Antibodies, antigen-binding fragments thereof and pharmaceutical uses thereof

Abstract

The present application relates to antibodies or antigen binding fragments and pharmaceutical uses thereof. In particular, the monoclonal antibody according to the present application can inhibit tumors, and thus can be used as a cancer therapeutic agent and targeted cancer therapy, including detection of various cancers, delivery of drugs to specific cancers, and the like.

Description

Technical Field

[0001] The present invention relates to antibodies, in particular to antibodies that are specific for epidermal growth factor receptor 3, and their uses, such as in cancer therapy. Background Art

[0002] Human epidermal growth factor receptor 3 (ErbB3, also known as HER3) is a receptor protein tyrosine kinase and belongs to the epidermal growth factor receptor (EGFR) subfamily of receptor protein tyrosine kinases, which subfamily also includes EGFR (HER1, ErbB1), HER2 (ErbB2, Neu), and HER4 (ErbB4). In addition, HER3 is a unique member of the HER family that has no or very little intracellular tyrosine kinase activity but still plays a role in tumor progression and drug resistance. HER3 is a single transmembrane protein composed of a ligand-binding extracellular domain, a transmembrane domain, an intracellular kinase domain, and a C-terminal tail. Although HER3 has been reported to have some kinase activity, it has been shown to be 1000-fold weaker than the kinase activity of fully activated EGFR. Since HER3 cannot form homodimers, HER3 is generally activated by extracellular ligand binding (such as NRG1), inducing a conformational change, and then forming an active heterodimer with other members of the ErbB family, most notably ligand-binding impaired HER2 or fully functional EGFR.

[0003] Targeted therapies against HER family members, such as EGFR and HER2, are widely and commonly used in cancer therapy by using monoclonal antibodies (mAbs). However, due to the adaptive nature of cancer treatment, some cancer patients develop drug resistance after long-term treatment. For example, approximately 70% of patients are resistant to trastuzumab, an anti-HER2 antibody, and some patients even exhibit primary drug resistance. Several studies have reported that strong expression of HER3 is observed after tumors become resistant to trastuzumab treatment, and thus HER3 has become a promising target for overcoming existing obstacles.

[0004] Because HER3 has only minimal kinase activity, antibodies against HER3 are by far the most pursued strategy for targeting HER3. Many monoclonal antibodies against HER3 are undergoing preclinical and clinical development. Currently, the active antibodies are HMBD-001 (NCT05057013) from Hummingbird Bioscience; ISU104 (NCT03552406) from ISU Abxis Co., Ltd.; and SIBP-03 (NCT05203601) from Shanghai Institute of Biological Products. However, the fully human IgG2 mAb Seribantumab (from Merrimack, MM-121) in combination with paclitaxel or exemestane (an aromatase inhibitor) did not reach the phase 2 clinical endpoint of progression-free survival (PFS) in patients with HER3+ ovarian and breast cancers (NCT03241810). In addition, in a phase 3 clinical study evaluating its efficacy against NSCLC, Patritumab (U3-1287 / AMG888) from Daiichi-Sankyo was tested together with erlotinib, and Patritumab also failed to meet the efficacy criteria (NCT02134015). Many HER3-targeted therapeutic antibodies have been tried to treat patients in clinical trials, but their efficacy can only be regarded as modest (J Exp Clin Cancer Res. October 21, 2022; 41(1):310). Therefore, there is an urgent need to incorporate new strategies to improve HER3-targeted antibody therapy. Summary of the Invention

[0005] Insufficient internalization of HER3-targeted monoclonal antibodies is an urgent problem to be solved. All previous anti-HER3 antibodies were generated based on binding rather than internalization. In addition, all anti-HER3 antibodies were isolated by phage display technology or traditional mouse hybridoma technology. We used fully humanized mice to screen for fully human antibodies against HER3, which is completely different from all previous anti-HER3 antibodies.

[0006] Specifically, the present invention encompasses the following aspects:

[0007] The present disclosure provides an anti-HER3 antibody or an antigen-binding fragment thereof, which comprises one or more CDR region sequences selected from the following sequences: the anti-HER3 antibody or an antigen-binding fragment thereof, which comprises: a variable region of an antibody heavy chain comprising HCDR1, HCDR2 and HCDR3 regions, and a variable region of an antibody light chain comprising LCDR1, LCDR2 and LCDR3 regions, wherein: a) HCDR1 is as shown in SEQ ID NO: 01, SEQ ID NO: 02, SEQ ID NO: 03, SEQ ID NO: 04, SEQ ID NO: 05, SEQ ID NO: 06, SEQ ID NO: 07, SEQ ID NO: 08, SEQ ID NO: 09, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16 or SEQ ID NO: 17; b) HCDR2 is as shown in SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35 or SEQ ID NO: 36; c) HCDR3 is as shown in SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57 or SEQ ID NO: 58;d) LCDR1 is as shown in SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75 or SEQ ID NO: 76; e) LCDR2 is as shown in SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86 or SEQ ID NO: 87; f) LCDR3 is as shown in SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103 or SEQ ID NO: 104.;

[0008] In some embodiments, the heavy chain variable region sequence comprises: HCDR1 as shown in SEQ ID NO: 01, HCDR2 as shown in SEQ ID NO: 18, and HCDR3 as shown in SEQ ID NO: 37, respectively; or HCDR1 as shown in SEQ ID NO: 02, HCDR2 as shown in SEQ ID NO: 19, and HCDR3 as shown in SEQ ID NO: 38, respectively; or HCDR1 as shown in SEQ ID NO: 03, HCDR2 as shown in SEQ ID NO: 20, and HCDR3 as shown in SEQ ID NO: 39, respectively; or HCDR1 as shown in SEQ ID NO: 04, HCDR2 as shown in SEQ ID NO: 21, and HCDR3 as shown in SEQ ID NO: 40, respectively; or HCDR1 as shown in SEQ ID NO: 05, HCDR2 as shown in SEQ ID NO: 22, and HCDR3 as shown in SEQ ID NO: 41, respectively; or HCDR1 as shown in SEQ ID NO: 06, HCDR2 as shown in SEQ ID NO: 23, and HCDR3 as shown in SEQ ID NO: 42, respectively; or HCDR1 as shown in SEQ ID NO: 07, HCDR2 as shown in SEQ ID NO: 24, and HCDR3 as shown in SEQ ID NO: 43, respectively; or HCDR1 as shown in SEQ ID NO: 06, HCDR2 as shown in SEQ ID NO: 25, and HCDR3 as shown in SEQ ID NO: 44, respectively; or HCDR1 as shown in SEQ ID NO: 06, HCDR2 as shown in SEQ ID NO: 26, and HCDR3 as shown in SEQ ID NO: 45, respectively; or HCDR1 as shown in SEQ ID NO: 08, HCDR2 as shown in SEQ ID NO: 27, and HCDR3 as shown in SEQ ID NO: 46, respectively; or HCDR1 as shown in SEQ ID NO: 09, HCDR2 as shown in SEQ ID NO: 28, and HCDR3 as shown in SEQ ID NO: 47, respectively; or HCDR1 as shown in SEQ ID NO: 10, HCDR2 as shown in SEQ ID NO: 29, and HCDR3 as shown in SEQ ID NO: 48, respectively; or HCDR1 as shown in SEQ ID NO: 11, HCDR2 as shown in SEQ ID NO: 30, and HCDR3 as shown in SEQ ID NO: 49, respectively; or HCDR1 as shown in SEQ ID NO: 12, HCDR2 as shown in SEQ ID NO: 31, and HCDR3 as shown in SEQ ID NO: 50, respectively;or HCDR1 as shown in SEQ ID NO: 01, HCDR2 as shown in SEQ ID NO: 21, and HCDR3 as shown in SEQ ID NO: 51, respectively; or HCDR1 as shown in SEQ ID NO: 06, HCDR2 as shown in SEQ ID NO: 32, and HCDR3 as shown in SEQ ID NO: 52, respectively; or HCDR1 as shown in SEQ ID NO: 13, HCDR2 as shown in SEQ ID NO: 33, and HCDR3 as shown in SEQ ID NO: 53, respectively; or HCDR1 as shown in SEQ ID NO: 14, HCDR2 as shown in SEQ ID NO: 33, and HCDR3 as shown in SEQ ID NO: 54, respectively; or HCDR1 as shown in SEQ ID NO: 15, HCDR2 as shown in SEQ ID NO: 34, and HCDR3 as shown in SEQ ID NO: 55, respectively; or HCDR1 as shown in SEQ ID NO: 16, HCDR2 as shown in SEQ ID NO: 35, and HCDR3 as shown in SEQ ID NO: 56, respectively; or HCDR1 as shown in SEQ ID NO: 17, HCDR2 as shown in SEQ ID NO: 36, and HCDR3 as shown in SEQ ID NO: 57, respectively; or HCDR1 as shown in SEQ ID NO: 06, HCDR2 as shown in SEQ ID NO: 32, and HCDR3 as shown in SEQ ID NO: 58, respectively.;

