Oncostatin M receptor beta binding antibodies and uses thereof

Abstract

The present invention relates to antibodies or antigen-binding fragments that specifically bind to OSMR [beta] protein. The invention also relates to nucleic acids encoding the antibodies or antigen binding fragments and host cells comprising the same, as well as methods of making the antibodies or antigen binding fragments. Furthermore, the present invention relates to the use of said antibody or antigen-binding fragment for disease prevention and / or treatment.

Description

Technical Field

[0001] The present invention generally relates to antibodies and their uses. More specifically, the present invention relates to antibodies and antigen-binding fragments that specifically bind to oncostatin M receptor beta (OSMRβ) and their uses. Background Art

[0002] Oncostatin M ( O nco s tatin-M, OSM) belongs to the pleiotropic cytokine in the IL-6 family members. It was first discovered and purified from the culture supernatant of PMA-activated U937 histiocytic lymphoma cells in 1986, and was named because it can inhibit the proliferation of melanoma cells in vitro. The OSM gene is located on chromosome 22q12, consists of 3 exons and 2 introns, and is adjacent to the Leukemia inhibitory factor (LIF) gene.

[0003] OSM signals through cell surface receptors containing the protein gp130. The cell surface receptors of OSM include type I OSM receptor and type II OSM receptor. The type I OSM receptor (gp130 / LIFRβ) is a heterodimer composed of a gp130 molecule and a LIF receptor subunit, which can bind to both LIF and OSM to initiate signal transduction. The type II OSM receptor (gp130 / OSMRβ) is a heterodimer composed of a gp130 molecule and an OSM receptor β subunit. The type II receptor is specific for OSM and cannot bind LIF and other cytokines in the IL-6 family.

[0004] In addition, OSMRβ activates the IL-31-induced signaling pathway by dimerizing with IL-31 receptor alpha (IL-31RA). IL-31 is associated with inflammatory and allergic diseases, such as atopic dermatitis / pruritus, intestinal inflammation, allergic rhinitis and asthma (Biochem Biophys Res Commun. 2022 Jul 23:614:114-119.doi:10.1016 / j.bbrc.2022.05.013).

[0005] Once the OSM receptor or IL-31 receptor binds to OSM or IL-31, OSMRβ plays an important role as a signal transduction regulator by phosphorylating various tyrosine residues in the intracellular domain. Then, the signal transduction is initiated by JAK related to OSMRβ, gp130 and IL-31RA. Subsequently, the pathways of STAT1 / 3 / 5, MAPK, PI3K / AKT and PKC subtypes are activated.

[0006] Therefore, OSMRβ mediates the signal transduction of interleukin-31 (IL-31) and oncostatin M (OSM). By targeting OSMRβ with blocking monoclonal antibodies, the functions of both IL-31 and OSM cytokines are blocked, which has potential application prospects in the treatment of many diseases and disorders related to OSMR (such as pruritus, inflammation, and fibrosis).

[0007] The disclosed drug pipelines targeting OSMR are very scarce. Currently, there is only vixarelimab (also known as "KPL-716") and it is still in clinical phase II. Given the good efficacy and safety of vixarelimab in clinical trials (ClinicalTrials.gov Identifier: NCT03858634) and the fact that there is no targeted drug developed for OSMR on the global market, there is still a need for new OSMRβ blocking antibodies in this field. The present invention meets this need by providing blocking antibodies that bind to OSMRβ with high target specificity and high affinity. Summary of the Invention

[0008] Through research, the inventors of the present invention have developed a new group of OSMRβ-binding antibodies that can bind to OSMRβ with high affinity and effectively block the signal transduction mediated by IL-31 and OSM.

[0009] Therefore, in a first aspect, the present invention provides an isolated antibody or antigen-binding fragment that specifically binds to the OSMRβ protein, which comprises

[0010] (a) three CDRs in the amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 1 and three CDRs in the amino acid sequence of the light chain variable region shown in SEQ ID NO: 2; or a variant having single or multiple CDRs with no more than 2 amino acid changes in each CDR region compared to the above six CDR regions;

[0011] (b) three CDRs in the amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 9 and three CDRs in the amino acid sequence of the light chain variable region shown in SEQ ID NO: 10; or a variant having single or multiple CDRs with no more than 2 amino acid changes in each CDR region compared to the above six CDR regions;

[0012] (c) three CDRs in the amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 17 and three CDRs in the amino acid sequence of the light chain variable region shown in SEQ ID NO: 18; or a variant having single or multiple CDRs with no more than 2 amino acid changes in each CDR region compared to the above six CDR regions;

[0013] (d) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 25 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 26; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0014] (e) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 33 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 34; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0015] (f) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 41 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 42; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0016] (g) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 49 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 50; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0017] (h) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 57 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 58; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0018] (i) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 65 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 66; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0019] (j) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 73 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 74; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0020] (k) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 81 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 82; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0021] (l) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 89 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 90; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0022] (m) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 97 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 98; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0023] (n) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 105 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 106; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0024] (o) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 113 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 114; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0025] (p) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 121 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 122; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions; or

[0026] (q) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 129 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 130; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions.

[0027] In some embodiments, the present invention provides an isolated antibody or antigen-binding fragment that specifically binds to the OSMRβ protein, comprising

[0028] (a) HCDR1 shown in SEQ ID NO: 3 or a variant thereof with no more than 2 amino acid changes of HCDR1 shown in SEQ ID NO: 3, HCDR2 shown in SEQ ID NO: 4 or a variant thereof with no more than 2 amino acid changes of HCDR2 shown in SEQ ID NO: 4, and HCDR3 shown in SEQ ID NO: 5 or a variant thereof with no more than 2 amino acid changes of HCDR3 shown in SEQ ID NO: 5; LCDR1 shown in SEQ ID NO: 6 or a variant thereof with no more than 2 amino acid changes of LCDR1 shown in SEQ ID NO: 6, LCDR2 shown in SEQ ID NO: 7 or a variant thereof with no more than 2 amino acid changes of LCDR2 shown in SEQ ID NO: 7, and LCDR3 shown in SEQ ID NO: 8 or a variant thereof with no more than 2 amino acid changes of LCDR3 shown in SEQ ID NO: 8;

[0029] (b) HCDR1 shown in SEQ ID NO: 11 or a variant thereof with no more than 2 amino acid changes of HCDR1 shown in SEQ ID NO: 11, HCDR2 shown in SEQ ID NO: 12 or a variant thereof with no more than 2 amino acid changes of HCDR2 shown in SEQ ID NO: 12, and HCDR3 shown in SEQ ID NO: 13 or a variant thereof with no more than 2 amino acid changes of HCDR3 shown in SEQ ID NO: 13; LCDR1 shown in SEQ ID NO: 14 or a variant thereof with no more than 2 amino acid changes of LCDR1 shown in SEQ ID NO: 14, LCDR2 shown in SEQ ID NO: 15 or a variant thereof with no more than 2 amino acid changes of LCDR2 shown in SEQ ID NO: 15, and LCDR3 shown in SEQ ID NO: 16 or a variant thereof with no more than 2 amino acid changes of LCDR3 shown in SEQ ID NO: 16;

[0030] (c) The HCDR1 shown in SEQ ID NO: 19 or a variant of the HCDR1 shown in SEQ ID NO: 19 with no more than 2 amino acid changes, the HCDR2 shown in SEQ ID NO: 20 or a variant of the HCDR2 shown in SEQ ID NO: 20 with no more than 2 amino acid changes, and the HCDR3 shown in SEQ ID NO: 21 or a variant of the HCDR3 shown in SEQ ID NO: 21 with no more than 2 amino acid changes; the LCDR1 shown in SEQ ID NO: 22 or a variant of the LCDR1 shown in SEQ ID NO: 22 with no more than 2 amino acid changes, the LCDR2 shown in SEQ ID NO: 23 or a variant of the LCDR2 shown in SEQ ID NO: 23 with no more than 2 amino acid changes, and the LCDR3 shown in SEQ ID NO: 24 or a variant of the LCDR3 shown in SEQ ID NO: 24 with no more than 2 amino acid changes;

[0031] (d) The HCDR1 shown in SEQ ID NO: 27 or a variant of the HCDR1 shown in SEQ ID NO: 27 with no more than 2 amino acid changes, the HCDR2 shown in SEQ ID NO: 28 or a variant of the HCDR2 shown in SEQ ID NO: 28 with no more than 2 amino acid changes, and the HCDR3 shown in SEQ ID NO: 29 or a variant of the HCDR3 shown in SEQ ID NO: 29 with no more than 2 amino acid changes; the LCDR1 shown in SEQ ID NO: 30 or a variant of the LCDR1 shown in SEQ ID NO: 30 with no more than 2 amino acid changes, the LCDR2 shown in SEQ ID NO: 31 or a variant of the LCDR2 shown in SEQ ID NO: 31 with no more than 2 amino acid changes, and the LCDR3 shown in SEQ ID NO: 32 or a variant of the LCDR3 shown in SEQ ID NO: 32 with no more than 2 amino acid changes;

[0032] (e) The HCDR1 shown in SEQ ID NO: 35 or a variant of the HCDR1 shown in SEQ ID NO: 35 with no more than 2 amino acid changes, the HCDR2 shown in SEQ ID NO: 36 or a variant of the HCDR2 shown in SEQ ID NO: 36 with no more than 2 amino acid changes, and the HCDR3 shown in SEQ ID NO: 37 or a variant of the HCDR3 shown in SEQ ID NO: 37 with no more than 2 amino acid changes; the LCDR1 shown in SEQ ID NO: 38 or a variant of the LCDR1 shown in SEQ ID NO: 38 with no more than 2 amino acid changes, the LCDR2 shown in SEQ ID NO: 39 or a variant of the LCDR2 shown in SEQ ID NO: 39 with no more than 2 amino acid changes, and the LCDR3 shown in SEQ ID NO: 40 or a variant of the LCDR3 shown in SEQ ID NO: 40 with no more than 2 amino acid changes;

[0033] (f) The HCDR1 shown in SEQ ID NO: 43 or a variant of the HCDR1 shown in SEQ ID NO: 43 with no more than 2 amino acid changes, the HCDR2 shown in SEQ ID NO: 44 or a variant of the HCDR2 shown in SEQ ID NO: 44 with no more than 2 amino acid changes, and the HCDR3 shown in SEQ ID NO: 45 or a variant of the HCDR3 shown in SEQ ID NO: 45 with no more than 2 amino acid changes; the LCDR1 shown in SEQ ID NO: 46 or a variant of the LCDR1 shown in SEQ ID NO: 46 with no more than 2 amino acid changes, the LCDR2 shown in SEQ ID NO: 47 or a variant of the LCDR2 shown in SEQ ID NO: 47 with no more than 2 amino acid changes, and the LCDR3 shown in SEQ ID NO: 48 or a variant of the LCDR3 shown in SEQ ID NO: 48 with no more than 2 amino acid changes;

[0034] (g) The HCDR1 shown in SEQ ID NO: 51 or a variant of the HCDR1 shown in SEQ ID NO: 51 with no more than 2 amino acid changes, the HCDR2 shown in SEQ ID NO: 52 or a variant of the HCDR2 shown in SEQ ID NO: 52 with no more than 2 amino acid changes, and the HCDR3 shown in SEQ ID NO: 53 or a variant of the HCDR3 shown in SEQ ID NO: 53 with no more than 2 amino acid changes; the LCDR1 shown in SEQ ID NO: 54 or a variant of the LCDR1 shown in SEQ ID NO: 54 with no more than 2 amino acid changes, the LCDR2 shown in SEQ ID NO: 55 or a variant of the LCDR2 shown in SEQ ID NO: 55 with no more than 2 amino acid changes, and the LCDR3 shown in SEQ ID NO: 56 or a variant of the LCDR3 shown in SEQ ID NO: 56 with no more than 2 amino acid changes;

[0035] (h) The HCDR1 shown in SEQ ID NO: 59 or a variant of the HCDR1 shown in SEQ ID NO: 59 with no more than 2 amino acid changes, the HCDR2 shown in SEQ ID NO: 60 or a variant of the HCDR2 shown in SEQ ID NO: 60 with no more than 2 amino acid changes, and the HCDR3 shown in SEQ ID NO: 61 or a variant of the HCDR3 shown in SEQ ID NO: 61 with no more than 2 amino acid changes; the LCDR1 shown in SEQ ID NO: 62 or a variant of the LCDR1 shown in SEQ ID NO: 62 with no more than 2 amino acid changes, the LCDR2 shown in SEQ ID NO: 63 or a variant of the LCDR2 shown in SEQ ID NO: 63 with no more than 2 amino acid changes, and the LCDR3 shown in SEQ ID NO: 64 or a variant of the LCDR3 shown in SEQ ID NO: 64 with no more than 2 amino acid changes;

[0036] (i) The HCDR1 shown in SEQ ID NO: 67 or a variant thereof with no more than 2 amino acid changes of the HCDR1 shown in SEQ ID NO: 67, the HCDR2 shown in SEQ ID NO: 68 or a variant thereof with no more than 2 amino acid changes of the HCDR2 shown in SEQ ID NO: 68, and the HCDR3 shown in SEQ ID NO: 69 or a variant thereof with no more than 2 amino acid changes of the HCDR3 shown in SEQ ID NO: 69; the LCDR1 shown in SEQ ID NO: 70 or a variant thereof with no more than 2 amino acid changes of the LCDR1 shown in SEQ ID NO: 70, the LCDR2 shown in SEQ ID NO: 71 or a variant thereof with no more than 2 amino acid changes of the LCDR2 shown in SEQ ID NO: 71, and the LCDR3 shown in SEQ ID NO: 72 or a variant thereof with no more than 2 amino acid changes of the LCDR3 shown in SEQ ID NO: 72;

