ROR1-binding protein and its uses

Abstract

The present invention relates to the field of disease treatment, in particular to anti-ROR1 antibodies or antigen-binding fragments thereof, nucleic acid molecules encoding them, and methods for producing them. The anti-ROR1 antibodies or antigen-binding fragments thereof of the present invention have high specificity and high affinity for ROR1, and can effectively bind to ROR1 and mediate the killing of ROR1-expressing cells. Thus, the present invention further relates to pharmaceutical compositions comprising said antibodies or antigen-binding fragments thereof, and their use in the manufacture of medicaments for preventing and / or treating tumors.

Description

[Technical field]

[0001] The present invention is in the field of therapeutic monoclonal antibodies, more specifically, to antibodies against ROR1 and further to the use of said antibodies in the treatment of diseases. [Background technology]

[0002] Receptor tyrosine kinases (RTKs) are multifunctional transmembrane proteins that act on cytokines, growth factors, hormones and other signaling molecule receptors and play important roles in various cellular processes including growth, differentiation, angiogenesis and the progression of various cancers. Receptor tyrosine kinase-like orphan receptor 1 (ROR1), a member of the receptor RTKs family, has a very high homology to the tyrosine kinase domain of growth factor receptors, is low expressed during embryonic development and highly expressed in various solid and hematological malignancies, including various leukemias, non-Hodgkin's lymphomas, breast cancer, ovarian cancer, melanoma, lung cancer, etc. Therefore, ROR1 is a novel drug target with broad-spectrum anticancer potential.

[0003] In recent years, genetically engineered antibodies targeting ROR1, including single-chain fragment variables (scFvs), chimeric antibodies, Fab-based antibodies, antibody-drug conjugates (ADC), chimeric antigen receptors (CAR) and bispecific antibodies (BiAb), have been successively developed in the research of tumor immunotherapy. At present, the anti-ROR1 monoclonal antibody that is being researched rapidly is cirmutuzumab from Oncternal Therapeutics, which has a high anti-cancer effect according to clinical data and can effectively inhibit the proliferation, migration and survival of chronic leukemia tumor cells.

[0004] Currently, there is no antibody drug targeting ROR1 on the market, so there is an urgent need to develop anti-ROR1 antibodies with higher specificity, lower toxicity and side effects, better clinical efficacy, and more convenient administration methods, which will provide patients with more administration choices. Summary of the Invention [Problem to be solved by the invention]

[0005] In this application, the inventors first developed a mouse-derived antibody with excellent properties that can specifically recognize / bind to ROR1 without binding to ROR2. Based on this, the inventors have made a great deal of creative efforts to intensively study and modify the mouse-derived antibody to develop a chimeric antibody and a humanized antibody of the mouse-derived antibody. The humanized antibody of the present invention not only has a very high level of humanization, but also has substantially the same (or even better) biological functions as a mouse-derived antibody and a human-mouse chimeric antibody (wherein the chimeric antibody has the exact same heavy chain variable region and light chain variable region as the mouse-derived antibody).

[0006] Therefore, the antibodies of the present invention (especially humanized antibodies) are particularly advantageous, not only maintaining the functions and properties of the parent mouse-derived antibodies, but also having the ability to prevent and treat tumors, for example, because they bind to ROR1 with high affinity and specificity. In addition, the antibodies of the present invention can more effectively induce ROR1-mediated endocytosis when bound to ROR1 on the cell surface, and therefore can be used as vectors for targeted therapy. The humanized antibodies of the present invention have a very high level of humanization, and therefore can be safely administered to human subjects without inducing an immunogenic response. Thus, the antibodies of the present invention have significant clinical value. [Means for solving the problem]

[0007] Antibodies of the Invention In one aspect, the invention provides an antibody or antigen-binding fragment thereof capable of specifically binding to ROR1.

[0008] In some embodiments, the invention provides antibodies or antigen-binding fragments thereof capable of specifically binding to the ROR1 extracellular domain (ECD).

[0009] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (a) CDR-H1, CDR-H2 and CDR-H3 contained in the heavy chain variable region (VH) shown in any one of SEQ ID NOs: 1, 102 to 106, and / or CDR-L1, CDR-L2 and CDR-L3 contained in the light chain variable region (VL) shown in any one of SEQ ID NOs: 2, 107 to 110; Or, (b) CDR-H1, CDR-H2 and CDR-H3 contained in the heavy chain variable region (VH) shown in any one of SEQ ID NOs: 3, 84 to 86, and / or CDR-L1, CDR-L2 and CDR-L3 contained in the light chain variable region (VL) shown in any one of SEQ ID NOs: 4, 87 to 101; Or, (c) CDR-H1, CDR-H2 and CDR-H3 contained in the heavy chain variable region (VH) shown in any one of SEQ ID NOs: 5, 111 to 115, and / or CDR-L1, CDR-L2 and CDR-L3 contained in the light chain variable region (VL) shown in any one of SEQ ID NOs: 6, 107, and 116 to 118; Or, (d) The heavy chain variable region (VH) comprises complementarity determining regions (CDRs) CDR-H1, CDR-H2, and CDR-H3, and / or CDR-L1, CDR-L2, and CDR-L3, which are contained in the light chain variable region (VL) described below, and the heavy chain variable region (VH) and / or light chain variable region (VL) comprises, compared with the heavy chain variable region and / or light chain variable region described in any one of (a) to (c), at least one CDR comprises a mutation which is one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of one, two, or three amino acids), and preferably the substitutions are conservative substitutions.

[0010] In some preferred embodiments, the CDRs are defined according to the Chothia, AbM, Kabat or IMGT numbering systems, preferably the VH and / or VL of the antibody or antigen-binding fragment thereof comprise immunoglobulin framework regions (FRs) of human or mouse origin, and preferably the antibody or antigen-binding fragment thereof binds to human ROR1.

[0011] In some embodiments, an antibody or antigen-binding fragment thereof capable of specifically binding to ROR1 is provided, the antibody or antigen-binding fragment thereof comprising a heavy chain variable region (VH) and / or a light chain variable region (VL).

[0012] In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention have CDRs as defined by the Chothia numbering system: (a) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in sequence SEQ ID NO:64, CDR-H2 as set forth in sequence SEQ ID NO:65, and CDR-H3 as set forth in sequence SEQ ID NO:47; and / or A light chain variable region (VL) comprising three CDRs: CDR-L1 shown in any one of SEQ ID NOs: 48 to 55, CDR-L2 shown in any one of SEQ ID NOs: 56 to 58, and CDR-L3 shown in SEQ ID NO: 44; Or, (b) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in sequence SEQ ID NO: 31, CDR-H2 as shown in sequence SEQ ID NO: 32 to 34, and CDR-H3 as shown in sequence SEQ ID NO: 20; and / or A light chain variable region (VL) comprising three CDRs: CDR-L1 shown in any one of SEQ ID NOs: 21 to 23 and 77, CDR-L2 shown in SEQ ID NO: 24 or 25, and CDR-L3 shown in SEQ ID NO: 15; Or, (c) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in sequence SEQ ID NO:82, CDR-H2 as set forth in sequence SEQ ID NO:83, and CDR-H3 as set forth in sequence SEQ ID NO:74; and / or It comprises a light chain variable region (VL) comprising three CDRs: CDR-L1 shown in any one of SEQ ID NOs: 75 to 77, CDR-L2 shown in SEQ ID NO: 24 or 78, and CDR-L3 shown in SEQ ID NO: 15.

[0013] In some embodiments, the antibody or antigen-binding fragment thereof has CDRs defined by the Chothia numbering system: (1) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO:64, CDR-H2 as set forth in the sequence SEQ ID NO:65, and CDR-H3 as set forth in the sequence SEQ ID NO:47; and / or A light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 48, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (2) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 64, CDR-H2 as set forth in the sequence SEQ ID NO: 65, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in sequence SEQ ID NO: 48, CDR-L2 as set forth in sequence SEQ ID NO: 57, and CDR-L3 as set forth in sequence SEQ ID NO: 44; Or, (3) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 64, CDR-H2 as set forth in the sequence SEQ ID NO: 65, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 49, CDR-L2 as shown in sequence SEQ ID NO: 57, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (4) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 64, CDR-H2 as set forth in the sequence SEQ ID NO: 65, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:50, CDR-L2 as shown in sequence SEQ ID NO:58, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (5) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 64, CDR-H2 as set forth in the sequence SEQ ID NO: 65, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:51, CDR-L2 as shown in sequence SEQ ID NO:56, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (6) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 64, CDR-H2 as set forth in the sequence SEQ ID NO: 65, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in sequence SEQ ID NO:52, CDR-L2 as set forth in sequence SEQ ID NO:56, and CDR-L3 as set forth in sequence SEQ ID NO:44; Or, (7) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 64, CDR-H2 as set forth in the sequence SEQ ID NO: 65, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in sequence SEQ ID NO:53, CDR-L2 as set forth in sequence SEQ ID NO:56, and CDR-L3 as set forth in sequence SEQ ID NO:44; Or, (8) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 64, CDR-H2 as set forth in the sequence SEQ ID NO: 65, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in sequence SEQ ID NO:54, CDR-L2 as set forth in sequence SEQ ID NO:56, and CDR-L3 as set forth in sequence SEQ ID NO:44; Or, (9) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 64, CDR-H2 as set forth in the sequence SEQ ID NO: 65, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:55, CDR-L2 as shown in sequence SEQ ID NO:56, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (10) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 32, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:21, CDR-L2 as shown in sequence SEQ ID NO:24, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (11) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 32, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (12) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 32, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:22, CDR-L2 as shown in sequence SEQ ID NO:25, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (13) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 32, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:23, CDR-L2 as shown in sequence SEQ ID NO:25, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (14) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 33, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (15) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 33, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:22, CDR-L2 as shown in sequence SEQ ID NO:25, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (16) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 33, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:23, CDR-L2 as shown in sequence SEQ ID NO:25, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (17) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 34, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (18) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 34, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:22, CDR-L2 as shown in sequence SEQ ID NO:25, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (19) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 34, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:23, CDR-L2 as shown in sequence SEQ ID NO:25, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (20) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 82, CDR-H2 as shown in the sequence SEQ ID NO: 83, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 75, CDR-L2 as shown in sequence SEQ ID NO: 24, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (21) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 82, CDR-H2 as shown in the sequence SEQ ID NO: 83, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 78, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (22) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 82, CDR-H2 as shown in the sequence SEQ ID NO: 83, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or and a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in sequence SEQ ID NO:76, CDR-L2 as set forth in sequence SEQ ID NO:78, and CDR-L3 as set forth in sequence SEQ ID NO:15.

[0014] In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention have CDRs as defined by the AbM numbering system: (a) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in sequence SEQ ID NO:45, CDR-H2 as set forth in sequence SEQ ID NO:46, and CDR-H3 as set forth in sequence SEQ ID NO:47; and / or A light chain variable region (VL) comprising three CDRs: CDR-L1 shown in any one of SEQ ID NOs: 48 to 55, CDR-L2 shown in any one of SEQ ID NOs: 56 to 58, and CDR-L3 shown in SEQ ID NO: 44; Or, (b) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in sequence SEQ ID NO: 16, CDR-H2 as shown in any one of sequences SEQ ID NO: 17 to 19, and CDR-H3 as shown in sequence SEQ ID NO: 20; and / or A light chain variable region (VL) comprising three CDRs: CDR-L1 shown in any one of SEQ ID NOs: 21 to 23 and 77, CDR-L2 shown in SEQ ID NO: 24 or 25, and CDR-L3 shown in SEQ ID NO: 15; Or, (c) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in sequence SEQ ID NO:72, CDR-H2 as set forth in sequence SEQ ID NO:73, and CDR-H3 as set forth in sequence SEQ ID NO:74; and / or It comprises a light chain variable region (VL) comprising three CDRs: CDR-L1 shown in any one of SEQ ID NOs: 75 to 77, CDR-L2 shown in SEQ ID NO: 24 or 78, and CDR-L3 shown in SEQ ID NO: 15.

[0015] In some embodiments, the antibody or antigen-binding fragment thereof has CDRs defined by the AbM numbering system: (1) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 45, CDR-H2 as set forth in the sequence SEQ ID NO: 46, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or A light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 48, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (2) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 45, CDR-H2 as set forth in the sequence SEQ ID NO: 46, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in sequence SEQ ID NO: 48, CDR-L2 as set forth in sequence SEQ ID NO: 57, and CDR-L3 as set forth in sequence SEQ ID NO: 44; Or, (3) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 45, CDR-H2 as set forth in the sequence SEQ ID NO: 46, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 49, CDR-L2 as shown in sequence SEQ ID NO: 57, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (4) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 45, CDR-H2 as set forth in the sequence SEQ ID NO: 46, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:50, CDR-L2 as shown in sequence SEQ ID NO:58, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (5) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 45, CDR-H2 as set forth in the sequence SEQ ID NO: 46, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:51, CDR-L2 as shown in sequence SEQ ID NO:56, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (6) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 45, CDR-H2 as set forth in the sequence SEQ ID NO: 46, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in sequence SEQ ID NO:52, CDR-L2 as set forth in sequence SEQ ID NO:56, and CDR-L3 as set forth in sequence SEQ ID NO:44; Or, (7) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 45, CDR-H2 as set forth in the sequence SEQ ID NO: 46, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in sequence SEQ ID NO:53, CDR-L2 as set forth in sequence SEQ ID NO:56, and CDR-L3 as set forth in sequence SEQ ID NO:44; Or, (8) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 45, CDR-H2 as shown in the sequence SEQ ID NO: 46, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in sequence SEQ ID NO:54, CDR-L2 as set forth in sequence SEQ ID NO:56, and CDR-L3 as set forth in sequence SEQ ID NO:44; Or, (9) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 45, CDR-H2 as shown in the sequence SEQ ID NO: 46, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:55, CDR-L2 as shown in sequence SEQ ID NO:56, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (10) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 17, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:21, CDR-L2 as shown in sequence SEQ ID NO:24, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (11) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 17, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (12) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 17, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:22, CDR-L2 as shown in sequence SEQ ID NO:25, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (13) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 17, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:23, CDR-L2 as shown in sequence SEQ ID NO:25, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (14) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 18, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (15) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 18, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:22, CDR-L2 as shown in sequence SEQ ID NO:25, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (16) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 18, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:23, CDR-L2 as shown in sequence SEQ ID NO:25, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (17) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 19, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (18) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 19, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:22, CDR-L2 as shown in sequence SEQ ID NO:25, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (19) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 19, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:23, CDR-L2 as shown in sequence SEQ ID NO:25, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (20) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 72, CDR-H2 as shown in the sequence SEQ ID NO: 73, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 75, CDR-L2 as shown in sequence SEQ ID NO: 24, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (21) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 72, CDR-H2 as shown in the sequence SEQ ID NO: 73, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 78, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (22) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 72, CDR-H2 as shown in the sequence SEQ ID NO: 73, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or and a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in sequence SEQ ID NO:76, CDR-L2 as set forth in sequence SEQ ID NO:78, and CDR-L3 as set forth in sequence SEQ ID NO:15.

[0016] In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention have CDRs as defined by the Kabat numbering system: (a) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 shown in sequence SEQ ID NO: 60, CDR-H2 shown in any one of sequences SEQ ID NO: 61 to 63, and CDR-H3 shown in sequence SEQ ID NO: 47; and / or A light chain variable region (VL) comprising three CDRs: CDR-L1 shown in any one of SEQ ID NOs: 48 to 55, CDR-L2 shown in any one of SEQ ID NOs: 56 to 58, and CDR-L3 shown in SEQ ID NO: 44; Or, (b) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in sequence SEQ ID NO: 27, CDR-H2 as shown in any one of sequences SEQ ID NO: 28 to 30, and CDR-H3 as shown in sequence SEQ ID NO: 20; and / or A light chain variable region (VL) comprising three CDRs: CDR-L1 shown in any one of SEQ ID NOs: 21 to 23 and 77, CDR-L2 shown in any one of SEQ ID NOs: 24 to 25, and CDR-L3 shown in SEQ ID NO: 15; Or, (c) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in sequence SEQ ID NO:79, CDR-H2 as set forth in sequence SEQ ID NO:80 or 81, and CDR-H3 as set forth in sequence SEQ ID NO:74; and / or It comprises a light chain variable region (VL) comprising three CDRs: CDR-L1 shown in any one of SEQ ID NOs: 75 to 77, CDR-L2 shown in SEQ ID NO: 24 or 78, and CDR-L3 shown in SEQ ID NO: 15.

[0017] In some embodiments, the antibody or antigen-binding fragment thereof has CDRs defined by the Kabat numbering system: (1) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in sequence SEQ ID NO: 60, CDR-H2 as set forth in sequence SEQ ID NO: 61, and CDR-H3 as set forth in sequence SEQ ID NO: 47; and / or A light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 48, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (2) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 60, CDR-H2 as set forth in the sequence SEQ ID NO: 62, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or A light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 48, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (3) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 60, CDR-H2 as set forth in the sequence SEQ ID NO: 62, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in sequence SEQ ID NO: 48, CDR-L2 as set forth in sequence SEQ ID NO: 57, and CDR-L3 as set forth in sequence SEQ ID NO: 44; Or, (4) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 60, CDR-H2 as set forth in the sequence SEQ ID NO: 62, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 49, CDR-L2 as shown in sequence SEQ ID NO: 57, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (5) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 60, CDR-H2 as set forth in the sequence SEQ ID NO: 62, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:50, CDR-L2 as shown in sequence SEQ ID NO:58, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (6) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 60, CDR-H2 as set forth in the sequence SEQ ID NO: 62, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:51, CDR-L2 as shown in sequence SEQ ID NO:56, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (7) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 60, CDR-H2 as set forth in the sequence SEQ ID NO: 63, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or A light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 48, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (8) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 60, CDR-H2 as set forth in the sequence SEQ ID NO: 63, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in sequence SEQ ID NO: 48, CDR-L2 as set forth in sequence SEQ ID NO: 57, and CDR-L3 as set forth in sequence SEQ ID NO: 44; Or, (9) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 60, CDR-H2 as set forth in the sequence SEQ ID NO: 63, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 49, CDR-L2 as shown in sequence SEQ ID NO: 57, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (10) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 60, CDR-H2 as set forth in the sequence SEQ ID NO: 63, and CDR-H3 as set forth in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:50, CDR-L2 as shown in sequence SEQ ID NO:58, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (11) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 63, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:51, CDR-L2 as shown in sequence SEQ ID NO:56, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (12) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 61, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in sequence SEQ ID NO: 48, CDR-L2 as set forth in sequence SEQ ID NO: 57, and CDR-L3 as set forth in sequence SEQ ID NO: 44; Or, (13) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 61, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 49, CDR-L2 as shown in sequence SEQ ID NO: 57, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (14) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 61, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:50, CDR-L2 as shown in sequence SEQ ID NO:58, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (15) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 61, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:51, CDR-L2 as shown in sequence SEQ ID NO:56, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (16) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 61, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in sequence SEQ ID NO:52, CDR-L2 as set forth in sequence SEQ ID NO:56, and CDR-L3 as set forth in sequence SEQ ID NO:44; Or, (17) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 61, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in sequence SEQ ID NO:53, CDR-L2 as set forth in sequence SEQ ID NO:56, and CDR-L3 as set forth in sequence SEQ ID NO:44; Or, (18) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 61, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in sequence SEQ ID NO:54, CDR-L2 as set forth in sequence SEQ ID NO:56, and CDR-L3 as set forth in sequence SEQ ID NO:44; Or, (19) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 61, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:55, CDR-L2 as shown in sequence SEQ ID NO:56, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (20) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 28, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:21, CDR-L2 as shown in sequence SEQ ID NO:24, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (21) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 28, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (22) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 28, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:22, CDR-L2 as shown in sequence SEQ ID NO:25, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (23) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 28, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:23, CDR-L2 as shown in sequence SEQ ID NO:25, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (24) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 29, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (25) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 29, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:22, CDR-L2 as shown in sequence SEQ ID NO:25, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (26) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 29, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:23, CDR-L2 as shown in sequence SEQ ID NO:25, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (27) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 30, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (28) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 30, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:22, CDR-L2 as shown in sequence SEQ ID NO:25, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (29) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 30, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:23, CDR-L2 as shown in sequence SEQ ID NO:25, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (30) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 79, CDR-H2 as shown in the sequence SEQ ID NO: 80, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 75, CDR-L2 as shown in sequence SEQ ID NO: 24, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (31) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 79, CDR-H2 as shown in the sequence SEQ ID NO: 81, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 78, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (32) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 79, CDR-H2 as shown in the sequence SEQ ID NO: 81, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 76, CDR-L2 as shown in sequence SEQ ID NO: 78, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (33) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 79, CDR-H2 as set forth in the sequence SEQ ID NO: 80, and CDR-H3 as set forth in the sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 78, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (34) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 79, CDR-H2 as shown in the sequence SEQ ID NO: 80, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or and a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in sequence SEQ ID NO:76, CDR-L2 as set forth in sequence SEQ ID NO:78, and CDR-L3 as set forth in sequence SEQ ID NO:15.

[0018] In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention have CDRs as defined by the IMGT numbering system: (a) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO:35, CDR-H2 as set forth in the sequence SEQ ID NO:36, and CDR-H3 as set forth in the sequence SEQ ID NO:37; and / or A light chain variable region (VL) comprising three CDRs: CDR-L1 shown in any one of SEQ ID NOs: 38 to 42, CDR-L2 shown in SEQ ID NO: 43, and CDR-L3 shown in SEQ ID NO: 44; Or, (b) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in sequence SEQ ID NO:7, CDR-H2 as shown in any one of sequences SEQ ID NO:8 to 10, and CDR-H3 as shown in sequence SEQ ID NO:11; and / or A light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 12 or 13, CDR-L2 as shown in sequence SEQ ID NO: 14, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (c) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in sequence SEQ ID NO:66, CDR-H2 as set forth in sequence SEQ ID NO:67, and CDR-H3 as set forth in sequence SEQ ID NO:68; and / or and a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:69 or 70, CDR-L2 as shown in sequence SEQ ID NO:71, and CDR-L3 as shown in sequence SEQ ID NO:15.

[0019] In some embodiments, the antibody or antigen-binding fragment thereof has CDRs defined according to the IMGT numbering system: (1) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 35, CDR-H2 as set forth in the sequence SEQ ID NO: 36, and CDR-H3 as set forth in the sequence SEQ ID NO: 37; and / or A light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 38, CDR-L2 as shown in sequence SEQ ID NO: 43, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (2) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 35, CDR-H2 as set forth in the sequence SEQ ID NO: 36, and CDR-H3 as set forth in the sequence SEQ ID NO: 37; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in sequence SEQ ID NO: 39, CDR-L2 as set forth in sequence SEQ ID NO: 43, and CDR-L3 as set forth in sequence SEQ ID NO: 44; Or, (3) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 35, CDR-H2 as set forth in the sequence SEQ ID NO: 36, and CDR-H3 as set forth in the sequence SEQ ID NO: 37; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 40, CDR-L2 as shown in sequence SEQ ID NO: 43, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (4) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 35, CDR-H2 as set forth in the sequence SEQ ID NO: 36, and CDR-H3 as set forth in the sequence SEQ ID NO: 37; and / or A light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 41, CDR-L2 as shown in sequence SEQ ID NO: 43, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (5) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 35, CDR-H2 as set forth in the sequence SEQ ID NO: 36, and CDR-H3 as set forth in the sequence SEQ ID NO: 37; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 42, CDR-L2 as shown in sequence SEQ ID NO: 43, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (6) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in sequence SEQ ID NO:7, CDR-H2 as shown in sequence SEQ ID NO:8, and CDR-H3 as shown in sequence SEQ ID NO:11; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 12, CDR-L2 as shown in sequence SEQ ID NO: 14, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (7) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO:7, CDR-H2 as shown in the sequence SEQ ID NO:8, and CDR-H3 as shown in the sequence SEQ ID NO:11; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 13, CDR-L2 as shown in sequence SEQ ID NO: 14, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (8) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO:7, CDR-H2 as shown in the sequence SEQ ID NO:9, and CDR-H3 as shown in the sequence SEQ ID NO:11; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 12, CDR-L2 as shown in sequence SEQ ID NO: 14, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (9) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO:7, CDR-H2 as shown in the sequence SEQ ID NO:9, and CDR-H3 as shown in the sequence SEQ ID NO:11; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 13, CDR-L2 as shown in sequence SEQ ID NO: 14, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (10) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 7, CDR-H2 as shown in the sequence SEQ ID NO: 10, and CDR-H3 as shown in the sequence SEQ ID NO: 11; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 12, CDR-L2 as shown in sequence SEQ ID NO: 14, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (11) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 7, CDR-H2 as shown in the sequence SEQ ID NO: 10, and CDR-H3 as shown in the sequence SEQ ID NO: 11; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 13, CDR-L2 as shown in sequence SEQ ID NO: 14, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (12) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 66, CDR-H2 as shown in the sequence SEQ ID NO: 67, and CDR-H3 as shown in the sequence SEQ ID NO: 68; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:69, CDR-L2 as shown in sequence SEQ ID NO:71, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (13) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 66, CDR-H2 as shown in the sequence SEQ ID NO: 67, and CDR-H3 as shown in the sequence SEQ ID NO: 68; and / or and a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:70, CDR-L2 as shown in sequence SEQ ID NO:71, and CDR-L3 as shown in sequence SEQ ID NO:15.

