Oncostatin m receptor β binding antibody and use thereof

Abstract

The present disclosure relates to an antibody or an antigen-binding fragment specifically binding to an OSMRβ protein. The present disclosure further relates to a nucleic acid encoding the antibody or the antigen-binding fragment, and a host cell containing same, and a method for preparing the antibody or the antigen-binding fragment. In addition, the present disclosure relates to the use of the antibody or the antigen-binding fragment in the prevention and / or treatment of diseases.

Description

Oncostatin M receptor beta binding antibodies and uses thereof Technical Field

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

[0002] Oncostatin-M (OSM) is a pleiotropic cytokine belonging to the IL-6 family. It was first discovered in 1986 after being isolated and purified from the culture supernatant of PMA-activated U937 histological lymphoma cells. It was named for its ability to inhibit melanoma cell proliferation in vitro. The OSM gene is located on chromosome 22q12 and consists of three exons and two introns, adjacent to the leukemia inhibitory factor (LIF) gene.

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

[0004] Additionally, OSMRβ activates IL-31-induced signaling pathways by dimerizing with IL-31 receptor α (IL-31RA). IL-31 is associated with inflammatory and allergic diseases such as atopic dermatitis / itch, 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 functions as a key signal transduction regulator by phosphorylating various tyrosine residues in its intracellular domain. Signal transduction is then initiated by OSMRβ, gp130, and the IL-31RA-associated Janus kinase (JAK). Subsequently, pathways through STAT1 / 3 / 5, MAPK, PI3K / AKT, and PKC isoforms are activated.

[0006] Therefore, OSMRβ mediates the signaling of interleukin-31 (IL-31) and oncostatin M (OSM). By using blocking monoclonal antibodies to target OSMRβ, the functions of both IL-31 and OSM cytokines can be blocked, which has potential application prospects in the treatment of many diseases and conditions associated with OSMR (e.g., itch, inflammation, and fibrosis).

[0007] The pipeline of publicly available drugs targeting OSMR is very limited, with only vixarelimab (also known as "KPL-716") currently in Phase II clinical trials (ClinicalTrials.gov Identifier: NCT03858634). Given that there are currently no marketed targeted drugs targeting OSMR, there remains a need for new OSMRβ blocking antibodies. The present disclosure addresses this need by providing blocking antibodies that bind to OSMRβ with high target specificity and affinity. Summary of the Invention

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

[0009] Thus, in a first aspect, the present disclosure provides an isolated antibody or antigen-binding fragment that specifically binds to OSMRβ protein, comprising

[0010] (a) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 1 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 2; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0011] (b) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 9 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 10; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0012] (c) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 17 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 18; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0013] (d) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 25 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 26; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0014] (e) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 33 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 34; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0015] (f) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO:41 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO:42; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0016] (g) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO:49 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO:50; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0017] (h) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 57 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 58; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0018] (i) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 65 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 66; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0019] (j) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 73 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 74; or variants thereof having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0020] (k) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO:81 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO:82; or variants thereof having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0021] (1) 3 CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 89 and 3 CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 90; or variants having a single or multiple CDRs with no more than 2 amino acid changes in each CDR region;

[0022] (m) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO:97 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO:98; or variants thereof having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0023] (n) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 105 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 106; or variants thereof having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0024] (o) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 113 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 114; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0025] (p) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 121 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 122; or a variant having a single or multiple CDRs with no more than two amino acid changes in each CDR region; or

[0026] (q) 3 CDRs in the heavy chain variable region amino acid sequence shown in SEQ ID NO: 129 and 3 CDRs in the light chain variable region amino acid sequence shown in SEQ ID NO: 130; or a variant having a single or multiple CDRs with no more than 2 amino acid changes in each CDR region.

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

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

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

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

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

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

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

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

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

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

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

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

[0039] (1) HCDR1 set forth in SEQ ID NO:91 or a variant of HCDR1 set forth in SEQ ID NO:91 with no more than two amino acid changes, HCDR2 set forth in SEQ ID NO:92 or a variant of HCDR2 set forth in SEQ ID NO:92 with no more than two amino acid changes, and HCDR3 set forth in SEQ ID NO:93 or a variant of HCDR3 set forth in SEQ ID NO:93 with no more than two amino acid changes; LCDR1 set forth in SEQ ID NO:94 or a variant of LCDR1 set forth in SEQ ID NO:94 with no more than two amino acid changes, LCDR2 set forth in SEQ ID NO:95 or a variant of LCDR2 set forth in SEQ ID NO:95 with no more than two amino acid changes, and LCDR3 set forth in SEQ ID NO:96 or a variant of LCDR3 set forth in SEQ ID NO:96 with no more than two amino acid changes;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0063] In some embodiments, an antibody of the present disclosure that specifically binds to an OSMRβ protein is an affinity matured variant of a parent antibody.

[0064] In some embodiments, the antigen-binding fragments of the present disclosure are 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.

[0065] In some embodiments, the isolated antibody of the present disclosure that specifically binds to OSMRβ protein is an IgG1, IgG2, IgG3, or IgG4 antibody; preferably, an IgG1 or IgG4 antibody; more preferably, a human IgG1 or human IgG4 antibody.

[0066] In a second aspect, the present disclosure provides nucleic acids encoding the antibodies or antigen-binding fragments described in the first aspect above, vectors (preferably, expression vectors) comprising the nucleic acids, and host cells comprising the nucleic acids or vectors. In some embodiments, the host cells are prokaryotic or eukaryotic, for example, selected from Escherichia coli cells, yeast cells, mammalian cells, or other cells suitable for preparing antibodies or antigen-binding fragments. In some embodiments, the host cells are HEK 293 cells or CHO cells.

[0067] In a third aspect, the present disclosure provides a method for preparing the antibody or antigen-binding fragment of the present disclosure, the method comprising culturing the host cell of the present disclosure under conditions suitable for expression of a nucleic acid encoding the antibody or antigen-binding fragment of the present disclosure, and optionally recovering the antibody or antigen-binding fragment of the present disclosure from the host cell or from the culture medium.

[0068] In a fourth aspect, the present disclosure provides a pharmaceutical composition comprising the antibody or antigen-binding fragment of the present disclosure, or the nucleic acid of the present disclosure, or the vector of the present disclosure, or the host cell of the present disclosure, and a pharmaceutically acceptable carrier.

[0069] In a fifth aspect, the present disclosure provides uses of the antibodies or antigen-binding fragments of the present disclosure, or the nucleic acids of the present disclosure, or the vectors of the present disclosure, or the host cells of the present disclosure for preparing a medicament for preventing and / or treating a disease, for example, an autoimmune disease, an inflammatory disease, or a disease associated with extracellular matrix deposition or remodeling, for example, 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, prurigo nodularis, and pain.

[0070] In a sixth aspect, the present disclosure provides a method for preventing and / or treating a disease, comprising administering an effective amount of an antibody or antigen-binding fragment of the present disclosure, or a nucleic acid of the present disclosure, or a vector of the present disclosure, or a host cell of the present disclosure to a subject in need thereof, 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, for example, 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, prurigo nodularis, and pain. DETAILED DESCRIPTION

[0071] Before describing the present disclosure in detail, it should be understood that the present disclosure is not limited to the specific methods and experimental conditions in this specification, because the methods and conditions can be changed. In addition, the terminology used herein is only for the purpose of describing specific embodiments and is not intended to be limiting.

[0072] I. Definition

[0073] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For the purposes of this disclosure, the following terms are defined below.

[0074] The term "about" when used in conjunction with a numerical value is meant to encompass the numerical value within a range having a lower limit that is 10% less than the specified numerical value and an upper limit that is 10% greater than the specified numerical value.

[0075] The term "and / or" when used to link two or more alternatives should be understood to mean any one of the alternatives or any two or more of the alternatives.

[0076] As used herein, the terms "comprising" or "including" are intended to include the recited elements, integers, or steps, but do not exclude any other elements, integers, or steps. In this document, when the terms "comprising" or "including" are used, unless otherwise indicated, the context of consisting of the recited elements, integers, or steps is also encompassed. For example, when reference is made to an antibody variable region "comprising" a specific sequence, it is intended to encompass an antibody variable region consisting of that specific sequence.

[0077] 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), cardiotrophic factor 1 (CT-1), and cardiotrophin-like cytokine (CLCF 1). Each IL-6 family member plays an important role in maintaining physiological regulation such as metabolic, inflammatory, and immune homeostasis.

[0078] The term "oncostatin M (OSM)" refers to a pleiotropic cytokine in the IL-6 family, primarily secreted by activated monocytes, macrophages, T lymphocytes, and dendritic cells. OSM exhibits diverse biological activities, playing a broad role in hematopoiesis, cell growth and differentiation, inflammatory responses, metabolic regulation, tumorigenesis, and immunomodulation. OSM signals through two distinct receptor complexes: 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. It can bind to both LIF and OSM to initiate signaling. 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 to LIF or other cytokines in the family.

[0079] 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".

[0080] The term "interleukin-31," also abbreviated as "IL-31" or "IL31," is an inflammatory cytokine that helps trigger cell-mediated immunity against pathogens. STAT3, and possibly STAT1 and STAT5, is activated through the IL31 heterodimeric receptor, composed of IL31RA and OSMR. IL31 has been identified as a key player in many chronic inflammatory diseases, including atopic dermatitis. It may have a role in skin immunity. IL-31 is produced by a variety of cells, including type 2 helper T cells (TH2). IL-31 signals through a receptor complex composed of IL31RA and oncostatin M receptor β (OSMRβ), which are expressed on immune and epithelial cells. These signals activate three pathways: the ERK1 / 2 MAP kinase, PI3K / AKT, and JAK1 / 2 signaling pathways.