[0009] In some embodiments, the light chain variable region sequence comprises: LCDR1 as shown in SEQ ID NO: 59, LCDR2 as shown in SEQ ID NO: 77, and LCDR3 as shown in SEQ ID NO: 58, respectively; or LCDR1 as shown in SEQ ID NO: 60, LCDR2 as shown in SEQ ID NO: 78, and LCDR3 as shown in SEQ ID NO: 89, respectively; or LCDR1 as shown in SEQ ID NO: 61, LCDR2 as shown in SEQ ID NO: 77, and LCDR3 as shown in SEQ ID NO: 90, respectively; or LCDR1 as shown in SEQ ID NO: 59, LCDR2 as shown in SEQ ID NO: 77, and LCDR3 as shown in SEQ ID NO: 90, respectively; or LCDR1 as shown in SEQ ID NO: 62, LCDR2 as shown in SEQ ID NO: 77, and LCDR3 as shown in SEQ ID NO: 91, respectively; or LCDR1 as shown in SEQ ID NO: 63, LCDR2 as shown in SEQ ID NO: 79, and LCDR3 as shown in SEQ ID NO: 92, respectively; or LCDR1 as shown in SEQ ID NO: 60, LCDR2 as shown in SEQ ID NO: 80, and LCDR3 as shown in SEQ ID NO: 93, respectively; or LCDR1 as shown in SEQ ID NO: 64, LCDR2 as shown in SEQ ID NO: 81, and LCDR3 as shown in SEQ ID NO: 94, respectively; or LCDR1 as shown in SEQ ID NO: 65, LCDR2 as shown in SEQ ID NO: 82, and LCDR3 as shown in SEQ ID NO: 95, respectively; or LCDR1 as shown in SEQ ID NO: 60, LCDR2 as shown in SEQ ID NO: 80, and LCDR3 as shown in SEQ ID NO: 89, respectively; or LCDR1 as shown in SEQ ID NO: 66, LCDR2 as shown in SEQ ID NO: 83, and LCDR3 as shown in SEQ ID NO: 96, respectively; or LCDR1 as shown in SEQ ID NO: 67, LCDR2 as shown in SEQ ID NO: 79, and LCDR3 as shown in SEQ ID NO: 97, respectively; or LCDR1 as shown in SEQ ID NO: 68, LCDR2 as shown in SEQ ID NO: 77, and LCDR3 as shown in SEQ ID NO: 98, respectively; or LCDR1 as shown in SEQ ID NO: 69, LCDR2 as shown in SEQ ID NO: 84, and LCDR3 as shown in SEQ ID NO: 99, respectively;or LCDR1 as shown in SEQ ID NO: 70, LCDR2 as shown in SEQ ID NO: 85, and LCDR3 as shown in SEQ ID NO: 100, respectively; or LCDR1 as shown in SEQ ID NO: 71, LCDR2 as shown in SEQ ID NO: 85, and LCDR3 as shown in SEQ ID NO: 100, respectively; or LCDR1 as shown in SEQ ID NO: 61, LCDR2 as shown in SEQ ID NO: 77, and LCDR3 as shown in SEQ ID NO: 90, respectively; or LCDR1 as shown in SEQ ID NO: 72, LCDR2 as shown in SEQ ID NO: 86, and LCDR3 as shown in SEQ ID NO: 101, respectively; or LCDR1 as shown in SEQ ID NO: 73, LCDR2 as shown in SEQ ID NO: 82, and LCDR3 as shown in SEQ ID NO: 103, respectively; or LCDR1 as shown in SEQ ID NO: 64, LCDR2 as shown in SEQ ID NO: 82, and LCDR3 as shown in SEQ ID NO: 103, respectively; or LCDR1 as shown in SEQ ID NO: 74, LCDR2 as shown in SEQ ID NO: 79, and LCDR3 as shown in SEQ ID NO: 92, respectively; or LCDR1 as shown in SEQ ID NO: 75, LCDR2 as shown in SEQ ID NO: 82, and LCDR3 as shown in SEQ ID NO: 104, respectively; or LCDR1 as shown in SEQ ID NO: 65, LCDR2 as shown in SEQ ID NO: 82, and LCDR3 as shown in SEQ ID NO: 95, respectively; or LCDR1 as shown in SEQ ID NO: 76, LCDR2 as shown in SEQ ID NO: 85, and LCDR3 as shown in SEQ ID NO: 100, respectively; or LCDR1 as shown in SEQ ID NO: 66, LCDR2 as shown in SEQ ID NO: 83, and LCDR3 as shown in SEQ ID NO: 96, respectively.;