[0020] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention comprises a heavy chain variable region (VH) and / or a light chain variable region (VL) in which at least one CDR contains a mutation that is one or more amino acid substitution, deletion, or addition (e.g., substitution, deletion, or addition of one, two, or three amino acids) compared to the heavy chain variable region and / or light chain variable region described in any one of (1) to (13) above as defined by Chothia, AbM, Kabat, or IMGT, and preferably the substitution is a conservative substitution.

[0021] In some preferred embodiments, the VH of the antibody or antigen-binding fragment thereof of the invention comprises a heavy chain variable region (VH) framework region (FR) derived from a mouse immunoglobulin, and / or the VL of the antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) framework region (FR) derived from a mouse immunoglobulin. Thus, in some preferred embodiments, the antibody or antigen-binding fragment thereof of the invention is of mouse origin.

[0022] In some preferred embodiments, the VH of the antibody or antigen-binding fragment thereof of the present invention comprises a heavy chain variable region (VH) framework region (FR) derived from a human immunoglobulin, and / or the VL of the antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) framework region (FR) derived from a human immunoglobulin. Thus, in some preferred embodiments, the antibody or antigen-binding fragment thereof of the present invention is humanized. In such embodiments, the heavy chain variable region FR and / or the light chain variable region FR of the antibody or antigen-binding fragment thereof of the present invention may comprise one or more amino acid residues of non-human origin (e.g., mouse origin), e.g., the heavy chain framework region FR and / or the light chain framework region FR may comprise one or more amino acid backmutations with the corresponding mouse-derived amino acid residues.

[0023] In some preferred embodiments, the antibodies or antigen-binding fragments thereof of the invention comprise: (a) a heavy chain framework region of a human immunoglobulin or a variant thereof having at most 20 conservative substitutions of amino acids (e.g., at most 15, at most 10 or at most 5 conservative substitutions of amino acids, e.g., 1, 2, 3, 4 or 5 conservative substitutions of amino acids) compared to the germline antibody gene sequence from which it is derived, and / or (b) a light chain framework region of a human immunoglobulin, or a variant thereof having at most 20 conservative substitutions of amino acids (e.g., at most 15, at most 10, or at most 5 conservative substitutions of amino acids, e.g., 1, 2, 3, 4, or 5 conservative substitutions of amino acids) compared to the germline antibody gene sequence from which it is derived.

[0024] In some preferred embodiments, the level of humanization of an antibody or antigen-binding fragment thereof of the invention is at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%.

[0025] In some embodiments, the antibody or antigen-binding fragment thereof of the invention comprises: (a) (i) a sequence shown in any one of SEQ ID NOs: 1, 3, 5, 84-86, 102-106, and 111-115; (ii) a sequence having one or more amino acid substitutions, deletions or additions (e.g., one, two, three, four or five amino acid substitutions, deletions or additions) compared to any one of the sequences set forth in SEQ ID NOs: 1, 3, 5, 84-86, 102-106, 111-115; or (iii) a heavy chain variable region (VH) comprising an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to any one of SEQ ID NOs: 1, 3, 5, 84-86, 102-106, and 111-115; and / or (b) (iv) a sequence shown in any one of SEQ ID NOs: 2, 4, 6, 87-101, 107-110, and 116-118; (v) a sequence having one or more amino acid substitutions, deletions or additions (e.g., one, two, three, four or five amino acid substitutions, deletions or additions) compared to any one of the sequences set forth in SEQ ID NOs: 2, 4, 6, 87-101, 107-110, 116-118; or (vi) a light chain variable region (VL) comprising an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to any one of SEQ ID NOs: 2, 4, 6, 87-101, 107-110, and 116-118.

[0026] In some embodiments, the antibodies or antigen-binding fragments thereof of the invention have a heavy chain variable region (VH) and / or a light chain variable region (VL) having a VH sequence set forth in any one of SEQ ID NOs: 1, 3, 5, 84-86, 102-106, 111-115, and / or a VL sequence set forth in any one of SEQ ID NOs: 2, 4, 6, 87-101, 107-110, 116-118.

[0027] In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention have a heavy chain variable region (VH) and / or a light chain variable region (VL) having a VH sequence set forth in any one of SEQ ID NOs:86, 102, 114, and / or a VL sequence set forth in any one of SEQ ID NOs:92, 107, 117.

[0028] In some embodiments, the VH and / or VL of the antibody or antigen-binding fragment thereof has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity compared to the VH sequence set forth in any one of SEQ ID NOs:86, 102, 114 and / or the VL sequence set forth in any one of SEQ ID NOs:92, 107, 117.

[0029] In some embodiments, the VH and / or VL of the antibody or antigen-binding fragment thereof has one or more amino acid substitutions, deletions or additions (e.g., 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions) compared to the VH sequence set forth in any one of SEQ ID NOs: 86, 102, 114 and / or the VL sequence set forth in any one of SEQ ID NOs: 92, 107, 117. In preferred embodiments, the substitutions are conservative substitutions.

[0030] In some preferred embodiments, the antibodies or antigen-binding fragments thereof of the invention comprise: (1) VH of the sequence shown in SEQ ID NO: 1 and VL of the sequence shown in SEQ ID NO: 2; (2) VH of the sequence shown in SEQ ID NO: 3 and VL of the sequence shown in SEQ ID NO: 4; (3) VH of the sequence shown in SEQ ID NO: 5 and VL of the sequence shown in SEQ ID NO: 6; (4) VH of the sequence shown in SEQ ID NO: 84 and VL of the sequence shown in SEQ ID NO: 87; (5) VH of the sequence shown in SEQ ID NO: 84 and VL of the sequence shown in SEQ ID NO: 88; (6) VH of the sequence depicted in SEQ ID NO: 84 and VL of the sequence depicted in SEQ ID NO: 89; (7) VH of the sequence depicted in SEQ ID NO: 84 and VL of the sequence depicted in SEQ ID NO: 90; (8) VH of the sequence depicted in SEQ ID NO: 84 and VL of the sequence depicted in SEQ ID NO: 91; (9) VH of the sequence shown in SEQ ID NO: 85 and VL of the sequence shown in SEQ ID NO: 87; (10) VH of the sequence shown in SEQ ID NO: 85 and VL of the sequence shown in SEQ ID NO: 88; (11) VH of the sequence shown in SEQ ID NO: 85 and VL of the sequence shown in SEQ ID NO: 92; (12) VH of the sequence depicted in SEQ ID NO: 85 and VL of the sequence depicted in SEQ ID NO: 90; (13) VH of the sequence depicted in SEQ ID NO: 85 and VL of the sequence depicted in SEQ ID NO: 91; (14) VH of the sequence shown in SEQ ID NO: 86 and VL of the sequence shown in SEQ ID NO: 87; (15) VH of the sequence shown in SEQ ID NO: 86 and VL of the sequence shown in SEQ ID NO: 88; (16) VH of the sequence shown in SEQ ID NO: 86 and VL of the sequence shown in SEQ ID NO: 89; (17) VH of the sequence depicted in SEQ ID NO: 86 and VL of the sequence depicted in SEQ ID NO: 90; (18) VH of the sequence depicted in SEQ ID NO: 86 and VL of the sequence depicted in SEQ ID NO: 91; (19) VH of the sequence depicted in SEQ ID NO: 86 and VL of the sequence depicted in SEQ ID NO: 92; (20) VH of the sequence depicted in SEQ ID NO: 86 and VL of the sequence depicted in SEQ ID NO: 93; (21) VH of the sequence depicted in SEQ ID NO: 86 and VL of the sequence depicted in SEQ ID NO: 94; (22) VH of the sequence depicted in SEQ ID NO: 86 and VL of the sequence depicted in SEQ ID NO: 95; (23) VH of the sequence depicted in SEQ ID NO: 86 and VL of the sequence depicted in SEQ ID NO: 96; (24) VH of the sequence depicted in SEQ ID NO: 86 and VL of the sequence depicted in SEQ ID NO: 97; (25) VH of the sequence depicted in SEQ ID NO: 86 and VL of the sequence depicted in SEQ ID NO: 98; (26) VH of the sequence depicted in SEQ ID NO: 86 and VL of the sequence depicted in SEQ ID NO: 99; (27) VH of the sequence depicted in SEQ ID NO: 86 and VL of the sequence depicted in SEQ ID NO: 100; (28) VH of the sequence depicted in SEQ ID NO: 86 and VL of the sequence depicted in SEQ ID NO: 101; (29) VH of the sequence depicted in SEQ ID NO: 102 and VL of the sequence depicted in SEQ ID NO: 107; (30) VH of the sequence depicted in SEQ ID NO: 102 and VL of the sequence depicted in SEQ ID NO: 108; (31) VH of the sequence depicted in SEQ ID NO: 102 and VL of the sequence depicted in SEQ ID NO: 109; (32) VH of the sequence depicted in SEQ ID NO: 102 and VL of the sequence depicted in SEQ ID NO: 110; (33) VH of the sequence depicted in SEQ ID NO: 103 and VL of the sequence depicted in SEQ ID NO: 107; (34) VH of the sequence depicted in SEQ ID NO: 103 and VL of the sequence depicted in SEQ ID NO: 108; (35) VH of the sequence depicted in SEQ ID NO: 103 and VL of the sequence depicted in SEQ ID NO: 109; (36) VH of the sequence depicted in SEQ ID NO: 103 and VL of the sequence depicted in SEQ ID NO: 110; (37) VH of the sequence depicted in SEQ ID NO: 104 and VL of the sequence depicted in SEQ ID NO: 107; (38) VH of the sequence depicted in SEQ ID NO: 104 and VL of the sequence depicted in SEQ ID NO: 108; (39) VH of the sequence depicted in SEQ ID NO: 104 and VL of the sequence depicted in SEQ ID NO: 109; (40) VH of the sequence depicted in SEQ ID NO: 104 and VL of the sequence depicted in SEQ ID NO: 110; (41) VH of the sequence depicted in SEQ ID NO: 105 and VL of the sequence depicted in SEQ ID NO: 107; (42) VH of the sequence depicted in SEQ ID NO: 105 and VL of the sequence depicted in SEQ ID NO: 108; (43) VH of the sequence depicted in SEQ ID NO: 105 and VL of the sequence depicted in SEQ ID NO: 109; (44) VH of the sequence depicted in SEQ ID NO: 105 and VL of the sequence depicted in SEQ ID NO: 110; (45) VH of the sequence depicted in SEQ ID NO: 106 and VL of the sequence depicted in SEQ ID NO: 107; (46) VH of the sequence depicted in SEQ ID NO: 106 and VL of the sequence depicted in SEQ ID NO: 108; (47) VH of the sequence depicted in SEQ ID NO: 106 and VL of the sequence depicted in SEQ ID NO: 109; (48) VH of the sequence depicted in SEQ ID NO: 106 and VL of the sequence depicted in SEQ ID NO: 110; (49) VH of the sequence depicted in SEQ ID NO: 111 and VL of the sequence depicted in SEQ ID NO: 107; (50) VH of the sequence depicted in SEQ ID NO: 111 and VL of the sequence depicted in SEQ ID NO: 116; (51) VH of the sequence depicted in SEQ ID NO: 111 and VL of the sequence depicted in SEQ ID NO: 117; (52) VH of the sequence depicted in SEQ ID NO: 111 and VL of the sequence depicted in SEQ ID NO: 118; (53) VH of the sequence depicted in SEQ ID NO: 112 and VL of the sequence depicted in SEQ ID NO: 107; (54) VH of the sequence depicted in SEQ ID NO: 112 and VL of the sequence depicted in SEQ ID NO: 116; (55) VH of the sequence depicted in SEQ ID NO: 112 and VL of the sequence depicted in SEQ ID NO: 117; (56) VH of the sequence depicted in SEQ ID NO: 112 and VL of the sequence depicted in SEQ ID NO: 118; (57) VH of the sequence depicted in SEQ ID NO: 113 and VL of the sequence depicted in SEQ ID NO: 107; (58) VH of the sequence depicted in SEQ ID NO: 113 and VL of the sequence depicted in SEQ ID NO: 116; (59) VH of the sequence depicted in SEQ ID NO: 113 and VL of the sequence depicted in SEQ ID NO: 117; (60) VH of the sequence depicted in SEQ ID NO: 113 and VL of the sequence depicted in SEQ ID NO: 118; (61) VH of the sequence depicted in SEQ ID NO: 114 and VL of the sequence depicted in SEQ ID NO: 107; (62) VH of the sequence depicted in SEQ ID NO: 114 and VL of the sequence depicted in SEQ ID NO: 116; (63) VH of the sequence depicted in SEQ ID NO: 114 and VL of the sequence depicted in SEQ ID NO: 117; (64) VH of the sequence depicted in SEQ ID NO: 114 and VL of the sequence depicted in SEQ ID NO: 118; (65) VH of the sequence depicted in SEQ ID NO: 115 and VL of the sequence depicted in SEQ ID NO: 107; (66) VH of the sequence depicted in SEQ ID NO: 115 and VL of the sequence depicted in SEQ ID NO: 116; (67) VH of the sequence depicted in SEQ ID NO: 115 and VL of the sequence depicted in SEQ ID NO: 117, and (68) comprising a VH having the sequence shown in SEQ ID NO: 115 and a VL having the sequence shown in SEQ ID NO: 118.

[0031] In some preferred embodiments, the heavy chain variable region (VH) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity, and / or the light chain variable region (VL) has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity, compared to any one of sets (1) to (68).

[0032] In some preferred embodiments, compared to any one of sets (1) to (68), the heavy chain variable region (VH) has one or more amino acid substitutions, deletions, or additions (e.g., 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions), and / or the light chain variable region (VL) has one or more amino acid substitutions, deletions, or additions (e.g., 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions), preferably the substitutions are conservative substitutions.

[0033] In any of the above aspects, the antibody or antigen-binding fragment thereof of the present invention may further comprise a constant region sequence derived from a mammalian (e.g., murine or human) immunoglobulin, or a variant thereof. In some embodiments, the heavy chain of the antibody or antigen-binding fragment thereof of the present invention comprises a heavy chain constant region (CH) of a human or mouse immunoglobulin or a variant thereof, which variant has one or more amino acid substitutions, deletions or additions compared to the wild-type sequence from which it is derived (e.g., at most 20, at most 15, at most 10 or at most 5 amino acid substitutions, deletions or additions, e.g., 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions), and / or the light chain of the antibody or antigen-binding fragment thereof of the present invention comprises a light chain constant region (CL) of a human or mouse immunoglobulin or a variant thereof, which variant has one or more amino acid substitutions, deletions or additions compared to the wild-type sequence from which it is derived (e.g., at most 20, at most 15, at most 10 or at most 5 amino acid substitutions, deletions or additions, e.g., 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions).

[0034] In some preferred embodiments, the heavy chain of the antibody or antigen-binding fragment thereof of the invention comprises a heavy chain constant region (CH) of a human immunoglobulin or a variant thereof, which variant has at most 20 amino acid conservative substitutions (e.g. at most 15, at most 10 or at most 5 amino acid conservative substitutions, e.g. at most 1, 2, 3, 4 or 5 amino acid conservative substitutions) compared to the wild-type sequence from which it is derived, and / or the light chain of the antibody or antigen-binding fragment thereof comprises a light chain constant region (CL) of a human immunoglobulin or a variant thereof, which variant has at most 20 amino acid conservative substitutions (e.g. at most 15, at most 10 or at most 5 amino acid conservative substitutions, e.g. at most 1, 2, 3, 4 or 5 amino acid conservative substitutions) compared to the wild-type sequence from which it is derived.

[0035] In some embodiments, the heavy chain of the antibody or antigen-binding fragment thereof of the present invention comprises a heavy chain constant region (CH) of a mouse immunoglobulin or a variant thereof, which variant has at most 20 amino acid conservative substitutions (e.g., at most 15, at most 10, or at most 5 amino acid conservative substitutions, e.g., 1, 2, 3, 4, or 5 amino acid conservative substitutions) compared to the wild-type sequence from which it is derived, and / or the light chain of the antibody or antigen-binding fragment thereof comprises a light chain constant region (CL) of a mouse immunoglobulin or a variant thereof, which variant has at most 20 amino acid conservative substitutions (e.g., at most 15, at most 10, or at most 5 amino acid conservative substitutions, e.g., 1, 2, 3, 4, or 5 amino acid conservative substitutions) compared to the wild-type sequence from which it is derived.

[0036] In some embodiments, the constant region is altered, e.g., mutated, to modify the properties of the anti-ROR1 antibody molecule (e.g., to change one or more of the following characteristics: Fc receptor binding, antibody glycosylation, number of cysteine ​​residues, effector cell function, or complement function). By replacing at least one amino acid residue in the antibody constant region with a different residue, the function can be altered, e.g., the affinity of the antibody for the effector ligand (FcR or complement C1q) can be changed to alter (e.g., enhance) the effector function. The Fc region of an antibody mediates several important effector functions, e.g., ADCC, phagocytosis, CDC, etc. In some cases, these effector functions are required for a therapeutic antibody.

[0037] In some embodiments, the anti-ROR1 antibody molecule has a heavy chain constant region (Fc) selected from, for example, IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD and IgE heavy chain constant regions, specifically, for example, IgG1, IgG2, IgG3 and IgG4 heavy chain constant regions, more specifically, IgG1 or IgG4 (e.g., human IgG1 or IgG4). In some embodiments, the anti-ROR1 antibody molecule has a light chain constant region selected from, for example, kappa or lambda light chain constant regions, preferably a kappa light chain constant region (e.g., human kappa light chain).

[0038] In some embodiments, the antibody or antigen-binding fragment thereof comprises: (1) a human IgG1 heavy chain constant region, or (2) a human IgG4 heavy chain constant region.

[0039] In some preferred embodiments, the antibodies or antigen-binding fragments thereof of the invention comprise: (a) (i) the sequence set forth in SEQ ID NO:119; (ii) a sequence having one or more amino acid substitutions, deletions or additions (e.g., one, two, three, four or five amino acid substitutions, deletions or additions) compared to the sequence set forth in SEQ ID NO:119; or (iii) a heavy chain constant region (CH) comprising an amino acid sequence selected from the group consisting of a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence set forth in SEQ ID NO:119; and / or (b) (iv) the sequence depicted in SEQ ID NO: 120; (v) a sequence having one or more amino acid substitutions, deletions or additions (e.g., one, two, three, four or five amino acid substitutions, deletions or additions) compared to the sequence set forth in SEQ ID NO:120; or (vi) a light chain constant region (CL) comprising an amino acid sequence selected from a sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence set forth in SEQ ID NO:120.

[0040] In some preferred embodiments, the substitutions described in (ii) or (v) are conservative substitutions.

[0041] In some preferred embodiments, the antibodies or antigen-binding fragments thereof of the invention comprise a heavy chain constant region (CH) set forth in SEQ ID NO:119 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0042] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:1 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:2 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0043] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:3 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:4 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0044] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:5 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:6 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0045] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:84 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:87 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0046] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:84 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:88 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0047] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:84 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:89 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0048] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:84 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:90 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0049] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:84 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:91 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0050] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:85 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:87 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0051] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:85 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:88 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0052] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:85 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:92 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0053] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:85 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:90 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0054] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:85 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:91 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0055] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:86 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:87 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0056] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:86 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:88 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0057] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:86 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:89 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0058] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:86 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:90 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0059] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:86 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:91 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0060] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:86 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:92 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0061] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:86 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:93 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0062] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:86 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:94 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0063] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:86 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:95 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0064] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:86 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:96 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0065] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:86 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:97 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0066] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:86 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:98 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0067] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:86 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:99 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0068] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:86 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:100 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0069] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:86 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:101 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0070] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:102 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:107 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0071] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:102 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:108 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0072] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:102 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:109 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0073] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:102 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:110 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0074] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:103 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:107 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0075] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:103 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:108 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0076] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:103 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:109 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0077] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:103 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:110 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0078] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:104 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:107 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0079] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:104 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:108 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0080] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:104 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:109 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0081] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:104 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:110 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0082] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:105 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:107 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0083] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:105 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:108 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0084] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:105 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:109 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0085] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:105 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:110 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0086] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:106 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:107 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0087] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:106 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:108 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0088] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:106 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:109 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0089] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:106 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:110 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0090] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:111 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:107 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0091] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:111 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:116 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0092] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:111 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:117 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0093] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:111 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:118 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0094] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:112 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:107 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0095] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:112 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:116 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0096] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:112 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:117 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0097] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:112 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:118 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0098] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:113 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:107 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0099] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:113 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:116 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0100] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:113 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:117 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0101] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:113 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:118 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0102] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:114 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:107 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0103] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:114 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:116 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0104] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:114 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:117 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0105] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:114 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:118 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0106] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:115 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:107 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0107] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:115 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:116 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0108] In some preferred embodiments, an antibody of the invention comprises a heavy chain having a VH of the sequence set forth in SEQ ID NO:115 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:117 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0109] In some preferred embodiments, the antibodies of the invention comprise a heavy chain having a VH of the sequence set forth in SEQ ID NO:115 and a heavy chain constant region (CH) set forth in SEQ ID NO:119, and a light chain having a VL of the sequence set forth in SEQ ID NO:118 and a light chain constant region (CL) set forth in SEQ ID NO:120.

[0110] In some preferred embodiments, the antibody of the invention is a chimeric or humanized antibody. In some preferred embodiments, the antibody or antigen-binding fragment thereof of the invention is selected from an ScFv, a Fab, a Fab', a (Fab')2, an Fv fragment, a disulfide-linked Fv (dsFv), a diabody, a bispecific antibody, and a multispecific antibody.

[0111] In some embodiments, the antibody molecule or antigen-binding fragment thereof of the invention comprises: (a) binding to ROR1 (e.g., human ROR1) with a KD of less than about 100 nM, e.g., about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 1 nM, 0.1 nM or less, e.g., the KD is measured by biolayer interferometry (BLI) (e.g., ForteBio Octet®); (b) binding to ROR1 (e.g., human ROR1) with an EC50 of less than about 500 nM, for example, about 100 nM, 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM or less, for example, the EC50 being measured by flow cytometry or competitive ELISA; (c) the property of not binding to ROR2 (e.g., human ROR2).

[0112] In some embodiments, the antibody or antigen-binding fragment thereof has ADCC activity.

[0113] In some embodiments, the antibody or antigen-binding fragment thereof has CDC activity.

[0114] In some preferred embodiments, the antibody or antigen-binding fragment thereof has ADCC and CDC activity.