[0081] The term "antibody" is used in the broadest sense herein and includes, but is not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), as long as they show the desired antigen-binding activity. Antibodies can be complete antibodies (e.g., having two full-length light chains and two full-length heavy chains) of any type and subtype (e.g., IgM, IgD, IgG1, IgG2, IgG3, IgG4, IgE, IgA1, and IgA2). The monomer of a complete antibody is a tetrapeptide chain molecule formed by two full-length light chains and two full-length heavy chains connected by disulfide bonds, also referred to as a monomer of an Ig molecule. Antibody monomers are the basic structures that constitute antibodies.

[0082] The term "affinity matured antibody" refers to an antibody that has one or more amino acid residue changes in one or more hypervariable regions (CDRs) and three positions near each hypervariable region (CDR) relative to a parent antibody, wherein the amino acid residue changes result in improved affinity and / or biological activity of the antibody for the antigen compared to the parent antibody that does not have the amino acid residue changes.

[0083] The term "parent antibody" herein refers to an antibody that serves as a starting point or basis for preparing antibody variants. In some embodiments, the parent antibody is any one of the antibodies shown in Table 1.

[0084] As used herein, an "isolated antibody" refers to an antibody that is substantially free of other antibodies (Abs) having different antigenic specificities (e.g., an isolated antibody or antigen-binding fragment thereof that specifically binds to an OSMRβ protein is substantially free of Abs that specifically bind to antigens other than an OSMRβ protein). In certain embodiments, the antibody is purified to greater than 95% or 99% purity, as determined by, for example, electrophoresis (e.g., SDS-PAGE isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reversed-phase HPLC).

[0085] The term "antigen-binding fragment" is a portion or segment of an intact or complete antibody having fewer amino acid residues than the intact or complete antibody, which is capable of binding to an antigen or competing with the intact antibody (i.e., the intact antibody from which the antigen-binding fragment is derived) for antigen binding. Antigen-binding fragments can be prepared by recombinant DNA technology, 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, diabodies, single-domain antibodies (sdAb, nanobodies), camelid Ig, Ig NAR, F(ab)'3 fragment, bis-scFv, (scFv)2, minibodies, diabodies, triabodies, tetrabodies, disulfide-stabilized Fv proteins ("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), heterojunction antibodies (e.g., bispecific antibodies), and antigen-binding fragments thereof. For a more detailed description, see: Pierce Catalog and Handbook, 1994-1995 (Pierce Chemical Co., Rockford, IL); Kuby, Journal of Immunology, 3rd ed., WH Freeman & Co., New York, 1997.

[0086] 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 (HC) and two light chains (LC) 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 comprising α, δ, ε, γ, and μ heavy chains are classified as immunoglobulins (Ig) A, IgD, IgE, IgG, and IgM. Complete antibodies form a "Y" shape. The stem of the Y is composed of the second and third constant regions of the two heavy chains (and the fourth constant region for IgE and IgM), and disulfide bonds (between chains) are formed in the hinge. The heavy chains γ, α, and δ have a constant region consisting of three tandem (in a row) Ig domains and a hinge region for increasing flexibility; the heavy chains μ and ε have a constant region consisting of four immunoglobulin domains. The second and third constant regions are called "CH2 domains" and "CH3 domains," respectively. Each arm of the Y includes the variable region and the first constant region of a single heavy chain bound 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.

[0087] The light chain variable region and the heavy chain variable region each comprise a "framework" region interspersed with three hypervariable regions (also referred to as "complementarity determining regions" or "CDRs"). "Complementarity determining regions" or "CDR regions" or "CDRs" or "hypervariable regions" (used interchangeably herein with hypervariable regions "HVRs") are regions in the antibody variable domain that are highly variable in sequence and form structurally determined loops ("hypervariable loops") and / or contain antigen contact residues ("antigen contact points"). CDRs are primarily responsible for binding to antigenic epitopes. The CDRs of the heavy and light chains are typically referred to as CDR1, CDR2, and CDR3, and are numbered sequentially from the N-terminus. The CDRs located within the antibody heavy chain variable domain are referred to as HCDR1, HCDR2, and HCDR3, while the CDRs located within the antibody light chain variable domain are referred to as LCDR1, LCDR2, and LCDR3. In a given light chain variable region or heavy chain variable region amino acid sequence, 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 antibodies and the topology of the CDR loops (Chothia et al. (1989) Nature 342:877-883, Al-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 Edition, US Department of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath), Contact (University College London), International ImMunoGeneTics 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.

[0088] 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 variable regions of the same antibody defined under different assignment systems may differ. For example, as shown in Table 1 in 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.

[0089] Thus, when reference is made to an antibody defined by a specific CDR sequence as defined herein, the scope of that antibody also encompasses antibodies whose variable region sequences comprise the specific CDR sequences but whose declared CDR boundaries differ from the specific CDR boundaries defined herein due to application of a different scheme (e.g., a different assignment system rule or combination).

[0090] The CDRs of the disclosed antibodies can be manually assessed to determine boundaries according to any protocol or combination thereof known in the art. Unless otherwise indicated, in the present disclosure, the term "CDR" or "CDR sequence" encompasses CDR sequences determined in any of the above manners.

[0091] The sequences of the framework regions of different light or heavy chains are relatively conserved within species (e.g., humans). The framework region of an antibody (which is the combined framework region of the component light and heavy chains) is used to locate and align the CDRs in three-dimensional space. CDRs are primarily responsible for binding to the epitope of the antigen. Antibodies with different specificities (i.e., having different combination sites for different antigens) have different CDRs. Although the CDRs differ from antibody to antibody, only a limited number of amino acid positions within the CDRs are directly involved in antigen binding. These positions within the CDRs are referred to as specificity determining residues (SDRs).

[0092] A "monoclonal antibody" is an antibody produced by a single clone of B lymphocytes or by a cell into which the light and heavy chain genes for a single antibody have been transfected. Monoclonal antibodies are produced by methods known to those skilled in the art, for example, by preparing hybrid antibody-forming cells by fusion of myeloma cells with immune spleen cells.

[0093] "Fv" is the smallest antibody fragment containing a complete antigen binding site. In one embodiment, the two-chain Fv species is composed of a dimer of a heavy chain variable domain and a light chain variable domain in a 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 so that the light chain and the heavy chain can be associated in a "dimerization" structure similar to the two-chain Fv species. In this configuration, the three hypervariable regions (HVRs) of each variable domain interact to define the antigen binding site on the surface of the VH-VL dimer. The six HVRs collectively confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three HVRs specific for an antigen) has the ability to recognize and bind antigens, but the affinity is lower than the complete binding site.

[0094] The Fab fragment contains the heavy and light chain variable domains, as well as the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. Fab' fragments differ from Fab fragments in that a few residues are added to the carboxyl terminus of the heavy chain CH1 domain, including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine ​​residues of the constant domains bear a free thiol group. F(ab')2 antibody fragments were originally produced as pairs of Fab' fragments with hinge cysteines between them.

[0095] The term "specific binding" or "binding" used when referring to an antigen and an antibody means that the antibody forms a complex with the antigen which is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to 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.

[0096] "Affinity" refers to the strength of the sum of all non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y can often be expressed in terms of the association dissociation equilibrium constant (K D Affinity can be measured by common methods known in the art, including those known in the art and described herein.

[0097] As used herein, the term "variant" refers to a heavy chain variable region or light chain variable region that has been modified by at least one, e.g., 1, 2, or 3 amino acid substitutions, deletions, or additions, wherein the modified antigen-binding protein comprising 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%, or 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 of 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 sequence corresponding to the CDR has 100% identity with the CDR 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 comprising 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%, or 100% of the biological characteristics of the antigen-binding protein before modification. It will 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.

[0098] "Polynucleotide" or "nucleic acid," used interchangeably herein, refers to a chain of nucleotides of any length and includes DNA and RNA. The 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.

[0099] Calculation of sequence identity between sequences is performed as follows.

[0100] To determine the percent identity of 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. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then 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.

[0101] Mathematical algorithms can be used to compare sequences and calculate percent identity between two sequences. In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needlema and Wunsch ((1970) J. Mol. Biol. 48:444-453) algorithm (available at http: / / www.gcg.com), which has been integrated into the GAP program in the GCG software package. The Blossum 62 matrix or the PAM250 matrix is ​​used, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 is used, and a length weight of 1, 2, 3, 4, 5, or 6 is used. In another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at http: / / www.gcg.com). A particularly preferred parameter set (and the one 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.

[0102] The percent identity between two amino acid or nucleotide sequences can also be determined using the algorithm of E. Meyers and W. Miller, (1989) CABIOS, 4: 11-17), which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weighted remainder table, a gap length penalty of 12, and a gap penalty of 4.

[0103] Additionally or alternatively, one can further use the nucleic acid sequences and protein sequences described herein as a "query sequence" to perform searches against public databases to, for example, identify other family member sequences or related sequences.

[0104] 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 genes or sequences 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 coagulants, DNA or RNA expression vectors encapsulated in liposomes, and certain eukaryotic cells, such as production cells.

[0105] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably in this disclosure and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of these cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and progeny derived therefrom, regardless of the number of passages. Progeny may not be completely identical to the parent cell in nucleic acid content, but may contain mutations. Mutant progeny having the same function or biological activity as the cell screened or selected in the initial transformed cell are included herein.

[0106] The present disclosure also relates to a method for producing a monoclonal antibody, which comprises culturing the host cell described in the present disclosure to thereby produce the monoclonal antibody described in the present disclosure.