[0010] In a preferred embodiment, the anti-HER3 antibody or antigen-binding fragment comprises: a) a heavy chain variable region sequence comprising HCDR1, HCDR2, and HCDR3 as set forth in SEQ ID NO: 08, SEQ ID NO: 27, and SEQ ID NO: 46, respectively; and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NO: 66, SEQ ID NO: 83, and SEQ ID NO: 96, respectively; or b) a heavy chain variable region sequence comprising HCDR1, HCDR2, and HCDR3 as set forth in SEQ ID NO: 09, SEQ ID NO: 28, and SEQ ID NO: 47, respectively; and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NO: 67, SEQ ID NO: 79, and SEQ ID NO: 97, respectively; or c) a heavy chain variable region sequence comprising HCDR1, HCDR2, and HCDR3 as set forth in SEQ ID NO: 10, SEQ ID NO: 29, and SEQ ID NO: 48, respectively; and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NO: 68, SEQ ID NO: 77, and SEQ ID NO: 98, respectively; or d) a heavy chain variable region sequence comprising HCDR1, HCDR2, and HCDR3 as set forth in SEQ ID NO: 11, SEQ ID NO: 30, and SEQ ID NO: 49, respectively; and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NO: 69, SEQ ID NO: 84, and SEQ ID NO: 99, respectively; or e) a heavy chain variable region sequence comprising HCDR1, HCDR2, and HCDR3 as set forth in SEQ ID NO: 12, SEQ ID NO: 31, and SEQ ID NO: 50, respectively; and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NO: 70, SEQ ID NO: 85, and SEQ ID NO: 100, respectively; or f) a heavy chain variable region sequence comprising HCDR1, HCDR2, and HCDR3 as set forth in SEQ ID NO: 12, SEQ ID NO: 31, and SEQ ID NO: 50, respectively; and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NO: 71, SEQ ID NO: 85, and SEQ ID NO: 100, respectively; or g) a heavy chain variable region sequence comprising HCDR1, HCDR2, and HCDR3 as set forth in SEQ ID NO: 01, SEQ ID NO: 21, and SEQ ID NO: 51, respectively;and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 61, SEQ ID NO: 77, and SEQ ID NO: 90, respectively; or h) a heavy chain variable region sequence comprising HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 06, SEQ ID NO: 32, and SEQ ID NO: 52, respectively; and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 72, SEQ ID NO: 86, and SEQ ID NO: 101, respectively; or i) a heavy chain variable region sequence comprising HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 06, SEQ ID NO: 32, and SEQ ID NO: 52, respectively; and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 73, SEQ ID NO: 87, and SEQ ID NO: 102, respectively; or j) a heavy chain variable region sequence comprising HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 13, SEQ ID NO: 33, and SEQ ID NO: 53, respectively; and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 73, SEQ ID NO: 82, and SEQ ID NO: 103, respectively; or k) a heavy chain variable region sequence comprising HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 14, SEQ ID NO: 33, and SEQ ID NO: 54, respectively; and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 64, SEQ ID NO: 82, and SEQ ID NO: 103, respectively; or l) a heavy chain variable region sequence comprising HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 15, SEQ ID NO: 34, and SEQ ID NO: 55, respectively; and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 74, SEQ ID NO: 79, and SEQ ID NO: 92, respectively; or m) a heavy chain variable region sequence comprising HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 16, SEQ ID NO: 35, and SEQ ID NO: 56, respectively; and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 75, SEQ ID NO: 82, and SEQ ID NO: 104, respectively;or n) a heavy chain variable region sequence comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 16, SEQ ID NO: 35 and SEQ ID NO: 56 respectively; and a light chain variable region sequence comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 65, SEQ ID NO: 82 and SEQ ID NO: 95 respectively; or o) a heavy chain variable region sequence comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 17, SEQ ID NO: 36 and SEQ ID NO: 57 respectively; and a light chain variable region sequence comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 76, SEQ ID NO: 85 and SEQ ID NO: 100 respectively; or p) a heavy chain variable region sequence comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 06, SEQ ID NO: 32 and SEQ ID NO: 58 respectively; and a light chain variable region sequence comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 66, SEQ ID NO: 83 and SEQ ID NO: 96 respectively; or q) a heavy chain variable region sequence comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 01, SEQ ID NO: 18 and SEQ ID NO: 37 respectively; and a light chain variable region sequence comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 59, SEQ ID NO: 77 and SEQ ID NO: 88 respectively; or r) a heavy chain variable region sequence comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 02, SEQ ID NO: 19 and SEQ ID NO: 38 respectively; and a light chain variable region sequence comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 60, SEQ ID NO: 78 and SEQ ID NO: 89 respectively; or s) a heavy chain variable region sequence comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 03, SEQ ID NO: 20 and SEQ ID NO: 39 respectively; and a light chain variable region sequence comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 61, SEQ ID NO: 77 and SEQ ID NO: 90 respectively; or t) a heavy chain variable region sequence comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 04, SEQ ID NO: 21 and SEQ ID NO: 40 respectively;and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 59, SEQ ID NO: 77, and SEQ ID NO: 90, respectively; or u) a heavy chain variable region sequence comprising HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 05, SEQ ID NO: 22, and SEQ ID NO: 41, respectively; and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 62, SEQ ID NO: 77, and SEQ ID NO: 91, respectively; or v) a heavy chain variable region sequence comprising HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 06, SEQ ID NO: 23, and SEQ ID NO: 42, respectively; and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 63, SEQ ID NO: 79, and SEQ ID NO: 92, respectively; or w) a heavy chain variable region sequence comprising HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 07, SEQ ID NO: 24, and SEQ ID NO: 43, respectively; and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 60, SEQ ID NO: 80, and SEQ ID NO: 93, respectively; or x) a heavy chain variable region sequence comprising HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 06, SEQ ID NO: 25, and SEQ ID NO: 44, respectively; and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 64, SEQ ID NO: 81, and SEQ ID NO: 94, respectively; or y) a heavy chain variable region sequence comprising HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 06, SEQ ID NO: 26, and SEQ ID NO: 45, respectively; and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 65, SEQ ID NO: 82, and SEQ ID NO: 95, respectively; or z) a heavy chain variable region sequence comprising HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 08, SEQ ID NO: 27, and SEQ ID NO: 46, respectively; and a light chain variable region sequence comprising LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 60, SEQ ID NO: 80, and SEQ ID NO: 89, respectively);

[0011] In a preferred embodiment, the antibody or antigen-binding fragment thereof is selected from murine antibodies, chimeric antibodies, humanized antibodies, human antibodies or antigen-binding fragments thereof.

[0012] In some embodiments, the antibody or antigen-binding fragment thereof comprises: a heavy chain variable region comprising an amino acid sequence selected from SEQ ID NO: 127, 129, 131, 133, 135, 137, 139, 141, 144, 145, 147, 149, 151, 153, 155, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, and 125 or having at least 80%, 85%, 90%, 95%, or 99% sequence identity thereto; and / or a light chain variable region comprising an amino acid sequence selected from SEQ ID NO: 128, 130, 132, 134, 136, 138, 140, 142, 143, 146, 148, 150, 152, 154, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, and 126 or having at least 80%, 85%, 90%, 95%, or 99% sequence identity thereto.

[0013] In some embodiments, the antibody or antigen-binding fragment thereof comprises: a-1) a heavy chain variable region as set forth in SEQ ID NO: 127 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as set forth in SEQ ID NO: 128 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or a-2) a heavy chain variable region as set forth in SEQ ID NO: 127 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as set forth in SEQ ID NO: 126 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or b) a heavy chain variable region as set forth in SEQ ID NO: 129 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as set forth in SEQ ID NO: 130 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or c) a heavy chain variable region as set forth in SEQ ID NO: 131 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as set forth in SEQ ID NO: 132 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or d) a heavy chain variable region as set forth in SEQ ID NO: 133 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as set forth in SEQ ID NO: 134 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or e-1) a heavy chain variable region as set forth in SEQ ID NO: 135 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as set forth in SEQ ID NO: 136 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or e-2) a heavy chain variable region as set forth in SEQ ID NO: 137 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as set forth in SEQ ID NO: 138 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or f) a heavy chain variable region as set forth in SEQ ID NO: 139 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as set forth in SEQ ID NO: 140 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto;or g-1) a heavy chain variable region as shown in SEQ ID NO: 141 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 142 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or g-2) a heavy chain variable region as shown in SEQ ID NO: 141 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 143 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or g-3) a heavy chain variable region as shown in SEQ ID NO: 144 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 142 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or h) a heavy chain variable region as shown in SEQ ID NO: 145 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 146 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or i) a heavy chain variable region as shown in SEQ ID NO: 147 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 148 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or j) a heavy chain variable region as shown in SEQ ID NO: 149 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 150 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or k-1) a heavy chain variable region as shown in SEQ ID NO: 151 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 152 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or k-2) a heavy chain variable region as shown in SEQ ID NO: 151 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 122 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or l) a heavy chain variable region as shown in SEQ ID NO: 153 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto;and / or a light chain variable region as shown in SEQ ID NO: 154 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or m) a heavy chain variable region as shown in SEQ ID NO: 155 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 126 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or n) a heavy chain variable region as shown in SEQ ID NO: 105 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 106 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or o) a heavy chain variable region as shown in SEQ ID NO: 107 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 108 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or p) a heavy chain variable region as shown in SEQ ID NO: 109 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 110 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or q) a heavy chain variable region as shown in SEQ ID NO: 111 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 112 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or r) a heavy chain variable region as shown in SEQ ID NO: 113 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 114 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or s) a heavy chain variable region as shown in SEQ ID NO: 115 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 116 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or t) a heavy chain variable region as shown in SEQ ID NO: 117 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 118 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto;or u) a heavy chain variable region as shown in SEQ ID NO: 119 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 120 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or v) a heavy chain variable region as shown in SEQ ID NO: 121 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 122 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or w-1) a heavy chain variable region as shown in SEQ ID NO: 123 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 124 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or w-2) a heavy chain variable region as shown in SEQ ID NO: 125 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 126 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or x) a heavy chain variable region as shown in SEQ ID NO: 123 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 126 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto.;