[0115] In some preferred embodiments, the antibody or antigen-binding fragment thereof has enhanced ADCC and / or CDC activity.

[0116] In some preferred embodiments, the antibodies or antigen-binding fragments thereof of the invention comprise: (a) its biological function of inducing apoptosis in tumor cells; (b) the biological function of inhibiting tumor cell growth, proliferation, differentiation, and / or angiogenesis; (c) the biological function of inducing and / or increasing complement-dependent cytotoxicity; (d) the biological function of inducing and / or increasing antibody-dependent cellular cytotoxicity; (e) the biological function of inhibiting the expression and activation of ROR1; (f) its biological function of inhibiting ROR1-mediated cell signaling; (g) a biological function of preventing and / or treating a ROR1-mediated disease / condition; and (h) a biological function of promoting internalization of ROR1 in a cell (e.g., a tumor cell); or (i) Any combination of (a) to (h).

[0117] In some preferred embodiments, the antibodies or antigen-binding fragments thereof of the present invention possess any combination of the above biological functions.

[0118] Regarding induced antibodies The antibodies or antigen-binding fragments thereof of the present invention may be derivatized so as to be linked to other molecules (e.g., other polypeptides or proteins). Typically, derivatization (e.g., labeling) of the antibodies or antigen-binding fragments thereof does not adversely affect binding to ROR1 (particularly human ROR1). Thus, the antibodies or antigen-binding fragments thereof of the present invention are also intended to include such forms of derivatization. For example, the antibodies or antigen-binding fragments thereof of the present invention can be functionally linked (by chemical coupling, genetic fusion, non-covalent linkage or other methods) to one or more other molecular groups, such as other antibodies (e.g., to form bispecific antibodies), detectable reagents, medicinal reagents, and / or proteins or polypeptides that mediate binding of the antibodies or antigen-binding fragments to other molecules (e.g., avidin or polyhistidine tags).

[0119] Certain types of derivatized antibodies (e.g., bispecific antibodies) are produced by cross-linking two or more antibodies (belonging to the same type or different types). Methods for obtaining bispecific antibodies are known in the art, examples of which include, but are not limited to, chemical cross-linking, cell engineering (hybridoma method) or genetic engineering.

[0120] Another type of derivatized antibody is a labeled antibody. For example, the antibody of the present invention or an antigen-binding fragment thereof may be linked to a detectable label. A detectable label according to the present invention may be any substance that can be detected by fluorescent, spectral, photochemical, biochemical, immunological, electrical, optical or chemical means. Such labels are well known in the art, and examples include, but are not limited to, enzymes (e.g., horseradish peroxidase, alkaline phosphatase, β-galactosidase, urease, glucose oxidase, etc.), radionuclides (e.g., 3H, 125I, 35S, 14C, or 32P), fluorescent dyes (e.g., fluorescein isothiocyanate (FITC), fluorescein, tetramethylrhodamine isothiocyanate (TRITC), phycoerythrin (PE), Texas Red, rhodamine, quantum dots, or cyanine dye derivatives (e.g., Cy7, Alexa 750)), acridinium ester-based compounds, magnetic beads (e.g., Dynabeads®), colorimetric labels (e.g., colloidal gold, colored glass or plastic (e.g., polystyrene, polypropylene, latex, etc.) beads), and biotin that binds to avidin (e.g., streptavidin) modified with the above labels. Patents teaching the use of such labels include, but are not limited to, U.S. Patent Nos. 3,817,837, 3,850,752, 3,939,350, 3,996,345, 4,277,437, 4,275,149, and 4,366,241, all of which are incorporated herein by reference. Such detectable labels can be detected by methods known in the art. For example, radioactive labels can be detected using photographic film or scintillation detectors, and fluorescent labels can be detected using photodetectors to detect emitted light. Enzyme labels are generally detected by providing a substrate for the enzyme and detecting the reaction product generated by the action of the enzyme on the substrate, and colorimetric labels are detected by simply visualizing the colored label. In some embodiments, such labels can be applied to immunological detection (e.g., enzyme-linked immunoassay, radioimmunoassay, fluorescent immunoassay, chemiluminescent immunoassay, etc.).In some embodiments, such detectable labels can be linked to the antibodies or antigen-binding fragments of the invention by linkers of different lengths to reduce potential steric hindrance.

[0121] In addition, the antibodies or antigen-binding fragments thereof of the present invention may be further derivatized with chemical groups, such as polyethylene glycol (PEG), methyl groups, ethyl groups, or glycosyl groups, which can improve the biological properties of the antibody, such as increasing the serum half-life.

[0122] As a derivative of an antibody, the present invention provides a conjugate comprising a monoclonal antibody of the invention or an antigen-binding fragment thereof and a coupling moiety selected from a detectable label, a radioisotope, a fluorescent substance, a luminescent substance, a colored substance, an enzyme, polyethylene glycol (PEG), a nuclide, a nucleic acid, a small molecule toxin, a polypeptide, a protein, a receptor, and a ligand having binding activity, and other active substances that inhibit tumor cell growth and promote apoptosis or necrosis of tumor cells.

[0123] As a derivative of an antibody, the present invention provides a chimeric antigen receptor comprising said monoclonal antibody or an antigen-binding fragment thereof. In some preferred embodiments, said chimeric antigen receptor comprises a monoclonal antibody of the present invention or an antigen-binding fragment thereof (e.g., ScFv), a transmembrane domain, and one or more intracellular T cell signaling domains. The present invention also provides a host cell, e.g., an immune cell (e.g., T lymphocyte, NK cell), that comprises or expresses said chimeric antigen receptor.

[0124] As a derivative of an antibody, the present invention provides a multispecific antibody, which is formed by coupling a primary antibody or a fragment thereof with another antibody or a fragment thereof or an antibody analogue, each antibody or fragment thereof or antibody analogue retaining its original binding specificity, the primary antibody or a fragment thereof being an antibody or an antigen-binding fragment thereof according to the present invention, and preferably the multispecific antibody being a bispecific, trispecific or tetraspecific antibody.

[0125] Antibody production The antibody of the present invention can be produced by various methods known in the art, for example, by recombinant gene engineering. For example, DNA molecules encoding the heavy and light chain genes of the antibody of the present invention are obtained by chemical synthesis or PCR amplification. The obtained DNA molecules are inserted into an expression vector, and then the host cells are transfected. The transfected host cells are then cultured under specific conditions to express the antibody of the present invention.

[0126] The antigen-binding fragments of the present invention may be obtained by hydrolysis of intact antibody molecules (see Morimoto et al., J. Biochem. Biophys. Methods 24:107-117 (1992) and Brennan et al., Science 229:81 (1985)). These antigen-binding fragments may also be produced directly from recombinant host cells (reviewed in Hudson, Curr. Opin. Immunol. 11: 548-557 (1999); Little et al., Immunol. Today, 21: 364-370 (2000)). For example, Fab' fragments may be obtained directly from host cells or may be chemically coupled to form F(ab')2 fragments (Carter et al., Bio / Technology, 10: 163-167 (1992)). Alternatively, Fv, Fab or F(ab')2 fragments may be obtained by direct isolation from recombinant host cell culture medium. Those skilled in the art are fully aware of other techniques for producing these antigen-binding fragments.

[0127] Thus, in another aspect, the present invention provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding an antibody or antigen-binding fragment thereof of the present invention, or a heavy chain variable region and / or a light chain variable region thereof. In accordance with the codon degeneracy of the art, in some embodiments, the nucleotide sequence is one that can be substituted according to codon degeneracy. In some embodiments, the nucleotide sequence is one that is codon optimized.

[0128] In some preferred embodiments, the present invention provides isolated nucleic acid molecules comprising a nucleic acid molecule encoding an antibody heavy chain variable region and / or a nucleic acid molecule encoding an antibody light chain variable region, wherein the nucleic acid molecule encoding the antibody heavy chain variable region has a sequence selected from: (a) a nucleotide sequence set forth in any one of SEQ ID NOs: 121, 123, 125, 127-129, 145-149, 154-158; (b) a sequence that is essentially the same as the nucleotide sequence set forth in (a) (e.g., a sequence having at least about 85%, 90%, 95%, 99% or more sequence identity compared to the nucleotide sequence set forth in (a), or a sequence substituted with one or more nucleotides); or (c) a sequence that differs from the nucleotide sequence set forth in (a) by 3, 6, 15, 30, or 45 nucleotides. The nucleic acid molecule encoding the antibody light chain variable region has a sequence selected from (d), a nucleotide sequence set forth in any one of SEQ ID NOs: 122, 124, 126, 130 to 144, 150 to 153, and 159 to 161; (e), a sequence that is essentially the same as the nucleotide sequence described in (d) (for example, a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to the nucleotide sequence described in (d), or a sequence substituted with one or more nucleotides); or (f), a sequence that differs from the nucleotide sequence described in (d) by 3, 6, 15, 30, or 45 nucleotides.

[0129] In some preferred embodiments, the nucleic acid molecule encoding the antibody heavy chain variable region has a nucleotide sequence set forth in any one of SEQ ID NOs: 121, 123, 125, 127-129, 145-149, and 154-158, and the nucleic acid molecule encoding the antibody light chain variable region has a nucleotide sequence set forth in any one of SEQ ID NOs: 122, 124, 126, 130-144, 150-153, and 159-161. In some preferred embodiments, an isolated nucleic acid molecule of the invention comprises a nucleic acid molecule encoding an antibody heavy chain variable region set forth in any one of SEQ ID NOs: 121, 123, 125, 127-129, 145-149, 154-158, and / or a nucleic acid molecule encoding an antibody light chain variable region set forth in any one of SEQ ID NOs: 122, 124, 126, 130-144, 150-153, 159-161.

[0130] In some preferred embodiments, the present invention provides isolated nucleic acid molecules comprising a nucleic acid molecule encoding an antibody heavy chain constant region and / or a nucleic acid molecule encoding an antibody light chain constant region, wherein the nucleic acid molecule encoding the antibody heavy chain constant region has a sequence selected from: (a) the nucleotide sequence set forth in SEQ ID NO:59; (b) essentially the same sequence as the nucleotide sequence set forth in (a) (e.g., a sequence having at least about 85%, 90%, 95%, 99% or more sequence identity to, or a sequence substituted with one or more nucleotides compared to, the nucleotide sequence set forth in (a); or (c) a sequence that differs from the nucleotide sequence set forth in (a) by 3, 6, 15, 30 or 45 nucleotides; and / or the nucleic acid molecule encoding the antibody light chain constant region has a sequence selected from: (a) the nucleotide sequence set forth in SEQ ID NO:59; The nucleotide sequence is selected from the group consisting of the nucleotide sequence shown in SEQ ID NO:26, a sequence essentially the same as the nucleotide sequence shown in (e) or (d) (e.g., a sequence having at least about 85%, 90%, 95%, 99% or more sequence identity compared to the nucleotide sequence shown in (d), or a sequence substituted with one or more nucleotides), or a sequence differing by 3, 6, 15, 30 or 45 nucleotides from the nucleotide sequence shown in (f) or (d).

[0131] In some preferred embodiments, a nucleic acid molecule encoding the antibody heavy chain constant region has a nucleotide sequence set forth in SEQ ID NO:59 and / or a nucleic acid molecule encoding the antibody light chain constant region has a nucleotide sequence set forth in SEQ ID NO:26. In some preferred embodiments, an isolated nucleic acid molecule of the invention has a nucleotide sequence encoding an antibody heavy chain constant region set forth in SEQ ID NO:59 and / or has a nucleotide sequence encoding an antibody light chain constant region set forth in SEQ ID NO:26.

[0132] In another aspect of the invention, the invention provides a vector (e.g., a cloning vector or an expression vector) comprising an isolated nucleic acid molecule of the invention. In some preferred embodiments, the vector of the invention is, for example, a plasmid, cosmid, phage, lentivirus, etc. In some preferred embodiments, the vector is capable of expressing an antibody or antigen-binding fragment thereof of the invention in a subject (e.g., a mammal, e.g., a human).

[0133] In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention may be used to construct a chimeric antigen receptor (CAR), the chimeric antigen receptor comprising an extracellular antigen-binding domain (e.g., ScFv) that specifically binds to ROR1, a transmembrane domain, and one or more intracellular T cell signaling domains. In such embodiments, the isolated nucleic acid molecule of the present invention may comprise a nucleotide sequence encoding a chimeric antigen receptor, which further comprises a nucleotide sequence encoding an antibody or antigen-binding fragment thereof (e.g., ScFv) of the present invention. In some embodiments, the isolated nucleic acid molecule of the present invention encodes a chimeric antigen receptor comprising an antigen-binding fragment of an antibody of the present invention (e.g., ScFv).

[0134] In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention are used to construct chimeric antigen receptor-modified immune cells, the chimeric antigen receptor-modified immune cells comprising a chimeric antigen receptor (CAR) and an immune cell (e.g., a T lymphocyte, a NK cell).

[0135] In another aspect of the invention, the present invention provides a host cell comprising the isolated nucleic acid molecule of the invention or the vector of the invention. The host cell may be a eukaryotic cell (e.g., a mammalian cell, an insect cell, a yeast cell) or a prokaryotic cell (e.g., E. coli). Suitable eukaryotic cells include, but are not limited to, NS0 cells, Vero cells, Hela cells, COS cells, CHO cells, ExpiCHO cells, HEK293 cells, Expi293 cells, BHK cells, and MDCKII cells. Suitable insect cells include, but are not limited to, Sf9 cells. In some preferred embodiments, the host cell of the invention is a mammalian cell, for example, CHO (e.g., CHO-K1, CHO-S, CHO DXB11, ExpiCHO, CHO DG44).

[0136] In some embodiments, the host cell of the invention may be a chimeric antigen receptor T cell (CAR-T). In such embodiments, the isolated nucleic acid molecule contained in the host cell may comprise a nucleotide sequence encoding a chimeric antigen receptor, which further comprises a nucleotide sequence encoding an antibody of the invention or an antigen-binding fragment thereof (e.g., an ScFv). In some embodiments, the isolated nucleic acid molecule contained in the host cell encodes a chimeric antigen receptor comprising an antigen-binding fragment of an antibody of the invention (e.g., an ScFv).

[0137] Another aspect of the invention provides a method for producing an antibody or antigen-binding fragment thereof of the invention, comprising culturing a host cell of the invention under conditions allowing expression of said antibody or antigen-binding fragment thereof, and recovering said antibody or antigen-binding fragment thereof from the culture of the cultured host cells.

[0138] Therapeutic Methods and Pharmaceutical Compositions In another aspect of the invention, a pharmaceutical composition is disclosed comprising an antibody or antigen-binding fragment thereof, a vector, a host cell, a complex, a chimeric antigen receptor, or a multispecific antibody of the invention, and a pharma- ceutically acceptable carrier and / or excipient.

[0139] In some preferred embodiments, pharmaceutical compositions of the invention comprise an antibody or antigen-binding fragment thereof of the invention, and a pharma- ceutically acceptable carrier and / or excipient.

[0140] In some preferred embodiments, the pharmaceutical composition of the invention comprises a vector or host cell of the invention and a pharma- ceutically acceptable carrier and / or excipient. In such embodiments, the isolated nucleic acid molecule contained in the vector comprises a nucleotide sequence encoding a chimeric antigen receptor, which further comprises a nucleotide sequence encoding an antibody or an antigen-binding fragment thereof (e.g., ScFv) of the invention. The host cell comprises such an isolated nucleic acid molecule or vector. In some preferred embodiments, the isolated nucleic acid molecule encodes a chimeric antigen receptor comprising an antigen-binding fragment of an antibody of the invention (e.g., ScFv). In some preferred embodiments, the host cell is a T cell. In some preferred embodiments, the host cell is a chimeric antigen receptor T cell (CAR-T).

[0141] In some preferred embodiments, the pharmaceutical composition may further comprise another pharmacologic active agent. In some preferred embodiments, the other pharmacologic active agent is a drug for treating lymphoma, breast cancer, colorectal cancer, ovarian cancer, lung cancer, and / or pancreatic cancer. In some preferred embodiments, the other pharmacologic active agent is a drug with antitumor activity. In some preferred embodiments, the other pharmacologic active agent is one or more selected from epidermal growth factor receptor (EGFR) inhibitors, immune checkpoint inhibitors, B cell antigen inhibitors, BTK inhibitors, and chemotherapeutic agents.

[0142] In some preferred embodiments, the pharmaceutical composition includes an antibody or antigen-binding fragment thereof of the invention and the other pharmacologic agent, both of which are provided as separate components or as components of the same composition, and thus the antibody or antigen-binding fragment thereof of the invention and the other pharmacologic agent can be administered simultaneously, separately, or sequentially.

[0143] In some preferred embodiments, the pharmaceutical composition may further comprise another pharma- ceutical active agent, which is one or more selected from an epidermal growth factor receptor (EGFR) inhibitor, an immune checkpoint inhibitor, a B cell antigen inhibitor, a BTK inhibitor, and a chemotherapeutic agent.

[0144] In some preferred embodiments, the other pharmacologic active agent is one or more selected from an anti-PD1 / PD-L1 antibody, an anti-CD20 antibody, and an anti-EGFR antibody.

[0145] In another aspect, the antibody or antigen-binding fragment thereof, vector, host cell, complex, chimeric antigen receptor, or multispecific antibody in the pharmaceutical composition of the invention is administered to a subject: (a) Induce apoptosis of tumor cells; (b) inhibiting tumor cell growth, proliferation, differentiation, and / or angiogenesis; (c) inducing and / or increasing complement-dependent cytotoxicity; (d) inducing and / or increasing antibody-dependent cellular cytotoxicity; (e) inhibiting the expression and activation of ROR1; (f) inhibiting ROR1-mediated cell signaling; (g) preventing and / or treating a ROR1-mediated disease / condition; or (h) Any combination of (a) to (g) may be used.

[0146] In another aspect of the invention there is provided the use of an antibody or antigen-binding fragment thereof, vector, host cell, complex, chimeric antigen receptor, or multispecific antibody of the invention in the manufacture of a medicament, said medicament comprising: (a) Induce apoptosis of tumor cells; (b) inhibiting tumor cell growth, proliferation, differentiation, and / or angiogenesis; (c) inducing and / or increasing complement-dependent cytotoxicity; (d) inducing and / or increasing antibody-dependent cellular cytotoxicity; (e) inhibiting the expression and activation of ROR1; (f) inhibiting ROR1-mediated cell signaling; (g) preventing and / or treating a ROR1-mediated disease / condition; or (h) Any combination of (a) to (g) may be used.

[0147] In some preferred embodiments, when the vector or host cell of the invention is used for the manufacture of a drug, the isolated nucleic acid molecule contained in the vector comprises a nucleotide sequence encoding a chimeric antigen receptor, which further comprises a nucleotide sequence encoding an antibody or an antigen-binding fragment thereof (e.g., ScFv) of the invention. The host cell comprises such an isolated nucleic acid molecule or vector. In some preferred embodiments, the isolated nucleic acid molecule encodes a chimeric antigen receptor comprising an antigen-binding fragment of an antibody of the invention (e.g., ScFv). In some preferred embodiments, the host cell is a T cell. In some preferred embodiments, the host cell is a chimeric antigen receptor T cell (CAR-T).

[0148] In some preferred embodiments, when the vectors or host cells of the invention are used for the manufacture of a medicament, the medicament treats a tumor in a subject (eg, a human).

[0149] In some preferred embodiments, the tumor for which the antibody or antigen-binding fragment thereof, vector, host cell, conjugate, chimeric antigen receptor, or multispecific antibody according to the invention is administered is selected from lymphoma, breast cancer, colorectal cancer, ovarian cancer, lung cancer and / or pancreatic cancer.

[0150] In some preferred embodiments, the tumor for which the antibody or antigen-binding fragment thereof according to the invention is directed is selected from lymphoma, breast cancer, colorectal cancer, ovarian cancer, lung cancer and / or pancreatic cancer.

[0151] In some preferred embodiments, the tumors for which the antibodies or antigen-binding fragments thereof described in the present invention are ROR1 positive.

[0152] In another aspect, the invention provides a method of preventing and / or treating a tumor in a subject. In another aspect, the invention provides a method of delaying the progression of a tumor in a subject. In another aspect, the invention provides a method of reducing or inhibiting the recurrence of a tumor in a subject. The above-mentioned methods comprise administering to a subject in need thereof an effective amount of an antibody or antigen-binding fragment thereof, vector, host cell, complex, chimeric antigen receptor, or multispecific antibody, and pharmaceutical composition according to the invention.

[0153] In some embodiments, the invention provides a method for preventing and / or treating a tumor in a subject comprising administering to a subject in need thereof an effective amount of an antibody or antigen-binding fragment thereof, vector, host cell, complex, chimeric antigen receptor, or multispecific antibody according to the invention, and other pharmacologic active agents, which may be administered separately, in combination, simultaneously, or sequentially.

[0154] In some preferred embodiments, the other pharmacologic active agent is one or more selected from an epidermal growth factor receptor (EGFR) inhibitor, an immune checkpoint inhibitor, a B cell antigen inhibitor, a BTK inhibitor, and a chemotherapeutic agent.

[0155] In some preferred embodiments, the other pharmacologic active agent is one or more selected from an anti-PD1 / PD-L1 antibody, an anti-CD20 antibody, and an anti-EGFR antibody.

[0156] When the host cell of the invention is used in the above-mentioned methods, the host cell expresses a chimeric antigen receptor comprising an antigen-binding fragment (e.g., ScFv) of an antibody of the invention. Thus, in some preferred embodiments, the isolated nucleic acid molecule contained in the host cell comprises a nucleotide sequence encoding a chimeric antigen receptor, which further comprises a nucleotide sequence encoding an antibody of the invention or an antigen-binding fragment thereof (e.g., ScFv). In some preferred embodiments, the isolated nucleic acid molecule encodes a chimeric antigen receptor comprising an antigen-binding fragment (e.g., ScFv) of an antibody of the invention. In some preferred embodiments, the host cell is a T cell. In some preferred embodiments, the host cell is a chimeric antigen receptor T cell (CAR-T).

[0157] In other aspects, the methods described above further comprise administering to the subject a second therapy selected from surgery, chemotherapy, radiation therapy, immunotherapy, gene therapy, DNA therapy, RNA therapy, nanotherapy, viral therapy, adjunctive therapy, and any combination thereof.

[0158] In some embodiments, the second therapy can be administered separately or in combination with the methods described above. Alternatively, the second therapy can be administered separately, in combination, simultaneously, or sequentially with the methods described above.

[0159] In some preferred embodiments, the tumor for which the antibody or antigen-binding fragment thereof, vector, host cell, conjugate, chimeric antigen receptor or immune cell modified therewith, or multispecific antibody according to the invention is selected from lymphoma, breast cancer, colorectal cancer, ovarian cancer, lung cancer and / or pancreatic cancer.

[0160] In some preferred embodiments, the tumor for which the antibody or antigen-binding fragment thereof according to the invention is directed is selected from lymphoma, breast cancer, colorectal cancer, ovarian cancer, lung cancer and / or pancreatic cancer.

[0161] In some preferred embodiments, the tumors for which the antibodies or antigen-binding fragments thereof described in the present invention are ROR1 positive.

[0162] The antibody or antigen-binding fragment thereof of the present invention and the pharmaceutical composition of the present invention can be prepared into any dosage form known in the medical field, such as tablets, pills, suspensions, emulsions, solutions, gels, capsules, powders, granules, elixirs, troches, suppositories, injections (including injection solutions, sterile powders for injections, and concentrated solutions for injections), inhalants, sprays, etc. The preferred dosage form depends on the desired mode of administration and therapeutic use. The pharmaceutical composition of the present invention should be sterile and stable under production and storage conditions. The preferred dosage form is an injection. Such an injection may be a sterile injection solution. For example, a sterile injection solution may be prepared by adding a required dose of the recombinant protein of the present invention to a suitable solvent, optionally adding other desired components (including, but not limited to, pH adjusters, surfactants, adjuvants, ionic strength enhancers, isotonicity agents, preservatives, diluents, or any combination thereof) at the same time, and then filtering and sterilizing. The sterile injection solution may also be manufactured into a sterile lyophilized powder (e.g., by vacuum drying or lyophilization) for ease of storage and use. Such sterile, lyophilized powder may be dispersed in a suitable carrier, for example, sterile, pyrogen-free water, before use.