[0037] (j) The HCDR1 shown in SEQ ID NO: 75 or a variant thereof with no more than 2 amino acid changes of the HCDR1 shown in SEQ ID NO: 75, the HCDR2 shown in SEQ ID NO: 76 or a variant thereof with no more than 2 amino acid changes of the HCDR2 shown in SEQ ID NO: 76, and the HCDR3 shown in SEQ ID NO: 77 or a variant thereof with no more than 2 amino acid changes of the HCDR3 shown in SEQ ID NO: 77; the LCDR1 shown in SEQ ID NO: 78 or a variant thereof with no more than 2 amino acid changes of the LCDR1 shown in SEQ ID NO: 78, the LCDR2 shown in SEQ ID NO: 79 or a variant thereof with no more than 2 amino acid changes of the LCDR2 shown in SEQ ID NO: 79, and the LCDR3 shown in SEQ ID NO: 80 or a variant thereof with no more than 2 amino acid changes of the LCDR3 shown in SEQ ID NO: 80;

[0038] (k) The HCDR1 shown in SEQ ID NO: 83 or a variant thereof with no more than 2 amino acid changes of the HCDR1 shown in SEQ ID NO: 83, the HCDR2 shown in SEQ ID NO: 84 or a variant thereof with no more than 2 amino acid changes of the HCDR2 shown in SEQ ID NO: 84, and the HCDR3 shown in SEQ ID NO: 85 or a variant thereof with no more than 2 amino acid changes of the HCDR3 shown in SEQ ID NO: 85; the LCDR1 shown in SEQ ID NO: 86 or a variant thereof with no more than 2 amino acid changes of the LCDR1 shown in SEQ ID NO: 86, the LCDR2 shown in SEQ ID NO: 87 or a variant thereof with no more than 2 amino acid changes of the LCDR2 shown in SEQ ID NO: 87, and the LCDR3 shown in SEQ ID NO: 88 or a variant thereof with no more than 2 amino acid changes of the LCDR3 shown in SEQ ID NO: 88;

[0039] (l) The HCDR1 shown in SEQ ID NO: 91 or a variant thereof with no more than 2 amino acid changes of the HCDR1 shown in SEQ ID NO: 91, the HCDR2 shown in SEQ ID NO: 92 or a variant thereof with no more than 2 amino acid changes of the HCDR2 shown in SEQ ID NO: 92, and the HCDR3 shown in SEQ ID NO: 93 or a variant thereof with no more than 2 amino acid changes of the HCDR3 shown in SEQ ID NO: 93; the LCDR1 shown in SEQ ID NO: 94 or a variant thereof with no more than 2 amino acid changes of the LCDR1 shown in SEQ ID NO: 94, the LCDR2 shown in SEQ ID NO: 95 or a variant thereof with no more than 2 amino acid changes of the LCDR2 shown in SEQ ID NO: 95, and the LCDR3 shown in SEQ ID NO: 96 or a variant thereof with no more than 2 amino acid changes of the LCDR3 shown in SEQ ID NO: 96;

[0040] (m)HCDR1 shown in SEQ ID NO: 99 or a variant of HCDR1 shown in SEQ ID NO: 99 with no more than 2 amino acid changes, HCDR2 shown in SEQ ID NO: 100 or a variant of HCDR2 shown in SEQ ID NO: 100 with no more than 2 amino acid changes, and HCDR3 shown in SEQ ID NO: 101 or a variant of HCDR3 shown in SEQ ID NO: 101 with no more than 2 amino acid changes; LCDR1 shown in SEQ ID NO: 102 or a variant of LCDR1 shown in SEQ ID NO: 102 with no more than 2 amino acid changes, LCDR2 shown in SEQ ID NO: 103 or a variant of LCDR2 shown in SEQ ID NO: 103 with no more than 2 amino acid changes, and LCDR3 shown in SEQ ID NO: 104 or a variant of LCDR3 shown in SEQ ID NO: 104 with no more than 2 amino acid changes;

[0041] (n)HCDR1 shown in SEQ ID NO: 107 or a variant of HCDR1 shown in SEQ ID NO: 107 with no more than 2 amino acid changes, HCDR2 shown in SEQ ID NO: 108 or a variant of HCDR2 shown in SEQ ID NO: 108 with no more than 2 amino acid changes, and HCDR3 shown in SEQ ID NO: 109 or a variant of HCDR3 shown in SEQ ID NO: 109 with no more than 2 amino acid changes; LCDR1 shown in SEQ ID NO: 110 or a variant of LCDR1 shown in SEQ ID NO: 110 with no more than 2 amino acid changes, LCDR2 shown in SEQ ID NO: 111 or a variant of LCDR2 shown in SEQ ID NO: 111 with no more than 2 amino acid changes, and LCDR3 shown in SEQ ID NO: 112 or a variant of LCDR3 shown in SEQ ID NO: 112 with no more than 2 amino acid changes;

[0042] (o)The HCDR1 shown in SEQ ID NO: 115 or a variant of the HCDR1 shown in SEQ ID NO: 115 with no more than 2 amino acid changes, the HCDR2 shown in SEQ ID NO: 116 or a variant of the HCDR2 shown in SEQ ID NO: 116 with no more than 2 amino acid changes, and the HCDR3 shown in SEQ ID NO: 117 or a variant of the HCDR3 shown in SEQ ID NO: 117 with no more than 2 amino acid changes; the LCDR1 shown in SEQ ID NO: 118 or a variant of the LCDR1 shown in SEQ ID NO: 118 with no more than 2 amino acid changes, the LCDR2 shown in SEQ ID NO: 119 or a variant of the LCDR2 shown in SEQ ID NO: 119 with no more than 2 amino acid changes, and the LCDR3 shown in SEQ ID NO: 120 or a variant of the LCDR3 shown in SEQ ID NO: 120 with no more than 2 amino acid changes;

[0043] (p)The HCDR1 shown in SEQ ID NO: 123 or a variant of the HCDR1 shown in SEQ ID NO: 123 with no more than 2 amino acid changes, the HCDR2 shown in SEQ ID NO: 124 or a variant of the HCDR2 shown in SEQ ID NO: 124 with no more than 2 amino acid changes, and the HCDR3 shown in SEQ ID NO: 125 or a variant of the HCDR3 shown in SEQ ID NO: 125 with no more than 2 amino acid changes; the LCDR1 shown in SEQ ID NO: 126 or a variant of the LCDR1 shown in SEQ ID NO: 126 with no more than 2 amino acid changes, the LCDR2 shown in SEQ ID NO: 127 or a variant of the LCDR2 shown in SEQ ID NO: 127 with no more than 2 amino acid changes, and the LCDR3 shown in SEQ ID NO: 128 or a variant of the LCDR3 shown in SEQ ID NO: 128 with no more than 2 amino acid changes; or

[0044] (q) The HCDR1 shown in SEQ ID NO: 131 or a variant of the HCDR1 shown in SEQ ID NO: 131 with no more than 2 amino acid changes, the HCDR2 shown in SEQ ID NO: 132 or a variant of the HCDR2 shown in SEQ ID NO: 132 with no more than 2 amino acid changes, and the HCDR3 shown in SEQ ID NO: 133 or a variant of the HCDR3 shown in SEQ ID NO: 133 with no more than 2 amino acid changes; the LCDR1 shown in SEQ ID NO: 134 or a variant of the LCDR1 shown in SEQ ID NO: 134 with no more than 2 amino acid changes, the LCDR2 shown in SEQ ID NO: 135 or a variant of the LCDR2 shown in SEQ ID NO: 135 with no more than 2 amino acid changes, and the LCDR3 shown in SEQ ID NO: 136 or a variant of the LCDR3 shown in SEQ ID NO: 136 with no more than 2 amino acid changes.

[0045] In some embodiments, the isolated antibody or antigen-binding fragment that specifically binds to the OSMRβ protein of the present invention comprises

[0046] (a) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 1 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 2 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0047] (b) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 9 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 10 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0048] (c) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 17 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 18 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0049] (d) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 25 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 26 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0050] (e) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 33 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 34 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0051] (f) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 41 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 42 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0052] (g) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 49 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 50 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0053] (h) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 57 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 58 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0054] (i) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 65 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 66 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0055] (j) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 73 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 74 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0056] (k) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 81 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 82 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0057] (l) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 89 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 90 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0058] (m) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 97 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 98 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0059] (n) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 105 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 106 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0060] (o) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 113 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 114 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0061] (p) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 121 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 122 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; or

[0062] (q) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 129 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 130 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto.

[0063] In some embodiments, the antigen-binding fragment of the present invention is Fab, Fab’, F(ab’)2, Fv, single-chain Fv, bispecific single-chain Fv, trispecific single-chain Fv, single-chain Fab, bispecific Fab dimer (Fab2), trispecific Fab trimer (Fab3), diabody.

[0064] In some embodiments, the isolated antibody that specifically binds to the OSMRβ protein of the present invention is an IgG1, IgG2, IgG3, or IgG4 antibody; preferably, it is an IgG1 or IgG4 antibody; more preferably, it is a human IgG1 or human IgG4 antibody.

[0065] In a second aspect, the present invention provides a nucleic acid encoding the antibody or antigen-binding fragment described in the first aspect above, a vector (preferably, an expression vector) containing the nucleic acid, and a host cell containing the nucleic acid or the vector. In some embodiments, the host cell is prokaryotic or eukaryotic, for example, selected from Escherichia coli cells, yeast cells, mammalian cells, or other cells suitable for preparing an antibody or antigen-binding fragment. In some embodiments, the host cell is a HEK 293 cell or a CHO cell.

[0066] In a third aspect, the present invention provides a method for preparing the antibody or antigen-binding fragment of the present invention, the method comprising culturing the host cell of the present invention under conditions suitable for expressing the nucleic acid encoding the antibody or antigen-binding fragment of the present invention, and optionally recovering the antibody or antigen-binding fragment of the present invention from the host cell or from the culture medium.

[0067] In a fourth aspect, the present invention provides a pharmaceutical composition comprising the antibody or antigen-binding fragment of the present invention, or the nucleic acid of the present invention, or the vector of the present invention, or the host cell of the present invention, and a pharmaceutically acceptable carrier.

[0068] In a fifth aspect, the present invention provides the use of the antibody or antigen-binding fragment of the present invention, or the nucleic acid of the present invention, or the vector of the present invention, or the host cell of the present invention, for preparing a drug for preventing and / or treating a disease, for example, the disease is an autoimmune disease, an inflammatory disease, or a disease related to extracellular matrix deposition or remodeling, for example, fibrosis, cartilage degeneration, arthritis, rheumatoid arthritis, scleroderma, scleroderma-related interstitial lung disease, idiopathic pulmonary fibrosis, cirrhosis, psoriasis, atopic dermatitis, systemic cutaneous amyloidosis, primary cutaneous amyloidosis, pruritic inflammation, prurigo nodularis, and pain.

[0069] In a sixth aspect, the present invention provides a method for preventing and / or treating a disease, the method comprising administering to a subject in need thereof an effective amount of an antibody or antigen-binding fragment of the present invention, or a nucleic acid of the present invention, or a vector of the present invention, or a host cell of the present invention, wherein the subject is a mammal; preferably, the subject is a human; wherein the disease is, for example, an autoimmune disease, an inflammatory disease or a disease associated with extracellular matrix deposition or remodeling, such as fibrosis, cartilage degradation, arthritis, rheumatoid arthritis, scleroderma, scleroderma-associated interstitial lung disease, idiopathic pulmonary fibrosis, cirrhosis, psoriasis, atopic dermatitis, systemic cutaneous amyloidosis, primary cutaneous amyloidosis, pruritic inflammation, nodular prurigo and pain. Detailed Description

[0070] Before describing the present invention in detail, it should be understood that the present invention is not limited to the specific methods and experimental conditions in this specification, as such methods and conditions can be changed. Additionally, the terms used herein are for the purpose of describing specific embodiments only and are not intended to be limiting.

[0071] I. Definitions

[0072] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For the purposes of the present invention, the following terms are defined below.

[0073] The term "about", when used in conjunction with a numerical value, means to encompass a numerical value within a range that has a lower limit 10% less than the specified numerical value and an upper limit 10% greater than the specified numerical value.

[0074] The term "and / or", when used to connect two or more alternatives, should be understood to mean any one of the alternatives or any two or more of the alternatives.

[0075] As used herein, the term "comprising" or "including" means including the recited elements, integers or steps, but not excluding any other elements, integers or steps. In this context, when the term "comprising" or "including" is used, unless otherwise specified, the case consisting of the recited elements, integers or steps is also covered. For example, when referring to an antibody variable region "comprising" a specific sequence, it is also intended to cover an antibody variable region consisting of that specific sequence.

[0076] The term "interleukin-6 (IL-6) family" refers to a group of cytokines that can be produced by a variety of cells and play a role in signal transduction in autocrine, paracrine, and endocrine forms. The IL-6 cytokine family includes IL-6, IL-11, IL-27, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), and cardiotrophin-like cytokine factor 1 (CLCF 1), etc. Each member of the IL-6 family plays an important role in physiological regulation such as maintaining metabolism, inflammation, and immune homeostasis.