[0107] As used herein, "subject," "individual," or "subject" refers to an animal, preferably a mammal, and more preferably a human, in need of alleviation, prevention, and / or treatment of a disease or condition, 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 who have a disease or are at risk of having a disease. In the present disclosure, administering an antibody described herein or a pharmaceutical composition or preparation described herein to a subject in need thereof means administering an effective amount of the antibody, pharmaceutical composition, or preparation, etc.

[0108] As used in this disclosure, the term "effective amount" refers to an amount of a drug or pharmaceutical agent that elicits the biological or pharmaceutical response of a tissue, system, animal, or human that is being sought, for example, by a researcher or clinician. Additionally, the term "therapeutically effective amount" refers to an amount that results in improved treatment, cure, prevention, or alleviation of a disease, condition, or side effect, or reduces the rate of progression of a disease or condition, compared to a corresponding subject that has not received that amount. The term also includes within its scope amounts that are effective to enhance normal physiological function.

[0109] II. OSMR-binding antibodies of the present disclosure

[0110] The present disclosure provides antibodies and antigen-binding fragments thereof directed against OSMRβ. The terms "antibodies that bind to OSMRβ protein," "antibodies that bind to OSMRβ," "antibodies against OSMRβ protein," "antibodies that bind to OSMR," "antibodies that bind to OSMR," "antibodies against OSMR protein," "OSMR-binding antibodies," "isolated antibodies that bind to OSMRβ protein," "antibodies against OSMRβ," "antibodies against OSMR," and "OSMRβ protein antibodies" are used interchangeably herein to refer to antibodies of the present disclosure that are capable of binding to OSMRβ protein with sufficient affinity such that the antibodies can be used as prophylactic and / or therapeutic agents targeting OSMRβ protein.

[0111] The antibodies and antigen-binding fragments disclosed herein specifically bind to OSMRβ protein with high affinity, comprising

[0112] (a) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 1 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 2; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0113] (b) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 9 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 10; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0114] (c) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 17 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 18; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0115] (d) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 25 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 26; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0116] (e) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 33 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 34; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0117] (f) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO:41 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO:42; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0118] (g) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO:49 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO:50; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0119] (h) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 57 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 58; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0120] (i) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 65 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 66; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0121] (j) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 73 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 74; or variants thereof having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0122] (k) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO:81 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO:82; or variants thereof having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0123] (1) 3 CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 89 and 3 CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 90; or variants having a single or multiple CDRs with no more than 2 amino acid changes in each CDR region;

[0124] (m) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO:97 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO:98; or variants thereof having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0125] (n) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 105 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 106; or variants thereof having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0126] (o) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 113 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 114; or variants having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0127] (p) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 121 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 122; or a variant having a single or multiple CDRs with no more than two amino acid changes in each CDR region; or

[0128] (q) three CDRs in the heavy chain variable region amino acid sequence set forth in SEQ ID NO: 129 and three CDRs in the light chain variable region amino acid sequence set forth in SEQ ID NO: 130; or variants thereof having a single or multiple CDRs with no more than two amino acid changes in each CDR region;

[0129] 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.

[0130] In some embodiments, the OSMRβ protein antibodies of the present disclosure bind to mammalian OSMRβ protein, such as human OSMRβ protein.

[0131] In some embodiments, the OSMRβ protein antibodies of the present disclosure have one or more of the following characteristics:

[0132] (a) Measured in biofilm interferometry, with a 10 -7 M or smaller, such as 10 -8 M or smaller, 10 -9 M or smaller, 10 -10 M or smaller, 10 -11 M or smaller, 10 -12 M or smaller, or 10 -13 The binding and dissociation equilibrium constant K is M or smaller. D Binds to human OSMRβ protein;

[0133] (b) blocks OSM-mediated signaling with an IC50 of less than about 650 ng / mL, e.g., 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, less than about 75 ng / mL, less than about 50 ng / mL, less than about 25 ng / mL, or less than about 20 ng / mL as measured in SW1271-STAT3-Luc cells; and

[0134] (c) blocks IL-31 mediated signaling with an IC50 of less than about 800 ng / mL, e.g., 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, less than about 150 ng / mL, less than about 100 ng / mL, less than about 75 ng / mL, less than about 50 ng / mL, as measured in SW1271-STAT3-Luc cells.

[0135] In some embodiments, the OSMRβ protein antibody or antigen-binding fragment of the present disclosure comprises

[0136] (a) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a sequence of SEQ ID NO: 1, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the light chain variable region comprises a sequence of SEQ ID NO: 2, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto;

[0137] (b) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a sequence of SEQ ID NO: 9, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the light chain variable region comprises a sequence of SEQ ID NO: 10, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto;

[0138] (c) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a sequence of SEQ ID NO: 17, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the light chain variable region comprises a sequence of SEQ ID NO: 18, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto;

[0139] (d) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a sequence of SEQ ID NO: 25, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the light chain variable region comprises a sequence of SEQ ID NO: 26, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto;

[0140] (e) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a sequence of SEQ ID NO: 33, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the light chain variable region comprises a sequence of SEQ ID NO: 34, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto;

[0141] (f) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a sequence of SEQ ID NO: 41, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the light chain variable region comprises a sequence of SEQ ID NO: 42, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto;

[0142] (g) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a sequence of SEQ ID NO: 49, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the light chain variable region comprises a sequence of SEQ ID NO: 50, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto;

[0143] (h) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a sequence of SEQ ID NO: 57, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the light chain variable region comprises a sequence of SEQ ID NO: 58, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto;

[0144] (i) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a sequence of SEQ ID NO: 65, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the light chain variable region comprises a sequence of SEQ ID NO: 66, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto;

[0145] (j) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a sequence of SEQ ID NO: 73, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the light chain variable region comprises a sequence of SEQ ID NO: 74, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto;

[0146] (k) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a sequence of SEQ ID NO: 81, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the light chain variable region comprises a sequence of SEQ ID NO: 82, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto;

[0147] (l) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a sequence of SEQ ID NO: 89, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the light chain variable region comprises a sequence of SEQ ID NO: 90, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto;

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

[0149] (n) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a sequence of SEQ ID NO: 105, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the light chain variable region comprises a sequence of SEQ ID NO: 106, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto;

[0150] (o) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a sequence of SEQ ID NO: 113, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the light chain variable region comprises a sequence of SEQ ID NO: 114, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto;

[0151] (p) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a sequence of SEQ ID NO: 121, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the light chain variable region comprises a sequence of SEQ ID NO: 122, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto; or

[0152] (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 at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the light chain variable region comprises the sequence of SEQ ID NO: 130, or a sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical thereto.

[0153] Preferably, the amino acid changes do not occur in the CDR regions.

[0154] In some embodiments, the OSMRβ protein antibodies of the present disclosure comprise an Fc region 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.

[0155] A specific OSMRβ protein antibody disclosed herein comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2. This antibody clone is designated 98F11.

[0156] The present disclosure provides antibodies that can specifically bind to OSMRβ protein and compete with antibody 98F11 for binding to an epitope of OSMRβ protein. In one embodiment, this antibody binds to the same epitope as 98F11. The present disclosure also provides affinity matured variants of the 98F11 antibody. In some embodiments, the affinity matured variants of the 98F11 antibody comprise a heavy chain variable region sequence that is at least about 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 1 and a light chain variable region sequence that is at least about 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 2. In some embodiments, the affinity matured variants of the 98F11 antibody comprise a heavy chain variable region sequence of SEQ ID NO: 1 with one, two, three, four, five, six or seven amino acid changes, particularly one, two or three amino acid substitutions. In some embodiments, the affinity matured variant of the 98F11 antibody comprises a light chain variable region sequence having one, two, three, four, five, six or seven amino acid changes, particularly one, two or three amino acid substitutions, of SEQ ID NO: 2. In some embodiments, the affinity matured variant of the 98F11 antibody comprises a heavy chain variable region that is identical to the heavy chain variable region of 98F11 and a light chain variable region that is different from the light chain variable region of 98F11, or vice versa.

[0157] In some embodiments, the affinity matured variant of the 98F11 antibody is an antibody obtained by changing one or more amino acid residues selected from each hypervariable region (CDR) and three positions near each hypervariable region (CDR) of the 98F11 antibody, wherein the amino acid residue changes result in improved affinity of the antibody for OSMRβ protein and / or improved biological activity compared to the parent antibody 98F11 that does not have the amino acid residue changes.

[0158] In some embodiments, the affinity matured variants of the 98F11 antibody comprise a heavy chain variable region and a light chain variable region, wherein i) the heavy chain variable region comprises the sequence of any one of SEQ ID NO: SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 141, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 144, SEQ ID NO: 145, SEQ ID NO: 146, SEQ ID NO: 152, SEQ ID NO: 154, SEQ ID NO: 156, or SEQ ID NO: 157, and the light chain variable region comprises the sequence of SEQ ID NO: 2; ii) the heavy chain variable region comprises the sequence of SEQ ID NO: 1, and the light chain variable region comprises the sequence of any one of SEQ ID NO: 147, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 150, SEQ ID NO: 151, SEQ ID NO: 153, or SEQ ID NO: 158; iii) the heavy chain variable region comprises the sequence of SEQ ID NO: NO: 141, and the light chain variable region comprises the sequence of any one of SEQ ID NO: 147, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 150, SEQ ID NO: 151 or SEQ ID NO: 153; iv) the heavy chain variable region comprises the sequence of any one of SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 144, SEQ ID NO: 145, SEQ ID NO: 152, SEQ ID NO: 154, SEQ ID NO: 155, SEQ ID NO: 156 or SEQ ID NO: 159, and the light chain variable region comprises the sequence of SEQ ID NO: 148; v) the heavy chain variable region comprises the sequence of any one of SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 144, SEQ ID NO: 152 or SEQ ID NO: 156, and the light chain variable region comprises the sequence of SEQ ID NO: 149; or vi) the heavy chain variable region comprises the sequence of SEQ ID NO: 143 or SEQ ID NO: ID NO: 152, and the light chain variable region comprises the sequence of SEQ ID NO: 153.