[0163] Also, for ease of administration, the antibodies or antigen-binding fragments thereof of the present invention may be presented in pharmaceutical compositions in unit dosage amounts.

[0164] The antibodies or antigen-binding fragments thereof, and pharmaceutical compositions of the present invention may be administered in any suitable manner known in the art, including, but not limited to, orally, bucally, sublingually, ocularly, topically, parenterally, rectally, intrathecally, intracisternally, inguinally, intravesically, topically (e.g., powders, salves or drops), or nasally. However, for many therapeutic applications, the preferred route / mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, and intramuscular injection). As will be appreciated by those skilled in the art, the route and / or mode of administration will vary depending on the desired purpose. In one preferred embodiment, the antibodies or antigen-binding fragments thereof, and pharmaceutical compositions of the present invention are administered by intravenous infusion or injection.

[0165] The pharmaceutical compositions of the invention may contain a "therapeutically effective amount" or a "prophylactically effective amount" of an antibody or antigen-binding fragment thereof of the invention. A "prophylactically effective amount" is an amount sufficient to prevent, inhibit, or delay the onset of a disease. A "therapeutically effective amount" is an amount sufficient to cure or at least partially inhibit the disease and its complications in a patient suffering from the disease. The therapeutically effective amount of an antibody or antigen-binding fragment thereof of the invention may vary depending on the severity of the disease being treated, the overall state of the patient's own immune system, the general condition of the patient (e.g., age, weight, and sex), the form of administration of the drug, and other treatments administered simultaneously, etc.

[0166] In the present invention, the dosing regimen may be adjusted to obtain the optimum desired response (e.g., a therapeutic or prophylactic response), for example, by administering a single dose or multiple doses over a period of time, with the dosage proportionately reduced or increased depending on the exigencies of the therapeutic situation.

[0167] In the present invention, the subject may be a mammal, for example a human.

[0168] Detection Method and Kit The antibody or antigen-binding fragment thereof of the present invention can detect the presence or level of ROR1 in a sample by specifically binding to ROR1.

[0169] Thus, in another aspect, the present invention provides a kit comprising the antibody or antigen-binding fragment thereof of the present invention. In some preferred embodiments, the antibody or antigen-binding fragment thereof of the present invention is detectably labeled. In one preferred embodiment, the kit further comprises a secondary antibody that specifically recognizes the antibody or antigen-binding fragment thereof of the present invention. Preferably, the secondary antibody further comprises a detectable label.

[0170] In the present invention, the detectable label may be any substance that can be detected by fluorescent, spectral, photochemical, biochemical, immunological, electrical, optical or chemical means. Particularly preferably, such a label is applicable to immunological detection (e.g., enzyme-linked immunoassay, radioimmunoassay, fluorescent immunoassay, chemiluminescent immunoassay, etc.). Such labels are well known in the art and include, but are not limited to, enzymes (e.g., horseradish peroxidase, alkaline phosphatase, β-galactosidase, urease, glucose oxidase, etc.), radionuclides (e.g., 3H, 125I, 35S, 14C, or 32P), fluorescent dyes (e.g., fluorescein isothiocyanate (FITC), fluorescein, tetramethylrhodamine isothiocyanate (TRITC), phycoerythrin (PE), Texas Red, rhodamine, quantum dots, or cyanine dye derivatives (e.g., Cy7, Alexa 750)), acridinium ester-based compounds, magnetic beads (e.g., Dynabeads®), colorimetric labels (e.g., colloidal gold, colored glass or plastic (e.g., polystyrene, polypropylene, latex, etc.) beads), and biotin that binds to avidin (e.g., streptavidin) modified with the above labels. Patents teaching the use of such labels include, but are not limited to, U.S. Patent Nos. 3,817,837, 3,850,752, 3,939,350, 3,996,345, 4,277,437, 4,275,149, and 4,366,241, all of which are incorporated herein by reference. Labels contemplated in the present invention can be detected by methods known in the art. For example, radioactive labels can be detected using photographic film or a scintillation detector, and fluorescent labels can be detected using a photodetector to detect emitted light. Enzyme labels are generally detected by providing the enzyme with a substrate and detecting the reaction product resulting from the action of the enzyme on the substrate, and colorimetric labels are detected by simply visualizing the colored label. In some embodiments, such detectable labels can be linked to the recombinant proteins of the present invention by linkers of different lengths to reduce potential steric hindrance.

[0171] In another aspect, the invention provides a method for detecting the presence or level of ROR1 in a sample, comprising using an antibody or antigen-binding fragment thereof of the invention. In a preferred embodiment, the antibody or antigen-binding fragment thereof of the invention is further labeled with a detectable label. In another preferred embodiment, the method further comprises detecting the antibody or antigen-binding fragment thereof of the invention using a detectably labeled reagent. The method may be used for diagnostic or non-diagnostic purposes (e.g., the sample is a cell sample rather than a sample from a patient).

[0172] In another aspect, the invention provides a method for detecting the presence or level of ROR1 in a sample, comprising contacting the sample with an antibody or antigen-binding fragment thereof described in the invention under conditions allowing the antibody or antigen-binding fragment thereof and ROR1 to form a complex, and detecting formation of the complex.

[0173] In another aspect, the invention provides the use of an antibody or antigen-binding fragment thereof of the invention in the manufacture of a kit for detecting the presence or level of ROR1 in a sample.In another aspect, the invention provides a diagnostic or therapeutic kit comprising an antibody or antigen-binding fragment thereof, a vector, a host cell, a complex, a chimeric antigen receptor, or a multispecific antibody according to the invention, and instructions for use.

[0174] Considering that ROR1 is low or absent in normal tissues and is expressed or highly expressed in some cancers, tumors and tumor metastasis can be diagnosed by detecting the presence or level of ROR1 in a sample. Thus, the antibody or antigen-binding fragment thereof, conjugate, multispecific antibody, or kit of the present invention can diagnose tumors and tumor metastasis. Thus, in another aspect, there is provided a use of the antibody or antigen-binding fragment thereof, conjugate, multispecific antibody, or kit of the present invention in the diagnosis of tumors and tumor metastasis.

[0175] The antibody of the present invention has high binding affinity to ROR1 and very high specificity. Therefore, the antibody of the present invention has the ability to prevent and / or treat tumors. The humanized antibody of the present invention retains the functions and properties of the parent mouse-derived antibody. And, since the humanized antibody of the present invention has a high level of humanization, it can be safely administered to human subjects without inducing an immunogenic response. Therefore, the antibody of the present invention (especially the humanized antibody) has significant clinical value.

[0176] [Table 1]

[0177] definition In the present invention, unless otherwise specified, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. In addition, the operation steps of cell culture, biochemistry, nucleic acid chemistry, immunology laboratory, etc. used herein are all common steps widely used in the corresponding fields. In addition, in order to better understand the present invention, the following provides definitions and interpretations of related terms.

[0178] As used herein, the term "antibody" generally refers to an immunoglobulin molecule consisting of two pairs of polypeptide chains, each pair having one light chain (LC) and one heavy chain (HC). Antibody light chains can be classified as kappa and lambda light chains. Heavy chains can be classified as μ, δ, γ, α or ε, defining the antibody isotype as IgM, IgD, IgG, IgA and IgE, respectively. Within light and heavy chains, the variable and constant regions are linked via a "J" region of about 12 or more amino acids, and heavy chains also include a "D" region of about 3 or more amino acids. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region consists of three domains (CH1, CH2 and CH3). Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The light chain constant region consists of one domain CL. The constant domains are not directly involved in binding of antibodies to antigens, but exhibit various effector functions, such as mediating the binding of immunoglobulins to host tissues or factors, including the binding of various cells of the immune system (e.g., effector cells) to the first component (C1q) of the classical complement system. The VH and VL regions are subdivided into highly variable regions (called complementarity determining regions (CDRs)) with relatively conserved regions, called framework regions (FRs), dispersed between them. Each VH and VL consists of three CDRs and four FRs arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions (VH and VL) of each heavy / light chain pair form an antigen-binding site, respectively. The assignment of amino acids to each region or domain can follow the definitions in Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987 and 1991)), or Chothia & Lesk (1987) J. Mol. Biol. 196:901-917; Chothia et al., (1989) Nature 342:878-883.

[0179] In this specification, unless otherwise specified, when the term "antibody" is referred to, it is intended to include not only complete antibodies but also antigen-binding fragments of antibodies.

[0180] As used herein, the term "complementarity determining region" or "CDR" refers to the amino acid residues in an antibody variable region that are responsible for antigen binding. The exact boundaries of these amino acid residues can be defined by various numbering systems known in the art, for example, according to the definitions in the AbM numbering system (Martin ACR, Cheetham JC, Rees AR (1989) Modelling antibody hypervariable loops: A combined algorithm. Proc Natl Acad Sci USA 86:9268-9272) or the IMGT numbering system (Lefranc et al., Dev. Comparat. Immunol. 27:55-77, 2003). For a given antibody, a person skilled in the art can easily identify the CDRs defined by each numbering system. Also, the correspondence between different numbering systems is well known to those skilled in the art (see, for example, Lefranc et al., Dev. Comparat. Immunol. 27:55-77, 2003).

[0181] In the present invention, the CDRs contained in the antibody or antigen-binding fragment thereof of the present invention can be determined based on various numbering systems known in the art. In some embodiments, the CDRs contained in the antibody or antigen-binding fragment thereof of the present invention are preferably determined by the Kabat, Chothia, AbM, and IMGT numbering systems.

[0182] As used herein, the term "framework region" or "FR" residues are those amino acid residues in an antibody variable domain other than the CDR residues as defined above.

[0183] A "germline antibody gene" is a non-lymphocyte-encoded immunoglobulin sequence that has not undergone the maturation process that induces genetic rearrangement and maturation leading to the expression of a specific immunoglobulin. One advantage provided by various embodiments of the present invention comes from the recognition that germline antibody genes retain more of the characteristic and important amino acid sequence structure of an individual animal species than mature antibody genes, and are therefore less likely to be recognized by the species as a foreign substance when applied to the species for therapeutic purposes.

[0184] The term "antibody" is not limited by any particular method of producing the antibody. For example, it includes recombinant antibodies, monoclonal antibodies, and polyclonal antibodies. The antibody may be of different isotypes, for example, IgG (e.g., IgG1, IgG2, IgG3, or IgG4 subtypes), IgA1, IgA2, IgD, IgE, or IgM antibodies.

[0185] As used herein, the term "antigen-binding fragment" of an antibody refers to a polypeptide that is a fragment of an antibody, e.g., a polypeptide that is a fragment of a full-length antibody, that retains the ability to specifically bind to the same antigen bound by the full-length antibody and / or competes with the full-length antibody for specific binding to antigen, also referred to as "antigen-binding portion." See generally, Fundamental Immunology, Ch. 7 (Paul, W., ed., 2nd ed., Raven Press, NY (1989), which is incorporated herein by reference in its entirety and for all purposes. Antigen-binding fragments of antibodies can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. Non-limiting examples of antigen-binding fragments include Fab, Fab', F(ab')2, Fd, Fv, dAb and complementarity determining region (CDR) fragments, single chain antibodies (e.g., scFv), chimeric antibodies, diabodies, linear antibodies, nanobodies (technology derived from Domantis), domain antibodies (technology derived from Ablynx), and polypeptides comprising at least a sufficient portion of an antibody to confer specific antigen-binding capability to the polypeptide. Engineered antibody variants are reviewed in Holliger et al., 2005; Nat Biotechnol, 23: 1126-1136.

[0186] As used herein, the term "full-length antibody" refers to an antibody consisting of two "full-length heavy chains" or "heavy chains" and two "full-length light chains" or "light chains". A "full-length heavy chain" or "heavy chain" refers to a polypeptide chain consisting of a heavy chain variable region (VH), a heavy chain constant region CH1 domain, a hinge region (HR), a heavy chain constant region CH2 domain, and a heavy chain constant region CH3 domain from the N-terminus to the C-terminus, and optionally further including a heavy chain constant region CH4 domain if the full-length antibody is an IgE isotype. Preferably, a "full-length heavy chain" refers to a polypeptide chain consisting of VH, CH1, HR, CH2, and CH3 from the N-terminus to the C-terminus. A "full-length light chain" or "light chain" refers to a polypeptide chain consisting of a light chain variable region (VL) and a light chain constant region (CL) from the N-terminus to the C-terminus. The two pairs of full-length antibody chains are linked by a disulfide bond between CL and CH1 and a disulfide bond between the HRs of the two full-length heavy chains. The full-length antibody of the present invention may be derived from a single species, such as human, or may be a chimeric or humanized antibody. The full-length antibody of the present invention comprises two antigen-binding sites, each formed by a VH and VL pair, and these two antigen-binding sites specifically recognize / bind to the same antigen.

[0187] As used herein, the term "Fd fragment" refers to an antibody fragment consisting of the VH and CH1 domains. The term "dAb fragment" refers to an antibody fragment consisting of the VH domain (Ward et al., Nature 341:544 546 (1989)). The term "Fab fragment" refers to an antibody fragment consisting of the VL, VH, CL and CH1 domains. The term "F(ab')2 fragment" refers to an antibody fragment containing two Fab fragments linked by disulfide bonds in the hinge region. The term "Fab' fragment" refers to a fragment obtained by restoring the disulfide bonds linking the two heavy chain fragments in the F(ab')2 fragment, and consists of one complete light chain and heavy chain Fd fragment (consisting of the VH and CH1 domains).

[0188] As used herein, the term "Fv fragment" refers to an antibody fragment consisting of the VL and VH domains of a single arm of an antibody. The Fv fragment is generally considered to be the smallest antibody fragment capable of forming a complete antigen-binding site. In general, six CDRs are considered to confer antigen-binding specificity to an antibody. However, even a single variable region (e.g., an Fd fragment containing only three CDRs specific for an antigen) can recognize and bind to an antigen, although its affinity may be lower than that of a complete binding site.

[0189] As used herein, the term "Fc fragment" refers to an antibody fragment formed by binding the second and third constant regions of the first heavy chain and the second and third constant regions of the second heavy chain of an antibody via disulfide bonds. The Fc fragment of an antibody has a variety of different functions, but is not involved in antigen binding.

[0190] As used herein, the term "scFv" refers to a single polypeptide chain comprising a VL and a VH domain, said VL and VH being linked by a linker (see, e.g., Bird et al., Science 242:423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988); and Pluckthun, The Pharmacology of Monoclonal Antibodies, Vol. 113, Eds. Roseburg and Moore, Springer-Verlag, New York, pp. 269-315 (1994)). Such scFv molecules have the general structure NH2-VL-linker-VH-COOH or NH2-VH-linker-VL-COOH. Suitable prior art linkers consist of overlapping GGGGS amino acid sequences or variants thereof. For example, a linker having the amino acid sequence (GGGGS)4 may be used, although variants thereof may also be used (Holliger et al. (1993), Proc. Natl. Acad. Sci. USA 90: 6444-6448). Other linkers that can be used in the present invention are described by Alfthan et al. (1995), Protein Eng. 8:725-731; Choi et al. (2001), Eur. J. Immunol. 31: 94-106; Hu et al. (1996), Cancer Res. 56:3055-3061; Kipriyanov et al. (1999), J. Mol. Biol. 293:41-56 and Roovers et al. (2001), Cancer Immunol. In some cases, a disulfide bond may be present between the VH and VL of the scFv. As used herein, the term "di-scFv" refers to an antibody fragment formed by the linkage of two scFvs.

[0191] As used herein, the term "diabody" refers to a VH and VL domain expressed on a single polypeptide chain, but which pairs with the complementary domains of another chain by using a linker that is too short to allow pairing between the two domains on the same chain, and generates two antigen-binding sites (see, e.g., Holliger P. et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993); and Poljak RJ et al., Structure 2:1121-1123 (1994)).

[0192] Each of the above antibody fragments retains the ability to specifically bind to the same antigen bound by the full-length antibody and / or competes with the full-length antibody for specific binding to antigen.

[0193] As used herein, the term "multispecific antibody" refers to an antibody having multiple different antigen-binding specificities, including, for example, bispecific antibodies, trispecific antibodies, and tetraspecific antibodies. A "bispecific antibody" refers to an antibody having two different antigen-binding specificities, and is a complex formed by coupling arms of a first antibody (or a fragment thereof) and a second antibody (or a fragment thereof) or an antibody analog, and the coupling methods include, but are not limited to, chemical reaction, gene fusion, and enzymes. A "multispecific antibody" refers to, for example, trispecific antibodies and tetraspecific antibodies, where a trispecific antibody is an antibody having three different antigen-binding specificities, and a tetraspecific antibody is an antibody having four different antigen-binding specificities.

[0194] As used herein, "antibody mimetics" are those that specifically bind to antigens in the same way as antibodies, but without the antibody structure. They are generally artificial peptides or proteins with a molar mass of about 3-20 kDa. For example, ankyrin repeat proteins (DARPins) and fynomers. Designed ankyrin repeat proteins (DARPins) are linked or conjugated to IgG antibodies and scFv-Fc antibody fragments, see for example CN104341529A. Anti-IL-17a fynomers are conjugated to anti-IL-6R antibodies, see for example WO2015141862A1.

[0195] As used herein, a "chimeric antigen receptor (CAR)" is a tumor antigen binding domain fused to an intracellular signaling domain and capable of activating T cells. Generally, the extracellular binding domain of a CAR is derived from a murine, humanized or human monoclonal antibody.

[0196] As used herein, "immunoglobulin" or "Ig" is a type of protein that acts as an antibody. Antibodies expressed by B cells are sometimes called chimeric antigen receptors or antigen receptors. Five members of such proteins are IgA, IgG, IgM, IgD and IgE, with IgG being the most common circulating antibody. It is the most effective immunoglobulin in agglutination, complement fixation and other antibody responses, and is important in defense against bacteria and viruses.

[0197] As used herein, the technique for obtaining an antibody involves obtaining an antigen-binding fragment of an antibody (e.g., the above-mentioned antibody fragment) from a given antibody (e.g., the antibody of the present invention) using a general technique known to those skilled in the art (e.g., recombinant DNA technique or enzymatic or chemical cleavage method), and specifically screening the antigen-binding fragment of the antibody in a manner similar to that used for a complete antibody.

[0198] As used herein, the terms "monoclonal antibody", "monoclonal antibody" and "mAb" have the same meaning and may be used interchangeably, and refer to one antibody or one fragment of an antibody from a group of highly homologous antibody molecules, i.e., completely identical antibody molecules except for natural mutations that may spontaneously appear. A monoclonal antibody has high specificity for a single epitope on an antigen. A polyclonal antibody is directed against a monoclonal antibody and generally includes at least two or more different antibodies, which generally recognize different epitopes on an antigen. In addition, the modifier "monoclonal" indicates only that the characteristics of the antibody are obtained from a group of highly homologous antibodies, and cannot be understood to require the antibody to be produced by any particular method.

[0199] The monoclonal antibodies of the present invention can be produced by a variety of techniques, such as hybridoma techniques (see, e.g., Kohler et al. Nature, 256:495, 1975), recombinant DNA techniques (see, e.g., U.S. Patent Application No. 4,816,567), or phage antibody library techniques (see, e.g., Clackson et al. Nature 352:624-628, 1991, or Marks et al. J. Mol. Biol. 222:581-597, 1991).

[0200] For example, monoclonal antibodies can be produced as follows. First, an immunogen (with an adjuvant added if necessary) is injected into a mouse or other suitable host animal for immunization. The immunogen or adjuvant is generally injected subcutaneously at multiple points or intraperitoneally. The immunogen can be pre-coupled to a known protein, such as serum albumin or soybean trypancreatin inhibitor, to enhance the immunogenicity of the antigen in the host. The adjuvant can be Freund's adjuvant or MPL-TDM, etc. After immunization, the animal produces lymphocytes in the body that secrete antibodies that specifically bind to the immunogen. The lymphocytes can also be obtained by ex vivo immunization. The target lymphocytes are collected and fused with myeloma cells using a suitable fusing agent such as PEG to obtain hybridoma cells (Goding, Monoclonal Antibodies: Principles and Practice, pp.59-103, Academic Press, 1996). The hybridoma cells prepared as above may be inoculated and grown in a suitable culture medium, preferably containing one or more substances capable of inhibiting the growth of unfused maternal myeloma cells. For example, for maternal myeloma cells lacking hypoxanthine-guanine phosphoribosyltransferase (HGPRT or HPRT), the growth of HGPRT-deficient cells can be inhibited by adding substances such as hypoxanthine, aminopterin and thymine (HAT medium) to the culture medium. The preferred myeloma cells should have characteristics such as a high fusion rate, stable antibody secretion ability, and sensitivity to HAT medium. The myeloma cells are preferably selected from mouse-derived myelomas, such as MOP-21 or MC-11 mouse tumor-derived lines (THE Salk Institute Cell Distribution Center, San Diego, Calif. USA), and SP-2 / 0 or X63-Ag8-653 cell lines (American Type Culture Collection, Rockville, Md. USA).Other studies have also reported the production of human monoclonal antibodies using human myeloma and human-mouse heteromyeloma cell lines (Kozbor, J. Immunol., 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63, Marcel Dekker, Inc., New York, 1987). The culture medium in which the hybridoma cells are grown is used to detect the production of monoclonal antibodies against specific antigens. Methods for measuring the binding specificity of monoclonal antibodies produced from hybridoma cells include immunoprecipitation or in vitro binding assays, such as radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA). For example, the affinity of monoclonal antibodies can be measured using the Scatchard analysis method described by Munson et al. in Anal. Biochem. 107:220 (1980). After determining the specificity, affinity and reactivity of the antibodies produced by the hybridomas, the cell line of interest can be subcloned by standard limiting dilution methods as described in (Goding, Monoclonal Antibodies: Principles and Practice, pp. 59-103, Academic Press, 1996). Suitable culture media can be DMEM or RPMI-1640, etc. Hybridoma cells can also be grown in animals in the form of ascites tumors. Monoclonal antibodies secreted by the subcloned cells can be isolated from cell culture fluid, ascites fluid or serum using conventional immunoglobulin purification methods, such as protein A agarose gel, hydroxyapatite chromatography, gel electrophoresis, dialysis or affinity chromatography.

[0201] Monoclonal antibodies can also be obtained by recombinant gene engineering techniques. DNA molecules encoding the heavy and light chain genes of a monoclonal antibody can be isolated from hybridoma cells by PCR amplification using nucleic acid primers that specifically bind to the heavy and light chain genes of the monoclonal antibody. The resulting DNA molecules can then be inserted into an expression vector, followed by transfecting host cells (e.g., E. coli cells, COS cells, CHO cells, or other myeloma cells that do not produce immunoglobulins) and culturing them under appropriate conditions to obtain the desired antibody of recombinant expression.

[0202] Antibodies can be purified by known techniques, for example, by affinity chromatography with Protein A or Protein G. Thereafter, or alternatively, the specific antigen (the target molecule recognized by the antibody) or its antigenic epitope can be immobilized on a column and the immunospecific antibody purified by immunoaffinity chromatography. For the purification of immunoglobulins, see, for example, D. Wilkinson (The Scientist, published by The Scientist, Inc., Philadelphia Pa., Vol. 14, No. 8 (Apr. 17, 2000), pp. 25-28).

[0203] As used herein, the term "mouse-derived antibody" refers to an antibody obtained by fusing B cells and myeloma cells from an immunized mouse, then screening mouse hybridoma fusion cells that can grow indefinitely and secrete antibodies, and then performing further screening, antibody production, and antibody purification. Alternatively, after an antigen enters the mouse body, B cells differentiate and grow to form plasma cells, which can produce secretory antibodies. Antibodies are produced by stimulation with a specific antigen, and for the production of antigens, after an antigen enters the human body, it causes the interaction of various immune cells, which causes B cells in lymphocytes to differentiate and grow to form plasma cells, which can produce secretory antibodies.