[0014] In some embodiments, the antibody or its antigen-binding fragment comprises: a-1) a heavy chain variable region as shown in SEQ ID NO: 127; and / or a light chain variable region as shown in SEQ ID NO: 128; a-2) a heavy chain variable region as shown in SEQ ID NO: 127; and / or a light chain variable region as shown in SEQ ID NO: 126; b) a heavy chain variable region as shown in SEQ ID NO: 129; and / or a light chain variable region as shown in SEQ ID NO: 130; c) a heavy chain variable region as shown in SEQ ID NO: 131; and / or a light chain variable region as shown in SEQ ID NO: 132; d) a heavy chain variable region as shown in SEQ ID NO: 133; and / or a light chain variable region as shown in SEQ ID NO: 134; e-1) a heavy chain variable region as shown in SEQ ID NO: 135; and / or a light chain variable region as shown in SEQ ID NO: 136; e-2) a heavy chain variable region as shown in SEQ ID NO: 137; and / or a light chain variable region as shown in SEQ ID NO: 138; f) a heavy chain variable region as shown in SEQ ID NO: 139; and / or a light chain variable region as shown in SEQ ID NO: 140; g-1) a heavy chain variable region as shown in SEQ ID NO: 141; and / or a light chain variable region as shown in SEQ ID NO: 142; g-2) a heavy chain variable region as shown in SEQ ID NO: 141; and / or a light chain variable region as shown in SEQ ID NO: 143; g-3) a heavy chain variable region as shown in SEQ ID NO: 144; and / or a light chain variable region as shown in SEQ ID NO: 142; h) a heavy chain variable region as shown in SEQ ID NO: 145; and / or a light chain variable region as shown in SEQ ID NO: 146; i) a heavy chain variable region as shown in SEQ ID NO: 147; and / or a light chain variable region as shown in SEQ ID NO: 148; j) a heavy chain variable region as shown in SEQ ID NO: 149; and / or a light chain variable region as shown in SEQ ID NO: 150; k-1) a heavy chain variable region as shown in SEQ ID NO: 151; and / or a light chain variable region as shown in SEQ ID NO: 152; k-2) a heavy chain variable region as shown in SEQ ID NO: 151; and / or a light chain variable region as shown in SEQ ID NO: 122; l) a heavy chain variable region as shown in SEQ ID NO: 153; and / or a light chain variable region as shown in SEQ ID NO: 154; m) a heavy chain variable region as shown in SEQ ID NO: 155; and / or a light chain variable region as shown in SEQ ID NO: 126; n) a heavy chain variable region as shown in SEQ ID NO: 105;and / or a light chain variable region as shown in SEQ ID NO: 106; o) a heavy chain variable region as shown in SEQ ID NO: 107; and / or a light chain variable region as shown in SEQ ID NO: 108; p) a heavy chain variable region as shown in SEQ ID NO: 109; and / or a light chain variable region as shown in SEQ ID NO: 110; q) a heavy chain variable region as shown in SEQ ID NO: 111; and / or a light chain variable region as shown in SEQ ID NO: 112; r) a heavy chain variable region as shown in SEQ ID NO: 113; and / or a light chain variable region as shown in SEQ ID NO: 114; s) a heavy chain variable region as shown in SEQ ID NO: 115; and / or a light chain variable region as shown in SEQ ID NO: 116; t) a heavy chain variable region as shown in SEQ ID NO: 117; and / or a light chain variable region as shown in SEQ ID NO: 118; u) a heavy chain variable region as shown in SEQ ID NO: 119; and / or a light chain variable region as shown in SEQ ID NO: 120; v) a heavy chain variable region as shown in SEQ ID NO: 121; and / or a light chain variable region as shown in SEQ ID NO: 122; w-1) a heavy chain variable region as shown in SEQ ID NO: 123; and / or a light chain variable region as shown in SEQ ID NO: 124; w-2) a heavy chain variable region as shown in SEQ ID NO: 125; and / or a light chain variable region as shown in SEQ ID NO: 126; x) a heavy chain variable region as shown in SEQ ID NO: 123; and / or a light chain variable region as shown in SEQ ID NO: 126.;

[0015] In a preferred embodiment, the antibody or its antigen-binding fragment comprises: a-1) a heavy chain variable region as shown in SEQ ID NO: 127 and a light chain variable region as shown in SEQ ID NO: 128; a-2) a heavy chain variable region as shown in SEQ ID NO: 127 and a light chain variable region as shown in SEQ ID NO: 126; b) a heavy chain variable region as shown in SEQ ID NO: 129 and a light chain variable region as shown in SEQ ID NO: 130; c) a heavy chain variable region as shown in SEQ ID NO: 131 and a light chain variable region as shown in SEQ ID NO: 132; d) a heavy chain variable region as shown in SEQ ID NO: 133 and a light chain variable region as shown in SEQ ID NO: 134; e-1) a heavy chain variable region as shown in SEQ ID NO: 135 and a light chain variable region as shown in SEQ ID NO: 136; e-2) a heavy chain variable region as shown in SEQ ID NO: 137 and a light chain variable region as shown in SEQ ID NO: 138; f) a heavy chain variable region as shown in SEQ ID NO: 139 and a light chain variable region as shown in SEQ ID NO: 140; g-1) a heavy chain variable region as shown in SEQ ID NO: 141 and a light chain variable region as shown in SEQ ID NO: 142; g-2) a heavy chain variable region as shown in SEQ ID NO: 141 and a light chain variable region as shown in SEQ ID NO: 143; g-3) a heavy chain variable region as shown in SEQ ID NO: 144 and a light chain variable region as shown in SEQ ID NO: 142; h) a heavy chain variable region as shown in SEQ ID NO: 145 and a light chain variable region as shown in SEQ ID NO: 146; i) a heavy chain variable region as shown in SEQ ID NO: 147 and a light chain variable region as shown in SEQ ID NO: 148; j) a heavy chain variable region as shown in SEQ ID NO: 149 and a light chain variable region as shown in SEQ ID NO: 150; k-1) a heavy chain variable region as shown in SEQ ID NO: 151 and a light chain variable region as shown in SEQ ID NO: 152; k-2) a heavy chain variable region as shown in SEQ ID NO: 151 and a light chain variable region as shown in SEQ ID NO: 122; l) a heavy chain variable region as shown in SEQ ID NO: 153 and a light chain variable region as shown in SEQ ID NO: 154; m) a heavy chain variable region as shown in SEQ ID NO: 155 and a light chain variable region as shown in SEQ ID NO: 126; n) a heavy chain variable region as shown in SEQ ID NO: 105 and a light chain variable region as shown in SEQ ID NO: 106; o) a heavy chain variable region as shown in SEQ ID NO: 107 and a light chain variable region as shown in SEQ ID NO: 108;p) A heavy chain variable region as shown in SEQ ID NO: 109 and a light chain variable region as shown in SEQ ID NO: 110; q) A heavy chain variable region as shown in SEQ ID NO: 111 and a light chain variable region as shown in SEQ ID NO: 112; r) A heavy chain variable region as shown in SEQ ID NO: 113 and a light chain variable region as shown in SEQ ID NO: 114; s) A heavy chain variable region as shown in SEQ ID NO: 115 and a light chain variable region as shown in SEQ ID NO: 116; t) A heavy chain variable region as shown in SEQ ID NO: 117 and a light chain variable region as shown in SEQ ID NO: 118; u) A heavy chain variable region as shown in SEQ ID NO: 119 and a light chain variable region as shown in SEQ ID NO: 120; v) A heavy chain variable region as shown in SEQ ID NO: 121 and a light chain variable region as shown in SEQ ID NO: 122; w-1) A heavy chain variable region as shown in SEQ ID NO: 123 and a light chain variable region as shown in SEQ ID NO: 124; w-2) A heavy chain variable region as shown in SEQ ID NO: 125 and a light chain variable region as shown in SEQ ID NO: 126; x) A heavy chain variable region as shown in SEQ ID NO: 123 and a light chain variable region as shown in SEQ ID NO: 126.