[0159] 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 refers to the substitution of one amino acid with another within the same amino acid class, e.g., an acidic amino acid with another acidic amino acid, a basic amino acid with another basic amino acid, or a neutral amino acid with another neutral amino acid. Exemplary substitutions are shown in Table A below.

[0160] Table A. Example amino acid substitutions

[0161] In preferred embodiments, the amino acid changes described herein occur in regions outside of the CDRs (e.g., in the FRs). More preferably, the amino acid changes described herein occur in the Fc region. In some embodiments, anti-OSMRβ protein antibodies are provided that include an Fc domain containing one or more mutations that enhance or diminish binding of the antibody to the FcRn receptor, for example, at acidic pH compared to neutral pH. For example, the present disclosure includes CDRs in the Fc domain. H 2 or C H An anti-OSMRβ protein antibody comprising a mutation in region 3, wherein the one or more mutations increase the affinity of the Fc domain for FcRn in an acidic environment (e.g., in endosomes at a pH 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, e.g., modifications at position 250 (e.g., E or Q), positions 250 and 428 (e.g., L or F), position 252 (e.g., L / Y / F / W or T), position 254 (e.g., S or T), and position 256 (e.g., S / R / Q / E / D or T); or modifications at positions 428 and / or 433 (e.g., H / L / R / S / P / Q or K) and / or 434 (e.g., A, W, H, F, or Y [N434A, N434W, N434H, N434F, or N434Y]); or modifications at positions 250 and / or 428; or modifications at positions 307 or 308 (e.g., 308F, V308F) and 434. In one embodiment, the modification includes 428L (e.g., M428L) and 434S (e.g., N434S) modification; 428L, 259I (e.g., V259I) and 308F (e.g., V308F) modification; 433K (e.g., H433K) and 434 (e.g., 434Y) modification; 252, 254 and 256 (e.g., 252Y, 254T and 256E) modification; 250Q and 428L modification (e.g., T250Q and M428L); and 307 and / or 308 modification (e.g., 308F or 308P). In yet another embodiment, the modification includes 265A (e.g., D265A) and / or 297A (e.g., N297A) modification.

[0162] For example, the present disclosure includes anti-OSMRβ protein antibodies comprising an Fc domain comprising one or more pairs (sets) of mutations selected from the group consisting of: 250Q and 248L (e.g., T250Q and M248L); 252Y, 254T, and 256E (e.g., M252Y, S254T, and T256E); 428L and 434S (e.g., M428L and N434S); ); 257I and 311I (e.g., P257I and Q311I); 257I and 434H (e.g., P257I and N434H); 376V and 434H (e.g., D376V and N434H); 307A, 380A, and 434A (e.g., T307A, E380A, and N434A); and 433K and 434F (e.g., H433K and N434F). Any possible combination of the aforementioned Fc domain mutations and other mutations within the antibody variable domains disclosed herein is within the scope of the present disclosure.

[0163] In some embodiments, the OSMRβ protein antibodies provided herein are altered to increase or decrease their degree of glycosylation. Addition or deletion of glycosylation sites to OSMRβ protein antibodies can be conveniently achieved by altering the amino acid sequence to create or remove one or more glycosylation sites. When the OSMRβ protein antibody comprises an Fc region, the carbohydrate attached to the Fc region can be altered. In some applications, modifications to remove unwanted glycosylation sites can be useful, such as removing fucose moieties to enhance antibody-dependent cellular cytotoxicity (ADCC) function (see Shield et al. (2002) JBC 277: 26733). In other applications, galactosylation modifications can be performed 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, such as to enhance the effectiveness of the OSMRβ protein antibodies disclosed herein in preventing and / or treating diseases.

[0164] In some embodiments, the present disclosure provides multispecific antibodies, eg, bispecific antibodies or trispecific antibodies, comprising an OSMRβ protein antibody portion of the present disclosure.

[0165] In some embodiments, the epitope that a bispecific antibody binds is from the same antigen. In other embodiments, the epitope that a bispecific antibody binds is 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-light chains.

[0166] III. Nucleic acids of the present disclosure and host cells containing the same

[0167] In one aspect, the present disclosure 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 producing antibodies or antigen-binding fragments thereof. In another embodiment, the host cell is prokaryotic.

[0168] For example, the nucleic acid of the present disclosure comprises a nucleic acid encoding an amino acid sequence selected from any one of SEQ ID NOs: 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, 139-159, or a nucleic acid encoding an amino acid sequence selected from any one of SEQ ID NOs: A nucleic acid having an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth in any one of 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, 139-159.

[0169] The present disclosure also encompasses nucleic acids that hybridize under stringent conditions to the following nucleic acids, or nucleic acids that encode a polypeptide sequence having one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions compared to the following nucleic acids: nucleic acids comprising a nucleic acid sequence encoding an amino acid sequence selected from any one of SEQ ID NOs: 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, 139-159; or nucleic acids that encode a polypeptide sequence having one or more amino acid substitutions (e.g., conservative substitutions), deletions, or insertions compared to the following nucleic acids. A nucleic acid comprising a nucleic acid sequence having an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth in any one of 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, 139-159.

[0170] 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, lambda phages, or yeast artificial chromosomes (YACs).

[0171] 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 culture medium and screened for suitable activity. Methods and conditions for cultivating the transfected cells produced and for recovering the antibody molecules produced are known to those skilled in the art and can be based on this specification and methods known in the prior art, according to the specific expression vector and mammalian host cell used, change or optimize.

[0172] In addition, can allow to select one or more markers of transfected host cell by introducing, select the cell that stablizes DNA and is incorporated into its chromosome.Marker can for example provide prototrophy, biocidal resistance (for example, antibiotic) or heavy metal (such as copper) resistance etc. to auxotrophic host.Selectable marker gene can be directly connected with dna sequence dna to be expressed or be introduced into identical cell by cotransformation.Also may need extra element so that best synthetic mRNA.These elements can comprise splicing signal, and transcription promoter, enhancer and termination signal.

[0173] In one embodiment, a host cell comprising a polynucleotide of the present disclosure is provided. In some embodiments, a host cell comprising an expression vector of the present disclosure 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 a filamentous fungus or yeast, or various eukaryotic cells, such as insect cells. Vertebrate cells can also be used as hosts. For example, a mammalian cell line modified to be suitable for suspension growth can be used. Examples of useful mammalian host cell lines include SV40-transformed monkey kidney CV1 line (COS-7); human embryonic kidney line (HEK 293 or 293F cells), baby hamster kidney cells (BHK), monkey kidney cells (CV1), African green monkey kidney cells (VERO-76), human cervical carcinoma cells (HELA), canine 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, NSO, P3X63 and Sp2 / 0, etc. For a review of mammalian host cell lines suitable for protein production, see, for example, Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (BKCLo ed., Humana Press, Totowa, NJ), pp. 255-268 (2003). In a preferred embodiment, the host cell is a HEK 293 cell or a CHO cell, for example, a HEK 293-6E cell.

[0174] IV. Production and Purification of OSMRβ Protein Antibodies of the Present Disclosure

[0175] In one embodiment, the present disclosure 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 expression of 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).

[0176] To recombinantly produce the OSMRβ protein antibodies of the present disclosure, nucleic acid encoding the OSMRβ protein antibodies of the present disclosure is first isolated and inserted into a vector for further cloning and / or expression in a host cell. Such nucleic acid is readily isolated and sequenced using conventional procedures, for example, by using oligonucleotide probes that are capable of specifically binding to nucleic acid encoding the OSMRβ protein antibodies of the present disclosure.

[0177] The OSMRβ protein antibodies of the present disclosure, prepared as described herein, can be purified by known techniques such as high performance liquid chromatography, ion exchange chromatography, gel electrophoresis, affinity chromatography, size exclusion chromatography, and the like. The actual conditions used to purify a particular protein will also depend on factors such as net charge, hydrophobicity, hydrophilicity, and the like, and will be apparent to those skilled in the art. The purity of the OSMRβ protein antibodies of the present disclosure can be determined by any of a variety of well-known analytical methods, including size exclusion chromatography, gel electrophoresis, high performance liquid chromatography, and the like.

[0178] V. Activity Assays for OSMRβ Protein Antibodies Disclosed

[0179] The OSMRβ protein antibodies provided herein can be identified, screened, or characterized for their physical / chemical properties and / or biological activity using a variety of assays known in the art. In one aspect, the OSMRβ protein antibodies disclosed herein are tested for antigen binding activity, for example, by known methods such as ELISA. Binding to OSMRβ protein can be determined using methods known in the art, exemplary methods of which are disclosed herein. In some embodiments, binding of the OSMRβ protein antibodies disclosed herein to OSMRβ protein is determined using SPR or biofilm interferometry.

[0180] The present disclosure also provides assays for identifying OSMRβ protein antibodies with biological activity. 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.

[0181] VI. Drug Combinations and Pharmaceutical Formulations

[0182] In some embodiments, the present disclosure provides compositions comprising any of the OSMRβ protein antibodies described herein, preferably compositions comprising pharmaceutical compositions. In one embodiment, the composition further comprises a pharmaceutical excipient. In one embodiment, the composition (e.g., a pharmaceutical composition) comprises an OSMRβ protein antibody disclosed herein, and a combination of one or more other therapeutic agents (e.g., a chemotherapeutic drug, a tumor vaccine, an antibody that binds to a specific antigen on a tumor cell, an antibody that depletes a tumor cell).