[0204] As used herein, the term "chimeric antibody" refers to an antibody in which a portion of the light or / and heavy chain is derived from one antibody (from a particular species or belonging to a particular antibody class or subspecies) and another portion of the light or / and heavy chain is derived from another antibody (from the same or different species or belonging to the same or different antibody class or subspecies), but in any case maintains binding activity to the antigen of interest (USP 4816567 to Cabilly et al.; Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851 6855 (1984)). For example, the term "chimeric antibody" may include an antibody in which the variable regions of the heavy and light chains are derived from a first antibody (e.g., a mouse-derived antibody) and the constant regions of the heavy and light chains are derived from a second antibody (e.g., a human antibody) (e.g., a human-mouse chimeric antibody).

[0205] As used herein, the term "humanized antibody" refers to a genetically engineered non-human antibody whose amino acid sequence is modified to improve homology with the sequence of a human antibody. Generally, all or a portion of the CDR region of a humanized antibody is derived from a non-human antibody (donor antibody), and all or a portion of the non-CDR region (e.g., variable region FR and / or constant region) is derived from a human immunoglobulin (acceptor antibody). A humanized antibody generally maintains the desired properties of the donor antibody, including but not limited to antigen specificity, affinity, reactivity, ability to improve immune cell activity, ability to enhance immune response, etc. The donor antibody may be a mouse, rat, rabbit, or non-human primate (e.g., cynomolgus monkey) antibody having the desired properties (e.g., antigen specificity, affinity, reactivity, ability to improve immune cell activity and / or ability to enhance immune response).

[0206] Humanized antibodies are particularly advantageous because they can maintain the desired properties of a non-human donor antibody (e.g., a mouse-derived antibody) while effectively reducing the immunogenicity of the non-human donor antibody (e.g., a mouse-derived antibody) in a human subject. However, due to matching problems between the CDRs of the donor antibody and the FRs of the recipient antibody, the desired properties of the humanized antibody (e.g., antigen specificity, affinity, reactivity, ability to improve immune cell activity and / or ability to enhance immune response) are generally lower than those of the non-human donor antibody (e.g., a mouse-derived antibody).

[0207] Thus, although those skilled in the art have intensively studied antibody humanization and have obtained some success (see, e.g., Jones et al., Nature, 321:522 525 (1986); Reichmann et al., Nature, 332:323 329 (1988); Presta, Curr. Op. Struct. Biol., 2:593 596 (1992); and Clark, Immunol. Today 21: 397 402 (2000)), the prior art does not provide detailed guidance on how to sufficiently humanize a donor antibody so that the produced humanized antibody has the highest possible level of humanization while maintaining as much of the desired properties of the donor antibody as possible. Those skilled in the art can explore, study and modify a particular donor antibody and, so long as it requires considerable effort, obtain a humanized antibody that has a high level of humanization (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% humanization level) while retaining the desired properties of the particular donor antibody.

[0208] In the present invention, in order for the humanized antibody to maintain the properties of the donor antibody as much as possible (including, for example, antigen specificity, affinity, reactivity, ability to improve immune cell activity and / or ability to enhance immune responses), the framework region (FR) in the humanized antibody of the present invention contains not only amino acid residues of a human-derived acceptor antibody but also the corresponding amino acid residues of a non-human-derived donor antibody.

[0209] Chimeric or humanized antibodies of the invention may be produced according to the sequences of the mouse monoclonal antibodies produced above. DNA encoding the heavy and light chains may be obtained from the mouse hybridoma of interest and engineered using standard molecular biology techniques to contain non-mouse (e.g., human) immunoglobulin sequences.

[0210] To produce chimeric antibodies, mouse immunoglobulin variable regions may be linked to human immunoglobulin constant regions using methods known in the art (see, e.g., U.S. Patent No. 4,816,567 to Cabilly et al.). For example, DNA encoding VH is operatively linked to another DNA molecule encoding a heavy chain constant region to obtain a full-length heavy chain gene. Sequences of human heavy chain constant region genes are known in the art (see, e.g., Kabat, EA et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242), and DNA fragments containing these regions may be obtained by standard PCR amplification. The heavy chain constant region may be an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region, but generally is preferably an IgG1 or IgG4 constant region. For example, the DNA encoding the VL is operably linked to another DNA molecule encoding the light chain constant region CL to obtain a full-length light chain gene (and a Fab light chain gene). Sequences of human light chain constant region genes are known in the art (see, for example, Kabat, EA et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDepartment of Health and Human Services, NIH Publication No. 91-3242), and DNA fragments containing these regions may be obtained by standard PCR amplification. The light chain constant region may be a kappa or lambda constant region, although generally it is preferred that it is a kappa constant region.

[0211] To produce humanized antibodies, murine CDR regions may be inserted into human-derived frame sequences using methods known in the art (see U.S. Patent No. 5,225,539 to Winter, U.S. Patent Nos. 5,530,101, 5,585,089, 5,693,762, and 6,180,370 to Queen et al., and Lo, Benny, KC, editor, in Antibody Engineering: Methods and Protocols, volume 248, Humana Press, New Jersey, 2004). Transgenic animals may also be utilized that are capable of producing complete human antibody libraries after immunization without producing endogenous immunoglobulins. For example, it has been reported that homozygous deletion of the antibody heavy-chain joining region (JH) gene in chimeric and germ-line mutant mice completely prevents the production of endogenous antibodies, and that subsequent transfer of human germ-line immunoglobulin gene sequences into the germ-line mutant mice enables the mice to produce human antibodies upon antigenic stimulation (see, e.g., Jakobovits et al., 1993, Proc. Natl. Acad. Sci. USA 90:2551; Jakobovits et al., 1993, Nature 362:255-258; Bruggermann et al., 1993, Year in Immunology 7:33; and Duchosal et al., 1992, Nature 355:258). Non-limiting examples of such transgenic animals include, but are not limited to, the HuMAb Mouse (Medarex, Inc.), which contains a miniloci of human immunoglobulin genes encoding unrearranged human heavy (μ and γ) and κ light chain immunoglobulin sequences, but also targeted mutations to inactivate the endogenous μ and κ chain loci (see, e.g., Lonberg et al. (1994) Nature 368(6474):856-859), or the "KM Mouse™" carrying a human heavy chain transgene and a human light chain transchromosome (see patent application WO 02 / 43478).Other methods for antibody humanization further include phage display technology (see Hoogenboom et al., 1991, J. Mol. Biol. 227:381; Marks et al., J. Mol. Biol. 1991, 222:581-597; Vaughan et al., 1996, Nature Biotech 14:309).

[0212] As used herein, the term "humanization level" refers to an index for evaluating the number of non-human amino acid residues in a humanized antibody. From the humanization level of a humanized antibody, the homology between the variable region sequence and the human V domain can be predicted, for example, by DomainGapAlign on the IMGT site.

[0213] As used herein, the term "alloantibody" refers to an antibody variant comprising amino acid sequences contained in the heavy and light chain variable regions that are homologous to the amino acid sequences of an antibody or antigen-binding fragment thereof according to the present specification, and which variant maintains the desired functional properties of the anti-ROR1 antibody of the present invention.

[0214] Methods for matching sequences for comparison are well known in the art. Various programs and matching algorithms are described in Smith TF and Waterman MS, Adv. Appl. Math., 2:482, 1981; Higgins DG and Sharp PM, CABIOS 5:151, 1989. Altschul SF et al., Nature Genet., 6:119, 1994, provide detailed concepts for sequence matching methods and homology calculations.

[0215] As used herein, the term "specific binding" refers to a non-random binding reaction between two molecules, such as the reaction between an antibody and its corresponding antigen. The strength or affinity of a specific binding interaction may be expressed as the equilibrium dissociation constant (KD) or the half maximal effective concentration (EC50) of the interaction.

[0216] The nature of the specific binding between the two molecules may be measured using methods known in the art. One method involves measuring the rates of formation and dissociation of the antigen-binding site / antigen complex. The "association rate constant" (ka or k) and the "dissociation rate constant" (k or k) may both be calculated from the concentration and the actual rates of association and dissociation (see Malmqvist M, Nature, 1993, 361:186-187). The ratio of k / k is equal to the dissociation constant K (see Davies et al., Annual Rev Biochem, 1990, 59:439-473). The values ​​of K, k and k may be measured by any valid method. In some embodiments, the dissociation constant may be measured by bioluminescence interferometry (e.g., ForteBio Octet). Alternatively, the dissociation constant may be measured by surface plasmon resonance technology (e.g., Biacore) or Kinexa.

[0217] As used herein, the term "vector" refers to a nucleic acid delivery tool into which a polynucleotide is inserted. If the vector can express a protein encoded by the inserted polynucleotide, the vector is called an expression vector. The genetic elements carried by the vector can be expressed in a host cell by introducing the vector into the host cell by transformation, transduction or transfection. Vectors are known to those skilled in the art and include, but are not limited to, plasmids, phagemids, cosplasmids, artificial chromosomes (e.g., yeast artificial chromosomes (YAC), bacterial artificial chromosomes (BAC) or P1-derived artificial chromosomes (PAC)), phages (e.g., lambda phage or M13 phage), and animal viruses. Animal viruses used as vectors include, but are not limited to, retroviruses (including lentiviruses), adenoviruses, adeno-associated viruses, herpes viruses (e.g., herpes simplex viruses), poxviruses, baculoviruses, papilloma viruses, papova viruses (e.g., SV40), and the like. A vector may contain various elements that control expression, including, but not limited to, promoter sequences, transcription initiation sequences, enhancer sequences, selection elements, and reporter genes. A vector may also contain a replication origin.

[0218] Expression and cloning vectors contain a nucleic acid sequence that allows the vector to replicate in one or more selected host cells. Generally, in cloning vectors, this sequence allows the vector to replicate independently of the host chromosomal DNA and includes an origin of replication or an autonomously replicating sequence. As used herein, the term "expression vector" is a vector that contains a recombinant polynucleotide that includes an expression control sequence operatively linked to the nucleotide sequence to be expressed. An expression vector contains sufficient cis-acting elements for expression; other elements for expression may be provided by the host cell or an in vitro expression system. Expression vectors include those known in the art, such as cosmids, plasmids (e.g., exposed or contained within liposomes), and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses).

[0219] As used herein, the term "host cell" refers to a cell for introducing a vector, including, but not limited to, prokaryotic cells such as E. coli or Bacillus subtilis, fungal cells such as yeast cells or Aspergillus oryzae, insect cells such as S2 Drosophila cells or Sf9, or animal cells such as fibroblasts, NSO cells, Vero cells, Hela cells, COS cells, CHO cells (e.g., CHO-K1, CHO-S, CHO DXB11, ExpiCHO, CHO DG44 cells), ExpiCHO cells, HEK293 cells, Expi293 cells, BHK cells and MDCKII cells. In the present specification, the host cell further includes immune cells, such as T lymphocytes, NK cells, etc., for constructing chimeric antigen receptor T cells (CAR-T).

[0220] As used herein, the term "identity" refers to the matching of sequences between two polypeptides or two nucleic acids. If a position in two sequences is occupied by the same base or amino acid monomer subunit (e.g., a position in each of two DNA molecules is occupied by adenine or a position in each of two polypeptides is occupied by lysine), then the molecules are identical at that position. The "percent identity" of two sequences is a function of the number of matching positions shared by the two sequences / the number of positions compared x 100. For example, if 6 positions out of 10 positions of two sequences are matched, then the two sequences have 60% identity. For example, the DNA sequences CTGACT and CAGGTT have 50% identity (3 positions out of 6 positions are matched). Generally, two sequences are compared when matching to produce maximum identity. Such matching can be accomplished, for example, by using the method of Needleman et al. (1970) J. Mol. Biol. 48:443-453, which can be conveniently performed by a computer program such as the Align program (DNAstar, Inc.). The algorithm of E. Meyers and W. Miller (Comput. Appl Biosci., 4:11-17 (1988)) incorporated into the ALIGN program (version 2.0) can be used to measure percent identity between two amino acid sequences, using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. The Needleman and Wunsch (J MoI Biol. 48:444-453 (1970)) algorithm in the GAP program incorporated into the GCG software package (available at www.gcg.com) can also be used to measure the percent identity between two amino acid sequences using a Blossum 62 matrix or a PAM250 matrix, and gap weights of 16, 14, 12, 10, 8, 6, or 4 and length weights of 1, 2, 3, 4, 5, or 6.

[0221] As used herein, the term "conservative substitution" refers to an amino acid substitution that does not adversely affect or change the desired properties of the protein / polypeptide containing the amino acid sequence. For example, conservative substitutions can be introduced by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative substitution of amino acids includes replacing an amino acid residue with an amino acid residue having a similar side chain, e.g., a residue that is physically or functionally similar to the corresponding amino acid residue (e.g., has chemical properties including similar size, shape, charge, ability to form covalent or hydrogen bonds, etc.). Families of amino acid residues with similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine and histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), β-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). It is therefore preferred to substitute a corresponding amino acid residue with another amino acid residue from the same side chain family. Methods for identifying conservative amino acid substitutions are known in the art (see, e.g., Brummell et al., Biochem. 32:1180-1187 (1993); Kobayashi et al., Protein Eng. 12(10):879-884 (1999); and Burks et al., Proc. Natl Acad. Set USA 94:412-417 (1997), which are incorporated herein by reference).

[0222] The description of the 20 common amino acids according to the present invention follows the conventional method. See, for example, Immunology-A Synthesis (2nd Edition, ES Golub and DR Gren, Eds., Sinauer Associates, Sunderland, Mass. (1991)), which is incorporated herein by reference. In the present invention, the terms "polypeptide" and "protein" have the same meaning and may be used interchangeably. In the present invention, amino acids are generally represented by one-letter and three-letter abbreviations known in the art. For example, alanine may be represented by A or Ala.

[0223] As used herein, the term "pharmacologically acceptable carriers and / or excipients" refers to carriers and / or excipients that are pharmacologically and / or physiologically compatible with the subject and the active ingredient, and are known in the art (see, e.g., Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995), including, but not limited to, pH adjusting agents, surfactants, adjuvants, ionic strength enhancing agents, diluents, agents that maintain osmotic pressure, agents that delay absorption, and preservatives. For example, pH adjusting agents include, but are not limited to, phosphate buffers. Surfactants include, but are not limited to, cationic, anionic, or nonionic surfactants, e.g., Tween-80. Ionic strength enhancing agents include, but are not limited to, sodium chloride. Preservatives include, but are not limited to, various antibacterial and antifungal agents, e.g., parabens, chlorobutanol, phenol, sorbic acid, and the like. Agents for maintaining osmotic pressure include, but are not limited to, sugars, NaCl and analogs thereof. Agents for delaying absorption include, but are not limited to, monostearate salts and gelatin. Diluents include, but are not limited to, water, aqueous buffers (e.g., buffered saline), alcohols and polyhydric alcohols (e.g., glycerin). Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as thimerosal, 2-phenoxyethanol, parabens, chlorobutanol, phenol, sorbic acid, and the like. Stabilizers have the meaning commonly understood by those skilled in the art and can stabilize the desired activity of the active ingredient in the drug, and include, but are not limited to, sodium glutamate, gelatin, SPGA, sugars (e.g., sorbitol, mannitol, starch, sucrose, lactose, dextran, or glucose), amino acids (e.g., glutamic acid and glycine), proteins (e.g., dried whey, albumin, or casein) or their decomposition products (e.g., lactalbumin hydrolysate), and the like.

[0224] As used herein, the term "prevention" refers to a method performed to prevent or delay the occurrence of a disease, illness, or condition (e.g., a tumor) in a subject. As used herein, the term "treatment" refers to a method performed to obtain beneficial or desired clinical results. For the purposes of the present invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, which may be detectable or undetectable, narrowing the extent of the disease, stabilizing (i.e., not worsening) the disease state, delaying or alleviating disease progression, improving or alleviating the disease state, and alleviating symptoms (whether partial or complete). "Treatment" may also be a method that increases survival time beyond the desired survival time (if the treatment is not administered).

[0225] As used herein, the term "subject" refers to a mammal, such as a primate mammal, such as a human. In some embodiments, the subject (e.g., a human) is afflicted with a tumor or is at risk of being afflicted with the above-mentioned disease.

[0226] As used herein, the term "effective amount" refers to an amount sufficient to obtain or at least partially obtain a desired effect. For example, an effective amount for preventing a disease (e.g., tumor) is an amount sufficient to prevent, inhibit or delay the onset of the disease (e.g., tumor), and an effective amount for treating a disease is an amount sufficient to cure or at least partially inhibit the disease and its complications in a patient suffering from the disease. Measuring such effective amounts is within the capabilities of a person skilled in the art. For example, an effective amount for therapeutic use depends on the severity of the disease to be treated, the overall state of the patient's own immune system, the general condition of the patient (e.g., age, weight and sex), the form of administration of the drug, and other treatments administered simultaneously, etc.

[0227] As used herein, the term "effector function" refers to a biological activity attributable to an antibody Fc region (a native sequence Fc region or an amino acid sequence variant Fc region), which varies depending on the antibody isotype. Examples of antibody effector functions include, but are not limited to, Fc receptor binding affinity, antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), down-regulation of cell surface receptors (e.g., B cell receptors), activation of B cells, secretion of cytokines, half-life / clearance rate of antibodies and antigen-antibody complexes, and the like. Methods for altering the effector function of an antibody are known in the art and can be achieved, for example, by introducing mutations into the Fc region.

[0228] As used herein, the term "antibody-dependent cell-mediated cytotoxicity (ADCC)" refers to a form of cytotoxicity in which Ig binds to Fc receptors (FcR) present on cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, or macrophages), causing these cytotoxic effector cells to specifically bind to target cells bearing antigens, and then secrete cytotoxins to kill the target cells. Methods for detecting the ADCC activity of an antibody are known in the art, and may be evaluated, for example, by measuring the binding activity of a test antibody to an Fc receptor (e.g., CD16a).

[0229] As used herein, the term "complement-dependent cytotoxicity (CDC)" refers to a form of cytotoxicity in which the complement component C1q binds to an antibody Fc, thereby activating the complement cascade. Methods for detecting the CDC activity of an antibody are known in the art, and may be evaluated, for example, by measuring the binding activity of a test antibody to an Fc receptor (e.g., C1q).

[0230] As used herein, the term "pharmaceutical acceptable" means that a molecular entity, molecular fragment, or composition does not cause any adverse, allergic, or other problems when appropriately administered to an animal or human. Specific examples of some substances as pharmaceutically acceptable carriers or components thereof include sugars (e.g., lactose), starch, cellulose and its derivatives, vegetable oils, gelatin, polyhydric alcohols (e.g., propylene glycol), alginic acid, and the like.

[0231] As used herein, combination therapy includes the use of an anti-ROR1 antibody or antigen-binding fragment thereof of the present invention in combination with one or more other active therapeutic agents of a second therapy (e.g., chemotherapeutic agents) or other prophylactic or therapeutic modes (e.g., radiation therapy).

[0232] In such combination therapy, the various active agents often have different complementary mechanisms of action, and the combination therapy can achieve synergistic effects. The combination therapy includes a therapeutic agent that affects the immune response (e.g., enhancing or activating response) and a therapeutic agent that affects (e.g., inhibiting or killing) tumor / cancer cells. The combination therapy can reduce the likelihood of drug-resistant cancer cells developing. The combination therapy allows for a reduced dosage of one or more of the agents, reducing or eliminating defects associated with one or more of the agents. Such combination therapy has a synergistic therapeutic or prophylactic effect against an underlying disease, condition, or condition.

[0233] As used herein, "combination" includes therapies that can be administered separately, such as by formulating them separately and administering them alone (e.g., they can be provided in a kit), and therapies that can be administered in a single formulation (i.e., a "combined formulation"). In some embodiments, the anti-ROR1 antibodies or antigen-binding fragments thereof of the invention may be administered sequentially. In other embodiments, the anti-ROR1 antibodies or antigen-binding fragments thereof may be administered simultaneously. The anti-ROR1 antibodies or antigen-binding fragments thereof of the invention may be used in any combination with at least one other (active) agent.

[0234] As used herein, ROR1 positivity is achieved by immunohistochemistry and staining intensity assessment by an expert clinical pathologist.

[0235] The terms "cancer" and "tumor" may be used interchangeably and are a large category of diseases characterized by the uncontrolled growth of abnormal cells in the body. Uncontrolled cell division can result in the formation of malignant tumors or cells that invade nearby tissues and can metastasize to distal sites in the body via the lymphatic system or bloodstream. Cancer includes benign or malignant cancers, as well as dormant tumors or micrometastases. Cancer also includes hematological malignancies.

[0236] The term "hematological malignancies" includes lymphomas, leukemias, myelomas or lymphatic malignancies, as well as splenic and lymph node tumors. Exemplary lymphomas include B-cell lymphomas and T-cell lymphomas. B-cell lymphomas include, for example, Hodgkin's lymphoma. T-cell lymphomas include, for example, cutaneous T-cell lymphoma. Hematological malignancies include leukemias, for example, secondary leukemia or acute lymphocytic leukemia. Hematological malignancies further include myelomas (e.g., multiple myeloma), and other hematological and / or B-cell or T-cell related cancers.

[0237] Hereinafter, the embodiments of the present application will be described in detail with reference to the drawings and examples, but it will be understood by those skilled in the art that the following drawings and examples are merely for the purpose of illustrating the present invention and are not intended to limit the scope of the present invention. Based on the drawings and the following detailed description of the preferred embodiments, various objects and advantages of the present invention will be realized by those skilled in the art. [Brief description of the drawings]

[0238] [Figure 1] Detection of Ba / F3 cells overexpressing human ROR1 protein. [Diagram 2] Detection of binding between mouse anti-human ROR1 antibody and ROR1-positive cells. [Diagram 3] Detection of binding between mouse anti-human ROR1 antibody and human ROR2 extracellular domain protein. [Figure 4] Measurement of binding of anti-human ROR1 chimeric antibody to cells. [Diagram 5] Measurement of ADCC cellular activity of anti-human ROR1 humanized candidate antibodies. [Figure 6] Measurement of the endocytosis-inducing activity of anti-human ROR1 candidate antibodies (Mab-ZAP method). [Figure 7A] Measurement of endocytosis activity using anti-human ROR1 candidate antibodies (acid washing method). [Figure 7B] Measurement of endocytosis activity using anti-human ROR1 candidate antibodies (acid washing method). [Figure 8] Measurement of endocytosis activity using anti-human ROR1 candidate antibodies (pHrodo dye (Thermo) method).

[0239] Sequence information The sequence information of the present invention is set forth in the table below.

[0240] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21] [Table 1-22] [Table 1-23] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0241] The present invention will now be described with reference to examples of the invention which are intended to illustrate, but not limit, the invention.

[0242] Unless otherwise specified, the molecular biology experimental methods and immunodetection methods used in the present invention are basically performed with reference to the methods described in J. Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd Edition, Reizei Port Laboratory Publishing Co., 1989, and FMAusubel et al., Compiled Molecular Biology Laboratory Manual, 3rd Edition, John Wiley & Sons, Inc., 1995. As known to those skilled in the art, the examples are intended to illustrate the present invention by way of example and are not intended to limit the scope of the present invention.

[0243] Example 1: Generation of mouse anti-human ROR1 antibodies 1) Antibody production and preparation of identification materials (1) Construction of human ROR1 stable expression cell line: To verify the specificity and function of human ROR1 antibody, Ba / F3 cells are infected with lentivirus (G&P Biosciences, product number: LTV-ROR1) containing the complete coding sequence of human ROR1 (gene number: Q01973), positive transformed cells are screened by puromycin, and monoclonal screening is performed by finite dilution method to obtain monoclonal BA / F3-ROR1 stable cell line. The expression of ROR1 is identified by flow cytometry (Luminex, Guava easyCyte HT). Anti-human ROR1 antibody D10 (patent document: US Patent No. 9217040B2) is used as the detection antibody. As shown in Figure 1, the flow cytometry results show that the positive rate of Ba / F3-ROR1 is very high (close to 100%) and can be used for subsequent experiments.