[0016] In some embodiments, the antibody is a full-length antibody, which further comprises a human antibody constant region; preferably, the heavy chain constant region of the human antibody constant region is selected from the constant regions of human IgG1, IgG2, IgG3, and IgG4 and their conservative variants, and the light chain constant region of the human antibody constant region is selected from the kappa chain constant region and lambda chain constant region of human antibodies and their conservative variants; more preferably, the full-length antibody comprises the human antibody heavy chain constant region of SEQ ID NO: 156 and the human light chain constant region of SEQ ID NO: 157.

[0017] In some embodiments, the antigen-binding fragment is selected from: Fab, Fab', F(ab')2, variable fragment (Fv), single-chain variable fragment (scFv), dimeric domain V (diabody), disulfide-stabilized Fv (dsFv), and CDR-containing peptides.

[0018] In a preferred embodiment, the antibody or antigen-binding fragment thereof comprises: a-1) a heavy chain as shown in SEQ ID NO: 180 and a light chain as shown in SEQ ID NO: 181; a-2) a heavy chain as shown in SEQ ID NO: 180 and a light chain as shown in SEQ ID NO: 179; b) a heavy chain as shown in SEQ ID NO: 182 and a light chain as shown in SEQ ID NO: 183; c) a heavy chain as shown in SEQ ID NO: 184 and a light chain as shown in SEQ ID NO: 185; g) a heavy chain as shown in SEQ ID NO: 186 and a light chain as shown in SEQ ID NO: 187; e-1) a heavy chain as shown in SEQ ID NO: 188 and a light chain as shown in SEQ ID NO: 189; e-2) a heavy chain as shown in SEQ ID NO: 190 and a light chain as shown in SEQ ID NO: 191; f) a heavy chain as shown in SEQ ID NO: 192 and a light chain as shown in SEQ ID NO: 193; g-1) a heavy chain as shown in SEQ ID NO: 194 and a light chain as shown in SEQ ID NO: 195; g-2) a heavy chain as shown in SEQ ID NO: 194 and a light chain as shown in SEQ ID NO: 196; g-3) a heavy chain as shown in SEQ ID NO: 197 and a light chain as shown in SEQ ID NO: 195; h) a heavy chain as shown in SEQ ID NO: 198 and a light chain as shown in SEQ ID NO: 199; i) a heavy chain as shown in SEQ ID NO: 200 and a light chain as shown in SEQ ID NO: 201; j) a heavy chain as shown in SEQ ID NO: 202 and a light chain as shown in SEQ ID NO: 203; k-1) a heavy chain as shown in SEQ ID NO: 204 and a light chain as shown in SEQ ID NO: 205; k-2) a heavy chain as shown in SEQ ID NO: 204 and a light chain as shown in SEQ ID NO: 175; l) a heavy chain as shown in SEQ ID NO: 206 and a light chain as shown in SEQ ID NO: 207; m) a heavy chain as shown in SEQ ID NO: 208 and a light chain as shown in SEQ ID NO: 179; n) a heavy chain as shown in SEQ ID NO: 158 and a light chain as shown in SEQ ID NO: 159; o) a heavy chain as shown in SEQ ID NO: 160 and a light chain as shown in SEQ ID NO: 161; p) a heavy chain as shown in SEQ ID NO: 162 and a light chain as shown in SEQ ID NO: 163; q) a heavy chain as shown in SEQ ID NO: 164 and a light chain as shown in SEQ ID NO: 165;r) a heavy chain as shown in SEQ ID NO: 166 and a light chain as shown in SEQ ID NO: 167; s) a heavy chain as shown in SEQ ID NO: 168 and a light chain as shown in SEQ ID NO: 169; t) a heavy chain as shown in SEQ ID NO: 170 and a light chain as shown in SEQ ID NO: 171; u) a heavy chain as shown in SEQ ID NO: 172 and a light chain as shown in SEQ ID NO: 173; v) a heavy chain as shown in SEQ ID NO: 174 and a light chain as shown in SEQ ID NO: 175; w-1) a heavy chain as shown in SEQ ID NO: 176 and a light chain as shown in SEQ ID NO: 177; w-2) a heavy chain as shown in SEQ ID NO: 178 and a light chain as shown in SEQ ID NO: 179; x) a heavy chain as shown in SEQ ID NO: 176 and a light chain as shown in SEQ ID NO: 179.;

[0019] In some embodiments, the present disclosure provides an isolated nucleic acid molecule encoding any antibody or antigen-binding fragment thereof.

[0020] The antibodies or antigen-binding fragments thereof of the present invention can be used to form bispecific or multispecific binding molecules. The antibodies or antigen-binding fragments thereof of the present invention can be part of a bispecific or multispecific binding molecule that includes a second functional module (such as a second antibody) having a different binding specificity compared to the antibodies or antigen-binding fragments thereof of the present invention, thereby being capable of binding to at least two different binding sites and / or target molecules.

[0021] Thus, in one aspect, the present disclosure provides a bispecific or multispecific binding molecule comprising an antibody or antigen-binding fragment thereof of the present invention.

[0022] The antibodies or antigen-binding fragments thereof of the present invention can be linked to a therapeutic agent to form an immunoconjugate. Because immunoconjugates have the ability to selectively deliver one or more therapeutic agents to a target tissue. In certain embodiments, the immunoconjugate is an antibody-drug conjugate (ADC) and the therapeutic agent is a cytotoxic agent.

[0023] Thus, in one aspect, the present disclosure provides an immunoconjugate comprising an antibody or antigen-binding fragment thereof of the present invention.

[0024] In another aspect, the present disclosure provides a chimeric antigen receptor comprising the antigen-binding domain of an antibody or antigen-binding fragment thereof of the present invention.

[0025] In certain embodiments, the antigen-binding domain comprises the heavy chain variable region and the light chain variable region of an antibody or antigen-binding fragment thereof of the present invention.

[0026] In certain embodiments, the antigen-binding domain is a scFv;

[0027] In certain embodiments, the chimeric antigen receptor is expressed by an immune effector cell (e.g., a T cell).

[0028] In one aspect, the present disclosure also provides a recombinant vector comprising the above-mentioned isolated nucleic acid molecule.