[0183] In some embodiments, the pharmaceutical compositions or pharmaceutical formulations of the present disclosure contain suitable pharmaceutical excipients, such as pharmaceutical carriers, pharmaceutical excipients, including buffers, known in the art.

[0184] As used herein, "pharmaceutical carrier" includes any and all solvents, dispersion media, isotonic agents, and absorption delaying agents that are physiologically compatible. Pharmaceutical carriers suitable for the present disclosure can be sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. When the pharmaceutical composition is administered intravenously, water is a preferred carrier. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly 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 of excipients and their applications, see also "Handbook of Pharmaceutical Excipients", Fifth Edition, R.C. Rowe, P.J. Seskey, and S.C. Owen, Pharmaceutical Press, London, Chicago. If desired, the composition may also contain a small amount of a wetting agent or emulsifier, or a pH buffer. 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.

[0185] Pharmaceutical formulations containing the OSMRβ protein antibodies described herein can be prepared by mixing the OSMRβ protein antibodies of the present disclosure having the desired degree of purity with one or more optional pharmaceutical excipients (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. ed. (1980)), preferably in the form of lyophilized formulations or aqueous solutions.

[0186] The pharmaceutical compositions or formulations disclosed herein may also contain more than one active ingredient, the active ingredients being required for the specific indication being treated, preferably those with complementary activities that do not adversely affect each other. When used to treat cancer, such active ingredients include, but are not limited to, anticancer agents and chemotherapeutic agents; when used to treat infectious diseases, such active ingredients include, but are not limited to, antiviral agents and antibiotics. The active ingredients are suitably combined in amounts effective for the intended use.

[0187] Sustained-release preparations can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the OSMRβ protein antibodies of the present disclosure, which matrices are in the form of shaped articles, eg, films, or microcapsules.

[0188] VII. Combination Products or Kits

[0189] In some embodiments, the present disclosure also provides combination products, which contain at least one OSMRβ protein antibody or antigen-binding fragment thereof disclosed herein, or further contain one or more other therapeutic agents (e.g., other anti-itch, anti-inflammatory and anti-fibrotic drugs, etc.).

[0190] In some embodiments, two or more components of the combination product may be co-administered to a subject sequentially, separately, or simultaneously.

[0191] In some embodiments, the present disclosure also provides kits comprising an OSMRβ protein antibody, pharmaceutical composition, or combination product of the present disclosure, and optionally a package insert directing administration.

[0192] In some embodiments, the present disclosure also provides pharmaceutical products comprising the OSMRβ protein antibodies, pharmaceutical compositions, and combination products of the present disclosure, optionally further comprising a package insert for guiding administration.

[0193] VIII. Preventive and / or therapeutic uses of the OSMRβ protein antibodies disclosed herein

[0194] The present disclosure provides methods for preventing a disease or condition associated with OSMRβ-mediated signaling in a subject, comprising administering an antibody of the present disclosure to the subject.

[0195] In some embodiments, the OSMR-binding antibodies and antigen-binding fragments thereof disclosed herein are used, for example, to block OSMRβ-mediated signaling. In some embodiments, physicians can enhance, for example, anti-pruritic, anti-inflammatory, and anti-fibrotic activity in patients by administering the OSMR-binding antibodies or antigen-binding fragments thereof disclosed herein, alone or in combination with other therapeutic agents (sequentially or simultaneously).

[0196] The OSMR-binding antibodies and antigen-binding fragments thereof disclosed herein can be used to prevent and / or treat diseases including, but 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, cirrhosis, cartilage degeneration, bone degradation, arthritis, rheumatoid arthritis, juvenile arthritis, juvenile rheumatoid arthritis, oligoarticular juvenile rheumatoid arthritis, multiarticular spondylosis, ... Juvenile rheumatoid arthritis of the joints, juvenile rheumatoid arthritis with systemic onset, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile reactive arthritis, juvenile Reiter's syndrome (Reter's Syndrome), SEA syndrome (seronegative, terminal disease, arthropathy syndrome), juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, oligoarticular rheumatoid arthritis, multiarticular rheumatoid arthritis, systemic rheumatoid arthritis, ankylosing spondylitis, enteropathic arthritis, reactive arthritis, Reiter's syndrome, SEA syndrome (seronegative, terminal disease, arthropathy syndrome), dermatomyositis, psoriatic arthritis, scleroderma, scleroderma-related interstitial lung disease, vasculitis, myelitis, polymyositis, dermatomyositis, polyarteritis nodosa, Wegener's granulomatosis, arteritis, polymyositis rheumatica, sarcoidosis, scleroderma, sclerosis, primary biliary sclerosis, sclerocholangitis, Sjögren's syndrome, psoriasis, plaque psoriasis, guttate psoriasis, plica 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 hn's disease), ulcerative colitis, celiac disease, multiple sclerosis (MS), asthma, COPD, sinusitis, nasal polyps with sinusitis, eosinophilic esophagitis, eosinophilic bronchitis, bronchitis, Guillain-Barré syndrome, type I diabetes, thyroiditis (such as Graves' disease), Addison's disease, Raynaud's phenomenon, autoimmune hepatitis, GVHD, transplant rejection, renal damage, cardiovascular disease, infection, sepsis, HIV infection, trauma, renal allograft nephropathy, IgA nephropathy,Diabetic nephropathy, diabetic retinopathy, macular degeneration, biliary atresia, congestive heart failure, atherosclerosis, restenosis, radiation-induced fibrosis, chemical-induced fibrosis, burns, surgical trauma, glomerulosclerosis, and the like. In preferred embodiments, the autoimmune disorder, inflammatory disorder, or disorder associated with extracellular matrix deposition or remodeling is 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, inflammation, pruritic inflammation, prurigo nodularis, and pain.

[0197] The OSMR-binding antibodies or antigen-binding fragments thereof of the present disclosure can be administered without other therapeutic treatments, i.e., as a stand-alone therapy (monotherapy). Alternatively, treatment with the OSMR-binding antibodies or antigen-binding fragments thereof of the present disclosure can include at least one other therapeutic treatment (combination therapy), such as another antipruritic agent, an anti-inflammatory agent, and an anti-fibrotic agent.

[0198] The following examples are described to assist in understanding the present disclosure, but are not intended to, and should not be interpreted in any way as, limiting the scope of protection of the present disclosure.

[0199] Example

[0200] The present disclosure 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 disclosure. These examples are not intended to represent that the experiments below are all or the only experiments performed.

[0201] Example 1 Obtaining mice with high titer resistance to recombinant human OSMRβ protein

[0202] 1.1. Preparation of immunogens:

[0203] Highly purified human OSMRβ-Fc protein (hereinafter also referred to as "huOSMRβ-Fc" protein, whose amino acid sequence is shown in SEQ ID NO: 137) was prepared and used for immunization of mice.

[0204] 1.2. Mouse immunization:

[0205] 8-week-old mice (AceMouse) were immunized with the huOSMRβ-Fc protein prepared in Example 1.1. TM , which are fully human antibody transgenic mice independently developed by Shanghai Taijin Biotechnology Co., Ltd.). All mice were housed in an SPF-grade environment, and their health status and weight were observed before immunization.

[0206] For the primary immunization, 50 μg of the immunogen huOSMRβ-Fc was emulsified in complete Freund's adjuvant (Sigma-Aldrich, F5881) and injected subcutaneously into mice. The first, second, and third booster immunizations were administered 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 huOSMRβ-Fc in incomplete Freund's adjuvant (Sigma-Aldrich, F5506). Ten days after the third booster immunization, the final immunization was performed, with each mouse receiving an intraperitoneal injection of 50 μg of huOSMRβ-Fc. Seven days after the final immunization, mouse sera were harvested and assayed for anti-huOSMRβ antibody levels by ELISA.

[0207] 1.3. ELISA method for detecting anti-huOSMRβ antibody levels:

[0208] Human OSMRβ-His protein (hereinafter also referred to as "huOSMRβ-His" protein, the amino acid sequence of which is shown in SEQ ID NO: 138) was prepared.

[0209] 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. The plate was then sealed with plastic wrap and incubated at 4°C overnight. The next day, the supernatant was discarded, the plate was inverted on absorbent paper, patted dry, rinsed once with PBS, and patted dry again. 200 μl of 10% PBSF (PBS containing 10% FBS) was added per well, the plate was sealed with plastic wrap, and incubated at 37°C for 1 hour. The supernatant was discarded and the plate was patted dry. Mouse serum obtained in Example 1.2 was diluted threefold with PBS starting from the starting concentration and added at 100 μl per well. The plate was incubated at room temperature for 1 hour. The supernatant was discarded and the plate was patted dry. The plate was then washed three times with PBST (PBST is freshly prepared PBS containing 0.05% Tween-20 (Sigma-Aldrich)) and patted dry. Then, 50 μl of HRP goat anti-mouse IgG (Biolegend) diluted 1:1000 in PBS containing 5% FBS was added to each well and incubated at room temperature for 1 hour. The cells were washed three times with PBST and patted dry on absorbent paper. 50 μl of TMB (Thermo Scientific) was added to each well for 4 minutes of color development. The reaction was then terminated by adding 50 μl of 0.5 M sulfuric acid to each well. The plate was placed on a multi-function microplate reader (Envision 2105, PerkinElmer), and absorbance was measured at 450 nm to determine the titer of anti-huOSMRβ antibodies in serum.