[0244] (2) Express and purify recombinant human ROR ECD-his, ECD-mouse Fc, and ECD-T cell epitope fusion proteins (ECD: extracellular domain aa30-406) in Expi293 or ExpiCHO mammalian cells, and identify the resulting proteins with antibody D10 by ELISA. Construct and amplify the pcDNA3.4 plasmid carrying the full-length human ROR1 coding sequence by gene synthesis (Genscript, Piscataway, NJ).

[0245] 2) Mouse immunization Wild-type mice were immunized with the above-mentioned differently tagged human ROR1 ECD proteins, pcDNA3.4 plasmids encoding the full-length ROR1 sequence, and Ba / F3-ROR1 cells. Four mouse strains, Balb / c, C57Bl / 6, NZB, and A / J, were used for immunization. The following three immunization methods were used, and the outline is as follows: 1) First, 1-2 tail vein injections were performed using pcDNA3.4 plasmids containing the complete coding sequence of human ROR1, followed by boosting with 2-4x106 Ba / F3-ROR1 cells, with an interval of 2-3 weeks between each immunization. 2) First, 1-2 tail vein injections were performed using pcDNA3.4 plasmids containing the complete coding sequence of human ROR1, followed by boosting with a mixture of incomplete Freund's adjuvant (IFA) and 50-100μg of recombinant ROR1 ECD protein, with an interval of 2-3 weeks between each immunization. 3) First, immunize with 50 μg of recombinant ROR1 ECD protein mixed with complete Freund's adjuvant (CFA), then boost with 50 μg of recombinant ROR1 ECD protein mixed with IFA, with an interval of 2 to 3 weeks between each immunization. After the second boost, measure serum titers using Ba / F3-ROR1 cells by flow cytometry. Select mice with high titers and boost with ROR-1 ECD protein 3 to 5 days before fusion.

[0246] 3) Production and screening of mouse-derived hybridomas producing anti-human ROR1 antibodies Using a standard chemical fusion program, mouse spleen cells are fused with mouse myeloma SP2 / 0 cells (ATCC, product number: CRL-1581) using polyethylene glycol (molecular weight 1500 Da, Roche, product number: 10783641001) at a ratio of 5:1. The cells are adjusted to 5 x 105 spleen cells / mL using DMEM medium (Gibco, product number: 12430-47) containing 20% ​​fetal bovine serum (Hyclone, product number: SH30080.03). 0.2 mL of cells are added to each well of a 96-well plate and cultured in a 37°C, 5% CO2 incubator. Two days after fusion, HAT (Sigma, product number: H0262-10VL) is added to each well for screening selection. A clone capable of producing an antibody that binds to Ba / F3-ROR1 cells is selected by high-pass flow cytometry (Sartorius, model number: iQue Screener Plus). Furthermore, a positive clone that binds only to Ba / F3-ROR1 cells but not to Ba / F3 wild-type cells is selected by flow cytometry (Luminex, model number: Guava easyCyte HT). Finally, a monoclonal hybridoma is obtained by finite dilution and its binding to ROR1 cells is confirmed by FACS. Small-scale antibody purification is performed from each selected positive monoclonal hybridoma. Hybridoma cells are cultured in 50-100 mL of serum-free medium (Thermo Fisher, Hybridoma-SFM, product number: 12045084), and the antibody in the supernatant is purified and eluted by protein A (GE Healthecare, MabSelect SuRe, product number: 17543802), and the obtained monoclonal antibody is dialyzed against 150 mM NaCl. The resulting antibodies were filtered and sterilized through a 0.2 μm filter. The binding of the purified antibodies to Ba / F3-ROR1 cells was detected by flow cytometry, and three mouse anti-human ROR1 monoclonal antibodies (3D8.2.3, 19F6.2.3, and 38F8.1.1) were selected as candidate molecules for further characterization.

[0247] Example 2: Detection of affinity of mouse anti-human ROR1 monoclonal antibody The affinity of the candidate antibody to ROR1 on the human cell surface is detected by flow cytometry. In addition to Ba / F3-ROR1 overexpressing cells, human histopathological lymphoma cell line Jeko-1 (ATCC, Cat. No. CRL-3006), human colon cancer cell line HT-29 (ATCC, Cat. No. HTB-38), and human lung cancer cell line A 549 (ATCC, Cat. No. CCL-185) are also used for binding analysis. Anti-human ROR1 antibody UC961 (patent: WO2018237335A1) with mouse or human IgG1 Fc is used as a positive control, and anti-2,4,6-trinitrophenol antibody with corresponding mouse or human IgG1 Fc (ATCC) is used as a negative control. Mouse IgG isotype control (Thermo Fisher, Cat. No. 31903) is also used as a negative control. Ba / F3-ROR1, Jeko-1, HT-29 and A549 cells were incubated with different concentrations of purified mouse-derived antibodies and control antibodies on ice for 30 minutes, then washed twice with flow buffer (PBS + 2% FBS), and further incubated with goat anti-human or mouse fluorescent secondary antibodies (Jackson ImmunoResearch, product numbers: 109-605-098 or 115-605-071) on ice for 30 minutes, and finally detected by flow cytometry (Luminex, product number: Guava easyCyte HT).

[0248] The detection results are shown in FIG. 2. All three anti-human ROR1 mouse-derived antibodies can specifically recognize human ROR1 on the surface of Ba / F3-ROR1, Jeko-1, HT-29 and A549 cells.

[0249] Using the extracellular domain (ECD) protein of human ROR2, confirm that the binding specificity of the candidate antibody to human ROR1 is higher than that to human ROR2 by ELISA. The specific method is as follows: 1 μg / mL of human ROR2 extracellular domain (ECD) protein (Sino Biologicals, product code: 16133-H08H) is coated on a 96-well ELISA enzyme-labeled plate (Thermo Fisher, product code: 5129) overnight at 4 ° C. Wash three times with 200 μL of washing buffer (1 × TBS containing 0.05% polysorbate-20), add 100 μL of different concentrations of 8 purified mouse anti-human ROR1 candidate antibodies and UC961, and incubate at 37 ° C for 1 hour, and use mouse anti-human ROR2 antibody (R & D systems, product code: MAB2064) as a positive control. Wash three times with 200 μL of wash buffer, add 100 μL of anti-human IgG (Rockland Inc, Part No.: 609-1304) or anti-mouse IgG secondary antibody (Rockland Inc, Part No.: 610-1304) diluted at a ratio of 1:10000 to each well, and incubate at 37 °C for 1 hour. Wash three times with 200 μL of wash buffer, add 100 μL of TMB (Thermo Fisher, Part No.: TMBW-1000-01) to develop in the dark for 10 minutes, then add 100 μL of stop solution (Thermo Fisher, Part No.: 13361-100-10) to stop the color reaction, and read at 450 nm using a microplate reader. As shown in Figure 3, all three antibodies detected do not bind to human ROR2 ECD protein.

[0250] Example 3: Identification of subtypes of anti-human ROR1 mouse-derived antibodies and amplification of variable regions The subtypes of all mouse anti-human ROR1 candidate antibodies (3D8.2.3, 19F6.2.3, 38F8.1.1) are identified using the Pierce Rapid Isotyping Kit (purchased from Thermo Fisher, part number: 26179). The identification results show that the candidate clone heavy chain is IgG1 subtype and the light chain is Kappa subtype.

[0251] To clone the variable region genes, total RNA is extracted from the dissociated hybridoma cells, and the first strand cDNA is synthesized using a cDNA reverse transcription kit (purchased from Thermo Fisher, part number: 18080-200). The VH and VK genes are amplified by PCR using Platinum Taq DNA polymerase (purchased from Thermo Fisher, part number: 1304011) with specific primers for the antibody. The PCR products are purified with a DNA purification kit (purchased from Qiagen, part number: 28104), and ligated into a TOPO TA cloning vector (purchased from Thermo Fisher, part number: K 457540) for E. coli transformation. Approximately 6 to 12 E. coli clones are selected from each ligation reaction and sequenced. The sequencing results were analyzed by Vector NTI 11.5 (purchased from Thermo Fisher) and Sequencer 5.4.6 (purchased from Genecodes), and the variable region sequences and CDR sequences of the anti-human ROR1 mouse-derived candidate antibodies were obtained, as shown in the sequence information table in Table 1.

[0252] Table 1. Variable region and CDR amino acid sequences of anti-human ROR1 mouse-derived antibodies

[0253] [Table 2]

[0254] Example 4: Detection of affinity of anti-human ROR1 chimeric antibody The light and heavy chain variable regions of 3D8.2.3, 19F6.2.3 and 38F8.1.1 are engineered to be linked to the human light chain kappa constant region (SEQ ID NO:120) and human IgG1 heavy chain constant region (SEQ ID NO:119), respectively, to construct chimeric antibodies. The DNA sequences coding for the heavy and light chains of each antibody are synthesized and codon optimized, and then cloned into pcDNA3.4 plasmid (commissioned from Suzhou Hongxun Technology Co., Ltd.). The pcDNA3.4 plasmids corresponding to the heavy and light chains of each chimeric antibody are co-transfected into Expi293F cells (Thermo Fisher, product number: A14527), and the antibodies expressed in the supernatant are purified using protein A. The resulting chimeric antibodies are named 3D8-Chi, 19F6-Chi and 38F8-Chi, respectively.

[0255] The binding affinity of the purified anti-human ROR1 chimeric antibody to Ba / F3-ROR1, Jeko-1, HT-29 and A549 cells is analyzed by flow cytometry. The specific experimental steps are as follows: Ba / F3-ROR1, Jeko-1, HT-29 and A549 cells are incubated with different concentration gradients of purified chimeric antibodies on ice for 30 minutes, and then anti-ROR1 antibody UC961 with human IgG1 and anti-TNP antibody are used as positive and negative controls, respectively. Wash twice with flow buffer (PBS+2%FBS), further incubate with goat anti-human fluorescent secondary antibody (Jackson ImmunoResearch, Part No.: 109-605-098) on ice for 30 minutes, and finally detect using flow cytometry.

[0256] The results are shown in Figure 4 and Table 2, which indicate that the affinity EC50 of 19F6-Chi to cells is lower than that of the positive control antibody UC961, and the anti-human ROR1 chimeric antibody has a higher affinity than UC961. The affinity EC50 of 38F8-Chi and 3D8-Chi is equivalent to that of the control antibody UC961.

[0257] Table 2. Measurement of cell affinity of anti-human ROR1 chimeric antibody

[0258] [Table 3]

[0259] * indicates that the value is the average of two measurements.

[0260] Octet ForteBio is widely used to detect antibody-antigen dynamic affinity, and this method measures the dynamic affinity of candidate chimeric antibodies 3D8-Chi, 19F6-Chi and 38F8-Chi and positive control antibody UC961 to human ROR1. The specific experimental steps are as follows: first, anti-human IgG Fc AHC probe (ForteBio, product number: 18-5060) binds to the antibody, which is measured to a response signal value of 0.8-1.0 nm, and the dynamic affinity is measured by immersing the antibody-coated probe into wells containing human ROR1 ECD protein at different concentrations (4, 2, 1, 0.5, 0.25, 0.13, 0.06 and 0 μg / mL), and dissociating for 10 minutes after binding for 5 minutes, and a 1:1 kinetic binding model is used for all fitting analyses. As shown in Table 3, the dissociation rates of 3D8-Chi, 19F6-Chi and 38F8-Chi were significantly slower than that of the control antibody UC961 (shown in Kdis values), and the affinities of 3D8-Chi, 19F6-Chi and 38F8-Chi were 2.0-fold, 34.6-fold and 5.0-fold higher, respectively, than that of the control antibody UC961 (shown in KD values).

[0261] Table 3. Measurement of dynamic affinity of anti-human ROR1 chimeric antibodies to human ROR1

[0262] [Table 4]

[0263] * indicates that the value is the average of two measurements.

[0264] From the above, the antibodies of the present invention show stronger antigen-binding ability compared to the control antibody.

[0265] Example 5: Humanization of anti-human ROR1 mouse-derived antibodies The mouse anti-human ROR1 monoclonal antibodies 3D8.2.3, 19F6.2.3 and 38F8.1.1 are humanized according to the CDR grafting method described in the literature (Winter and Milstein, Nature, 1991, 349:293-299; Rader et al., Proc. Nat. Acad. Sci. USA, 1998, 95:8910-8915; Steinberger et al., J. Biol. Chem., 2000, 275:36073-36078; and Queen et al., Proc. Natl. Acad. Sci. USA, 1989, 86:10029-10033). Briefly, the humanized antibody is generated by replacing most or all of the frame sequences of the mouse antibody with the frame sequences of the corresponding human germline antibody, while maintaining the antigen-specific binding variable regions or CDRs of the mouse antibody. This produces hybrid molecules, of which only the CDRs consist of non-human sequences. Typically, some key mouse-derived amino acids are backmutated and grafted into the human germline antibody framework, and potential deamidation, isomerization and glycosylation sites in the CDRs are mutated to improve biological properties, while maximally maintaining the antigen-binding affinity of the parent antibody.

[0266] The sequences of the humanized heavy and light chain variants of the three murine monoclonal antibody clones (3D8.2.3, 19F6.2.3 and 38F8.1.1) are shown in Table 4 below.

[0267] Table 4-1 Amino acid sequences of the variable and constant regions of the 19F6 anti-human ROR1 humanized antibody

[0268] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7]

[0269] Table 4-2 Amino acid sequences of the variable and constant regions of the 3D8 anti-human ROR1 humanized antibody

[0270] [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4]

[0271] Table 4-3 Amino acid sequences of the variable and constant regions of the 38F8 anti-human ROR1 humanized antibody

[0272] [Table 7-1] [Table 7-2] [Table 7-3]

[0273] Example 6: Determination of affinity of anti-human ROR1 humanized candidate antibodies To evaluate the anti-human ROR1 humanized candidate antibodies, the DNA sequences encoding the candidate humanized antibodies (3D8, 38F8, 19F6) in Example 5 were synthesized and codon-optimized, and then cloned into pcDNA3.4 plasmid (ordered from Suzhou Hongxun Technology Co., Ltd.). The pcDNA3.4 plasmids corresponding to the heavy and light chains of each humanized antibody were simultaneously transfected into Expi293F cells, and the expressed antibodies in the supernatant were purified using protein A.

[0274] Flow cytometry is used to detect the affinity of anti-human ROR1 humanized antibodies with Ba / F3-ROR1, Jeko-1, HT-29 and A549 cells. The specific experimental steps are as follows: Ba / F3-ROR1, Jeko-1, HT-29 and A549 cells are incubated with different concentration gradients of purified humanized antibodies on ice for 30 minutes, and then anti-ROR1 antibody UC961 with human IgG1 and anti-TNP antibody are used as positive and negative controls, respectively. Wash twice with flow buffer (PBS+2%FBS), further incubate with goat anti-human fluorescent secondary antibody (Jackson ImmunoResearch, Part No.: 109-605-098) on ice for 30 minutes, and finally detect by flow cytometry.

[0275] The results are shown in Table 5, and the affinity EC50 of the humanized molecules 19F6-Hu35V1, 3D8-HuC24 and 38F8-Hu57 generated by the three mouse-derived antibodies for all four cells was lower than that of the positive control antibody UC961, indicating that the above anti-human ROR1 humanized antibodies have comparable or higher affinity than UC961.

[0276] Table 5-1 Cell affinity detection of 19F6 anti-human ROR1 humanized antibody

[0277] Table 5-1A

[0278] [Table 8]

[0279] Table 5-1B

[0280] [Table 9]

[0281] Table 5-2. Detection of cell affinity of 3D8 anti-human ROR1 humanized antibody

[0282] [Table 10]

[0283] Table 5-3. Detection of cell affinity of 38F8 anti-human ROR1 humanized antibody

[0284] [Table 11]

[0285] The Octet ForteBio method is used to measure the kinetic affinity of humanized molecules 19F6-Hu35V1, 3D8-HuC24 and 38F8-Hu57 and positive control antibody UC961 to human ROR1 ECD protein. The specific experimental steps are as follows: first, anti-human IgG Fc AHC probe (ForteBio, part number: 18-5060) is bound to the antibody, which is measured to a response signal value of 0.8-1.2 nm, and the kinetic affinity is measured by immersing the antibody-coated probe into wells containing human ROR1 ECD protein at different concentrations (16, 8, 4, 2, 1, 0.5, 0.25 and 0 μg / mL), which is bound for 2-4 minutes and then dissociated for 4-6 minutes, and the 1:1 kinetic binding model is used for all fitting analyses.

[0286] As shown in Table 6, the dissociation rate of the humanized molecule 19F6-Hu35V1 is significantly slower than that of the control antibody UC961 (as shown in the Kdis value), and the affinity is 5.4 times higher than that of the control antibody UC961 (as shown in the KD value). 3D8-HuC24 and 38F8-Hu57 show affinities comparable to that of the control antibody UC961.

[0287] Table 6. Measurement of dynamic affinity of anti-human ROR1 humanized antibodies to human ROR1

[0288] [Table 12]

[0289] * indicates that the value is the average of three measurements.

[0290] Example 7: Measurement of ADCC cellular activity of anti-human ROR1 humanized candidate antibodies The humanized anti-human ROR1 candidate antibodies 19F6-Hu35V1, 3D8-HuC24 and 38F8-Hu57 are IgG1 subtypes and have high antibody-dependent cell-mediated cytotoxicity (ADCC) activity. In order to measure the ADCC activity of 19F6-Hu35V1, 3D8-HuC24 and 38F8-Hu57, the NK cell killing method is used in the present invention. The specific experimental steps are as follows: Ba / F3-ROR1 cells are centrifuged and then resuspended in culture medium, and the cell density is adjusted to 1×104 cells / 40 μL / well and added to the corresponding wells of a 96-well plate. NK92MI-mCD16a-hFceRI cells are centrifuged and then resuspended in empty MEMA medium, and the cell density is adjusted to 5×104 / 50 μL / well and added to the corresponding wells. The 19F6-Hu35V1, 3D8-HuC24, 38F8-Hu57 and UC961 antibodies are diluted in blank MEMA medium starting at 1000 nM and diluted 4-fold to set up 10 concentration points. The diluted antibody was added to the corresponding wells at 10 μL / well, and the wells were placed in a cell incubator at 37°C and 5% CO2 for 5.5 hours of static co-culture with Ba / F3-ROR1 and NK92MI-mCD16a-hFceRI. After that, 5 μL of 4% Triton-X 100 (Fisher Scientific, catalog number BP151-500) was added to the positive control wells, and the wells were left to stand for another 5 to 10 minutes. After that, 30 μL / well of CytoTox-Glo Cytotoxicity Detection Reagent (Promega, product number: G9291) was added. After 15 minutes, the luminescence value was read using a microplate reader (MD, SpectraMax M2), and the results were imported into Graphpad Prism for curve fitting. As shown in FIG. 5 and Table 7, the ADCC killing activity EC50 of humanized antibodies 19F6-Hu35V1, 3D8-HuC24 and 38F8-Hu57 against Ba / F3-ROR1 cells is comparable to that of the control antibody UC961.

[0291] Table 7. Measurement of cellular activity of anti-human ROR1 humanized candidate antibodies ADCC

[0292] [Table 13]

[0293] Example 8: Measurement of endocytosis-inducing activity of anti-human ROR1 candidate antibodies Antibodies may bind to target proteins on the cell surface and induce the internalization of antibody-antigen complexes. The present invention uses Mab-ZAP kit (ATSBio, IT-04) to measure the endocytosis-inducing activity of mouse anti-human ROR1 candidate antibodies (Kohls MD and Lappi DA BioTechniques 2000, 28:162). The specific experimental steps are as follows: count Jeko-1 with a cell counter, adjust the cell concentration to 7500 cells / well, then add 90uL of cells to a 96-well plate and incubate overnight in an incubator at 37℃ and 5%CO2. On the second day, mouse antibodies 19F6.2.3, 3D8.2.3, 38F8.1.1 and UC961 control antibody are diluted 5-fold from 10ug / ml with complete medium to set up 8 concentration points. Transfer 10ul of different concentrations of antibodies to Jeko-1 cells. Prepare Mab-zap solution with a concentration of 10ug / mL (50x) according to the kit's instructions, add 2ul to each well, and incubate the cells at 37℃, 5%CO2 for 3 days. Preincubate CTG2.0 (Promega, Part No.: G9241) in the dark at room temperature, and add 100uL of CTG reagent to each well, cover with aluminum foil, place in a rotary oscillator for 2 minutes, then incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read the luminescence value with a plate reader. As shown in Figure 6, the endocytosis-inducing activity of antibodies 19F6.2.3, 3D8.2.3, and 38F8.1.1 against Jeko-1 cells is higher than that of the control antibody UC961. It is 23.4-fold, 3.8-fold, and 5.3-fold higher than the control antibody UC961, respectively (shown in IC50 value).

[0294] Example 9: Detection of endocytosis activity of anti-human ROR1 candidate antibodies The present invention measures the endocytosis activity of anti-human ROR1 candidate antibodies by acid washing method. The specific experimental steps are as follows: HCC827 and MDA-MB-231 cells are digested with pancreatic enzymes, the cell concentration is adjusted to 200000 cells / well after counting, the cells are washed twice with PBS, and then resuspended in 2% BSA, and then 50uL of cells are added to a 96-well plate. In addition, the antibodies 19F6-Hu35V1, 38F8-Hu57, UC961 control antibody, and IgG antibody (chicken lysozyme antibody) are diluted 3-fold from 15μg / mL to set 8 or 9 concentration points. 50μL of antibodies at different concentrations are transferred to the cells and mixed evenly (plate 1). In addition, a 96-well plate (plate 2) is prepared separately, and each antibody at the highest concentration point is mixed with the cells, and the two plates are incubated at 4℃ for 40min. After the incubation is completed, wash the cells twice with PBS and centrifuge at 500g for 3 min. Dilute the secondary antibody anti-human IgG Alexa Fluor 488 at 1:150, add 50μL / well to the cells, mix evenly and incubate at 4℃ for 20 min. After the incubation is completed, wash the cells twice with PBS, centrifuge at 500g for 3 min, resuspend the cells in 200μL of the corresponding complete medium, place plate 1 at 37℃ and plate 2 at 4℃ and continue to incubate for 4h. After the incubation is completed, the medium is removed by centrifugation at 500g for 3 min, 100 μL of acid (obtained by adjusting 150 mM NaCl and 0.1 M glycine to pH 2.0 with hydrochloric acid) is added to each well and resuspended for 2 minutes, and 60 ul of base (3 g / L Tris base and 9 g / L NaCl adjusted to pH 13 with NaOH) is added, mixed uniformly to neutralize, the supernatant is removed, PBS is added, and the cells are resuspended and then detected by flow cytometry. The results are shown in Figure 7A to Figure 7B, and the endocytosis activity of two types of cells, HCC827 and MDA-MB-231, by antibody 19F6-Hu35V1 is equivalent to that of the control antibody UC961, the maximum signal of endocytosis of antibody 19F6-Hu35V1 is slightly stronger, and the endocytosis activity of the whole 38F8-Hu57 is slightly lower.The negative control antibody IgG does not induce endocytic behavior in either of the two cell types.