[0077] The term "oncostatin M (OSM)" belongs to the pleiotropic cytokines among the members of the IL-6 family and is mainly secreted by activated monocytes, macrophages, T lymphocytes, and dendritic cells. OSM has a variety of biological activities and plays a wide range of roles in hematopoiesis, cell growth and differentiation, inflammatory response, metabolic regulation, tumor formation, and immune regulation. OSM signals through two different receptor complexes. The OSM receptor is divided into two types, type I and type II. The type I OSM receptor (gp130 / LIFRβ) is a heterodimer composed of a gp130 molecule and a LIF receptor subunit, which can bind to both LIF and OSM to initiate signal transduction. The type II OSM receptor (gp130 / OSMRβ) is a heterodimer composed of a gp130 molecule and an OSM receptor β subunit. The type II receptor is specific for OSM and cannot bind LIF and other cytokines in the family.

[0078] As used herein, the term "OSM receptor β subunit" is also referred to as "OSMR", "OSMRβ", "OSMRB", "IL-31 receptor β subunit", "IL-31Rβ", "IL-31RB".

[0079] The term "interleukin-31" is also abbreviated as "IL-31", "IL31", and is an inflammatory cytokine that helps trigger cell-mediated immunity against pathogens. Activating STAT3 through the IL31 heterodimeric receptor composed of IL31RA and OSMR may also activate STAT1 and STAT5. IL31 has been identified as a major player in many chronic inflammatory diseases, including atopic dermatitis. It may have skin immune functions. IL-31 is produced by a variety of cells, including type 2 helper T cells (TH2). IL-31 sends signals through a receptor complex composed of IL31RA and oncostatin M receptor β (OSMRβ) expressed on immune cells and epithelial cells. These signals activate three pathways: the ERK1 / 2 MAP kinase, PI3K / AKT, and JAK1 / 2 signaling pathways.

[0080] The term "antibody" is used herein in the broadest sense and includes, but is not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), provided that they exhibit the desired antigen-binding activity. Antibodies can be intact antibodies of any isotype and subtype (e.g., IgM, IgD, IgG1, IgG2, IgG3, IgG4, IgE, IgA1, and IgA2) (e.g., having two full-length light chains and two full-length heavy chains). The monomer of an intact antibody is a four-peptide chain molecule formed by disulfide bonds linking two full-length light chains and two full-length heavy chains, also referred to as the monomer of an Ig molecule. The antibody monomer is the basic structure that makes up an antibody.

[0081] As used herein, an "isolated antibody" refers to an antibody that is substantially free of other antibodies (Abs) having different antigen specificities (e.g., an isolated antibody that specifically binds to the OSMRβ protein or an antigen-binding fragment thereof is substantially free of Abs that specifically bind to antigens other than the OSMRβ protein). In certain embodiments, the antibody is purified to greater than 95% or 99% purity, which is determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse-phase HPLC).

[0082] The term "antigen-binding fragment" refers to a part or segment of a whole or intact antibody that has fewer amino acid residues than the whole or intact antibody and is capable of binding an antigen or competing with the intact antibody (i.e., the intact antibody from which the antigen-binding fragment is derived) for binding to the antigen. Antigen-binding fragments can be prepared by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. Antigen-binding fragments include, but are not limited to, Fab, Fab’, F(ab’)2, Fv, single-chain Fv (scFv), single-chain Fab, diabody, single-domain antibody (sdAb, nanobody), camel Ig, Ig NAR, F(ab)′3 fragment, bis-scFv, (scFv)2, minibody, bifunctional antibody, trifunctional antibody, tetrafunctional antibody, disulfide-stabilized Fv protein ("dsFv"), bispecific single-chain Fv, trispecific single-chain Fv, single-chain Fab, bispecific Fab dimer (Fab2), trispecific Fab trimer (Fab3). The term also includes genetically engineered forms such as chimeric antibodies (e.g., humanized murine antibodies), heteroconjugate antibodies (e.g., bispecific antibodies) and their antigen-binding fragments. For a more detailed description, also see: Pierce Catalog and Handbook, 1994-1995 (Pierce Chemical Co., Rockford, IL); Kuby, Immunology, 3rd Edition, W.H. Freeman & Co., New York, 1997.

[0083] The terms "whole antibody", "full-length antibody", "complete antibody", and "intact antibody" are used interchangeably herein to refer to a glycoprotein comprising at least two heavy chains (HCs) and two light chains (LCs) interconnected by disulfide bonds. Each heavy chain consists of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region consists of three domains CH1, CH2, and CH3. Each light chain consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region consists of one domain CL. Mammalian heavy chains are classified as α, δ, ε, γ, and μ. Mammalian light chains are classified as λ or κ. Immunoglobulins containing α, δ, ε, γ, and μ heavy chains are classified as immunoglobulin (Ig) A, IgD, IgE, IgG, and IgM. A complete antibody forms a "Y" shape. The stem of the Y is composed of the second and third constant regions (and for IgE and IgM, the fourth constant region) of the two heavy chains bound together, and disulfide bonds (interchain) are formed in the hinge. Heavy chains γ, α, and δ have a constant region composed of three tandem (in a row) Ig domains, and a hinge region for increased flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The second and third constant regions are called the "CH2 domain" and the "CH3 domain", respectively. Each arm of the Y includes the variable region and the first constant region of a single heavy chain that binds to the variable and constant regions of a single light chain. The variable regions of the light and heavy chains are responsible for antigen binding.

[0084] The variable region of the light chain and the variable region of the heavy chain each contain a "framework" region interrupted by three hypervariable regions (also referred to as "complementary determining regions" or "CDRs"). The "complementary determining region" or "CDR region" or "CDR" or "hypervariable region" (which may be used interchangeably with the hypervariable region "HVR" herein) is the region in the variable domain of an antibody that is highly variable in sequence and forms structurally defined loops ("hypervariable loops") and / or contains antigen - contacting residues ("antigen - contact points"). The CDRs are primarily responsible for binding to the epitope. The CDRs of the heavy and light chains are commonly referred to as CDR1, CDR2, and CDR3, numbered sequentially from the N - terminus. The CDRs located within the variable domain of the heavy chain of the antibody are referred to as HCDR1, HCDR2, and HCDR3, while the CDRs located within the variable domain of the light chain of the antibody are referred to as LCDR1, LCDR2, and LCDR3. In a given amino acid sequence of a light - chain variable region or a heavy - chain variable region, the precise amino - acid sequence boundaries of each CDR can be determined using any one or a combination of a number of well - known antibody CDR assignment systems, including, for example: Chothia, based on the three - dimensional structure of the antibody and the topology of the CDR loops (Chothia et al. (1989) Nature 342:877 - 883, A1 - Lazikani et al., "Standard conformations for the canonical structures of immunoglobulins", Journal of Molecular Biology, 273, 927 - 948 (1997)), Kabat, based on antibody sequence variability (Kabat et al., Sequences of Proteins of Immunological Interest, 4th ed., U.S. Department of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath), Contact (University College London), the international hnMunoGeneTics database (IMGT) (world wide web: imgt.cines.fr / ), and the North CDR definition based on affinity propagation clustering using a large number of crystal structures.

[0085] However, it should be noted that the boundaries of the CDRs of the variable regions of the same antibody obtained based on different assignment systems may vary. That is, the CDR sequences of the same antibody variable region defined under different assignment systems are different. As shown in Table 1 of Antibody Structure and Function: The Basis for Engineering Therapeutics. Chiu ML, Goulet DR, Teplyakov A, Gilliland GL. Antibodies (Basel). 2019 Dec 3;8(4):55. doi: 10.3390 / antib8040055.

[0086] Therefore, when defining an antibody with a specific CDR sequence according to the present invention, the scope of the antibody also encompasses such an antibody, the variable region sequence of which contains the specific CDR sequence, but the claimed CDR boundaries thereof are different from the specific CDR boundaries defined by the present invention due to the application of different schemes (such as different assignment system rules or combinations).

[0087] The CDRs of the antibodies of the present invention can be artificially evaluated and the boundaries determined according to any scheme or combination thereof in the art. Unless otherwise specified, in the present invention, the term "CDR" or "CDR sequence" encompasses the CDR sequences determined in any of the above ways.

[0088] The sequences of the framework regions of different light or heavy chains are relatively conserved within a species (such as humans). The framework region of an antibody (which is the combined framework region of the component light and heavy chains) is used to localize and align the CDRs in three-dimensional space. The CDRs are mainly responsible for binding to the epitope of the antigen. Antibodies with different specificities (i.e., different combination sites for different antigens) have different CDRs. Although the CDRs are different between antibodies, only a limited number of amino acid positions within the CDRs are directly involved in antigen binding. These positions within the CDRs are called specificity-determining residues (SDRs).

[0089] A "monoclonal antibody" is an antibody produced by a single clone of B lymphocytes or by a cell in which the light and heavy chain genes of a single antibody have been transfected. Monoclonal antibodies are produced by methods known to those skilled in the art, such as by preparing hybrid antibody-forming cells by fusing myeloma cells with immune spleen cells.

[0090] "Fv" is the smallest antibody fragment that contains the complete antigen-binding site. In one embodiment, the dimeric Fv species consists of a dimer of a heavy-chain variable domain and a light-chain variable domain in tight non-covalent association. In the single-chain Fv (scFv) species, a heavy-chain variable domain and a light-chain variable domain can be covalently linked by a flexible peptide linker such that the light and heavy chains can associate in a "dimeric" structure similar to that of the dimeric Fv species. In this configuration, the three hypervariable regions (HVRs) of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. The six HVRs together confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three HVRs specific for the antigen) has the ability to recognize and bind the antigen, but with lower affinity than the intact binding site.

[0091] The Fab fragment contains the heavy-chain variable domain and the light-chain variable domain and also contains the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. The Fab′ fragment differs from the Fab fragment in that several residues, including one or more cysteines from the antibody hinge region, are added to the carboxyl terminus of the heavy-chain CH1 domain. Fab′-SH is the name used herein for Fab′, where the cysteine residue of the constant domain bears a free thiol group. The F(ab′)2 antibody fragment was originally generated as pairs of Fab′ fragments with hinge cysteines between them.

[0092] The terms "specifically bind" or "bind", when used in reference to an antigen and an antibody, mean that the antibody forms a complex with the antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds an antigen are well known in the art and include, for example, surface plasmon resonance assays, MSD assays (Estep, P. et al., High throughput solution-based measurement of antibody-antigen affinity and epitope binning, MAbs, 2013.5(2): p. 270-278), ForteBio affinity assays (Estep, P et al., High throughput solution Based measurement of antibody-antigen affinity and epitope binning. MAbs, 2013.5(2): p. 270-8), etc.

[0093] "Affinity" refers to the strength of the sum of all non-covalent interactions between a single binding site of a molecule (such as an antibody) and its binding partner (such as an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity reflecting the 1:1 interaction between the members of a binding pair (such as an antibody and an antigen). The affinity of molecule X for its partner Y is typically expressed by the binding dissociation equilibrium constant (K D ). Affinity can be measured by conventional methods known in the art, including those known in the prior art and described herein.

[0094] As used herein, the term "variant" refers to a heavy chain variable region or a light chain variable region that has been modified by at least one, such as 1, 2, or 3 amino acid substitutions, deletions, or additions, wherein the modified antigen-binding protein containing the heavy chain or light chain variant substantially retains the biological characteristics of the antigen-binding protein before modification. In one embodiment, the antigen-binding protein containing the variant heavy chain variable region or light chain variable region sequence retains 60%, 70%, 80%, 90%, 100% of the biological characteristics of the antigen-binding protein before modification. It should be understood that each heavy chain variable region or light chain variable region can be modified alone or in combination with another heavy chain variable region or light chain variable region. The antigen-binding proteins of the present disclosure comprise heavy chain variable region amino acid sequences that are 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% homologous to the heavy chain variable region amino acid sequences described herein. The antigen-binding proteins of the present disclosure include light chain variable region amino acid sequences that are 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% homologous to the light chain variable region amino acid sequences described herein. The percentage homology can be over the entire heavy chain variable region and / or the entire light chain variable region, or the percentage homology can be limited to the framework region, and the sequences corresponding to the CDRs have 100% identity to the CDRs disclosed herein within the heavy chain variable region and / or the light chain variable region. As used herein, the term "CDR variant" refers to a CDR that has been modified by at least one, such as 1, 2, or 3 amino acid substitutions, deletions, or additions, wherein the modified antigen-binding protein containing the CDR variant substantially retains the biological characteristics of the antigen-binding protein before modification. In one embodiment, the antigen-binding protein containing the variant CDR retains 60%, 70%, 80%, 90%, 100% of the biological characteristics of the antigen-binding protein before modification. It should be understood that each CDR that can be modified can be modified alone or in combination with another CDR. In one embodiment, the modification is a substitution, particularly a conservative substitution.

[0095] As used interchangeably herein, "polynucleotide" or "nucleic acid" refers to a nucleotide chain of any length and includes DNA and RNA. Nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate capable of being incorporated into a chain by DNA or RNA polymerase.

[0096] The sequence identity between sequences is calculated as follows.

[0097] To determine the percent identity between two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of the first and second amino acid or nucleic acid sequences for optimal alignment or non-homologous sequences can be discarded for comparison purposes). In a preferred embodiment, for comparison purposes, the length of the reference sequence being aligned is at least 30%, preferably at least 40%, more preferably at least 50%, 60% and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence. Subsequently, the amino acid residues or nucleotides at the corresponding amino acid positions or nucleotide positions are compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide at the corresponding position in the second sequence, then the molecules are identical at that position.

