;

(b) the antibody or antigen binding fragment thereof comprising a HCDR1 comprisingYYDIN as set forth in SEQ ID NO: 5, a HCDR2 comprising WIX₁₁PRDX₁₂STKYX₁₃X₁₄X₁₅FX₁₆G as set forth in SEQ ID NO: 42, a HCDR3 comprising EDSDYFDY as set forth inSEQ ID NO: 7, a LCDR1 comprising RASESVDRYGX₁₇SFMY as set forth inSEQ ID NO: 43, a LCDR2 comprising RASNLES as set forth inSEQ ID NO: 9, and a LCDR3 comprising QQSX₁₈EX₁₉PWT as set forth inSEQ ID NO: 44, where X₁₁is any one of F, L, and their conservative substitutions, X₁₂is any one of G, E, and their conservative substitutions, X₁₃ is any one of N, A, and their conservative substitutions, X₁₄ is any one of E, Q, and their conservative substitutions, X₁₅ is any one of R, K, and their conservative substitutions, X₁₆ is any one of K, Q, and their conservative substitutions, X₁₇ is any one of N, S, and their conservative substitutions, X₁₈ is any one of Y, A, and their conservative substitutions, X₁₉ is any one of D, Y, and their conservative substitutions;

(c) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 11 or SEQ ID NO: 11 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 30 or SEQ ID NO: 30 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 12 or SEQ ID NO: 12 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 27 or SEQ ID NO: 27 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 31 or SEQ ID NO: 31 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 13 or SEQ ID NO: 13 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 28 or SEQ ID NO: 28 with 1, 2, or 3 conservative substitutions, SEQ ID NO: 32 or SEQ ID NO: 32 with 1, 2, or 3 conservative substitutions, orSEQ ID NO: 33 or SEQ ID NO: 33 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 14 or SEQ ID NO: 14 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 15 or SEQ ID NO: 15 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 16 or SEQ ID NO: 16 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 29 or SEQ ID NO: 29 with 1, 2, or 3 conservative substitutions;

(d) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 5 or SEQ ID NO: 5 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 6 or SEQ ID NO: 6 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 34 or SEQ ID NO: 34 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 36 or SEQ ID NO: 36 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 7 or SEQ ID NO: 7 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 8 or SEQ ID NO: 8 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 22 or SEQ ID NO: 22 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 9 or SEQ ID NO: 9 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 10 or SEQ ID NO: 10 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 35 or SEQ ID NO: 35 with 1, 2, or 3 conservative substitutions, or SEQ ID NO: 37 or SEQ ID NO: 37 with 1, 2, or 3 conservative substitutions;

(e) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 11 or SEQ ID NO: 11 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 12 or SEQ ID NO: 12 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 13 or SEQ ID NO: 13 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 14 or SEQ ID NO: 14 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 15 or SEQ ID NO: 15 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 16 or SEQ ID NO: 16 with 1, 2, or 3 conservative substitutions;

(f) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 11 or SEQ ID NO: 11 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 27 or SEQ ID NO: 27 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 28 or SEQ ID NO: 28 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 14 or SEQ ID NO: 14 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 15 or SEQ ID NO: 15 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 29 or SEQ ID NO: 29 with 1, 2, or 3 conservative substitutions;

(g) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 30 or SEQ ID NO: 30 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 31 or SEQ ID NO: 31 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 32 or SEQ ID NO: 32 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 14 or SEQ ID NO: 14 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 15 or SEQ ID NO: 15 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 29 or SEQ ID NO: 29 with 1, 2, or 3 conservative substitutions;

(h) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 30 or SEQ ID NO: 30 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 31 or SEQ ID NO: 31 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 33 or SEQ ID NO: 33 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 14 or SEQ ID NO: 14 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 15 or SEQ ID NO: 15 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 29 or SEQ ID NO: 29 with 1, 2, or 3 conservative substitutions;

(i) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 5 or SEQ ID NO: 5 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 6 or SEQ ID NO: 6 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 7 or SEQ ID NO: 7 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 8 or SEQ ID NO: 8 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 9 or SEQ ID NO: 9 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 10 or SEQ ID NO: 10 with 1, 2, or 3 conservative substitutions;

(j) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 5 or SEQ ID NO: 5 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 34 or SEQ ID NO: 34 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 7 or SEQ ID NO: 7 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 8 or SEQ ID NO: 8 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 9 or SEQ ID NO: 9 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 35 or SEQ ID NO: 35 with 1, 2, or 3 conservative substitutions;

(k) the antibody or antigen binding fragment thereof comprising a HCDR1 comprising SEQ ID NO: 5 or SEQ ID NO: 5 with 1, 2, or 3 conservative substitutions; a HCDR2 comprising SEQ ID NO: 36 or SEQ ID NO: 36 with 1, 2, or 3 conservative substitutions; a HCDR3 comprising SEQ ID NO: 7 or SEQ ID NO: 7 with 1, 2, or 3 conservative substitutions; a LCDR1 comprising SEQ ID NO: 22 or SEQ ID NO: 22 with 1, 2, or 3 conservative substitutions; a LCDR2 comprising SEQ ID NO: 9 or SEQ ID NO: 9 with 1, 2, or 3 conservative substitutions; and a LCDR3 comprising SEQ ID NO: 37 or SEQ ID NO: 37 with 1, 2, or 3 conservative substitutions.
The combination of any one of claims8-10, wherein the TNF-α inhibitor is selected from TNF-α antibodies or antigen binding fragments thereof,

preferably, the TNF-α antibody or antigen binding fragment thereof comprises the 6 CDRs of Infliximab, Adalimumab, Afelimomab, CDP-571, CDP-870, Golimumab, or Nerelimomab,

more preferably, the TNF-α antibody or antigen binding fragment thereof is selected from Infliximab, Adalimumab, Afelimomab, CDP-571, CDP-870, Golimumab, orNerelimomab.
Pharmaceutical composition, comprising the combination of any one of claims 8-11, and pharmaceutically acceptable carriers or excipients.
A method oftreatingor preventing inflammatory diseases or autoimmune diseases in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the combination of any one of claims 8-11, or the pharmaceutical composition of claim 12,

preferably the inflammatory or autoimmunedisease is selected from diseases where OSMR activation plays a role, such as pruritus, hypersensitivity, lupus, graft-versus-host disease (GvHD) , vasculitis, Type I diabetes, multiple sclerosis, rheumatoid arthritis, alopecia areata, atherosclerosis, psoriasis, organ transplant rejection, Sjogren's Syndrome, Behcet's disease, atopic dermatitis, asthma, and inflammatory bowel disease (IBD) , preferably IBD including TNF-α resistant IBD.
The method of claim 13, wherein the combination or the pharmaceutical composition is administered in combination with another therapeutic agent,

preferably, the another therapeutic agent includes an antibody or antigen binding fragment thereof, a chemotherapeutic agent and a small molecule drug, such as PD-1 agonists, CTLA-4 agonists, Bruton’s tyrosine kinase (BTK) inhibitor, tyrosine kinase inhibitor, phosphodiesterase-4 (PDE-4) inhibitor, janus kinase 1 (JAK1) inhibitor, sphingosine-1 phosphate receptor (S1PR) modulator, CD20 inhibitors, antibodies to immune cell specific antigens or self-antigens or inflammatory factor, immune stimulatory antibodies, antibodies to targets for T cell engager, antibodies to virus-infected cell antigens, chemotherapeutic agent, NSAIDs, corticosteroids.