[0210] Mice with anti-huOSMRβ antibody titers in their serum that reached the standard were selected for subsequent hybridoma fusion experiments.

[0211] Example 2 Preparation and sequencing of anti-OSMRβ antibodies

[0212] The anti-OSMRβ antibodies disclosed herein can be prepared by any of the methods described below. However, the method for preparing the anti-OSMRβ antibodies disclosed herein is not limited to the method described in this example, and can also be prepared by other methods known in the art.

[0213] 2.1. Preparation by hybridoma method:

[0214] Spleen cells were isolated from mice whose serum titers of anti-huOSMRβ antibodies met the standard. Splenocytes were treated with red blood cell lysis buffer, resuspended, and counted. Splenocytes were mixed with sp2 / 0 myeloma cells at a ratio of 1:1 to 10:1 and centrifuged. After centrifugation, the cells were resuspended in electrofusion buffer (NEPA GENE: ECFG21) and fused at a density of at least 2e7 cells / ml. The fused cells were resuspended in medium containing HAT (Gibco, 21060017) and plated into 96-well plates at a density of 50,000 splenocytes / well. Culture was performed in a 37°C CO2 incubator for 10 days. Cell growth was monitored daily. On the third day, 100 μL of HAT-containing medium was added. On the sixth day, all medium was aspirated and 100 μL of fresh HAT-containing medium was added. On the eighth day, the medium was replaced with HAT-free medium. On the 11th day, the cell culture supernatant from each well of the 96-well plate was collected for blocking assay. Several anti-OSMRβ monoclonal antibodies that performed well in blocking experiments were screened.

[0215] 2.2. Isolation of Single B Cells Specific for OSMRβ

[0216] Conjugation of HuOSMRβ-his antigen with PE / R-Phycoerythrin (Abcam: ab10291); and then incubated with rabbit anti-His tag PE (AceMab) at 4°C overnight.

[0217] Spleens from mice with serum containing anti-huOSMRβ antibodies reaching the required titer were harvested and the splenocytes were ground and isolated into single cells. Splenocytes were treated with red blood cell lysis buffer, resuspended, and counted. Splenocytes were incubated with an antigen-antibody complex (i.e., HuOSMRβ-his antigen-rabbit anti-His tag PE). Antigen-specific single B cells were sorted using FACS (BECKMAN, CytoFLEX). Single B cells were cultured and the cell culture supernatant was collected for blocking assays. Multiple anti-OSMRβ monoclonal antibodies that performed well in blocking assays were screened.

[0218] 2.3 Sequences of anti-OSMRβ antibodies

[0219] The names, variable region and complementarity determining region (CDR) sequences of the anti-OSMRβ monoclonal antibodies obtained by Examples 2.1 and 2.2 (according to IMGT numbering) are shown in Table 1 below.

[0220] Table 1 Variable region and complementarity determining region sequences of anti-OSMRβ monoclonal antibodies

[0221] Example 3 Affinity detection of anti-OSMRβ antibodies

[0222] The antibody obtained in Example 2 was used to detect the binding kinetics of the antibody to HuOSMRβ-his protein by biolayer interferometry (BLI).

[0223] The test antibodies were diluted in a buffer solution (PBS (10 mM pH 7.4) + 0.02% Tween + 0.2% BSA) to 60 nM, 30 nM, 15 nM, 7.5 nM, 3.75 nM, and 1.875 nM, respectively, and added to a 96-well plate at 200 μl / well. HuOSMRβ-his was then diluted in a buffer solution (PBS (10 mM pH 7.4) + 0.02% Tween + 0.2% BSA) to 4 μg / ml and added to a 96-well plate (Gator). 250 μl of buffer solution (PBS (10 mM pH 7.4) + 0.02% Tween + 0.2% BSA) was added to each well of a Gator MAX plate, and the probes were immersed in the wells (soaking for at least 5 minutes before testing). Affinity was measured using the Gator Prime label-free biomolecular analyzer. The specific procedure for affinity detection is as follows: add buffer and run for 120 seconds; inject the above-mentioned antibody dilutions of each concentration for 60 seconds, add buffer and run for 120 seconds; the association time is 240 seconds, the dissociation time is 300 seconds, and regeneration is performed for 5 seconds using deionized water + 10mM glycine + 150mM NaCl, (pH 1.75); neutralize with buffer for 5 seconds, and repeat the regeneration and neutralization three times. The association rate (Kon) and dissociation rate (Koff) are calculated using a simple one-to-one Languir binding model, and the equilibrium dissociation constant (K D ) is calculated as the ratio Koff / Kon.

[0224] The antibody affinity test results are shown in Table 2 below.

[0225] Table 2 Affinity test results of antibodies and human OSMRβ protein

[0226] As can be seen from Table 2, all antibodies bind to human OSMRβ protein with high affinity.

[0227] Example 4 Antibody blocking experiment on OSM

[0228] The pSTAT3-Luc plasmid (Yisheng Bio) 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. 4 SW1271-STAT3-Luc cells were seeded in a 96-well plate and cultured overnight in a 37°C CO2 incubator. The anti-OSMRβ antibody obtained in Example 2 was then serially diluted, starting at 10 μg / mL and then three-fold diluted for a total of 10 concentrations. Twenty-five microliters of the diluted antibody was added to each well and incubated with the SW1271-STAT3-Luc cells for one hour. Twenty-five microliters of 4 ng / mL OSM was added, and the cells were incubated for six hours. Then, 50 microliters of Bright-Glo (Promega: E2620) was added to each well, incubated for 10 minutes, and chemiluminescence was detected using a microplate reader.

[0229] 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.

[0230] Table 3 IC of antibodies blocking OSM 50

[0231] Example 5 Antibody blocking experiment on IL31

[0232] 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. The anti-OSMRβ antibody obtained in Example 2 was then serially diluted, starting at 10 μg / mL and then three-fold diluted for a total of 10 concentrations. Twenty-five microliters of the diluted antibody was added to each well and incubated with the SW1271-STAT3-Luc cells for one hour. Twenty-five microliters of 40 ng / mL IL31 (Sino Biological) was added, and the cells were incubated for six hours. Then, 50 microliters of Bright-Glo (Promega) was added to each well, 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 antibodies blocking IL31 50

[0235] Example 6. Affinity maturation of humanized antibodies

[0236] In this example, antibody 98F11 was affinity matured to improve affinity and biological activity. Affinity maturation was performed using a single-point saturation mutagenesis technique and a high-throughput mammalian cell expression system. Single-point saturation mutagenesis involves replacing each amino acid residue in each CDR region of antibody 98F11 and at three positions near each CDR region with the remaining 17 amino acid residues (excluding the parent amino acid residue, methionine, and cysteine). This generates 17 mutants for each amino acid position in the CDR region and at three positions near the CDR region. ELISA was used to identify mutation hotspots that enhance antigen-specific binding, and these hotspots were then combined to further obtain candidate antibodies with improved affinity and biological activity relative to the parent antibody.

[0237] 6.1 Mutation Construction

[0238] For each amino acid site in the CDR region and its three nearby positions, primers containing 17 mutant amino acids were designed and synthesized (synthesized by Bio-Tech). PCR amplification was performed using Q5 High-Fidelity DNA Polymerase (NEB: M0491) according to the enzyme's instructions to obtain 17 antibody sequences with single-point mutations at that site. These sequences were inserted into a vector to construct a single-point saturation mutation plasmid library at that site (1402Quick Cloning Kit - Zhongsheng Quanpeptide Biochemical Co., Ltd.), which was then transfected into Top10 competent cells (Bio-Tech), plated on agar plates, and cultured overnight at 37°C.

[0239] 6.2 Plasmid extraction

[0240] Each agar plate corresponds to a specific locus, and the cell clones on each plate cover all 17 mutant plasmids at that locus. 88 single colonies were selected from each plate and cultured in 96-deep-well plates.

[0241] Monoclonal clones cultured in 96-deep-well plates were used to obtain mutant plasmids through high-throughput plasmid extraction. 88 monoclonal mutant plasmids were obtained for each mutation site, and the 88 monoclonal mutant plasmids covered all 17 types of mutant plasmids.

[0242] 6.3 High-throughput mammalian expression

[0243] The expression supernatant of the corresponding monoclonal mutant plasmid was obtained through the high-throughput 293F mammalian cell expression system. For each mutation site, 88 monoclonal mutant plasmid transfected antibody supernatants were obtained for subsequent hotspot screening ELISA.

[0244] 6.4 Hotspot Screening

[0245] The ELISA plate was coated with 1:5000 diluted goat anti-human IgG (Fc) (Jackson: 109-005-008) and incubated at 4°C for 16 hours; after washing, the plate was blocked with casein blocking solution (Baiying Bio) at 25°C for 1 hour; then the antibody supernatant to be tested was added and incubated at 37°C for 1 hour; after washing, biotin-labeled (SIGMA / H1759-5MG, the antigen was labeled in advance according to the instructions of the biotin labeling kit) OSMRβ antigen was added and incubated at 25°C for 5 minutes; incubated with PBS buffer at 25°C for another 30 minutes; after washing, SA-HRP (Sangon: D111054-0001) was added and incubated at 25°C for 45 minutes; after washing, TMB color development solution (Beyotime: P0209-500ml) was added and color was developed at 25°C in the dark for 4 minutes; finally, TMB color development stop solution (Beyotime: P0215-500ml) was added to terminate the reaction and the OD was read. 450 value.