[0098] Sequence comparison and calculation of percent identity between two sequences can be achieved using a mathematical algorithm. In a preferred embodiment, the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444 - 453) algorithm in the GAP program that has been integrated into the GCG software package (available at http: / / www.gcg.com) is used, using the Blossum 62 matrix or PAM250 matrix and gap weights 16, 14, 12, 10, 8, 6 or 4 and length weights 1, 2, 3, 4, 5 or 6 to determine the percent identity between two amino acid sequences. In yet another preferred embodiment, the GAP program in the GCG software package (available at http: / / www.gcg.com) is used, using the NWSgapdna.CMP matrix and gap weights 40, 50, 60, 70 or 80 and length weights 1, 2, 3, 4, 5 or 6 to determine the percent identity between two nucleotide sequences. A particularly preferred set of parameters (and a set of parameters that should be used unless otherwise stated) is the Blossum 62 scoring matrix with a gap penalty of 12, a gap extension penalty of 4 and a frameshift gap penalty of 5.

[0099] It is also possible to use a PAM120 weighted residue table, a gap length penalty of 12, and a gap penalty of 4), and to determine the percent identity between two amino acid sequences or nucleotide sequences using the E. Meyers and W. Miller algorithm ((1989) CABIOS, 4: 11-17) that has been incorporated into the ALIGN program (version 2.0).

[0100] Additionally or alternatively, the nucleic acid and protein sequences described herein can further be used as "query sequences" to perform a search against public databases to, for example, identify other family member sequences or related sequences.

[0101] As used herein, "vector" refers to a construct that is capable of delivering one or more genes or sequences of interest into a host cell and preferably expressing the gene or sequence in the host cell. Examples of vectors include, but are not limited to, viral vectors, naked DNA or RNA expression vectors, plasmids, cosmids or phage vectors, DNA or RNA expression vectors associated with cationic condensing agents, DNA or RNA expression vectors encapsulated in liposomes, and certain eukaryotic cells, such as producer cells.

[0102] In the present invention, the terms "host cell", "host cell line" and "host cell culture" are used interchangeably and refer to a cell into which exogenous nucleic acid has been introduced, including progeny of such cells. Host cells include "transformants" and "transformed cells", which include primary transformed cells and progeny derived therefrom, regardless of the number of passages. The progeny may not be completely identical in nucleic acid content to the parental cell, but may contain mutations. This includes mutant progeny having the same function or biological activity as the cells screened or selected in the initially transformed cell.

[0103] The present invention also relates to a method for producing a monoclonal antibody, the method comprising culturing the host cell of the present invention to produce the monoclonal antibody described above of the present invention.

[0104] As used herein, "subject", "individual" or "patient" refers to an animal, preferably a mammal, more preferably a human, in need of alleviation, prevention and / or treatment of a disease or disorder such as a viral infection. Mammals also include, but are not limited to, farm animals, racing animals, pets, primates, horses, dogs, cats, mice and rats. The term includes human subjects having a disease or at risk of having a disease. In the present invention, administering the antibody, pharmaceutical composition or article of the present invention to a subject in need thereof refers to administering an effective amount of the antibody or pharmaceutical composition or article, etc.

[0105] As used in the present invention, the term "effective amount" refers to the amount of a drug or agent that elicits a biological or pharmaceutical response in a tissue, system, animal, or human being, such as that sought by a researcher or clinician. In addition, the term "therapeutically effective amount" means an amount that causes an improvement in the treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or condition, compared to a corresponding subject who has not received that amount. The term also includes within its scope an amount that effectively enhances normal physiological functions.

[0106] II. OSMR-binding antibodies of the present invention

[0107] The present invention provides antibodies against OSMRβ and antigen-binding fragments thereof. The terms "antibody that binds to OSMRβ protein", "antibody that binds to OSMRβ", "antibody against OSMRβ protein", "antibody that binds to OSMR protein", "antibody that binds to OSMR", "antibody against OSMR protein", "OSMR-binding antibody", "isolated antibody that binds to OSMRβ protein", "antibody against OSMRβ", "antibody against OSMR", "OSMRβ protein antibody" are used interchangeably herein and refer to an antibody of the present invention that is capable of binding to OSMRβ protein with sufficient affinity such that the antibody can be used as a prophylactic and / or therapeutic agent targeting OSMRβ protein.

[0108] The antibodies and antigen-binding fragments of the present invention specifically bind to OSMRβ protein with high affinity and comprise

[0109] (a) three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 1 and three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 2; or a variant having single or multiple CDRs with no more than 2 amino acid changes in each CDR region compared to the above six CDR regions;

[0110] (b) three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 9 and three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 10; or a variant having single or multiple CDRs with no more than 2 amino acid changes in each CDR region compared to the above six CDR regions;

[0111] (c) three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 17 and three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 18; or a variant having single or multiple CDRs with no more than 2 amino acid changes in each CDR region compared to the above six CDR regions;

[0112] (d) The three CDRs in the amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 25 and the three CDRs in the amino acid sequence of the light chain variable region shown in SEQ ID NO: 26; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0113] (e) The three CDRs in the amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 33 and the three CDRs in the amino acid sequence of the light chain variable region shown in SEQ ID NO: 34; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0114] (f) The three CDRs in the amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 41 and the three CDRs in the amino acid sequence of the light chain variable region shown in SEQ ID NO: 42; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0115] (g) The three CDRs in the amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 49 and the three CDRs in the amino acid sequence of the light chain variable region shown in SEQ ID NO: 50; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0116] (h) The three CDRs in the amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 57 and the three CDRs in the amino acid sequence of the light chain variable region shown in SEQ ID NO: 58; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0117] (i) The three CDRs in the amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 65 and the three CDRs in the amino acid sequence of the light chain variable region shown in SEQ ID NO: 66; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0118] (j) The three CDRs in the amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 73 and the three CDRs in the amino acid sequence of the light chain variable region shown in SEQ ID NO: 74; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0119] (k) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 81 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 82; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0120] (l) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 89 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 90; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0121] (m) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 97 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 98; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0122] (n) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 105 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 106; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0123] (o) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 113 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 114; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0124] (p) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 121 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 122; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions; or

[0125] (q) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 129 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 130; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions;

[0126] Wherein the amino acid change is an addition, deletion or substitution of an amino acid, for example, the amino acid change is a conservative amino acid substitution.

[0127] In some embodiments, the OSMRβ protein antibody of the invention binds to mammalian OSMRβ protein, such as human OSMRβ protein.

[0128] In some embodiments, the OSMRβ protein antibody of the invention has one or more of the following properties:

[0129] (a) Measured by biolayer interferometry, having a binding dissociation equilibrium constant K of 10 -7 M or less, such as 10 -8 M or less, 10 -9 M or less, 10 -10 M or less, 10 -11 M or less, 10 -12 M or less, or 10 -13 M or less and binds to human OSMRβ protein; D binds to human OSMRβ protein;

[0130] (b) Measured in SW1271-STAT3-Luc cells, blocking OSM-mediated signal transduction with an IC50 of less than about 650 ng / mL, such as less than about 550 ng / mL, less than about 500 ng / mL, less than about 450 ng / mL, less than about 350 ng / mL, less than about 250 ng / mL, less than about 150 ng / mL, less than about 100 ng / mL; and

[0131] (c) Measured in SW1271-STAT3-Luc cells, blocking IL-31-mediated signal transduction with an IC50 of less than about 800 ng / mL, such as less than about 700 ng / mL, less than about 600 ng / mL, less than about 500 ng / mL, less than about 400 ng / mL, less than about 350 ng / mL, less than about 300 ng / mL, less than about 250 ng / mL.

[0132] In some embodiments, the OSMRβ protein antibody or antigen-binding fragment of the invention comprises

[0133] (a) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 1 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 2 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0134] (b) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 9 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 10 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0135] (c) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 17 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 18 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0136] (d) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 25 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 26 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0137] (e) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 33 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 34 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0138] (f) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 41 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 42 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0139] (g) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 49 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 50 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0140] (h) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 57 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 58 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0141] (i) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 65 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 66 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0142] (j) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 73 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 74 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0143] (k) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 81 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 82 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0144] (l) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 89 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 90 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0145] (m) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 97 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 98 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0146] (n) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 105 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 106 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0147] (o) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 113 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 114 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto;

[0148] (p) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 121 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 122 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; or

[0149] (q) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 129 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 130 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto.

[0150] Preferably, the amino acid change does not occur in the CDR region.

[0151] In some embodiments, the anti-OSMRβ protein antibody of the present invention comprises an Fc region, and the Fc region is derived from IgG, such as IgG1, IgG2, IgG3 or IgG4. In some embodiments, the Fc region is derived from IgG1 or IgG4. In some embodiments, the Fc region is derived from human IgG1 or human IgG4.

[0152] In some embodiments, the amino acid changes described herein include amino acid substitutions, insertions or deletions. Preferably, the amino acid changes described herein are amino acid substitutions, preferably conservative substitutions. A conservative substitution means that one amino acid is substituted by another amino acid within the same category, for example, an acidic amino acid is substituted by another acidic amino acid, a basic amino acid is substituted by another basic amino acid, or a neutral amino acid is substituted by another neutral amino acid. Exemplary substitutions are shown in Table A below:

[0153] Table A. Exemplary amino acid substitutions

[0154] Original residue Exemplary substitution Preferred substitution Ala(A) Val; Leu; Ile Val Arg(R) Lys; Gln; Asn Lys Asn(N) Gln; His; Asp, Lys; Arg Gln Asp(D) Glu; Asn Glu Cys(C) Ser; Ala Ser Gln(Q) Asn; Glu Asn Glu(E) Asp; Gln Asp Gly(G) Ala Ala His(H) Asn; G1n; Lys; Arg Arg Ile(I) Leu, Val; Met; Ala; Phe; norleucine Leu Leu(L) Norleucine; Ile; Val; Met; Ala; Phe Ile Lys(K) Arg; Gln; Asn Arg Met(M) Leu; Phe; Ile Leu Phe(F) Trp; Leu; Val; Ile; Ala; Tyr Tyr Pro(P) Ala Ala Ser(S) Thr Thr Thr(T) Val; Ser Ser Trp(W) Tyr; Phe Tyr Tyr(Y) Trp; Phe; Thr; Ser Phe Val(V) Ile; Leu; Met; Phe; Ala; norleucine Leu

[0155] In a preferred embodiment, the amino acid changes described in the present invention occur in regions outside the CDR (e.g., in the FR). More preferably, the amino acid changes described in the present invention occur in the Fc region. In some embodiments, an anti-OSMRβ protein antibody comprising an Fc domain containing one or more mutations that enhance or reduce the binding of the antibody to the FcRn receptor, for example, at acidic pH compared to neutral pH, is provided. For example, the present invention includes mutations in the CH2 or C of the Fc domain HRegion 3 contains a mutated anti-OSMRβ protein antibody, wherein one or more of the mutations enhance the affinity of the Fc domain for FcRn in an acidic environment (such as in an endosome with a pH in the range of about 5.5 to about 6.0). Such mutations can result in an increase in the serum half-life of the antibody when administered to an animal. Non-limiting examples of such Fc modifications include, for example: modifications at position 250 (such as E or Q), positions 250 and 428 (such as L or F), position 252 (such as L / Y / F / W or T), position 254 (such as S or T), and position 256 (such as S / R / Q / E / D or T); or modifications at position 428 and / or 433 (such as H / L / R / S / P / Q or K) and / or position 434 (such as A, W, H, F, or Y [N434A, N434W, N434H, N434F, or N434Y]); or modifications at position 250 and / or 428; or modifications at position 307 or 308 (such as 308F, V308F) and position 434. In one embodiment, the modifications include 428L (such as M428L) and 434S (such as N434S) modifications; 428L, 259I (such as V259I), and 308F (such as V308F) modifications; 433K (such as H433K) and 434 (such as 434Y) modifications; 252, 254, and 256 (such as 252Y, 254T, and 256E) modifications; 250Q and 428L modifications (such as T250Q and M428L); and 307 and / or 308 modifications (such as 308F or 308P). In yet another embodiment, the modifications include 265A (such as D265A) and / or 297A (such as N297A) modifications.

[0156] For example, the present invention includes an anti-OSMRβ protein antibody containing an Fc domain, the Fc domain comprising one pair (group) or more pairs (groups) of mutations selected from the following: 250Q and 248L (such as T250Q and M248L); 252Y, 254T, and 256E (such as M252Y, S254T, and T256E); 428L and 434S (such as M428L and N434S); 257I and 311I (such as P257I and Q311I); 257I and 434H (such as P257I and N434H); 376V and 434H (such as D376V and N434H); 307A, 380A, and 434A (such as T307A, E380A, and N434A); and 433K and 434F (such as H433K and N434F). Any possible combination of the foregoing Fc domain mutations and other mutations within the antibody variable domains disclosed herein is included within the scope of the present invention.

[0157] In some embodiments, the OSMRβ protein antibodies provided herein are modified to increase or decrease the degree of their glycosylation. Addition or deletion of glycosylation sites of the OSMRβ protein antibodies can be readily achieved by altering the amino acid sequence so as to create or remove one or more glycosylation sites. When the OSMRβ protein antibody comprises an Fc region, the sugars linked to the Fc region can be modified. In some applications, modification to remove unwanted glycosylation sites can be useful, for example, removal of fucose moieties to enhance antibody-dependent cell cytotoxicity (ADCC) function (see Shield et al. (2002) JBC 277:26733). In other applications, galactosylation modification can be carried out to modulate complement-dependent cytotoxicity (CDC). In certain embodiments, one or more amino acid modifications can be introduced into the Fc region of the OSMRβ protein antibodies provided herein to generate Fc region variants so as to enhance, for example, the effectiveness of the OSMRβ protein antibodies of the present invention in preventing and / or treating diseases.