[0029] In another aspect, the present disclosure also provides a host cell transformed with the above-mentioned recombinant vector, wherein the host cell is selected from prokaryotic cells and eukaryotic cells, preferably eukaryotic cells, more preferably mammalian cells.

[0030] In one aspect, the present disclosure also provides a method for producing the above-mentioned antibody or antigen-binding fragment in a culture medium to produce and accumulate the antibody or its antigen-binding fragment, and harvesting the antibody or its antigen-binding fragment from the culture.

[0031] In one aspect, the present disclosure also provides a method for immuno-detecting or measuring HER3, wherein the method comprises detecting HER3 by contacting with the above-mentioned antibody or antigen-binding fragment.

[0032] In one aspect, the present disclosure also provides a method for diagnosing a disease associated with human HER3-positive cells, wherein the method comprises detecting or measuring HER3 or HER3-positive cells by contacting with the above-mentioned antibody or antigen-binding fragment.

[0033] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned antibody or antigen-binding fragment, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0034] In some embodiments, the present disclosure also provides a method for treating or preventing a disease associated with HER3 overexpression, which comprises the step of administering a therapeutically effective amount of the above antibody or its antigen-binding fragment or the above pharmaceutical composition to a subject in need of treatment or prevention of the disease.

[0035] In some embodiments, the disease associated with HER3 overexpression is cancer; preferably, the cancer is selected from breast cancer, colorectal cancer, lung cancer, multiple myeloma, ovarian cancer, liver cancer, gastric cancer, pancreatic cancer, prostate cancer, acute myeloid leukemia, chronic myeloid leukemia, osteosarcoma, squamous cell carcinoma, peripheral nerve sheath tumor, schwannoma, head and neck cancer, bladder cancer, esophageal cancer, glioblastoma, soft tissue clear cell sarcoma, malignant mesothelioma, neurofibromatosis, renal cancer and melanoma.

[0036] In some embodiments, the present disclosure also provides the use of the above antibodies or their antigen-binding fragments or the above pharmaceutical compositions in the manufacture of a medicament for treating or preventing diseases associated with human HER3.

[0037] In some embodiments, the diseases associated with human HER3 are cancers having HER3 expression; preferably, the cancer is breast cancer, colorectal cancer, lung cancer, multiple myeloma, ovarian cancer, liver cancer, gastric cancer, pancreatic cancer, prostate cancer, acute myeloid leukemia, chronic myeloid leukemia, osteosarcoma, squamous cell carcinoma, peripheral nerve sheath tumor, schwannoma, head and neck cancer, bladder cancer, esophageal cancer, glioblastoma, soft tissue clear cell sarcoma, malignant mesothelioma, neurofibromatosis, kidney cancer, and melanoma.

[0038] The obtained antibodies have a series of excellent characteristics:

[0039] i) The variable region sequences are different from those of existing antibodies; all of our antibodies are fully human antibodies, which have a lower tendency to cause immunogenicity in the human body.

[0040] ii) The obtained antibodies have the ability to bind to humans with high affinity, which has been confirmed by flow cytometry and ELISA.

[0041] iii) The obtained antibodies have good internalization characteristics.

[0042] iv) The obtained antibodies are only slightly inhibited by equimolar concentrations of NRG1 molecules. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 . In vitro binding characterization of HER3 hybridoma clones to HER3+(T47D) and HER3-(Jurkat E6.1) cell lines was performed using flow cytometry analysis.

[0044] Figure 2 . The cellular internalization activity of the selected hybridoma clones was characterized using an indirect killing assay.

[0045] Figure 3 . Internalization assay of anti-HER3 recombinant antibodies in HER3+ CHO-K1-huHER3 cells.

[0046] Figure 4 . Effect of NRG1 on binding to SKBr3 cells. DETAILED DESCRIPTION

[0047] The present invention is based on the development of an antibody that can specifically bind to HER3. The headings used in this section are for convenience only and do not limit the present invention.

[0048] Unless otherwise defined herein, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, unless the context specifically requires otherwise, the singular forms include the plural forms and the plural forms include the singular forms.

[0049] Definitions

[0050] Before the present invention is described in detail below, it is to be understood that the invention is not limited to the specific methods, protocols, and reagents described herein as they may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention, which will be limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0051] For the interpretation of the specification, the following definitions will apply, and in any appropriate case, terms used in the singular form may also include the plural form and vice versa. It is to be understood that the terms used herein are for the purpose of describing specific embodiments only and are not intended to be limiting.

[0052] The term "antibody" refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or an antigen-binding portion thereof. Each heavy chain consists of a heavy-chain variable region (abbreviated herein as VH) and a heavy-chain constant region. Each light chain consists of a light-chain variable region (abbreviated herein as VL) and a light-chain constant region. The VH and VL regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with an antigen. The constant regions of the antibody can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (such as effector cells) and the first component (C1q) of the classical complement system.

[0053] As used herein, the term "antigen-binding fragment" of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., HER3). It has been shown that the antigen-binding function of an antibody can be achieved by fragments of a full-length antibody. Examples of binding fragments encompassed by the term "antigen-binding fragment" of an antibody include: (i) Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) F(ab')2 fragment, a bivalent fragment containing two Fab fragments linked by a disulfide bond in the hinge region; (iii) Fd fragment, which consists of the VH and CH1 domains; (iv) Fv fragment, which consists of the VL and VH domains of a single arm of an antibody; (v) dAb fragment (Ward et al., (1989) Nature 341:544-546), which consists of the VH domain; (vi) isolated complementarity-determining regions (CDRs); and (vii) combinations of two or more isolated CDRs, which may optionally be linked by a synthetic linker. In addition, although the two domains VL and VH of the Fv fragment are encoded by separate genes, they can be joined using recombinant methods by a synthetic linker such that they can be made into a single protein chain, in which the VL and VH regions pair to form a monovalent molecule (referred to as single-chain Fv (scFv); see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. 85:5879-5883). Such single-chain antibodies are also intended to be encompassed by the term "antigen-binding portion" of an antibody.

[0054] As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the present invention may contain amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by in vitro random or site-specific mutagenesis or by in vivo somatic mutation). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0055] As used herein, the term "recombinant human antibody" includes all human antibodies prepared, expressed, produced, or isolated by recombinant means, such as (a) antibodies isolated from transgenic or transchromosomal animals (e.g., mice) of the human immunoglobulin genes or from hybridomas prepared therefrom (further described in Section I below), (b) antibodies isolated from a host cell transformed to express the antibody (e.g., isolated from a transfectoma), (c) antibodies isolated from a recombinant combinatorial human antibody library, and (d) antibodies prepared, expressed, produced, or isolated by any other means involving splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies may be subjected to in vitro mutagenesis (or, when using animals transgenic for human Ig sequences, in vivo somatic mutagenesis), and thus the amino acid sequences of the VH and VL regions of the recombinant antibody are sequences that, although derived from and related to human germline VH and VL sequences, may not be those that occur naturally in the human antibody germline repertoire in vivo.

[0056] The term "CDR" refers to one of the six hypervariable regions within the variable domain of an antibody that contribute primarily to antigen binding. One of the most commonly used definitions of the six CDRs is provided by Kabat E.A. et al. (1991) Sequences of proteins of immunological interest. NIH Publication 91-3242. As used herein, the Kabat definition of CDR applies only to CDR1, CDR2, and CDR3 of the light chain variable domain (LCDR1, LCDR2, LCDR3 or L1, L2, L3), and CDR1, CDR2, and CDR3 of the heavy chain variable domain (HCDR1, HCDR2, HCDR3 or H1, H2, H3).