[0246] 6.5 Hotspot Sequencing and Expression

[0247] Single-point mutant clones with high OD (optical density) values ​​were selected, and expression plasmids were constructed to express the corresponding antibodies. The antibody names, variable region, and complementarity-determining region (CDR) sequences (according to IMGT numbering) of the expressed single-point mutants are shown in Table 5 below. Their blocking activities against the OSM pathway and IL-31 were assessed using cell-based assays as described in Examples 4 and 5, with the results shown in Table 6.

[0248] Table 5 Variable region and complementarity determining region sequences (IMGT numbering scheme) of antibodies obtained after single mutation of parental antibody 98F11 (SEQ ID NO:

[0249] *Naming convention for mutant antibodies: Parental antibody 98F11_Heavy chain H: single-letter amino acid code before mutation + mutation site + single-letter amino acid code after mutation_Light chain L: single-letter amino acid code before mutation + mutation site + single-letter amino acid code after mutation.

[0250] Table 6 Blocking activity of antibodies obtained after single mutation of parental antibody 98F11 on OSM pathway and IL31

[0251] 6.7 Hotspot Combination

[0252] Different single-point mutations were combined to construct expression plasmids for combined mutations, which were then transfected into 293F cells to express the corresponding antibodies. The antibody names, variable region, and complementarity-determining region (CDR) sequences (according to IMGT numbering) are shown in Table 7. The blocking activity of the combined mutation antibodies against the IL31 pathway was tested using cell-based assays as described in Example 5, with the results shown in Table 8.

[0253] Table 7 Variable region and complementarity determining region sequences (IMGT numbering scheme) of the antibodies obtained after multiple point mutations of the parent antibody 98F11 (SEQ ID NO:

[0254] *Naming convention for mutant antibodies: Parental antibody 98F11_Heavy chain H: single-letter amino acid code before mutation + mutation site + single-letter amino acid code after mutation_Light chain L: single-letter amino acid code before mutation + mutation site + single-letter amino acid code after mutation.

[0255] Table 8 Blocking activity of multi-point mutation antibodies against IL31

[0256] 6.8 Affinity Testing of Candidate Antibodies

[0257] The top three combined mutant antibodies were tested for their blocking activity against the OSM pathway and IL31, as described in Examples 4 and 5, and their affinity for the OSMR antigen. Specifically, the antibodies were diluted to 1 μg / mL using HBS-EP+ running buffer (Biacore Biotech) in a Biacore 8K system (Cytiva). The antibodies were coupled to a Protein A Chip (Cytiva: 29127556) at a flow rate of 10 μg / mL. The kinetics and affinity data for antigen-antibody binding were measured at a flow rate of 30 μg / mL and 6 μg / mL, with an association time of 120 s and a dissociation time of 600 s. The results shown in Table 9 were obtained.

[0258] Table 9 Affinity and blocking activity of multi-point mutation antibodies on OSM pathway and IL31

[0259] While the exemplary embodiments of the present disclosure are described above, it should be understood by those skilled in the art that these disclosures are merely exemplary and that various other replacements, adaptations, and modifications may be made within the scope of the present disclosure. Therefore, the present disclosure is not limited to the specific embodiments listed herein.