[0295] Example 10: Detection of endocytosis activity by anti-human ROR1 candidate antibodies The present invention further uses pHrodo dye (Thermo) to measure the endocytosis activity of anti-human ROR1 candidate antibodies. The specific experimental steps are as follows: digest N87 cells with pancreatic enzymes, count cells with a cell counter, adjust the cell concentration to 10000 cells / well, seed 100 μL of cells into a 96-well plate, and incubate overnight in an incubator at 37°C and 5% CO2. On the second day, antibody 19F6-Hu35V1, UC961 control antibody, and IgG antibody are diluted 5-fold with 1640 complete medium starting from 2.4 μg / ml, and set up 7 concentration points. In addition, pHrodo® Red dye is completely diluted to 12 μg / mL with 1640 complete medium, and 30 μL of different concentrations of antibodies are mixed uniformly with 30 μL of the diluted dye, and incubated in the dark at room temperature for 20 min. After the incubation is completed, the cell culture medium is discarded, and the antibody-dye mixed solution is added to the cells in each well and incubated overnight in an incubator at 37°C and 5% CO2. On the second day, the cells are digested with pancreatic enzymes and then detected by flow cytometry. The results are shown in Figure 8, and the endocytosis activity of N87 cells by antibody 19F6-Hu35V1 is higher than that of the control antibody UC961, about 7 times that of UC961. The negative control antibody IgG has no endocytosis-inducing activity in N87.

Claims

1. An antibody or antigen-binding fragment thereof that specifically binds to ROR1, (a) CDR-H1, CDR-H2 and CDR-H3 contained in the heavy chain variable region (VH) shown in any one of SEQ ID NOs: 3, 84 to 86, and / or CDR-L1, CDR-L2 and CDR-L3 contained in the light chain variable region (VL) shown in any one of SEQ ID NOs: 4, 87 to 101; Or, (b) CDR-H1, CDR-H2 and CDR-H3 contained in the heavy chain variable region (VH) shown in any one of SEQ ID NOs: 1, 102 to 106, and / or CDR-L1, CDR-L2 and CDR-L3 contained in the light chain variable region (VL) shown in any one of SEQ ID NOs: 2, 107 to 110; Or, (c) CDR-H1, CDR-H2 and CDR-H3 contained in the heavy chain variable region (VH) shown in any one of SEQ ID NOs: 5, 111 to 115, and / or CDR-L1, CDR-L2 and CDR-L3 contained in the light chain variable region (VL) shown in any one of SEQ ID NOs: 6, 107, 116 to 118; Or, (d) The heavy chain variable region (VH) includes CDR-H1, CDR-H2, and CDR-H3, and / or the light chain variable region (VL) includes CDR-L1, CDR-L2, and CDR-L3, as described below. The heavy chain variable region (VH) and / or the light chain variable region (VL) includes a mutation in at least one CDR that is a substitution, deletion, or addition of one or more amino acids (e.g., a substitution, deletion, or addition of one, two, or three amino acids) compared with the heavy chain variable region and / or the light chain variable region described in any one of (a) to (c), and preferably the substitution is a conservative substitution. Preferably, the CDRs are defined according to the Chothia, AbM, Kabat or IMGT numbering systems: Preferably, the antibody or antigen-binding fragment thereof binds to human ROR1.

2. (1) The CDRs are defined according to the Chothia numbering system; (a) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in sequence SEQ ID NO:64, CDR-H2 as set forth in sequence SEQ ID NO:65, and CDR-H3 as set forth in sequence SEQ ID NO:47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in any one of sequences SEQ ID NO: 48-55, CDR-L2 as set forth in any one of sequences SEQ ID NO: 56-58, and CDR-L3 as set forth in sequence SEQ ID NO: 44; Or, (b) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in sequence SEQ ID NO: 31, CDR-H2 as set forth in sequence SEQ ID NO: 32-34, and CDR-H3 as set forth in sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in any one of SEQ ID NOs: 21 to 23, 77, CDR-L2 as shown in SEQ ID NO: 24 or 25, and CDR-L3 as shown in SEQ ID NO: 15; Or, (c) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in sequence SEQ ID NO: 82, CDR-H2 as set forth in sequence SEQ ID NO: 83, and CDR-H3 as set forth in sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in any one of the sequences SEQ ID NO: 75 to 77, CDR-L2 as set forth in the sequence SEQ ID NO: 24 or 78, and CDR-L3 as set forth in the sequence SEQ ID NO: 15; or (2) the CDRs are defined according to the AbM numbering system; (a) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in sequence SEQ ID NO: 45, CDR-H2 as shown in sequence SEQ ID NO: 46, and CDR-H3 as shown in sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in any one of sequences SEQ ID NO: 48-55, CDR-L2 as set forth in any one of sequences SEQ ID NO: 56-58, and CDR-L3 as set forth in sequence SEQ ID NO: 44; Or, (b) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 16, CDR-H2 as set forth in any one of the sequences SEQ ID NO: 17 to 19, and CDR-H3 as set forth in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in any one of SEQ ID NOs: 21 to 23, 77, CDR-L2 as shown in SEQ ID NO: 24 or 25, and CDR-L3 as shown in SEQ ID NO: 15; Or, (c) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in sequence SEQ ID NO: 72, CDR-H2 as shown in sequence SEQ ID NO: 73, and CDR-H3 as shown in sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in any one of SEQ ID NOs: 75 to 77, CDR-L2 as set forth in SEQ ID NOs: 24 or 78, and CDR-L3 as set forth in SEQ ID NO: 15; Or, (3) the CDRs are defined according to the Kabat numbering system; (a) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in sequence SEQ ID NO: 60, CDR-H2 as set forth in any one of sequences SEQ ID NO: 61 to 63, and CDR-H3 as set forth in sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in any one of sequences SEQ ID NO: 48-55, CDR-L2 as set forth in any one of sequences SEQ ID NO: 56-58, and CDR-L3 as set forth in sequence SEQ ID NO: 44; Or, (b) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 27, CDR-H2 as set forth in any one of the sequences SEQ ID NO: 28 to 30, and CDR-H3 as set forth in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in any one of sequences SEQ ID NOs: 21-23, 77; CDR-L2 as set forth in any one of sequences SEQ ID NOs: 24-25; and CDR-L3 as set forth in sequence SEQ ID NO: 15; Or, (c) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in sequence SEQ ID NO: 79, CDR-H2 as set forth in sequence SEQ ID NO: 80 or 81, and CDR-H3 as set forth in sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in any one of SEQ ID NOs: 75 to 77, CDR-L2 as set forth in SEQ ID NOs: 24 or 78, and CDR-L3 as set forth in SEQ ID NO: 15; Or, (4) the CDRs are defined by the IMGT numbering system; (a) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 35, CDR-H2 as set forth in the sequence SEQ ID NO: 36, and CDR-H3 as set forth in the sequence SEQ ID NO: 37; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as set forth in any one of SEQ ID NOs: 38 to 42, CDR-L2 as set forth in SEQ ID NO: 43, and CDR-L3 as set forth in SEQ ID NO: 44; Or, (b) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in the sequence SEQ ID NO: 7, CDR-H2 as set forth in any one of the sequences SEQ ID NO: 8 to 10, and CDR-H3 as set forth in the sequence SEQ ID NO: 11; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 12 or 13, CDR-L2 as shown in sequence SEQ ID NO: 14, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (c) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as set forth in sequence SEQ ID NO:66, CDR-H2 as set forth in sequence SEQ ID NO:67, and CDR-H3 as set forth in sequence SEQ ID NO:68; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 69 or 70, CDR-L2 as shown in sequence SEQ ID NO: 71, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (5) A heavy chain variable region (VH) and / or a light chain variable region (VL) in which at least one CDR comprises a mutation that is one or more amino acid substitutions, deletions or additions (e.g., one, two or three amino acid substitutions, deletions or additions) compared to the heavy chain variable region and / or light chain variable region according to any one of (a) to (c) in (1) or (4), preferably the substitutions are conservative substitutions; The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof binds to human ROR1.

3. (i) the CDRs are defined according to the Chothia numbering system; (1) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in sequence SEQ ID NO: 64, CDR-H2 as shown in sequence SEQ ID NO: 65, and CDR-H3 as shown in sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 52, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (2) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in sequence SEQ ID NO: 64, CDR-H2 as shown in sequence SEQ ID NO: 65, and CDR-H3 as shown in sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 48, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (3) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in sequence SEQ ID NO: 64, CDR-H2 as shown in sequence SEQ ID NO: 65, and CDR-H3 as shown in sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 48, CDR-L2 as shown in sequence SEQ ID NO: 57, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (4) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 64, CDR-H2 as shown in the sequence SEQ ID NO: 65, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 49, CDR-L2 as shown in sequence SEQ ID NO: 57, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (5) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 64, CDR-H2 as shown in the sequence SEQ ID NO: 65, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:50, CDR-L2 as shown in sequence SEQ ID NO:58, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (6) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 64, CDR-H2 as shown in the sequence SEQ ID NO: 65, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 51, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (7) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 64, CDR-H2 as shown in the sequence SEQ ID NO: 65, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 53, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (8) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 64, CDR-H2 as shown in the sequence SEQ ID NO: 65, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:54, CDR-L2 as shown in sequence SEQ ID NO:56, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (9) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 64, CDR-H2 as shown in the sequence SEQ ID NO: 65, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:55, CDR-L2 as shown in sequence SEQ ID NO:56, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (10) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 32, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:21, CDR-L2 as shown in sequence SEQ ID NO:24, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (11) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 32, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (12) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 32, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 22, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (13) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 32, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 23, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (14) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 33, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (15) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 33, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 22, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (16) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 33, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 23, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (17) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 34, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (18) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 34, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 22, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (19) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 31, CDR-H2 as shown in the sequence SEQ ID NO: 34, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 23, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (20) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 82, CDR-H2 as shown in the sequence SEQ ID NO: 83, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 75, CDR-L2 as shown in sequence SEQ ID NO: 24, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (21) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 82, CDR-H2 as shown in the sequence SEQ ID NO: 83, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 78, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (22) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 82, CDR-H2 as shown in the sequence SEQ ID NO: 83, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 76, CDR-L2 as shown in sequence SEQ ID NO: 78, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (ii) the CDRs are defined according to the AbM numbering system; (1) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 45, CDR-H2 as shown in the sequence SEQ ID NO: 46, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 52, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (2) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 45, CDR-H2 as shown in the sequence SEQ ID NO: 46, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 48, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (3) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 45, CDR-H2 as shown in the sequence SEQ ID NO: 46, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 48, CDR-L2 as shown in sequence SEQ ID NO: 57, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (4) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 45, CDR-H2 as shown in the sequence SEQ ID NO: 46, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 49, CDR-L2 as shown in sequence SEQ ID NO: 57, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (5) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 45, CDR-H2 as shown in the sequence SEQ ID NO: 46, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:50, CDR-L2 as shown in sequence SEQ ID NO:58, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (6) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 45, CDR-H2 as shown in the sequence SEQ ID NO: 46, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 51, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (7) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 45, CDR-H2 as shown in the sequence SEQ ID NO: 46, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 53, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (8) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 45, CDR-H2 as shown in the sequence SEQ ID NO: 46, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:54, CDR-L2 as shown in sequence SEQ ID NO:56, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (9) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 45, CDR-H2 as shown in the sequence SEQ ID NO: 46, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:55, CDR-L2 as shown in sequence SEQ ID NO:56, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (10) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 17, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:21, CDR-L2 as shown in sequence SEQ ID NO:24, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (11) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 17, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (12) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 17, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 22, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (13) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 17, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 23, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (14) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 18, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (15) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 18, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 22, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (16) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 18, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 23, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (17) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 19, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (18) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 19, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 22, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (19) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 16, CDR-H2 as shown in the sequence SEQ ID NO: 19, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 23, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (20) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 72, CDR-H2 as shown in the sequence SEQ ID NO: 73, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 75, CDR-L2 as shown in sequence SEQ ID NO: 24, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (21) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 72, CDR-H2 as shown in the sequence SEQ ID NO: 73, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 78, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (22) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 72, CDR-H2 as shown in the sequence SEQ ID NO: 73, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 76, CDR-L2 as shown in sequence SEQ ID NO: 78, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (iii) the CDRs are defined according to the Kabat numbering system; (1) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in sequence SEQ ID NO: 60, CDR-H2 as shown in sequence SEQ ID NO: 61, and CDR-H3 as shown in sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 52, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (2) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in sequence SEQ ID NO: 60, CDR-H2 as shown in sequence SEQ ID NO: 61, and CDR-H3 as shown in sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 48, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (3) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in sequence SEQ ID NO: 60, CDR-H2 as shown in sequence SEQ ID NO: 62, and CDR-H3 as shown in sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 48, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (4) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in sequence SEQ ID NO: 60, CDR-H2 as shown in sequence SEQ ID NO: 62, and CDR-H3 as shown in sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 48, CDR-L2 as shown in sequence SEQ ID NO: 57, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (5) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 62, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 49, CDR-L2 as shown in sequence SEQ ID NO: 57, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (6) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 62, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:50, CDR-L2 as shown in sequence SEQ ID NO:58, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (7) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 62, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 51, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (8) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 63, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 48, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (9) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 63, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 48, CDR-L2 as shown in sequence SEQ ID NO: 57, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (10) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 63, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 49, CDR-L2 as shown in sequence SEQ ID NO: 57, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (11) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 63, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:50, CDR-L2 as shown in sequence SEQ ID NO:58, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (12) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 63, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 51, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (13) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 61, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 48, CDR-L2 as shown in sequence SEQ ID NO: 57, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (14) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 61, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 49, CDR-L2 as shown in sequence SEQ ID NO: 57, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (15) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 61, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:50, CDR-L2 as shown in sequence SEQ ID NO:58, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (16) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 61, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 51, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (17) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 61, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 53, CDR-L2 as shown in sequence SEQ ID NO: 56, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (18) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 61, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:54, CDR-L2 as shown in sequence SEQ ID NO:56, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (19) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 60, CDR-H2 as shown in the sequence SEQ ID NO: 61, and CDR-H3 as shown in the sequence SEQ ID NO: 47; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:55, CDR-L2 as shown in sequence SEQ ID NO:56, and CDR-L3 as shown in sequence SEQ ID NO:44; Or, (20) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 28, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:21, CDR-L2 as shown in sequence SEQ ID NO:24, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (21) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 28, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (22) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 28, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 22, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (23) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 28, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 23, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (24) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 29, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (25) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 29, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 22, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (26) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 29, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 23, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (27) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 30, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (28) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 30, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 22, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (29) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 27, CDR-H2 as shown in the sequence SEQ ID NO: 30, and CDR-H3 as shown in the sequence SEQ ID NO: 20; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 23, CDR-L2 as shown in sequence SEQ ID NO: 25, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (30) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 79, CDR-H2 as shown in the sequence SEQ ID NO: 80, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 75, CDR-L2 as shown in sequence SEQ ID NO: 24, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (31) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 79, CDR-H2 as shown in the sequence SEQ ID NO: 81, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 78, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (32) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 79, CDR-H2 as shown in the sequence SEQ ID NO: 81, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 76, CDR-L2 as shown in sequence SEQ ID NO: 78, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (33) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 79, CDR-H2 as shown in the sequence SEQ ID NO: 80, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 77, CDR-L2 as shown in sequence SEQ ID NO: 78, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (34) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 79, CDR-H2 as shown in the sequence SEQ ID NO: 80, and CDR-H3 as shown in the sequence SEQ ID NO: 74; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 76, CDR-L2 as shown in sequence SEQ ID NO: 78, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (iv) the CDRs are defined by the IMGT numbering system; (1) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 35, CDR-H2 as shown in the sequence SEQ ID NO: 36, and CDR-H3 as shown in the sequence SEQ ID NO: 37; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 39, CDR-L2 as shown in sequence SEQ ID NO: 43, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (2) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 35, CDR-H2 as shown in the sequence SEQ ID NO: 36, and CDR-H3 as shown in the sequence SEQ ID NO: 37; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 38, CDR-L2 as shown in sequence SEQ ID NO: 43, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (3) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 35, CDR-H2 as shown in the sequence SEQ ID NO: 36, and CDR-H3 as shown in the sequence SEQ ID NO: 37; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 40, CDR-L2 as shown in sequence SEQ ID NO: 43, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (4) a heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 35, CDR-H2 as shown in the sequence SEQ ID NO: 36, and CDR-H3 as shown in the sequence SEQ ID NO: 37; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 41, CDR-L2 as shown in sequence SEQ ID NO: 43, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (5) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 35, CDR-H2 as shown in the sequence SEQ ID NO: 36, and CDR-H3 as shown in the sequence SEQ ID NO: 37; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 42, CDR-L2 as shown in sequence SEQ ID NO: 43, and CDR-L3 as shown in sequence SEQ ID NO: 44; Or, (6) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 7, CDR-H2 as shown in the sequence SEQ ID NO: 8, and CDR-H3 as shown in the sequence SEQ ID NO: 11; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 12, CDR-L2 as shown in sequence SEQ ID NO: 14, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (7) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 7, CDR-H2 as shown in the sequence SEQ ID NO: 8, and CDR-H3 as shown in the sequence SEQ ID NO: 11; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 13, CDR-L2 as shown in sequence SEQ ID NO: 14, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (8) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 7, CDR-H2 as shown in the sequence SEQ ID NO: 9, and CDR-H3 as shown in the sequence SEQ ID NO: 11; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 12, CDR-L2 as shown in sequence SEQ ID NO: 14, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (9) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 7, CDR-H2 as shown in the sequence SEQ ID NO: 9, and CDR-H3 as shown in the sequence SEQ ID NO: 11; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 13, CDR-L2 as shown in sequence SEQ ID NO: 14, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (10) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 7, CDR-H2 as shown in the sequence SEQ ID NO: 10, and CDR-H3 as shown in the sequence SEQ ID NO: 11; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 12, CDR-L2 as shown in sequence SEQ ID NO: 14, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (11) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 7, CDR-H2 as shown in the sequence SEQ ID NO: 10, and CDR-H3 as shown in the sequence SEQ ID NO: 11; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO: 13, CDR-L2 as shown in sequence SEQ ID NO: 14, and CDR-L3 as shown in sequence SEQ ID NO: 15; Or, (12) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 66, CDR-H2 as shown in the sequence SEQ ID NO: 67, and CDR-H3 as shown in the sequence SEQ ID NO: 68; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:69, CDR-L2 as shown in sequence SEQ ID NO:71, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (13) A heavy chain variable region (VH) comprising three CDRs: CDR-H1 as shown in the sequence SEQ ID NO: 66, CDR-H2 as shown in the sequence SEQ ID NO: 67, and CDR-H3 as shown in the sequence SEQ ID NO: 68; and / or a light chain variable region (VL) comprising three CDRs: CDR-L1 as shown in sequence SEQ ID NO:70, CDR-L2 as shown in sequence SEQ ID NO:71, and CDR-L3 as shown in sequence SEQ ID NO:15; Or, (v) a heavy chain variable region (VH) and / or a light chain variable region (VL), in which at least one CDR comprises a mutation that is one or more amino acid substitutions, deletions or additions (e.g., one, two or three amino acid substitutions, deletions or additions) compared to the CDR regions according to any one of (i) to (iv), preferably said substitutions are conservative substitutions; The antibody or antigen-binding fragment thereof of claim 1 or 2, wherein the antibody or antigen-binding fragment thereof preferably binds to human ROR1. (a) a VH sequence as set forth in any one of SEQ ID NOs: 3, 84 to 86 or a variant thereof, and / or a VL sequence as set forth in any one of SEQ ID NOs: 4, 87 to 101 or a variant thereof, (b) a VH sequence as set forth in any one of SEQ ID NOs: 1, 102 to 106 or a variant thereof, and / or a VL sequence as set forth in any one of SEQ ID NOs: 2, 107 to 110 or a variant thereof; (c) a VH sequence or a variant thereof as set forth in any one of SEQ ID NOs: 5, 111 to 115, and / or a VL sequence or a variant thereof as set forth in any one of SEQ ID NOs: 6, 107, 116 to 118, Including, The antibody or antigen-binding fragment thereof of any one of claims 1 to 3, wherein the variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity compared to the sequence from which it is derived, or the variant has one or more amino acid substitutions, deletions or additions (e.g. 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions) compared to the sequence from which it is derived, preferably the substitutions are conservative substitutions.