[0158] In some embodiments, the present invention provides multispecific antibodies comprising portions of the OSMRβ protein antibodies of the present invention, e.g., bispecific antibodies or trispecific antibodies.

[0159] In some embodiments, the epitopes bound by the bispecific antibody are from the same antigen. In other embodiments, the epitopes bound by the bispecific antibody are from two different antigens. Methods for constructing bispecific antibodies are known in the art. For example, the recombinant production of bispecific antibodies is based on the co-expression of two pairs of immunoglobulin heavy-chain and light-chain.

[0160] III. Nucleic Acids of the Present Invention and Host Cells Comprising the Same

[0161] In one aspect, the present invention provides nucleic acids encoding any of the above OSMRβ protein antibodies or antigen-binding fragments thereof or any of their chains. In one embodiment, a vector comprising the nucleic acid is provided. In one embodiment, the vector is an expression vector. In one embodiment, a host cell comprising the nucleic acid or the vector is provided. In one embodiment, the host cell is eukaryotic. In another embodiment, the host cell is selected from yeast cells, mammalian cells (e.g., CHO cells or HEK 293 cells) or other cells suitable for preparing antibodies or antigen-binding fragments thereof. In another embodiment, the host cell is prokaryotic.

[0162] For example, the nucleic acid of the present invention comprises a nucleic acid encoding an amino acid sequence shown in any one of SEQ ID NO: 1, 2, 9, 10, 17, 18, 25, 26, 33, 34, 41, 42, 49, 50, 57, 58, 65, 66, 73, 74, 81, 82, 89, 90, 97, 98, 105, 106, 113, 114, 121, 122, 129, 130, or a nucleic acid encoding an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence shown in any one of SEQ ID NO: 1, 2, 9, 10, 17, 18, 25, 26, 33, 34, 41, 42, 49, 50, 57, 58, 65, 66, 73, 74, 81, 82, 89, 90, 97, 98, 105, 106, 113, 114, 121, 122, 129, 130.

[0163] The present invention also encompasses a nucleic acid that hybridizes to the following nucleic acid under stringent conditions or a nucleic acid that encodes a polypeptide sequence having one or more amino acid substitutions (e.g., conservative substitutions), deletions or insertions compared to the following nucleic acid: a nucleic acid comprising a nucleic acid sequence encoding an amino acid sequence shown in any one of SEQ ID NO: 1, 2, 9, 10, 17, 18, 25, 26, 33, 34, 41, 42, 49, 50, 57, 58, 65, 66, 73, 74, 81, 82, 89, 90, 97, 98, 105, 106, 113, 114, 121, 122, 129, 130; or a nucleic acid comprising a nucleic acid sequence encoding an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence shown in any one of SEQ ID NO: 1, 2, 9, 10, 17, 18, 25, 26, 33, 34, 41, 42, 49, 50, 57, 58, 65, 66, 73, 74, 81, 82, 89, 90, 97, 98, 105, 106, 113, 114, 121, 122, 129, 130.

[0164] In one embodiment, one or more vectors comprising the nucleic acid are provided. In one embodiment, the vector is an expression vector, such as a eukaryotic expression vector. Vectors include but are not limited to viruses, plasmids, cosmids, λ phages or yeast artificial chromosomes (YACs).

[0165] Once an expression vector or DNA sequence for expression has been prepared, the expression vector can be transfected or introduced into a suitable host cell. A variety of techniques can be used to achieve this purpose, for example, protoplast fusion, calcium phosphate precipitation, electroporation, retroviral transduction, viral transfection, gene gun, lipid-based transfection or other conventional techniques. In the case of protoplast fusion, the cells are cultivated in a medium and suitable activity is screened. Methods and conditions for culturing the resulting transfected cells and for recovering the resulting antibody molecules are known to those skilled in the art and can be varied or optimized based on the methods known from the present specification and the prior art, depending on the particular expression vector and mammalian host cell used.

[0166] In addition, cells that have stably incorporated DNA into their chromosomes can be selected by introducing one or more markers that allow selection of the transfected host cells. The markers can, for example, provide prototrophy to auxotrophic hosts, biocide resistance (e.g., antibiotics) or heavy metal (such as copper) resistance, etc. Selectable marker genes can be directly linked to the DNA sequence to be expressed or introduced into the same cells by co-transformation. Additional elements may also be required for optimal synthesis of mRNA. These elements can include splice signals, as well as transcriptional promoters, enhancers and termination signals.

[0167] In one embodiment, a host cell comprising the polynucleotide of the present invention is provided. In some embodiments, a host cell comprising the expression vector of the present invention is provided. In some embodiments, the host cell is selected from yeast cells, mammalian cells, or other cells suitable for preparing antibodies. Suitable host cells include prokaryotic microorganisms such as Escherichia coli. The host cell can also be a eukaryotic microorganism such as filamentous fungi or yeast, or various eukaryotic cells such as insect cells. Vertebrate cells can also be used as hosts. For example, mammalian cell lines that have been modified to be suitable for suspension growth can be used. Examples of useful mammalian host cell lines include the SV40-transformed monkey kidney CV1 line (COS-7); human embryonic kidney lines (HEK293 or 293F cells), baby hamster kidney cells (BHK), monkey kidney cells (CV1), African green monkey kidney cells (VERO-76), human cervical cancer cells (HELA), dog kidney cells (MDCK), Buffalo rat liver cells (BRL 3A), human lung cells (W138), human liver cells (Hep G2), Chinese hamster ovary cells (CHO cells), CHOS cells, NSO cells, myeloma cell lines such as Y0, NS0, P3X63, and Sp2 / 0, etc. A review of mammalian host cell lines suitable for producing proteins can be found, for example, in Yazaki and Wu, Methods in Molecular Biology, Volume 248 (edited by B.K.C. Lo, Humana Press, Totowa, NJ), pages 255-268 (2003). In a preferred embodiment, the host cell is a HEK293 cell or a CHO cell. For example, HEK 293-6E cells.

[0168] IV. Production and Purification of the OSMRβ Protein Antibody of the Present Invention

[0169] In one embodiment, the present invention provides a method for preparing an OSMRβ protein antibody, wherein the method comprises culturing a host cell comprising a nucleic acid encoding the OSMRβ protein antibody or an expression vector comprising the nucleic acid under conditions suitable for expressing the nucleic acid encoding the OSMRβ protein antibody, and optionally isolating the OSMRβ protein antibody. In a certain embodiment, the method further comprises recovering the OSMRβ protein antibody from the host cell (or host cell culture medium).

[0170] To recombinantly produce the OSMRβ protein antibody of the present invention, first, the nucleic acid encoding the OSMRβ protein antibody of the present invention is isolated and inserted into a vector for further cloning and / or expression in a host cell. Such nucleic acids are readily isolated and sequenced using conventional procedures, for example, by using oligonucleotide probes that can specifically bind to the nucleic acid encoding the OSMRβ protein antibody of the present invention.

[0171] The OSMRβ protein antibody of the present invention prepared as described herein can be purified by known prior art such as high performance liquid chromatography, ion exchange chromatography, gel electrophoresis, affinity chromatography, size exclusion chromatography, etc. The actual conditions used to purify a particular protein also depend on factors such as net charge, hydrophobicity, hydrophilicity, etc., and these are obvious to those skilled in the art. The purity of the OSMRβ protein antibody of the present invention can be determined by any one of a variety of well-known analytical methods, including size exclusion chromatography, gel electrophoresis, high performance liquid chromatography, etc.

[0172] V. Assay for the Activity of the OSMRβ Protein Antibody of the Present Invention

[0173] The OSMRβ protein antibody provided herein can be identified, screened, or characterized for its physical / chemical properties and / or biological activities by a variety of assays known in the art. On the one hand, the antigen-binding activity of the OSMRβ protein antibody of the present invention is tested, for example, by known methods such as ELISA. Methods known in the art can be used to determine the binding to the OSMRβ protein, and exemplary methods are disclosed herein. In some embodiments, surface plasmon resonance (SPR) or biolayer interferometry is used to determine the binding of the OSMRβ protein antibody of the present invention to the OSMRβ protein.

[0174] The present invention also provides an assay for identifying an OSMRβ protein antibody having biological activity. The biological activity can include, for example, measuring the blockade of OSMRβ-mediated interleukin-31 (IL-31) and oncostatin M (OSM) signaling using the SW1271-STAT3-Luc cell line.

[0175] VI. Drug Combinations and Pharmaceutical Preparations

[0176] In some embodiments, the present invention provides a composition comprising any of the OSMRβ protein antibodies described herein, preferably the composition is a pharmaceutical composition. In one embodiment, the composition further comprises a pharmaceutically acceptable excipient. In one embodiment, the composition (e.g., the pharmaceutical composition) comprises the OSMRβ protein antibody of the present invention, and a combination of one or more other therapeutic agents (e.g., chemotherapeutic drugs, tumor vaccines, antibodies that bind to specific antigens on tumor cells, antibodies that deplete tumor cells).

[0177] In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention comprises suitable pharmaceutically acceptable excipients, such as pharmaceutically acceptable carriers, pharmaceutically acceptable excipients known in the art, including buffers.

[0178] As used herein, "pharmaceutical carrier" includes any and all physiologically compatible solvents, dispersion media, isotonic agents, absorption delaying agents, and the like. Suitable pharmaceutical carriers for the present invention can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. When the pharmaceutical composition is administered intravenously, water is the preferred carrier. Aqueous saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, especially for injectable solutions. Suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, etc. For the use and application of excipients, see also "Handbook of Pharmaceutical Excipients", 5th Edition, R.C. Rowe, P.J. Seskey and S.C. Owen, Pharmaceutical Press, London, Chicago. If desired, the compositions may also contain minor amounts of wetting agents or emulsifying agents, or pH buffering agents. These compositions can be in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations, etc. Oral formulations may contain standard pharmaceutical carriers and / or excipients, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, saccharin.

[0179] A pharmaceutical formulation comprising the OSMRβ protein antibody described herein can be prepared by mixing the OSMRβ protein antibody of the present invention having the desired purity with one or more optional pharmaceutical excipients (Remington’s Pharmaceutical Sciences, 16th Edition, Osol, A. ed. (1980)), preferably in the form of a lyophilized formulation or an aqueous solution.

[0180] The pharmaceutical composition or formulation of the present invention may also contain more than one active ingredient, which are those required for the particular indication being treated, preferably those having complementary activities that do not adversely affect each other. When used for the treatment of cancer, such active ingredients include, but are not limited to, anti-cancer agents and chemotherapeutic agents; when used for the treatment of infectious diseases, such active ingredients include, but are not limited to, antiviral agents and antibiotics. The active ingredients are suitably combined in an amount effective for the intended use.

[0181] Sustained release formulations can be prepared. Suitable examples of sustained release formulations include semi-permeable matrices of solid hydrophobic polymers containing the OSMRβ protein antibody of the present invention, which matrices are in the form of shaped articles, such as films or microcapsules.

[0182] VII. Combination Products or Kits

[0183] In some embodiments, the present invention also provides a combination product comprising at least one OSMRβ protein antibody of the present invention or an antigen-binding fragment thereof, or further comprising one or more other therapeutic agents (e.g., other anti-itch, anti-inflammatory, and anti-fibrotic drugs, etc.).

[0184] In some embodiments, two or more components in the combination product can be administered to a subject sequentially, separately, or simultaneously in combination.

[0185] In some embodiments, the present invention also provides a kit comprising an OSMRβ protein antibody, a pharmaceutical composition, or a combination product of the present invention, and optionally a package insert for guiding administration.

[0186] In some embodiments, the present invention also provides a pharmaceutical product comprising an OSMRβ protein antibody, a pharmaceutical composition, or a combination product of the present invention. Optionally, the pharmaceutical product further includes a package insert for guiding administration.

[0187] VIII. Preventive and / or therapeutic uses of the OSMRβ protein antibody of the present invention

[0188] The present invention provides a method for preventing a disease or disorder associated with OSMRβ-mediated signal transduction in a subject, which comprises administering an antibody of the present invention to the subject.

[0189] In some embodiments, the OSMR-binding antibody of the present invention and its antigen-binding fragment are used, for example, to block OSMRβ-mediated signal transduction. In some embodiments, a doctor can administer the OSMR-binding antibody or its antigen-binding fragment of the present invention alone or in combination with other therapeutic agents (sequentially or simultaneously) to enhance, for example, the anti-itch, anti-inflammatory, and anti-fibrotic activities in a patient.