[0260] Exemplary sequences

Claims

1. An isolated antibody or antigen-binding fragment that specifically binds to 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 2 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 2 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 2 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 2 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 2 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 2 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 2 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 2 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 variants having single or multiple amino acid changes not exceeding two amino acids in each of 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 thereof with no more than 2 amino acid changes of the HCDR1 shown in SEQ ID NO: 19, the HCDR2 shown in SEQ ID NO: 20 or a variant thereof with no more than 2 amino acid changes of the HCDR2 shown in SEQ ID NO: 20, and the HCDR3 shown in SEQ ID NO: 21 or a variant thereof with no more than 2 amino acid changes of the HCDR3 shown in SEQ ID NO: 21; the LCDR1 shown in SEQ ID NO: 22 or a variant thereof with no more than 2 amino acid changes of the LCDR1 shown in SEQ ID NO: 22, the LCDR2 shown in SEQ ID NO: 23 or a variant thereof with no more than 2 amino acid changes of the LCDR2 shown in SEQ ID NO: 23, and the LCDR3 shown in SEQ ID NO: 24 or a variant thereof with no more than 2 amino acid changes of the LCDR3 shown in SEQ ID NO: 24; (d) The HCDR1 shown in SEQ ID NO: 27 or a variant thereof with no more than 2 amino acid changes of the HCDR1 shown in SEQ ID NO: 27, the HCDR2 shown in SEQ ID NO: 28 or a variant thereof with no more than 2 amino acid changes of the HCDR2 shown in SEQ ID NO: 28, and the HCDR3 shown in SEQ ID NO: 29 or a variant thereof with no more than 2 amino acid changes of the HCDR3 shown in SEQ ID NO: 29; the LCDR1 shown in SEQ ID NO: 30 or a variant thereof with no more than 2 amino acid changes of the LCDR1 shown in SEQ ID NO: 30, the LCDR2 shown in SEQ ID NO: 31 or a variant thereof with no more than 2 amino acid changes of the LCDR2 shown in SEQ ID NO: 31, and the LCDR3 shown in SEQ ID NO: 32 or a variant thereof with no more than 2 amino acid changes of the LCDR3 shown in SEQ ID NO: 32; (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; (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; (g) The HCDR1 shown in SEQ ID NO: 51 or a variant thereof with no more than 2 amino acid changes of the HCDR1 shown in SEQ ID NO: 51, the HCDR2 shown in SEQ ID NO: 52 or a variant thereof with no more than 2 amino acid changes of the HCDR2 shown in SEQ ID NO: 52, and the HCDR3 shown in SEQ ID NO: 53 or a variant thereof with no more than 2 amino acid changes of the HCDR3 shown in SEQ ID NO: 53; the LCDR1 shown in SEQ ID NO: 54 or a variant thereof with no more than 2 amino acid changes of the LCDR1 shown in SEQ ID NO: 54, the LCDR2 shown in SEQ ID NO: 55 or a variant thereof with no more than 2 amino acid changes of the LCDR2 shown in SEQ ID NO: 55, and the LCDR3 shown in SEQ ID NO: 56 or a variant thereof with no more than 2 amino acid changes of the LCDR3 shown in SEQ ID NO: 56; (h) The HCDR1 shown in SEQ ID NO: 59 or a variant thereof with no more than 2 amino acid changes of the HCDR1 shown in SEQ ID NO: 59, the HCDR2 shown in SEQ ID NO: 60 or a variant thereof with no more than 2 amino acid changes of the HCDR2 shown in SEQ ID NO: 60, and the HCDR3 shown in SEQ ID NO: 61 or a variant thereof with no more than 2 amino acid changes of the HCDR3 shown in SEQ ID NO: 61; the LCDR1 shown in SEQ ID NO: 62 or a variant thereof with no more than 2 amino acid changes of the LCDR1 shown in SEQ ID NO: 62, the LCDR2 shown in SEQ ID NO: 63 or a variant thereof with no more than 2 amino acid changes of the LCDR2 shown in SEQ ID NO: 63, and the LCDR3 shown in SEQ ID NO: 64 or a variant thereof with no more than 2 amino acid changes of the LCDR3 shown in SEQ ID NO: 64; (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 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; (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; (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 as shown in SEQ ID NO: 115 or a variant thereof with no more than 2 amino acid changes of HCDR1 as shown in SEQ ID NO: 115, HCDR2 as shown in SEQ ID NO: 116 or a variant thereof with no more than 2 amino acid changes of HCDR2 as shown in SEQ ID NO: 116, and HCDR3 as shown in SEQ ID NO: 117 or a variant thereof with no more than 2 amino acid changes of HCDR3 as shown in SEQ ID NO: 117; LCDR1 as shown in SEQ ID NO: 118 or a variant thereof with no more than 2 amino acid changes of LCDR1 as shown in SEQ ID NO: 118, LCDR2 as shown in SEQ ID NO: 119 or a variant thereof with no more than 2 amino acid changes of LCDR2 as shown in SEQ ID NO: 119, and LCDR3 as shown in SEQ ID NO: 120 or a variant thereof with no more than 2 amino acid changes of LCDR3 as shown in SEQ ID NO: 120; (p)HCDR1 as shown in SEQ ID NO: 123 or a variant thereof with no more than 2 amino acid changes of HCDR1 as shown in SEQ ID NO: 123, HCDR2 as shown in SEQ ID NO: 124 or a variant thereof with no more than 2 amino acid changes of HCDR2 as shown in SEQ ID NO: 124, and HCDR3 as shown in SEQ ID NO: 125 or a variant thereof with no more than 2 amino acid changes of HCDR3 as shown in SEQ ID NO: 125; LCDR1 as shown in SEQ ID NO: 126 or a variant thereof with no more than 2 amino acid changes of LCDR1 as shown in SEQ ID NO: 126, LCDR2 as shown in SEQ ID NO: 127 or a variant thereof with no more than 2 amino acid changes of LCDR2 as shown in SEQ ID NO: 127, and LCDR3 as shown in SEQ ID NO: 128 or a variant thereof with no more than 2 amino acid changes of LCDR3 as shown in SEQ ID NO: 128; 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 any one of the HCDR3s shown in SEQ ID NO: 5, SEQ ID NO: 161, SEQ ID NO: 162, SEQ ID NO: 163, SEQ ID NO: 164, SEQ ID NO: 165 or SEQ ID NO: 166; 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; The HCDR1 shown in SEQ ID NO: 3, the HCDR2 shown in SEQ ID NO: 160 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; 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: 168 or SEQ ID NO: 169, the LCDR2 shown in SEQ ID NO: 7 and the LCDR3 shown in SEQ ID NO: 8; HCDR1 as shown in SEQ ID NO:3, HCDR2 as shown in SEQ ID NO:4, and HCDR3 as shown in any one of SEQ ID NO:5, SEQ ID NO:162, SEQ ID NO:163, SEQ ID NO:164 or SEQ ID NO:165; LCDR1 as shown in SEQ ID NO:6, LCDR2 as shown in SEQ ID NO:170 and LCDR3 as shown in SEQ ID NO:8; HCDR1 as shown in SEQ ID NO:3, HCDR2 as shown in SEQ ID NO:4 and HCDR3 as shown in SEQ ID NO:5; LCDR1 as shown in SEQ ID NO:6, LCDR2 as shown in SEQ ID NO:7, and LCDR3 as shown in SEQ ID NO:171 or SEQ ID NO:172; HCDR1 as shown in SEQ ID NO:3, HCDR2 as shown in SEQ ID NO:4 and HCDR3 as shown in SEQ ID NO:162; LCDR1 as shown in SEQ ID NO:168 or SEQ ID NO:169, LCDR2 as shown in SEQ ID NO:7 and LCDR3 as shown in SEQ ID NO:8; HCDR1 as shown in SEQ ID NO:3, HCDR2 as shown in SEQ ID NO:4 and HCDR3 as shown in SEQ ID NO:163; LCDR1 as shown in SEQ ID NO:169, LCDR2 as shown in SEQ ID NO:7 and LCDR3 as shown in SEQ ID NO:8; HCDR1 as shown in SEQ ID NO:3, HCDR2 as shown in SEQ ID NO:4 and HCDR3 as shown in any one of SEQ ID NO:5, SEQ ID NO:162, SEQ ID NO:164 or SEQ ID NO:165; LCDR1 as shown in SEQ ID NO:169, LCDR2 as shown in SEQ ID NO:170 and LCDR3 as shown in SEQ ID NO:8; HCDR1 as shown in SEQ ID NO:3, HCDR2 as shown in SEQ ID NO:4 and HCDR3 as shown in any one of SEQ ID NO:5, SEQ ID NO:164, SEQ ID NO:165, SEQ ID NO:166 or SEQ ID NO:167; LCDR1 as shown in SEQ ID NO:169, LCDR2 as shown in SEQ ID NO:7 and LCDR3 as shown in SEQ ID NO:8; HCDR1 set forth in SEQ ID NO:3, HCDR2 set forth in SEQ ID NO:4, and HCDR3 set forth in SEQ ID NO:162; LCDR1 set forth in SEQ ID NO:6, LCDR2 set forth in SEQ ID NO:7, and LCDR3 set forth in SEQ ID NO:171 or SEQ ID NO:172; or HCDR1 set forth in SEQ ID NO:3, HCDR2 set forth in SEQ ID NO:4, and HCDR3 set forth in SEQ ID NO:5; LCDR1 set forth in SEQ ID NO:6, LCDR2 set forth in SEQ ID NO:170, and LCDR3 set forth in SEQ ID NO:171; Most preferably, the isolated antibody or antigen-binding fragment that specifically binds to the OSMRβ protein comprises HCDR1 set forth in SEQ ID NO:3, HCDR2 set forth in SEQ ID NO:4, and HCDR3 set forth in SEQ ID NO:5; LCDR1 set forth in SEQ ID NO:6, LCDR2 set forth in SEQ ID NO:7, and LCDR3 set forth in SEQ ID NO:8; HCDR1 set forth in SEQ ID NO:3, HCDR2 set forth in SEQ ID NO:4, and HCDR3 set forth in SEQ ID NO:162; LCDR1 set forth in SEQ ID NO:169, LCDR2 set forth in SEQ ID NO:7, and LCDR3 set forth in SEQ ID NO:8; HCDR1 set forth in SEQ ID NO:3, HCDR2 set forth in SEQ ID NO:4, and HCDR3 set forth in SEQ ID NO:162; LCDR1 set forth in SEQ ID NO:168, LCDR2 set forth in SEQ ID NO:7, and LCDR3 set forth in SEQ ID NO:8; HCDR1 set forth in SEQ ID NO:3, HCDR2 set forth in SEQ ID NO:4, and HCDR3 set forth in SEQ ID NO:163; LCDR1 set forth in SEQ ID NO:169, LCDR2 set forth in SEQ ID NO:7, and LCDR3 set forth in SEQ ID NO:8; (b) HCDR1 set forth in SEQ ID NO:11, HCDR2 set forth in SEQ ID NO:12, and HCDR3 set forth in SEQ ID NO:13; LCDR1 set forth in SEQ ID NO:14, LCDR2 set forth in SEQ ID NO:15, and LCDR3 set forth in SEQ ID NO:16; (c)HCDR1 shown in SEQ ID NO:19, HCDR2 shown in SEQ ID NO:20, and HCDR3 shown in SEQ ID NO:21; LCDR1 shown in SEQ ID NO:22, LCDR2 shown in SEQ ID NO:23, and LCDR3 shown in SEQ ID NO:24; (d)HCDR1 shown in SEQ ID NO:27, HCDR2 shown in SEQ ID NO:28, and HCDR3 shown in SEQ ID NO:29; LCDR1 shown in SEQ ID NO:30, LCDR2 shown in SEQ ID NO:31, and 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, HCDR2 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 HCDR3 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; (m)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 LCDR3 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 HCDR3 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; For example, wherein the heavy chain variable region comprises the sequence of any one of SEQ ID NO: 1, SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 141, SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 144, SEQ ID NO: 145, SEQ ID NO: 146, SEQ ID NO: 152, SEQ ID NO: 154, SEQ ID NO: 156 or SEQ ID NO: 157, and the light chain variable region comprises the sequence of SEQ ID NO: 2; wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 1, and the light chain variable region comprises the sequence of any one of SEQ ID NO: 147, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 150, SEQ ID NO: 151, SEQ ID NO: 153 or SEQ ID NO: 158; wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 141, and the light chain variable region comprises the sequence of any one of SEQ ID NO: 147, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 150, SEQ ID NO: 151 or SEQ ID NO: 153; wherein the heavy chain variable region comprises the sequence of any one of SEQ ID NO: 142, SEQ ID NO: 143, SEQ ID NO: 144, SEQ ID NO: 145, SEQ ID NO: 152, SEQ ID NO: 154, SEQ ID NO: 155, SEQ ID NO: 156 or SEQ ID NO: 159, and the light chain variable region comprises the sequence of SEQ ID NO: 148; or wherein the heavy chain variable region comprises the sequence of any one of SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:152 or SEQ ID NO:156, and the light chain variable region comprises the sequence of SEQ ID NO:149; or wherein the heavy chain variable region comprises the sequence of SEQ ID NO:143 or SEQ ID NO:152, and the light chain variable region comprises the sequence of SEQ ID NO:153; Preferably, wherein the heavy chain variable region comprises the sequence of SEQ ID NO:1, and the light chain variable region comprises the sequence of SEQ ID NO:2; wherein the heavy chain variable region comprises the sequence of SEQ ID NO:141, and the light chain variable region comprises the sequence of SEQ ID NO:148; wherein the heavy chain variable region comprises the sequence of SEQ ID NO:141, and the light chain variable region comprises the sequence of SEQ ID NO:174; wherein the heavy chain variable region comprises the sequence of SEQ ID NO:142, and the light chain variable region comprises the sequence of SEQ ID NO:148; (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; For example, wherein the heavy chain variable region comprises the sequence of SEQ ID NO:9, and the light chain variable region comprises the sequence of SEQ ID NO:10; (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; For example, wherein the heavy chain variable region comprises the sequence of SEQ ID NO:17, and the light chain variable region comprises the sequence of SEQ ID NO:18; (d) a heavy chain variable region and a 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; For example, a heavy chain variable region comprising the sequence of SEQ ID NO:25 and a light chain variable region comprising the sequence of SEQ ID NO:26; (e) A heavy chain variable region and a 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; For example, a heavy chain variable region comprising the sequence of SEQ ID NO:33 and a light chain variable region comprising the sequence of SEQ ID NO:34; (f) A heavy chain variable region and a 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; For example, a heavy chain variable region comprising the sequence of SEQ ID NO:41 and a light chain variable region comprising the sequence of SEQ ID NO:42; (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; For example, a heavy chain variable region comprising the sequence of SEQ ID NO:49 and a light chain variable region comprising the sequence of SEQ ID NO:50; (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; For example, a heavy chain variable region comprising the sequence of SEQ ID NO:57 and a light chain variable region comprising the sequence of SEQ ID NO:58; (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; For example, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 65, and the light chain variable region comprises the sequence of SEQ ID NO: 66; (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; For example, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 73, and the light chain variable region comprises the sequence of SEQ ID NO: 74; (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; For example, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 81, and the light chain variable region comprises the sequence of SEQ ID NO: 82; (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; For example, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 89, and the light chain variable region comprises the sequence of SEQ ID NO: 90; (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; For example, wherein the heavy chain variable region comprises the sequence of SEQ ID NO:105, and the light chain variable region comprises the sequence of SEQ ID NO:106; (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; For example, wherein the heavy chain variable region comprises the sequence of SEQ ID NO:113, and the light chain variable region comprises the sequence of SEQ ID NO:114; (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; For example, wherein the heavy chain variable region comprises the sequence of SEQ ID NO:121, and the light chain variable region comprises the sequence of SEQ ID NO:122; 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; For example, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 129 and the light chain variable region comprises the sequence of SEQ ID NO:

130.

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 biofilm 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 that 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, and 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, and 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, liver cirrhosis, psoriasis, atopic dermatitis, systemic cutaneous amyloidosis, primary cutaneous amyloidosis, pruritic inflammation, prurigo nodularis and pain.

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