5. (1) A VH having a sequence as shown in SEQ ID NO: 86 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 92 or a variant thereof; (2) a VH having a sequence as shown in SEQ ID NO: 84 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 87 or a variant thereof; (3) a VH having a sequence as shown in SEQ ID NO: 84 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 88 or a variant thereof; (4) VH or a variant thereof having the sequence shown in SEQ ID NO: 84, and VL or a variant thereof having the sequence shown in SEQ ID NO: 89; (5) a VH having a sequence as shown in SEQ ID NO: 84 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 90 or a variant thereof; (6) VH or a variant thereof having the sequence shown in SEQ ID NO: 84, and VL or a variant thereof having the sequence shown in SEQ ID NO: 91; (7) VH or a variant thereof having the sequence shown in SEQ ID NO: 85, and VL or a variant thereof having the sequence shown in SEQ ID NO: 87; (8) VH or a variant thereof having the sequence shown in SEQ ID NO: 85, and VL or a variant thereof having the sequence shown in SEQ ID NO: 88; (9) VH or a variant thereof having the sequence shown in SEQ ID NO: 85, and VL or a variant thereof having the sequence shown in SEQ ID NO: 92; (10) A VH having a sequence as shown in SEQ ID NO: 85 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 90 or a variant thereof; (11) A VH having a sequence as shown in SEQ ID NO: 85 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 91 or a variant thereof; (12) A VH having a sequence as shown in SEQ ID NO: 86 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 87 or a variant thereof; (13) A VH having a sequence as shown in SEQ ID NO: 86 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 88 or a variant thereof; (14) A VH having a sequence as shown in SEQ ID NO: 86 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 89 or a variant thereof; (15) A VH having a sequence as shown in SEQ ID NO: 86 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 90 or a variant thereof; (16) A VH having a sequence as shown in SEQ ID NO: 86 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 91 or a variant thereof; (17) A VH having a sequence as shown in SEQ ID NO: 86 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 93 or a variant thereof; (18) A VH having a sequence as shown in SEQ ID NO: 86 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 94 or a variant thereof; (19) A VH having a sequence as shown in SEQ ID NO: 86 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 95 or a variant thereof; (20) A VH having a sequence as shown in SEQ ID NO: 86 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 96 or a variant thereof; (21) A VH having a sequence as shown in SEQ ID NO: 86 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 97 or a variant thereof; (22) A VH having a sequence as shown in SEQ ID NO: 86 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 98 or a variant thereof; (23) A VH having a sequence as shown in SEQ ID NO: 86 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 99 or a variant thereof; (24) A VH having a sequence as shown in SEQ ID NO: 86 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 100 or a variant thereof; (25) A VH having a sequence as shown in SEQ ID NO: 86 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 101 or a variant thereof; (26) A VH having a sequence as shown in SEQ ID NO: 3 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 4 or a variant thereof; (27) A VH having the sequence shown in SEQ ID NO: 1 or a variant thereof, and a VL having the sequence shown in SEQ ID NO: 2 or a variant thereof; (28) A VH having a sequence as shown in SEQ ID NO: 5 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 6 or a variant thereof; (29) A VH having a sequence as shown in SEQ ID NO: 102 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 107 or a variant thereof; (30) A VH having a sequence as shown in SEQ ID NO: 102 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 108 or a variant thereof; (31) A VH having a sequence as shown in SEQ ID NO: 102 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 109 or a variant thereof; (32) A VH having a sequence as shown in SEQ ID NO: 102 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 110 or a variant thereof; (33) A VH having a sequence as shown in SEQ ID NO: 103 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 107 or a variant thereof; (34) A VH having a sequence as shown in SEQ ID NO: 103 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 108 or a variant thereof; (35) A VH having a sequence as shown in SEQ ID NO: 103 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 109 or a variant thereof; (36) A VH having a sequence as shown in SEQ ID NO: 103 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 110 or a variant thereof; (37) A VH having a sequence as shown in SEQ ID NO: 104 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 107 or a variant thereof; (38) A VH having a sequence as shown in SEQ ID NO: 104 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 108 or a variant thereof; (39) A VH having a sequence as shown in SEQ ID NO: 104 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 109 or a variant thereof; (40) A VH having a sequence as shown in SEQ ID NO: 104 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 110 or a variant thereof; (41) A VH having a sequence as shown in SEQ ID NO: 105 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 107 or a variant thereof; (42) A VH having a sequence as shown in SEQ ID NO: 105 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 108 or a variant thereof; (43) A VH having a sequence as shown in SEQ ID NO: 105 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 109 or a variant thereof; (44) A VH having a sequence as shown in SEQ ID NO: 105 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 110 or a variant thereof; (45) A VH having the sequence shown in SEQ ID NO: 106 or a variant thereof, and a VL having the sequence shown in SEQ ID NO: 107 or a variant thereof; (46) A VH having the sequence shown in SEQ ID NO: 106 or a variant thereof, and a VL having the sequence shown in SEQ ID NO: 108 or a variant thereof; (47) A VH having a sequence as shown in SEQ ID NO: 106 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 109 or a variant thereof; (48) A VH having the sequence shown in SEQ ID NO: 106 or a variant thereof, and a VL having the sequence shown in SEQ ID NO: 110 or a variant thereof; (49) A VH having a sequence as shown in SEQ ID NO: 111 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 107 or a variant thereof; (50) A VH having the sequence shown in SEQ ID NO: 111 or a variant thereof, and a VL having the sequence shown in SEQ ID NO: 116 or a variant thereof; (51) A VH having a sequence as shown in SEQ ID NO: 111 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 117 or a variant thereof; (52) A VH having a sequence as shown in SEQ ID NO: 111 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 118 or a variant thereof; (53) A VH having a sequence as shown in SEQ ID NO: 112 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 107 or a variant thereof; (54) A VH having the sequence shown in SEQ ID NO: 112 or a variant thereof, and a VL having the sequence shown in SEQ ID NO: 116 or a variant thereof; (55) A VH having a sequence as shown in SEQ ID NO: 112 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 117 or a variant thereof; (56) A VH having the sequence shown in SEQ ID NO: 112 or a variant thereof, and a VL having the sequence shown in SEQ ID NO: 118 or a variant thereof; (57) A VH having a sequence as shown in SEQ ID NO: 113 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 107 or a variant thereof; (58) A VH having a sequence as shown in SEQ ID NO: 113 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 116 or a variant thereof; (59) A VH having a sequence as shown in SEQ ID NO: 113 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 117 or a variant thereof; (60) A VH having a sequence as shown in SEQ ID NO: 113 or a variant thereof, and a VL having a sequence as shown in SEQ ID NO: 118 or a variant thereof; (61) A VH having the sequence shown in SEQ ID NO: 114 or a variant thereof, and a VL having the sequence shown in SEQ ID NO: 107 or a variant thereof; (62) A VH having the sequence shown in SEQ ID NO: 114 or a variant thereof, and a VL having the sequence shown in SEQ ID NO: 116 or a variant thereof; (63) A VH having the sequence shown in SEQ ID NO: 114 or a variant thereof, and a VL having the sequence shown in SEQ ID NO: 117 or a variant thereof; (64) A VH having the sequence shown in SEQ ID NO: 114 or a variant thereof, and a VL having the sequence shown in SEQ ID NO: 118 or a variant thereof; (65) A VH having the sequence shown in SEQ ID NO: 115 or a variant thereof, and a VL having the sequence shown in SEQ ID NO: 107 or a variant thereof; (66) A VH having the sequence shown in SEQ ID NO: 115 or a variant thereof, and a VL having the sequence shown in SEQ ID NO: 116 or a variant thereof; (67) A VH having the sequence shown in SEQ ID NO: 115 or a variant thereof, and a VL having the sequence shown in SEQ ID NO: 117 or a variant thereof; (68) The antibody comprises a heavy chain variable region (VH) and / or a light chain variable region (VL) selected from the VH sequence shown in SEQ ID NO: 115 or a variant thereof, and the VL sequence shown in SEQ ID NO: 118 or a variant thereof; The antibody or antigen-binding fragment thereof of any one of claims 1 to 4, wherein the variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity compared to the sequence from which it is derived, or the variant has one or more amino acid substitutions, deletions or additions (e.g. 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions) compared to the sequence from which it is derived, preferably the substitutions are conservative substitutions.

6. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, which is a mouse-derived antibody, a chimeric antibody or a humanized antibody.

7. The antibody or antigen-binding fragment thereof comprises: (a) a heavy chain constant region (CH) of a human immunoglobulin or a variant thereof having one or more amino acid substitutions, deletions or additions (e.g., at most 20, at most 15, at most 10 or at most 5 amino acid substitutions, deletions or additions, e.g., 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions) compared to the wild-type sequence from which it is derived; (b) a light chain constant region (CL) of a human immunoglobulin, or a variant thereof having one or more amino acid substitutions, deletions or additions compared to the wild-type sequence from which it is derived (e.g., at most 20, at most 15, at most 10 or at most 5 amino acid substitutions, deletions or additions, e.g., 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions); Preferably, the heavy chain constant region is an IgG heavy chain constant region, such as an IgG1, IgG2, IgG3 or IgG4 heavy chain constant region; Preferably, the antibody or antigen-binding fragment thereof comprises: (1) a human IgG1 heavy chain constant region; (2) a human IgG4 heavy chain constant region, Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region (CH) as set forth in SEQ ID NO: 119 or a variant thereof, wherein the variant has at most 20 amino acid conservative substitutions (e.g. at most 15, at most 10 or at most 5 amino acid conservative substitutions, e.g. 1, 2, 3, 4 or 5 amino acid conservative substitutions) compared to SEQ ID NO: 119; Preferably, the light chain constant region is a kappa light chain constant region, Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant region (CL) as set forth in SEQ ID NO: 120 or a variant thereof, wherein the variant has at most 20 amino acid conservative substitutions (e.g. at most 15, at most 10 or at most 5 amino acid conservative substitutions, e.g. 1, 2, 3, 4 or 5 amino acid conservative substitutions) compared to SEQ ID NO: 120; More preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region (CH) as set forth in SEQ ID NO: 119 and a light chain constant region (CL) as set forth in SEQ ID NO:

120.

8. The antibody is (1) a heavy chain comprising a VH sequence shown in SEQ ID NO: 86 and a heavy chain constant region (CH) shown in SEQ ID NO: 119, and a light chain comprising a VL sequence shown in SEQ ID NO: 92 and a light chain constant region (CL) shown in SEQ ID NO: 120; (2) a heavy chain comprising a VH sequence shown in SEQ ID NO: 84 and a heavy chain constant region (CH) shown in SEQ ID NO: 119, and a light chain comprising a VL sequence shown in SEQ ID NO: 87 and a light chain constant region (CL) shown in SEQ ID NO: 120; (3) a heavy chain comprising a VH sequence shown in SEQ ID NO: 84 and a heavy chain constant region (CH) shown in SEQ ID NO: 119, and a light chain comprising a VL sequence shown in SEQ ID NO: 88 and a light chain constant region (CL) shown in SEQ ID NO: 120; (4) a heavy chain comprising a VH sequence shown in SEQ ID NO: 84 and a heavy chain constant region (CH) shown in SEQ ID NO: 119, and a light chain comprising a VL sequence shown in SEQ ID NO: 89 and a light chain constant region (CL) shown in SEQ ID NO: 120; (5) a heavy chain comprising a VH sequence shown in SEQ ID NO: 84 and a heavy chain constant region (CH) shown in SEQ ID NO: 119, and a light chain comprising a VL sequence shown in SEQ ID NO: 90 and a light chain constant region (CL) shown in SEQ ID NO: 120; (6) a heavy chain comprising a VH sequence as set forth in SEQ ID NO: 84 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 91 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (7) a heavy chain comprising a VH sequence as set forth in SEQ ID NO: 85 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 87 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (8) a heavy chain comprising a VH sequence as set forth in SEQ ID NO: 85 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 88 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (9) a heavy chain comprising a VH sequence as set forth in SEQ ID NO: 85 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 92 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (10) A heavy chain comprising a VH sequence shown in SEQ ID NO: 85 and a heavy chain constant region (CH) shown in SEQ ID NO: 119, and a light chain comprising a VL sequence shown in SEQ ID NO: 90 and a light chain constant region (CL) shown in SEQ ID NO: 120; (11) A heavy chain comprising a VH sequence shown in SEQ ID NO: 85 and a heavy chain constant region (CH) shown in SEQ ID NO: 119, and a light chain comprising a VL sequence shown in SEQ ID NO: 91 and a light chain constant region (CL) shown in SEQ ID NO: 120; (12) A heavy chain comprising a VH sequence shown in SEQ ID NO: 86 and a heavy chain constant region (CH) shown in SEQ ID NO: 119, and a light chain comprising a VL sequence shown in SEQ ID NO: 87 and a light chain constant region (CL) shown in SEQ ID NO: 120; (13) A heavy chain comprising a VH sequence shown in SEQ ID NO: 86 and a heavy chain constant region (CH) shown in SEQ ID NO: 119, and a light chain comprising a VL sequence shown in SEQ ID NO: 88 and a light chain constant region (CL) shown in SEQ ID NO: 120; (14) A heavy chain comprising a VH sequence shown in SEQ ID NO: 86 and a heavy chain constant region (CH) shown in SEQ ID NO: 119, and a light chain comprising a VL sequence shown in SEQ ID NO: 89 and a light chain constant region (CL) shown in SEQ ID NO: 120; (15) A heavy chain comprising a VH sequence shown in SEQ ID NO: 86 and a heavy chain constant region (CH) shown in SEQ ID NO: 119, and a light chain comprising a VL sequence shown in SEQ ID NO: 90 and a light chain constant region (CL) shown in SEQ ID NO: 120; (16) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 86 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 91 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (17) A heavy chain comprising a VH sequence shown in SEQ ID NO: 86 and a heavy chain constant region (CH) shown in SEQ ID NO: 119, and a light chain comprising a VL sequence shown in SEQ ID NO: 93 and a light chain constant region (CL) shown in SEQ ID NO: 120; (18) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 86 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 94 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (19) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 86 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 95 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (20) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 86 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 96 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (21) A heavy chain comprising a VH sequence shown in SEQ ID NO: 86 and a heavy chain constant region (CH) shown in SEQ ID NO: 119, and a light chain comprising a VL sequence shown in SEQ ID NO: 97 and a light chain constant region (CL) shown in SEQ ID NO: 120; (22) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 86 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 98 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (23) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 86 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 99 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (24) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 86 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 100 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (25) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 86 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 101 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (26) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 3 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 4 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (27) A heavy chain comprising a VH having the sequence shown in SEQ ID NO: 1 and a heavy chain constant region (CH) having the sequence shown in SEQ ID NO: 119, and a light chain comprising a VL having the sequence shown in SEQ ID NO: 2 and a light chain constant region (CL) having the sequence shown in SEQ ID NO: 120; (28) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 5 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 6 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (29) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 102 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 107 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (30) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 102 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 108 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (31) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 102 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 109 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (32) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 102 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 110 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (33) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 103 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 107 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (34) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 103 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 108 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (35) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 103 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 109 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (36) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 103 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 110 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (37) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 104 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 107 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (38) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 104 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 108 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (39) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 104 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 109 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (40) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 104 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 110 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (41) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 105 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 107 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (42) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 105 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 108 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (43) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 105 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 109 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (44) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 105 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 110 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (45) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 106 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 107 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (46) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 106 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 108 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (47) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 106 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 109 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (48) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 106 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 110 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (49) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 111 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 107 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (50) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 111 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 116 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (51) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 111 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 117 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (52) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 111 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 118 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (53) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 112 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 107 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (54) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 112 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 116 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (55) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 112 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 117 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (56) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 112 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 118 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (57) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 113 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 107 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (58) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 113 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 116 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (59) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 113 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 117 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (60) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 113 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 118 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (61) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 114 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 107 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (62) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 114 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 116 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (63) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 114 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 117 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (64) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 114 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 118 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (65) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 115 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 107 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (66) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 115 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 116 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; (67) A heavy chain comprising a VH sequence as set forth in SEQ ID NO: 115 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 119, and a light chain comprising a VL sequence as set forth in SEQ ID NO: 117 and a light chain constant region (CL) as set forth in SEQ ID NO: 120; or (68) The antibody or antigen-binding fragment thereof according to any one of claims 1 to 7, which is any one pair selected from a heavy chain comprising a VH sequence shown in SEQ ID NO: 115 and a heavy chain constant region (CH) shown in SEQ ID NO: 119, and a light chain comprising a VL sequence shown in SEQ ID NO: 118 and a light chain constant region (CL) shown in SEQ ID NO:

120.

9. ScFv, Fab, Fab', F(ab') ２ The antibody or antigen-binding fragment thereof according to any one of claims 1 to 8, which is selected from an Fv fragment, a disulfide-linked Fv (dsFv), a diabody, a bispecific antibody and a multispecific antibody.

10. The antibody or antigen-binding fragment thereof of any one of claims 1 to 9, which is labeled, preferably with a detectable label, such as an enzyme (e.g., horseradish peroxidase), a radionuclide, a fluorescent dye, a luminescent substance (e.g., a chemiluminescent substance) or biotin.

11. The antibody or antigen-binding fragment thereof comprises: (i) binds to ROR1 (e.g., human ROR1) with an EC50 of less than about 500 nM, e.g., about 100 nM, 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM or less, preferably wherein the EC50 is measured by flow cytometry or cell competitive ELISA; (ii) binds to ROR1 (e.g., human ROR1) with a KD of less than about 100 nM, e.g., about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 1 nM, 0.1 nM or less, preferably wherein the KD is measured by biolayer interferometry (BLI); (iii) does not bind to ROR2 (e.g., human ROR2); (iv) having ADCC and / or CDC activity; (v) having enhanced ADCC and / or CDC activity The antibody or antigen-binding fragment thereof according to any one of claims 1 to 10, having one or more characteristics selected from the group consisting of:

12. Encoding the antibody or antigen-binding fragment thereof, its heavy chain and / or light chain, or its heavy chain variable region and / or light chain variable region according to any one of claims 1 to 11, Preferably, the encoded antibody or antigen-binding fragment thereof, its heavy and / or light chain, or its heavy chain variable region and / or light chain variable region comprises a heavy chain variable region and / or a light chain variable region as defined in any one of claims 1 to 5.

13. a nucleic acid molecule encoding an antibody heavy chain variable region and / or a nucleic acid molecule encoding an antibody light chain variable region, (1) The nucleic acid molecule encoding the antibody heavy chain variable region comprises: (a) the nucleotide sequences set forth in SEQ ID NOs: 121, 123, 125, 127-129, 145-149, and 154-158; (b) a sequence substantially identical to the nucleotide sequence set forth in (a) (e.g., a sequence having at least about 85%, 90%, 95%, 99% or more sequence identity to the nucleotide sequence set forth in (a), or a sequence having one or more nucleotide substitutions); or (c) a sequence which differs from the nucleotide sequence of (a) by no more than 3, 6, 15, 30 or 45 nucleotides; and / or (2) The nucleic acid molecule encoding the antibody light chain variable region comprises: (a) the nucleotide sequences set forth in SEQ ID NOs: 122, 124, 126, 130-144, 150-153, and 159-161; (b) a sequence substantially identical to the nucleotide sequence set forth in (a) (e.g., a sequence having at least about 85%, 90%, 95%, 99% or more sequence identity to the nucleotide sequence set forth in (a), or a sequence having one or more nucleotide substitutions); or 13. The isolated nucleic acid molecule of claim 12, wherein the nucleic acid sequence is selected from the group consisting of (c) a sequence that differs from the nucleotide sequence of (a) by no more than 3, 6, 15, 30, or 45 nucleotides.

14. a nucleic acid molecule encoding an antibody heavy chain constant region and / or a nucleic acid molecule encoding an antibody light chain constant region, (1) The nucleic acid molecule encoding the antibody heavy chain constant region comprises: (a) the nucleotide sequence set forth in SEQ ID NO:59; (b) a sequence substantially identical to the nucleotide sequence set forth in (a) (e.g., a sequence having at least about 85%, 90%, 95%, 99% or more sequence identity to the nucleotide sequence set forth in (a), or a sequence having one or more nucleotide substitutions); or (c) a sequence which differs from the nucleotide sequence of (a) by no more than 3, 6, 15, 30 or 45 nucleotides; and / or (2) The nucleic acid molecule encoding the antibody light chain constant region comprises: (a) the nucleotide sequence set forth in SEQ ID NO:26; (b) a sequence substantially identical to the nucleotide sequence set forth in (a) (e.g., a sequence having at least about 85%, 90%, 95%, 99% or more sequence identity to the nucleotide sequence set forth in (a), or a sequence having one or more nucleotide substitutions); or 14. The isolated nucleic acid molecule of claim 12 or 13, wherein the nucleic acid molecule is selected from the group consisting of a sequence that differs from the nucleotide sequence of (a) by no more than 3, 6, 15, 30 or 45 nucleotides.

15. A vector comprising the nucleic acid molecule according to any one of claims 12 to 14, preferably said vector being a cloning vector or an expression vector.

16. A host cell comprising a nucleic acid molecule according to any one of claims 12 to 14 or a vector according to claim 15.

17. 12. A method for producing an antibody or antigen-binding fragment thereof according to any one of claims 1 to 11, comprising culturing a host cell according to claim 16 under conditions allowing expression of the antibody or antigen-binding fragment thereof, and recovering the antibody or antigen-binding fragment thereof from a culture of the cultured host cells.

18. A conjugate comprising an antibody or an antigen-binding fragment thereof and a coupling moiety, wherein the antibody is an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 11.

19. the coupling moiety is selected from a detectable label or a second biologically functional fragment; Preferably, the detectable label is any one or any combination of a radioisotope, a fluorescent substance, a luminescent substance, a colored substance, and an enzyme; The complex of claim 18, wherein the second biologically functional fragment is any one selected from the group consisting of a polypeptide, a protein, a receptor or ligand, a polyethylene glycol (PEG), a nuclide, a nucleic acid, and a small molecule toxin, or any combination thereof, having binding activity.

20. A chimeric antigen receptor comprising the antibody or antigen-binding fragment thereof (e.g., ScFv) of any one of claims 1 to 11, a transmembrane domain, and one or more intracellular T cell signaling domains.

21. A multispecific antibody formed by coupling a primary antibody or a fragment thereof with another antibody or a fragment thereof, or an antibody analogue, each antibody or fragment thereof, or antibody analogue retains its original binding specificity, the primary antibody or fragment thereof being an antibody or antigen-binding fragment thereof according to any one of claims 1 to 11, preferably the multispecific antibody being a bispecific antibody, a trispecific antibody or a tetraspecific antibody.

22. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof according to any one of claims 1 to 11, or a vector according to claim 15, or a host cell according to claim 16, or a complex according to claim 18 or 19, or a chimeric antigen receptor according to claim 20, or a multispecific antibody according to claim 21, together with a pharma- ceutically acceptable carrier and / or excipient, Preferably, the pharmaceutical composition further comprises another pharma- ceutical active agent, More preferably, said other pharma- ceutical active agent is a drug having antitumor activity, More preferably, said other pharmacologic active agent is one or more selected from epidermal growth factor receptor (EGFR) inhibitors, immune checkpoint inhibitors, B cell antigen inhibitors, BTK inhibitors, and chemotherapeutic agents; More preferably, the antibody or antigen-binding fragment thereof and the other pharma- ceutical active agent are provided as isolated components or as components of the same composition; More preferably, the pharmaceutical composition wherein said other pharma- ceutical active agent is one or more selected from an anti-PD1 / PD-L1 antibody, an anti-CD20 antibody, an anti-EGFR antibody.

23. The antibody or antigen-binding fragment thereof in the pharmaceutical composition is administered to a subject. (a) inducing apoptosis in tumor cells; (b) inhibiting tumor cell growth, proliferation, differentiation, and / or angiogenesis; (c) inducing and / or increasing complement-dependent cytotoxicity; (d) inducing and / or increasing antibody-dependent cellular cytotoxicity; (e) inhibiting the expression and activation of ROR1; (f) inhibiting ROR1-mediated cell signaling; (g) preventing and / or treating a ROR1 mediated disease / condition, or (h) The pharmaceutical composition according to claim 22, which is used in any combination of (a) to (g).

24. A diagnostic or therapeutic kit comprising an antibody or antigen-binding fragment thereof according to any one of claims 1 to 11, or a vector according to claim 15, or a host cell according to claim 16, or a complex according to claim 18 or 19, or a chimeric antigen receptor according to claim 20, or a multispecific antibody according to claim 21, or a pharmaceutical composition according to any one of claims 22 to 23, and optionally instructions for use.

25. A pharmaceutical composition for preventing and / or treating and / or supportively treating a tumor, and / or for delaying tumor progression, and / or for reducing or inhibiting tumor recurrence, comprising: (i) an antibody or antigen-binding fragment thereof according to any one of claims 1 to 11, or (ii) a vector according to claim 15, or (iii) a host cell according to claim 16, or (iv) a complex according to claim 18 or 19, or (v) a chimeric antigen receptor according to claim 20, or (vi) a multispecific antibody according to claim 21, or (vii) a pharmaceutical composition according to any one of claims 22 to 23, Preferably, the antibody or antigen-binding fragment thereof according to any one of claims 1 to 11, or the vector according to claim 15, or the host cell according to claim 16, or the complex according to claim 18 or 19, or the chimeric antigen receptor according to claim 20, or the multispecific antibody according to claim 21, and the other pharmacologic active agent are administered separately, in combination, simultaneously or successively, More preferably, said other pharma- ceutical active agent is a drug having antitumor activity, More preferably, said other pharmacologic active agent is one or more selected from epidermal growth factor receptor (EGFR) inhibitors, immune checkpoint inhibitors, B cell antigen inhibitors, BTK inhibitors, and chemotherapeutic agents; More preferably, the pharmaceutical composition wherein said other pharma- ceutical active agent is one or more selected from an anti-PD1 / PD-L1 antibody, an anti-CD20 antibody, an anti-EGFR antibody.

26. A pharmaceutical composition comprising: (i) an antibody or antigen-binding fragment thereof according to any one of claims 1 to 11; or (ii) a vector according to claim 15; or (iii) a host cell according to claim 16; or (iv) a complex according to claim 18 or 19; or (v) a chimeric antigen receptor according to claim 20; or (vi) a multispecific antibody according to claim 21; or (vii) a pharmaceutical composition according to any one of claims 22 to 23, One of the following: (a) to induce apoptosis in tumor cells; (b) to inhibit tumor cell growth, proliferation, differentiation, and / or angiogenesis; (c) to induce and / or increase complement-dependent cytotoxicity; (d) to induce and / or increase antibody-dependent cellular cytotoxicity; (e) inhibiting the expression and activation of ROR1; (f) inhibiting ROR1-mediated cell signaling; (g) for preventing and / or treating a ROR1 mediated disease / condition, or (h) A pharmaceutical composition for any combination of (a)-(g).

27. the tumor is a ROR1 positive tumor; 27. The pharmaceutical composition according to claim 25 or 26, wherein the tumor is selected from lymphoma, breast cancer, colorectal cancer, ovarian cancer, lung cancer and / or pancreatic cancer.

28. 1. A method for detecting the presence or level of ROR1 in a sample, comprising: A method comprising contacting the sample with an antibody or antigen-binding fragment thereof described in any one of claims 1 to 11 under conditions that allow the antibody or antigen-binding fragment thereof and ROR1 to form a complex, and detecting formation of the complex.

29. Use of the antibody or antigen-binding fragment thereof according to any one of claims 1 to 11, the complex according to claim 18 or 19, or the multispecific antibody according to claim 20 in the manufacture of a diagnostic kit, comprising: The diagnostic kit is for diagnosing or differentiating a tumor or tumor metastasis, Preferably, the tumor is a ROR1 positive tumor; Preferably, said tumor is selected from lymphoma, breast cancer, colorectal cancer, ovarian cancer, lung cancer and / or pancreatic cancer.

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