[0190] The diseases for which the OSMR-binding antibody and antigen-binding fragment thereof of the present invention can be used for prevention and / or treatment include, but are not limited to, inflammation, pain, pruritus, prurigo nodularis, dermatitis, asthma, autoimmune diseases, tumor-associated autoimmune diseases, cartilage inflammation, fibrosis (including, but not limited to, pulmonary fibrosis and skin fibrosis), fibrotic diseases, chronic obstructive pulmonary disease (COPD), interstitial pneumonia, abnormal collagen deposition, systemic cutaneous amyloidosis, primary cutaneous amyloidosis, Behcet's disease, nasal polyposis, liver cirrhosis, cartilage degeneration, bone degradation, arthritis, rheumatoid arthritis, juvenile arthritis, juvenile rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemically-onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile reactive arthritis, juvenile Reiter's syndrome, SEA syndrome (seronegative, enthesopathy, arthropathy syndrome), juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, pauciarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemically-onset rheumatoid arthritis, ankylosing spondylitis, enteropathic arthritis, reactive arthritis, Reiter's syndrome, SEA syndrome (seronegative, enthesopathy, arthropathy syndrome), dermatomyositis, psoriatic arthritis, scleroderma, scleroderma-associated interstitial lung disease, vasculitis, myelitis, polymyositis, dermatomyositis, polyarteritis nodosa, Wegener's granulomatosis, arteritis, polymyalgia rheumatica, sarcoidosis, scleroderma, sclerosis, primary biliary sclerosis, sclerosing cholangitis, Sjogren's syndrome, psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, dermatitis, atopic dermatitis, atherosclerosis, lupus, Still's disease, systemic lupus erythematosus (SLE), myasthenia gravis, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, steatorrhea, multiple sclerosis (MS), asthma, COPD, sinusitis, nasal polyps with sinusitis, eosinophilic esophagitis, eosinophilic bronchitis, bronchitis, Guillain-Barre disease, type I diabetes, thyroiditis (such as Graves' disease), Addison's disease, Reynaud's phenomenon, autoimmune hepatitis, GVHD, transplant rejection, kidney damage, cardiovascular diseases, infections, sepsis, HIV infection, trauma, allograft nephropathy, IgA nephropathy,Diabetic nephropathy, diabetic retinopathy, macular degeneration, biliary atresia, congestive heart failure, atherosclerosis, restenosis, radiation-induced fibrosis, chemically-induced fibrosis, burns, surgical trauma, glomerulosclerosis, and the like. In a preferred embodiment, an autoimmune disorder, an inflammatory disorder, or a disorder associated with extracellular matrix deposition or remodeling is fibrosis, cartilage degeneration, arthritis, rheumatoid arthritis, scleroderma, scleroderma-associated interstitial lung disease, idiopathic pulmonary fibrosis, cirrhosis, psoriasis, atopic dermatitis, systemic cutaneous amyloidosis, primary cutaneous amyloidosis, inflammation, pruritic inflammation, prurigo nodularis, and pain.

[0191] The OSMR-binding antibody or antigen-binding fragment thereof of the present invention can be administered without other therapeutic treatment, i.e., as a monotherapy (single therapy). Alternatively, treatment with the OSMR-binding antibody or antigen-binding fragment thereof of the present invention can include at least one other therapeutic treatment (combination therapy), such as another anti-itch agent, anti-inflammatory agent, and anti-fibrotic agent.

[0192] The following examples are described to assist in the understanding of the present invention. It is not intended and should not in any way be construed as limiting the scope of protection of the present invention.

[0193] Examples

[0194] The present invention generally described herein will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended to limit the scope of the invention. These examples are not intended to represent that the following experiments are all or only the experiments conducted.

[0195] Example 1 Obtaining of Mice with High Titer Anti-Recombinant Human OSMRβ Protein

[0196] 1.1. Preparation of Immunogen:

[0197] High-purity human OSMRβ-Fc protein (hereinafter also referred to as "huOSMRβ-Fc" protein, the amino acid sequence of which is shown in SEQ ID NO: 137) was prepared for mouse immunization.

[0198] 1.2. Mouse Immunization:

[0199] Eight-week-old mice (AceMouse TM , a fully human antibody transgenic mouse independently developed by Shanghai Tajin Biotechnology Co., Ltd.) were immunized with the huOSMRβ-Fc protein prepared in Example 1.1. All mice were housed in a SPF-level environment, and the health status and body weight of the mice were observed before immunization.

[0200] The primary immunization was carried out by subcutaneously injecting 100 μl of an emulsion of 50 μg of the immunogenic protein huOSMRβ-Fc and Freund's complete adjuvant (Sigma-Aldrich) into mice. The first, second, and third booster immunizations were performed 10, 20, and 30 days after the primary immunization, respectively, with each mouse receiving a subcutaneous injection of 100 μl of an emulsion containing 40 μg of the immunogenic protein huOSMRβ-Fc and Freund's incomplete adjuvant (Sigma-Aldrich). The terminal immunization was carried out 10 days after the third booster immunization by intraperitoneally injecting 50 μg of the immunogenic protein huOSMRβ-Fc into each mouse. Blood was collected 7 days after the terminal immunization, and mouse sera were harvested. The anti-huOSMRβ antibody levels in the mouse sera were detected by ELISA.

[0201] 1.3. Detection of anti-huOSMRβ antibody levels by ELISA:

[0202] Human OSMRβ-His protein (hereinafter also referred to as "huOSMRβ-His" protein, whose amino acid sequence is shown in SEQ ID NO: 138) was prepared.

[0203] 100 μl of 100 ng OSMRβ-his protein (at a concentration of 1 μg / ml) was added to each well of a 96-well ELISA plate for coating, and then the 96-well plate was sealed with plastic wrap and incubated overnight at 4°C. The next day, the supernatant was discarded, the 96-well plate was inverted on absorbent paper to blot dry, washed once with PBS, and then blotted dry again on absorbent paper. 200 μl of 10% PBSF / well (10% PBSF is PBS containing 10% FBS) was added, and the plate was sealed with plastic wrap and incubated at 37°C for 1 hour; then the supernatant was discarded and blotted dry on absorbent paper. The mouse sera obtained in Example 1.2 were diluted with PBS in a 3-fold gradient starting from the initial concentration, and 100 μl / well was added and incubated at room temperature for 1 hour; then the supernatant was discarded and blotted dry on absorbent paper; washed 3 times with PBST (PBST is freshly prepared PBS containing 0.05% Tween-20 (Sigma-Aldrich)) and blotted dry on absorbent paper. Then, 50 μl of HRP goat anti-mouse IgG (Biolegend) diluted 1:1000 with PBS containing 5% FBS was added to each well and incubated at room temperature for 1 hour; washed 3 times with PBST and blotted dry on absorbent paper. 50 μl of TMB (Thermo Scientific) was added to each well for color development for 4 min; then 50 μl of 0.5 M sulfuric acid was added to each well to terminate the reaction. The plate was placed on a multi-functional microplate reader (Envision 2105, PerkinElmer), and the optical absorption was detected at a wavelength of 450 nm to obtain the anti-huOSMRβ antibody titer in the serum.

[0204] Select mice with the anti-huOSMRβ antibody titer in serum reaching the standard for subsequent hybridoma fusion experiments.

[0205] Example 2 Preparation and Sequencing of Anti-OSMRβ Antibody

[0206] The anti-OSMRβ antibody of the present invention can be prepared by any of the methods described below. However, the preparation method of the anti-OSMRβ antibody of the present invention is not limited to the method described in this example, and can also be prepared by other methods known in the art.

[0207] 2.1. Preparation by Hybridoma Method:

[0208] Take the spleen of mice with the anti-huOSMRβ antibody titer in serum reaching the standard, and isolate splenocytes. Treat the splenocytes with erythrocyte lysate, resuspend, and count. Mix the splenocytes with sp2 / 0 myeloma cells at a ratio of 1:1 to 10:1, and centrifuge. After centrifugation, resuspend the cells in electrofusion solution and perform fusion at no less than 2e7 cells / ml (NEPA GENE: ECFG21). Resuspend the fused cells in HAT medium and plate them in 96-well plates at 50,000 cells / well of splenocytes. Culture in a 37°C carbon dioxide incubator for 10 days. Observe the cell growth status every day during this period. Add 100 μL of HAT medium on the third day; aspirate all the medium on the sixth day and then add 100 μL of fresh HAT medium; change to medium without HAT on the eighth day. On the 11th day, take the cell culture supernatant from each well of the 96-well plate for blocking experiment detection. Screen multiple anti-OSMRβ monoclonal antibodies with good blocking experiment detection results.

[0209] 2.2. Sorting of Single B Cells Specifically Recognizing OSMRβ

[0210] Pre-incubate the HuOSMRβ-his antigen with PE / R-Phycoerythrin Conjugation (Abcam: ab10291); then incubate with rabbit anti-His tag PE (AceMab) at 4°C overnight.

[0211] Take the spleen of mice with the anti-huOSMRβ antibody titer in serum reaching the standard, grind and isolate the splenocytes into single cells. Treat the splenocytes with erythrocyte lysate, resuspend, and count. Incubate the splenocytes with the antigen-antibody complex (i.e., HuOSMRβ-his antigen-rabbit anti-His tag PE). Sort out antigen-specific single B cells by FACS. Culture the single B cells, and take the cell culture supernatant for blocking experiment detection. Screen multiple anti-OSMRβ monoclonal antibodies with good blocking experiment detection results.

[0212] 2.3 Sequence of Anti-OSMRβ Antibody

[0213] The names, variable regions, and complementarity-determining region (CDR) sequences (according to IMGT numbering) of the anti-OSMRβ monoclonal antibodies obtained through Examples 2.1 and 2.2 are shown in Table 1 below.

[0214] Table 1 Variable region and complementarity-determining region sequences of anti-OSMRβ monoclonal antibodies

[0215]

[0216]

[0217] Example 3 Affinity detection of anti-OSMRβ antibody

[0218] The antibodies obtained in Example 2 were used to detect the binding kinetics of the antibodies to HuOSMRβ-his protein by the method of Biolayer Interferometry (BLI).

[0219] The antibody to be tested was diluted to 60 nM, 30 nM, 15 nM, 7.5 nM, 3.75 nM, and 1.875 nM with buffer (PBS (10 mM pH 7.4) + 0.02% Tween + 0.2% BSA), and 200 μl / well was added to a 96-well plate. Then, HuOSMRβ-his was diluted to 4 μg / ml with buffer (PBS (10 mM pH 7.4) + 0.02% Tween + 0.2% BSA), and 200 μl / well was added to a 96-well plate (Gator). 250 μl of buffer (PBS (10 mM pH 7.4) + 0.02% Tween + 0.2% BSA) was added to each well in the MAX plate (Gator), and the probe was immersed in the well (soaked for at least 5 minutes before machine detection). The GatorPrime label-free biomolecular analyzer was used to detect the affinity. The specific procedure for detecting the affinity is as follows: buffer was added and run for 120 seconds; the antibody dilutions at the above concentrations were injected for 60 seconds respectively, and buffer was added and run for 120 seconds; the binding time was 240 seconds, the dissociation time was 300 seconds, and regeneration was performed for 5 seconds using deionized water + 10 mM glycine + 150 mM NaCl, (pH 1.75); neutralization was performed for 5 seconds using buffer, and the regeneration and neutralization were repeated 3 times. The association rate (Kon) and dissociation rate (Koff) were calculated using the simple one-to-one Langmuir binding model, and the equilibrium dissociation constant (K D ) was calculated as the ratio Koff / Kon.

[0220] The results of the antibody affinity detection are shown in Table 2 below.

[0221] Table 2 Results of antibody affinity detection for human OSMRβ protein

[0222]

[0223]

[0224] As can be seen from Table 2, all antibodies bind to human OSMRβ protein with high affinity.

[0225] Antibody OSM Blocking Experiment in Example 4

[0226] The pSTAT3-Luc plasmid (Yeasen Biotech) was transfected into the SW1271 cell line with high expression of IL31RA, GP130 and OSMRβ receptors to construct a stable transfected cell line, SW1271-STAT3-Luc cells. 50 μL containing 10 4 SW1271-STAT3-Luc cells were seeded in a 96-well plate and cultured overnight in a 37 °C CO2 incubator; then the anti-OSMRβ antibody obtained in Example 2 was serially diluted with an initial concentration of 10 μg / mL and diluted three-fold, with a total of 10 concentration gradients. 25 μL of the diluted antibody was added to each well and incubated with SW1271-STAT3-Luc cells for 1 hour. 25 μL of 4 ng / mL OSM was added and incubated for 6 hours; then 50 μL of Bright-Glo (Promega: E2620) was added to each well and incubated for 10 minutes, and chemiluminescence was detected using a microplate reader.

[0227] The IC of the antibody was calculated using the log(inhibitor) vs. response-Variable slop (four parameters) analysis method in GraphPad Prism 9 analysis software. 50 . The results are shown in Table 3.

[0228] Table 3 IC of Antibody against OSM Blocking 50

[0229]

[0230]

[0231] Antibody IL31 Blocking Experiment in Example 5

[0232] 50 μL containing 10 4SW1271-STAT3-Luc cells were seeded in 96-well plates and cultured overnight in a 37°C CO₂ incubator. Then, the anti-OSMRβ antibody obtained in Example 2 was serially diluted with a starting concentration of 10 μg / mL and diluted three-fold, resulting in a total of 10 concentration gradients. 25 μL of the diluted antibody was added to each well and incubated with SW1271-STAT3-Luc cells for 1 hour. 25 μL of 40 ng / mL IL31 (Sino Biological) was added and incubated for 6 hours. Then, 50 μL of Bright-Glo (Promega) was added to each well and incubated for 10 minutes, and chemiluminescence was detected using a microplate reader.

[0233] The IC of the antibody was calculated using the log(inhibitor) vs. response-Variable slop (four parameters) analysis method in GraphPad Prism 9 analysis software. 50 .