[0057] Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify the CDRs within the specified HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify CDR boundaries include, for example, Chothia (Chothia et al. (1989) Nature 342:877-883), which is based on the three-dimensional structure of the antibody and the topology of the CDR loops, Kabat (Kabat et al., Sequences of Proteins of Immunological Interest, 4th ed., US Department of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath), Contact (University College London), the International ImMunoGeneTics database (IMGT) (imgt.cines.fr / on the world wide web), and the North CDR definition based on affinity propagation clustering using a large number of crystal structures. Those skilled in the art can readily identify the CDRs defined by each numbering system.

[0058] Useful comparisons of CDR numbering are as follows:

[0059] CDR IMGT Kabat AbM <![CDATA[Chothia 1 > <![CDATA[Contact 2 > LCDR1 27-32 24-34 24-34 24-34 30-36 LCDR2 50-51 50-56 50-56 50-56 46-55 LCDR3 89-97 89-97 89-97 89-97 89-96 HCDR1 26-35B <![CDATA[31-35B (Kabat number) 3 > 26-35B 26-32..34 30-35B HCDR2 51-56 50-65 50-58 52-56 47-58 HCDR3 93-102 95-102 95-102 95-102 93-101 HCDR1 26-33 31 - 35 (Chothia numbering) 26-35 26-32 30-35

[0060] Note 1 : Some of these definitions (especially for Chothia loops) vary depending on the individual publications examined; Note 2 : Any numbering scheme can be used for these CDR definitions, except for the contact definition, which uses the Chothia or Martin (enhanced Chothia) definition; Note 3 : When numbering using the Kabat numbering convention, the end of the Chothia HCDR1 loop varies between H32 and H34, depending on the length of the loop. This is because the Kabat numbering scheme places insertions at H35A and H35B.

[0061] As used herein, the term "nucleic acid molecule" refers to DNA molecules and RNA molecules. Nucleic acid molecules can be single-stranded or double-stranded, but are preferably double-stranded DNA. A nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the coding sequence.

[0062] The method for preparing nucleic acid is a conventional preparation method in the art. Preferably, it includes the following steps: obtaining a nucleic acid molecule encoding the above protein through gene cloning technology, or obtaining a nucleic acid molecule encoding the above protein through the method of artificial full-length sequence synthesis.

[0063] Those skilled in the art know that the base sequence encoding the amino acid sequence of a protein can be appropriately substituted, deleted, altered, inserted, or added to provide polynucleotide homologs. Homologs of the polynucleotides of the present invention can be prepared by substituting, deleting, or adding one or more bases of the gene encoding the protein sequence within the range of maintaining antibody activity.

[0064] The term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it is linked. In one embodiment, the vector is a "plasmid", which refers to a circular double-stranded DNA ring to which additional DNA fragments can be ligated. In another embodiment, the vector is a viral vector, in which additional DNA fragments can be ligated into the viral genome. The vectors disclosed herein are capable of self-replicating in the host cells into which they are introduced (e.g., bacterial vectors with a bacterial origin of replication and episomal mammalian vectors), or can be incorporated into the genome of the host cell when introduced into the host cell, and thus replicate together with the host genome (e.g., non-episomal mammalian vectors).

[0065] The recombinant expression vector can be obtained by conventional methods in the art, i.e., by ligating the nucleic acid molecule of the present invention to various expression vectors, thereby being constructed. The expression vector is one of various conventional vectors in the art as long as it can carry the above nucleic acid molecule. The vector preferably includes: various plasmids, cosmids, phages, or viral vectors, etc.

[0066] As used herein, the term "transfectoma" includes recombinant eukaryotic host cells expressing antibodies, such as CHO cells, NS / 0 cells, HEK293 cells, plant cells, or fungi (including yeast cells).

[0067] The sequence of the DNA molecule of the antibody or its fragment according to the present invention can be obtained by conventional techniques (e.g., methods such as PCR amplification or genomic library screening). In addition, the sequences encoding the light chain and the heavy chain can be fused together to form a single-chain antibody.

[0068] Once the relevant sequence is obtained, the relevant sequence can be obtained in batches using recombinant methods. This is usually carried out by: through conventional methods, cloning the sequence into a vector, transforming cells with the vector, and then separating the relevant sequence from the proliferating host cells.

[0069] In addition, the relevant sequence can be artificially synthesized, especially when the fragment length is short. Usually, several small fragments are first synthesized and then ligated together to obtain a long-sequence fragment.

[0070] Currently, the DNA sequence encoding the antibody (or its fragment or its derivative) of the present invention can be obtained entirely by chemical synthesis. Then, the DNA sequence can be introduced into various existing DNA molecules (or vectors such as) and cells known in the art. In addition, mutations can be introduced into the protein sequence of the present invention by chemical synthesis.

[0071] Generally, host cells obtained by culturing under conditions suitable for expressing the antibody according to the present invention. Then, the antibody of the present invention is purified by using conventional immunoglobulin purification steps, such as conventional separation and purification means well-known to those skilled in the art, such as protein A-agarose, hydroxyapatite chromatography, gel electrophoresis, dialysis, ion exchange chromatography, hydrophobic chromatography, molecular sieve chromatography or affinity chromatography.

[0072] The obtained monoclonal antibodies can be identified by conventional means. For example, the binding specificity of monoclonal antibodies can be determined by immunoprecipitation or in vitro binding assays such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). The binding affinity of monoclonal antibodies can be determined by, for example, Scatchard analysis (Munson et al., Anal. Biochem., 107:220 (1980)).

[0073] The antibody according to the present invention can be expressed in cells or on cell membranes, or secreted extracellularly. If necessary, the recombinant protein can be separated and purified by various separation methods according to the physical, chemical and other properties of the recombinant protein. These methods are well-known to those skilled in the art. Examples of these methods include, but are not limited to: conventional renaturation treatment, treatment with protein precipitants (such as salt precipitation), centrifugation, cell lysis by osmosis, sonication, ultracentrifugation, molecular sieve chromatography (gel chromatography), adsorption chromatography, ion exchange chromatography, high performance liquid chromatography (HPLC) and any other liquid chromatography, and combinations thereof.

[0074] A "variant" of a polypeptide (e.g., an antigen-binding fragment, protein or antibody) is a polypeptide in which one or more amino acid residues are inserted, deleted, added and / or substituted as compared to another polypeptide sequence, and includes fusion polypeptides. In addition, protein variants include protein variants that are modified by proteolytic cleavage, phosphorylation or other post-translational modifications, but retain the biological activity of the antibodies disclosed herein, such as binding to and specificity for HER3. Variants can be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81% or 80% identical to the sequence of the antibodies or their antigen-binding fragments disclosed herein. The percentage of identity or homology can be calculated with reference to the following description.

[0075] In one embodiment, the percent homology or identity can be calculated as 100×[(number of identical positions) / min(TGA,TGB)], and in this formula, TGA and TGB are the sum of the number of residues of sequences A and B being compared and the number of internal gap positions (Russell et al., J. Mol Biol., 244:332-350 (1994)).

[0076] In the present invention, the antibodies of the present invention also include their conservative variants, which means that compared with the amino acid sequence of the antibodies of the present invention, up to 10, preferably up to 8, more preferably up to 5, and most preferably up to 3 amino acids are replaced by amino acids having similar or similar properties to form a polypeptide. These conservative variant polypeptides are preferably produced by amino acid substitution according to Table A.