[0234] Table 4 IC of antibody against IL31 blockade 50

[0235] Antibody <![CDATA[IC 50 (ng / mL)]]> Antibody <![CDATA[IC 50 (ng / mL)]]> 98F11 246.1 8B03 593.6 100B9 505.9 10D12 599.9 164G5 497.4 10E02 666.1 176D7 533.1 8A03 390 2H05 592.4 9B07 411.7 5C12 600.1 12C03 655.0 8A06 632.3 12D02 600.2 8A10 325.8 12H07 784.2 8E06 364.0

[0236] The exemplary embodiments of the present invention have been described above. Those skilled in the art should understand that these disclosures are merely exemplary, and various other substitutions, adaptations, and modifications can be made within the scope of the present invention. Therefore, the present invention is not limited to the specific embodiments listed herein.

[0237] Exemplary sequences

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

Claims

1. An isolated antibody or antigen-binding fragment that specifically binds to the oncostatin M receptor beta (OSMRβ) protein, comprising (a) three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 1 and three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 2; or a variant having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions; (b) three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 9 and three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 10; or a variant having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions; (c) three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 17 and three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 18; or a variant having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions; (d) three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 25 and three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 26; or a variant having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions; (e) three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 33 and three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 34; or a variant having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions; (f) three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 41 and three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 42; or a variant having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions; (g) three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 49 and three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 50; or a variant having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions; (h) three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 57 and three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 58; or a variant having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions; (i) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 65 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 66; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions; (j) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 73 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 74; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions; (k) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 81 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 82; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions; (l) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 89 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 90; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions; (m) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 97 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 98: or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions; (n) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 105 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 106; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions; (o) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 113 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 114; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions; (p) The three CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 121 and the three CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 122; or variants having single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions; or (q)The three CDRs in the amino acid sequence of the heavy chain variable region shown in SEQ ID NO: 129 and the three CDRs in the amino acid sequence of the light chain variable region shown in SEQ ID NO: 130; or a variant having a single or multiple CDRs with no more than two amino acid changes in each CDR region compared to the above six CDR regions.

2. An isolated antibody or antigen-binding fragment that specifically binds to the OSMRβ protein, comprising (a) HCDR1 shown in SEQ ID NO: 3 or a variant of HCDR1 shown in SEQ ID NO: 3 with no more than two amino acid changes, HCDR2 shown in SEQ ID NO: 4 or a variant of HCDR2 shown in SEQ ID NO: 4 with no more than two amino acid changes, and HCDR3 shown in SEQ ID NO: 5 or a variant of HCDR3 shown in SEQ ID NO: 5 with no more than two amino acid changes; LCDR1 shown in SEQ ID NO: 6 or a variant of LCDR1 shown in SEQ ID NO: 6 with no more than two amino acid changes, LCDR2 shown in SEQ ID NO: 7 or a variant of LCDR2 shown in SEQ ID NO: 7 with no more than two amino acid changes, and LCDR3 shown in SEQ ID NO: 8 or a variant of LCDR3 shown in SEQ ID NO: 8 with no more than two amino acid changes; (b) HCDR1 shown in SEQ ID NO: 11 or a variant of HCDR1 shown in SEQ ID NO: 11 with no more than two amino acid changes, HCDR2 shown in SEQ ID NO: 12 or a variant of HCDR2 shown in SEQ ID NO: 12 with no more than two amino acid changes, and HCDR3 shown in SEQ ID NO: 13 or a variant of HCDR3 shown in SEQ ID NO: 13 with no more than two amino acid changes; LCDR1 shown in SEQ ID NO: 14 or a variant of LCDR1 shown in SEQ ID NO: 14 with no more than two amino acid changes, LCDR2 shown in SEQ ID NO: 15 or a variant of LCDR2 shown in SEQ ID NO: 15 with no more than two amino acid changes, and LCDR3 shown in SEQ ID NO: 16 or a variant of LCDR3 shown in SEQ ID NO: 16 with no more than two amino acid changes; (c) The HCDR1 shown in SEQ ID NO: 19 or a variant of the HCDR1 shown in SEQ ID NO: 19 with no more than 2 amino acid changes, the HCDR2 shown in SEQ ID NO: 20 or a variant of the HCDR2 shown in SEQ ID NO: 20 with no more than 2 amino acid changes, and the HCDR3 shown in SEQ ID NO: 21 or a variant of the HCDR3 shown in SEQ ID NO: 21 with no more than 2 amino acid changes; the LCDR1 shown in SEQ ID NO: 22 or a variant of the LCDR1 shown in SEQ ID NO: 22 with no more than 2 amino acid changes, the LCDR2 shown in SEQ ID NO: 23 or a variant of the LCDR2 shown in SEQ ID NO: 23 with no more than 2 amino acid changes, and the LCDR3 shown in SEQ ID NO: 24 or a variant of the LCDR3 shown in SEQ ID NO: 24 with no more than 2 amino acid changes; (d) The HCDR1 shown in SEQ ID NO: 27 or a variant of the HCDR1 shown in SEQ ID NO: 27 with no more than 2 amino acid changes, the HCDR2 shown in SEQ ID NO: 28 or a variant of the HCDR2 shown in SEQ ID NO: 28 with no more than 2 amino acid changes, and the HCDR3 shown in SEQ ID NO: 29 or a variant of the HCDR3 shown in SEQ ID NO: 29 with no more than 2 amino acid changes; the LCDR1 shown in SEQ ID NO: 30 or a variant of the LCDR1 shown in SEQ ID NO: 30 with no more than 2 amino acid changes, the LCDR2 shown in SEQ ID NO: 31 or a variant of the LCDR2 shown in SEQ ID NO: 31 with no more than 2 amino acid changes, and the LCDR3 shown in SEQ ID NO: 32 or a variant of the LCDR3 shown in SEQ ID NO: 32 with no more than 2 amino acid changes; (e) The HCDR1 shown in SEQ ID NO: 35 or a variant thereof with no more than 2 amino acid changes of the HCDR1 shown in SEQ ID NO: 35, the HCDR2 shown in SEQ ID NO: 36 or a variant thereof with no more than 2 amino acid changes of the HCDR2 shown in SEQ ID NO: 36, and the HCDR3 shown in SEQ ID NO: 37 or a variant thereof with no more than 2 amino acid changes of the HCDR3 shown in SEQ ID NO: 37; the LCDR1 shown in SEQ ID NO: 38 or a variant thereof with no more than 2 amino acid changes of the LCDR1 shown in SEQ ID NO: 38, the LCDR2 shown in SEQ ID NO: 39 or a variant thereof with no more than 2 amino acid changes of the LCDR2 shown in SEQ ID NO: 39, and the LCDR3 shown in SEQ ID NO: 40 or a variant thereof with no more than 2 amino acid changes of the LCDR3 shown in SEQ ID NO: 40; (f) The HCDR1 shown in SEQ ID NO: 43 or a variant thereof with no more than 2 amino acid changes of the HCDR1 shown in SEQ ID NO: 43, the HCDR2 shown in SEQ ID NO: 44 or a variant thereof with no more than 2 amino acid changes of the HCDR2 shown in SEQ ID NO: 44, and the HCDR3 shown in SEQ ID NO: 45 or a variant thereof with no more than 2 amino acid changes of the HCDR3 shown in SEQ ID NO: 45; the LCDR1 shown in SEQ ID NO: 46 or a variant thereof with no more than 2 amino acid changes of the LCDR1 shown in SEQ ID NO: 46, the LCDR2 shown in SEQ ID NO: 47 or a variant thereof with no more than 2 amino acid changes of the LCDR2 shown in SEQ ID NO: 47, and the LCDR3 shown in SEQ ID NO: 48 or a variant thereof with no more than 2 amino acid changes of the LCDR3 shown in SEQ ID NO: 48; (g) The HCDR1 shown in SEQ ID NO: 51 or a variant of the HCDR1 shown in SEQ ID NO: 51 with no more than 2 amino acid changes, the HCDR2 shown in SEQ ID NO: 52 or a variant of the HCDR2 shown in SEQ ID NO: 52 with no more than 2 amino acid changes, and the HCDR3 shown in SEQ ID NO: 53 or a variant of the HCDR3 shown in SEQ ID NO: 53 with no more than 2 amino acid changes; the LCDR1 shown in SEQ ID NO: 54 or a variant of the LCDR1 shown in SEQ ID NO: 54 with no more than 2 amino acid changes, the LCDR2 shown in SEQ ID NO: 55 or a variant of the LCDR2 shown in SEQ ID NO: 55 with no more than 2 amino acid changes, and the LCDR3 shown in SEQ ID NO: 56 or a variant of the LCDR3 shown in SEQ ID NO: 56 with no more than 2 amino acid changes; (h) The HCDR1 shown in SEQ ID NO: 59 or a variant of the HCDR1 shown in SEQ ID NO: 59 with no more than 2 amino acid changes, the HCDR2 shown in SEQ ID NO: 60 or a variant of the HCDR2 shown in SEQ ID NO: 60 with no more than 2 amino acid changes, and the HCDR3 shown in SEQ ID NO: 61 or a variant of the HCDR3 shown in SEQ ID NO: 61 with no more than 2 amino acid changes; the LCDR1 shown in SEQ ID NO: 62 or a variant of the LCDR1 shown in SEQ ID NO: 62 with no more than 2 amino acid changes, the LCDR2 shown in SEQ ID NO: 63 or a variant of the LCDR2 shown in SEQ ID NO: 63 with no more than 2 amino acid changes, and the LCDR3 shown in SEQ ID NO: 64 or a variant of the LCDR3 shown in SEQ ID NO: 64 with no more than 2 amino acid changes; (i) The HCDR1 shown in SEQ ID NO: 67 or a variant of the HCDR1 shown in SEQ ID NO: 67 with no more than 2 amino acid changes, the HCDR2 shown in SEQ ID NO: 68 or a variant of the HCDR2 shown in SEQ ID NO: 68 with no more than 2 amino acid changes, and the HCDR3 shown in SEQ ID NO: 69 or a variant of the HCDR3 shown in SEQ ID NO: 69 with no more than 2 amino acid changes; the LCDR1 shown in SEQ ID NO: 70 or a variant of the LCDR1 shown in SEQ ID NO: 70 with no more than 2 amino acid changes, the LCDR2 shown in SEQ ID NO: 71 or a variant of the LCDR2 shown in SEQ ID NO: 71 with no more than 2 amino acid changes, and the LCDR3 shown in SEQ ID NO: 72 or a variant of the LCDR3 shown in SEQ ID NO: 72 with no more than 2 amino acid changes; (j) The HCDR1 shown in SEQ ID NO: 75 or a variant of the HCDR1 shown in SEQ ID NO: 75 with no more than 2 amino acid changes, the HCDR2 shown in SEQ ID NO: 76 or a variant of the HCDR2 shown in SEQ ID NO: 76 with no more than 2 amino acid changes, and the HCDR3 shown in SEQ ID NO: 77 or a variant of the HCDR3 shown in SEQ ID NO: 77 with no more than 2 amino acid changes; the LCDR1 shown in SEQ ID NO: 78 or a variant of the LCDR1 shown in SEQ ID NO: 78 with no more than 2 amino acid changes, the LCDR2 shown in SEQ ID NO: 79 or a variant of the LCDR2 shown in SEQ ID NO: 79 with no more than 2 amino acid changes, and the LCDR3 shown in SEQ ID NO: 80 or a variant of the LCDR3 shown in SEQ ID NO: 80 with no more than 2 amino acid changes; (k) The HCDR1 shown in SEQ ID NO: 83 or a variant of the HCDR1 shown in SEQ ID NO: 83 with no more than 2 amino acid changes, the HCDR2 shown in SEQ ID NO: 84 or a variant of the HCDR2 shown in SEQ ID NO: 84 with no more than 2 amino acid changes, and the HCDR3 shown in SEQ ID NO: 85 or a variant of the HCDR3 shown in SEQ ID NO: 85 with no more than 2 amino acid changes; the LCDR1 shown in SEQ ID NO: 86 or a variant of the LCDR1 shown in SEQ ID NO: 86 with no more than 2 amino acid changes, the LCDR2 shown in SEQ ID NO: 87 or a variant of the LCDR2 shown in SEQ ID NO: 87 with no more than 2 amino acid changes, and the LCDR3 shown in SEQ ID NO: 88 or a variant of the LCDR3 shown in SEQ ID NO: 88 with no more than 2 amino acid changes; (l) The HCDR1 shown in SEQ ID NO: 91 or a variant of the HCDR1 shown in SEQ ID NO: 91 with no more than 2 amino acid changes, the HCDR2 shown in SEQ ID NO: 92 or a variant of the HCDR2 shown in SEQ ID NO: 92 with no more than 2 amino acid changes, and the HCDR3 shown in SEQ ID NO: 93 or a variant of the HCDR3 shown in SEQ ID NO: 93 with no more than 2 amino acid changes; the LCDR1 shown in SEQ ID NO: 94 or a variant of the LCDR1 shown in SEQ ID NO: 94 with no more than 2 amino acid changes, the LCDR2 shown in SEQ ID NO: 95 or a variant of the LCDR2 shown in SEQ ID NO: 95 with no more than 2 amino acid changes, and the LCDR3 shown in SEQ ID NO: 96 or a variant of the LCDR3 shown in SEQ ID NO: 96 with no more than 2 amino acid changes; (m) The HCDR1 shown in SEQ ID NO: 99 or a variant of the HCDR1 shown in SEQ ID NO: 99 with no more than 2 amino acid changes, the HCDR2 shown in SEQ ID NO: 100 or a variant of the HCDR2 shown in SEQ ID NO: 100 with no more than 2 amino acid changes, and the HCDR3 shown in SEQ ID NO: 101 or a variant of the HCDR3 shown in SEQ ID NO: 101 with no more than 2 amino acid changes; the LCDR1 shown in SEQ ID NO: 102 or a variant of the LCDR1 shown in SEQ ID NO: 102 with no more than 2 amino acid changes, the LCDR2 shown in SEQ ID NO: 103 or a variant of the LCDR2 shown in SEQ ID NO: 103 with no more than 2 amino acid changes, and the LCDR3 shown in SEQ ID NO: 104 or a variant of the LCDR3 shown in SEQ ID NO: 104 with no more than 2 amino acid changes; (n) The HCDR1 shown in SEQ ID NO: 107 or a variant of the HCDR1 shown in SEQ ID NO: 107 with no more than 2 amino acid changes, the HCDR2 shown in SEQ ID NO: 108 or a variant of the HCDR2 shown in SEQ ID NO: 108 with no more than 2 amino acid changes, and the HCDR3 shown in SEQ ID NO: 109 or a variant of the HCDR3 shown in SEQ ID NO: 109 with no more than 2 amino acid changes; the LCDR1 shown in SEQ ID NO: 110 or a variant of the LCDR1 shown in SEQ ID NO: 110 with no more than 2 amino acid changes, the LCDR2 shown in SEQ ID NO: 111 or a variant of the LCDR2 shown in SEQ ID NO: 111 with no more than 2 amino acid changes, and the LCDR3 shown in SEQ ID NO: 112 or a variant of the LCDR3 shown in SEQ ID NO: 112 with no more than 2 amino acid changes; (o)HCDR1 shown in SEQ ID NO: 115 or a variant of HCDR1 shown in SEQ ID NO: 115 with no more than 2 amino acid changes, HCDR2 shown in SEQ ID NO: 116 or a variant of HCDR2 shown in SEQ ID NO: 116 with no more than 2 amino acid changes, and HCDR3 shown in SEQ ID NO: 117 or a variant of HCDR3 shown in SEQ ID NO: 117 with no more than 2 amino acid changes; LCDR1 shown in SEQ ID NO: 118 or a variant of LCDR1 shown in SEQ ID NO: 118 with no more than 2 amino acid changes, LCDR2 shown in SEQ ID NO: 119 or a variant of LCDR2 shown in SEQ ID NO: 119 with no more than 2 amino acid changes, and LCDR3 shown in SEQ ID NO: 120 or a variant of LCDR3 shown in SEQ ID NO: 120 with no more than 2 amino acid changes; (p)HCDR1 shown in SEQ ID NO: 123 or a variant of HCDR1 shown in SEQ ID NO: 123 with no more than 2 amino acid changes, HCDR2 shown in SEQ ID NO: 124 or a variant of HCDR2 shown in SEQ ID NO: 124 with no more than 2 amino acid changes, and HCDR3 shown in SEQ ID NO: 125 or a variant of HCDR3 shown in SEQ ID NO: 125 with no more than 2 amino acid changes; LCDR1 shown in SEQ ID NO: 126 or a variant of LCDR1 shown in SEQ ID NO: 126 with no more than 2 amino acid changes, LCDR2 shown in SEQ ID NO: 127 or a variant of LCDR2 shown in SEQ ID NO: 127 with no more than 2 amino acid changes, and LCDR3 shown in SEQ ID NO: 128 or a variant of LCDR3 shown in SEQ ID NO: 128 with no more than 2 amino acid changes; or (q) The HCDR1 shown in SEQ ID NO: 131 or a variant thereof with no more than 2 amino acid changes of the HCDR1 shown in SEQ ID NO: 131, the HCDR2 shown in SEQ ID NO: 132 or a variant thereof with no more than 2 amino acid changes of the HCDR2 shown in SEQ ID NO: 132, and the HCDR3 shown in SEQ ID NO: 133 or a variant thereof with no more than 2 amino acid changes of the HCDR3 shown in SEQ ID NO: 133; the LCDR1 shown in SEQ ID NO: 134 or a variant thereof with no more than 2 amino acid changes of the LCDR1 shown in SEQ ID NO: 134, the LCDR2 shown in SEQ ID NO: 135 or a variant thereof with no more than 2 amino acid changes of the LCDR2 shown in SEQ ID NO: 135, and the LCDR3 shown in SEQ ID NO: 136 or a variant thereof with no more than 2 amino acid changes of the LCDR3 shown in SEQ ID NO: 136; Preferably, the isolated antibody or antigen-binding fragment that specifically binds to the OSMRβ protein comprises (a) The HCDR1 shown in SEQ ID NO: 3, the HCDR2 shown in SEQ ID NO: 4, and the HCDR3 shown in SEQ ID NO: 5; the LCDR1 shown in SEQ ID NO: 6, the LCDR2 shown in SEQ ID NO: 7, and the LCDR3 shown in SEQ ID NO: 8; (b) The HCDR1 shown in SEQ ID NO: 11, the HCDR2 shown in SEQ ID NO: 12, and the HCDR3 shown in SEQ ID NO: 13; the LCDR1 shown in SEQ ID NO: 14, the LCDR2 shown in SEQ ID NO: 15, and the LCDR3 shown in SEQ ID NO: 16; (c) The HCDR1 shown in SEQ ID NO: 19, the HCDR2 shown in SEQ ID NO: 20, and the HCDR3 shown in SEQ ID NO: 21; the LCDR1 shown in SEQ ID NO: 22, the LCDR2 shown in SEQ ID NO: 23, and the LCDR3 shown in SEQ ID NO: 24; (d) The HCDR1 shown in SEQ ID NO: 27, the HCDR2 shown in SEQ ID NO: 28, and the HCDR3 shown in SEQ ID NO: 29; the LCDR1 shown in SEQ ID NO: 30, the LCDR2 shown in SEQ ID NO: 31, and the LCDR3 shown in SEQ ID NO: 32; (e)HCDR1 shown in SEQ ID NO: 35, HCDR2 shown in SEQ ID NO: 36, and HCDR3 shown in SEQ ID NO: 37; LCDR1 shown in SEQ ID NO: 38, LCDR2 shown in SEQ ID NO: 39, and LCDR3 shown in SEQ ID NO: 40; (f)HCDR1 shown in SEQ ID NO: 43, HCDR2 shown in SEQ ID NO: 44, and HCDR3 shown in SEQ ID NO: 45; LCDR1 shown in SEQ ID NO: 46, LCDR2 shown in SEQ ID NO: 47, and LCDR3 shown in SEQ ID NO: 48; (g)HCDR1 shown in SEQ ID NO: 51, HCDR2 shown in SEQ ID NO: 52, and HCDR3 shown in SEQ ID NO: 53; LCDR1 shown in SEQ ID NO: 54, LCDR2 shown in SEQ ID NO: 55, and LCDR3 shown in SEQ ID NO: 56; (h)HCDR1 shown in SEQ ID NO: 59, HCDR2 shown in SEQ ID NO: 60, and HCDR3 shown in SEQ ID NO: 61; LCDR1 shown in SEQ ID NO: 62, LCDR2 shown in SEQ ID NO: 63, and LCDR3 shown in SEQ ID NO: 64; (i)HCDR1 shown in SEQ ID NO: 67, HCD2 shown in SEQ ID NO: 68, and HCDR3 shown in SEQ ID NO: 69; LCDR1 shown in SEQ ID NO: 70, LCDR2 shown in SEQ ID NO: 71, and LCDR3 shown in SEQ ID NO: 72; (j)HCDR1 shown in SEQ ID NO: 75, HCDR2 shown in SEQ ID NO: 76, and HCDR3 shown in SEQ ID NO: 77; LCDR1 shown in SEQ ID NO: 78, LCDR2 shown in SEQ ID NO: 79, and LCDR3 shown in SEQ ID NO: 80; (k)HCDR1 shown in SEQ ID NO: 83, HCDR2 shown in SEQ ID NO: 84, and HCDR3 shown in SEQ ID NO: 85; LCDR1 shown in SEQ ID NO: 86, LCDR2 shown in SEQ ID NO: 87, and LCDR3 shown in SEQ ID NO: 88; (l)HCDR1 shown in SEQ ID NO: 91, HCDR2 shown in SEQ ID NO: 92, and HCD3 shown in SEQ ID NO: 93; LCDR1 shown in SEQ ID NO: 94, LCDR2 shown in SEQ ID NO: 95, and LCDR3 shown in SEQ ID NO: 96; ()HCDR1 shown in SEQ ID NO: 99, HCDR2 shown in SEQ ID NO: 100, and HCDR3 shown in SEQ ID NO: 101; LCDR1 shown in SEQ ID NO: 102, LCDR2 shown in SEQ ID NO: 103, and LCDR3 shown in SEQ ID NO: 104; (n)HCDR1 shown in SEQ ID NO: 107, HCDR2 shown in SEQ ID NO: 108, and HCDR3 shown in SEQ ID NO: 109; LCDR1 shown in SEQ ID NO: 110, LCDR2 shown in SEQ ID NO: 111, and LCD3 shown in SEQ ID NO: 112; (o)HCDR1 shown in SEQ ID NO: 115, HCDR2 shown in SEQ ID NO: 116, and HCDR3 shown in SEQ ID NO: 117; LCDR1 shown in SEQ ID NO: 118, LCDR2 shown in SEQ ID NO: 119, and LCDR3 shown in SEQ ID NO: 120; (p)HCDR1 shown in SEQ ID NO: 123, HCDR2 shown in SEQ ID NO: 124, and HCDR3 shown in SEQ ID NO: 125; LCDR1 shown in SEQ ID NO: 126, LCDR2 shown in SEQ ID NO: 127, and LCDR3 shown in SEQ ID NO: 128; or (q)HCDR1 shown in SEQ ID NO: 131, HCDR2 shown in SEQ ID NO: 132, and HCD3 shown in SEQ ID NO: 133; LCDR1 shown in SEQ ID NO: 134, LCDR2 shown in SEQ ID NO: 135, and LCDR3 shown in SEQ ID NO:

136.

3. The isolated antibody or antigen-binding fragment according to claim 1 or 2, comprising (a) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 1 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 2 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; (b) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 9 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 10 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; (c) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 17 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 18 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; (d) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 25 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 26 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; (e) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 33 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 34 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; (f) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 41 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 42 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; (g) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 49 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 50 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; (h) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 57 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 58 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; (i) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 65 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 66 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; (j) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 73 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 74 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; (k) Heavy chain variable region and light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 81 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 82 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; (l) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 89 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 90 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; (m) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 97 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 98 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; (n) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 105 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 106 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; (o) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 113 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 114 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; (p) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 121 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 122 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; or (q) A heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 129 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 130 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto.

4. The isolated antibody or antigen-binding fragment according to any one of claims 1 to 3, wherein the antigen-binding fragment is Fab, Fab’, F(ab’)2, Fv, single-chain Fv, bispecific single-chain Fv, trispecific single-chain Fv, single-chain Fab, bispecific Fab dimer (Fab2), trispecific Fab trimer (Fab3), diabody.

5. The isolated antibody or antigen-binding fragment according to any one of claims 1 to 3, which is an IgG1, IgG2, IgG3 or IgG4 antibody; preferably, it is an IgG1 or IgG4 antibody; more preferably, it is a human IgG1 or human IgG4 antibody.

6. The isolated antibody or antigen-binding fragment according to any one of claims 1 to 5, which has one or more of the following properties: (a) Measured by biomembrane layer interferometry, with a binding dissociation equilibrium constant K of 10 -7 M or less, such as 10 -8 M or less, 10 -9 M or less, 10 -10 M or less, 10 -11 M or less, 10 -12 M or less, or 10 -13 M or less, and binds to human OSMRβ protein; D ​ (b) Blocking OSM-mediated signal transduction; and (c) Blocking IL-31-mediated signal transduction.

7. An isolated nucleic acid encoding the antibody or antigen-binding fragment according to any one of claims 1 to 6.

8. A vector comprising the nucleic acid of claim 7, preferably the vector is an expression vector.

9. A host cell comprising the nucleic acid of claim 7 or the vector of claim 8, preferably, the host cell is prokaryotic or eukaryotic, more preferably selected from Escherichia coli cells, yeast cells, mammalian cells or other cells suitable for preparing antibodies or antigen-binding fragments, most preferably, the host cell is HEK 293 cells or CHO cells.

10. A method for preparing the antibody or antigen-binding fragment according to any one of claims 1 to 6, the method comprising culturing the host cell of claim 9 under conditions suitable for expressing the nucleic acid encoding the antibody or antigen-binding fragment according to any one of claims 1 to 6, optionally recovering the antibody or antigen-binding fragment according to any one of claims 1 to 6 from the host cell or from the culture medium.

11. A pharmaceutical composition comprising the antibody or antigen-binding fragment according to any one of claims 1 to 6, or the isolated nucleic acid of claim 7, or the vector of claim 8, or the host cell of claim 9, and a pharmaceutically acceptable carrier.

12. Use of the antibody or antigen-binding fragment according to any one of claims 1 to 6 for the preparation of a medicament for preventing and / or treating a disease, for example, the disease is an autoimmune disease, an inflammatory disease or a disease associated with extracellular matrix deposition or remodeling, for example, fibrosis, cartilage degeneration, arthritis, rheumatoid arthritis, scleroderma, scleroderma-associated interstitial lung disease, idiopathic pulmonary fibrosis, cirrhosis, psoriasis, atopic dermatitis, systemic cutaneous amyloidosis, primary cutaneous amyloidosis, pruritic inflammation, prurigo nodularis and pain.

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