[0077] Table A

[0078]

[0079]

[0080] As used herein, the term "K D "(M) is intended to refer to the dissociation equilibrium constant of a particular antibody-antigen interaction. "K D " refers to the dissociation constant, which is obtained from the ratio of K d to K a (i.e., K d / K a ) and is expressed as molar concentration (M). Given the present disclosure, methods known in the art can be used to determine the K D value of an antibody. For example, the K D of an antibody can be determined by using surface plasmon resonance, such as by using a biosensor system (e.g., the system) or by using biolayer interferometry techniques (such as the Octet RED96 system).

[0081] The term "affinity" is the strength of the interaction between an antibody or its antigen-binding fragment and an antigen, which is determined by the properties of the antigen, such as the size, shape, and / or charge of the antigen, and the CDR sequences of the antibody or antigen-binding fragment. Methods for determining affinity are known in the art, and the following can be referred to.

[0082] When the dissociation constant (K D ) < 10 6 M, the antibody or its antigen-binding fragment is said to "specifically bind" to its target (such as an antigen). When K D < 10 9 M, the antibody specifically binds to its target with "high affinity".

[0083] As used herein, the term "pharmaceutical composition" is intended to refer to a mixture containing one or more of the compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, and other chemical components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, which is beneficial for the absorption of the active ingredient and the exertion of its biological activity.

[0084] When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, "administer" and "treat" mean bringing the animal, human, subject, cell, tissue, organ, or biological fluid into contact with an exogenous pharmaceutical reagent, therapeutic reagent, diagnostic reagent, or composition. "Administer" and "treat" can refer to, for example, therapeutic methods, pharmacokinetic methods, diagnostic methods, research methods, and experimental methods. The treatment of cells encompasses bringing cells into contact with a reagent, as well as bringing a liquid into contact with a reagent, wherein the liquid comes into contact with the cells. "Administer" and "treat" also refer to in vitro treatment and ex vivo treatment, such as in vitro treatment and ex vivo treatment of cells by a reagent, diagnostic agent, binding composition, or by another cell. When applied to human, veterinary, or research subjects, "treatment" refers to therapeutic treatment, prophylactic or preventive measures, research, and diagnostic applications.

[0085] In addition, the present disclosure includes a drug for treating diseases related to HER3, which contains the antibody of the present disclosure or its antigen-binding fragment as an active ingredient.

[0086] There is no limitation on the diseases related to HER3, as long as it is a disease associated with HER3. For example, the therapeutic response induced by the molecules disclosed in the present disclosure can be reduced by binding to human HER3. Therefore, when in formulations and recipes suitable for therapeutic applications, the molecules of the present disclosure are very useful for those suffering from tumors, cancers, or infectious diseases.

[0087] In addition, the present disclosure relates to a method for immunodetecting or measuring HER3, a reagent for immunodetecting or measuring HER3, a method for immunodetecting or measuring cells expressing HER3, and a diagnostic reagent for diagnosing diseases associated with HER3-positive cells, which contain the antibody or antigen-binding fragment specifically recognizing human HER3 of the present disclosure as an active ingredient.

[0088] In the present disclosure, the method for detecting or determining the amount of HER3 can be any known method. For example, it includes immunodetection or assay.

[0089] Immunoassay or determination is a method for detecting or determining the amount of an antibody or antigen by using a labeled antigen or antibody. Examples of immunoassays or determinations include radioimmunoassay (RIA) using radioactive substances, enzyme immunoassay (EIA or ELISA), fluorescence immunoassay (FIA), luminescence immunoassay, Western blotting method, physicochemical method, etc.

[0090] The diseases associated with HER3-positive cells as described above can be diagnosed by detecting or measuring cells expressing HER3 using the antibody or antibody fragment of the present invention.

[0091] To detect cells expressing a polypeptide, known immunoassays can be used, and preferably immunoprecipitation, fluorescence cell staining, immunohistochemical staining, etc. can be used. In addition, the FMAT8100HTS system (Applied Biosystem) can be used to perform fluorescence antibody staining methods, etc.

[0092] Examples

[0093] The present invention is further illustrated by the following specific examples. It will be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental methods without detailed conditions in the following examples are generally carried out according to the conditions described in conventional conditions, such as those described in "Molecular Cloning: A Laboratory Manual" by Sambrook.J et al. (translated by Huang Peitang et al., Beijing: Science Press, 2002), or according to the conditions recommended by the manufacturer (such as the product manual). Unless otherwise specified, percentages and parts are by weight. Unless otherwise specified, the experimental materials and reagents used in the following examples are commercially available.

[0094] The room temperature described in the examples is the conventional room temperature in the art and is generally 10 - 30°C.

[0095] Example 1: Immunization and Antibody Screening

[0096] Example 1-1: Preparation of Immunogen

[0097] A combination of recombinant protein antigens huHER3-His and rhesus HER3-His was used to immunize humanized mice (AlloyGK MIX strain). Briefly, 10 μg is the typical amount of protein antigen used for subcutaneous or intraperitoneal injection in experiments using ATX-Gx mice. The antigen was mixed with a proprietary adjuvant for immunization. For subcutaneous injection, 2 sites (50 - 100 μl per site) were used; for intraperitoneal injection, we usually used 200 μl.

[0098] Example 1-2: Immunization

[0099] Immunization protocol:

[0100] Anti-HER3 antibodies were obtained by a two-armed immunization protocol using gene-modified mice encoding human immunoglobulin heavy chain variable region and κ light chain variable region by the RIMMS (repeated immunization at multiple sites) protocol. One group of mice was immunized and boosted with the recombinant protein antigen huHER3-His (AcroBio, catalog number ER3-H5223), while another group of mice was immunized with the same huHER3-His but boosted with rhesus HER3-His (Sino Bio, catalog number 90043-K08H). Antibody immune responses were monitored by HER3-specific immunoassays. When the desired immune response was achieved, splenocytes were harvested from each mouse and fused with mouse myeloma cells to maintain their viability and form hybridoma cells, and HER3 specificity was screened.

[0101] Examples 1-3: Splenocyte fusion

[0102] Splenic lymphocytes and myeloma cells Sp2 / 0 ( CRL-158) were fused by electrofusion or PEG fusion to obtain hybridoma cells. PEG fusion was performed using the Clonacell TM HY technology (STEMCELL technologies) according to the manufacturer's instructions. The ratio of primary cells to mouse myeloma cell line for electrofusion was 1:1 and for PEG fusion was 10:1.

[0103] Example 1-4: Screening of hybridoma clones specifically binding to HER3 protein by ELISA

[0104] ELISA was performed using the DuoSet ELISA Ancillary Kit (R&D System, DY008). ELISA plates were coated overnight with 1 μg / ml human HER3 (Acro Bio, catalog number ER3-H5223), rhesus HER3 (Sino Bio, catalog number 90043-K08H), mouse HER3 (Acro Bio, catalog number ER3-M52H5), rat HER3 (Sino Bio, catalog number 80111-r08H), or BSA. Excess unbound protein was washed away by washing the plates three times with wash buffer, and then blocked for 1 hour at room temperature. 50 μl of HER3 hybridoma supernatant was added to the wells in duplicate and incubated for 1 hour. Excess unbound antibody was washed away, and 50 μl of 1:20,000 diluted secondary antibody goat anti-mouse IgG Fc-HRP (ab5870) was added to each well for an additional 1 hour. The plates were washed according to the manufacturer's protocol, and then 50 μL of chemiluminescent reagent (Color A and Color B) was added. The reaction was stopped using 25 μL of 2N sulfuric acid. The optical density of the samples at 450 nm was measured using a microplate reader (PerkinElmer). All tested clones showed selective binding to human HER3 but not to BSA, demonstrating HER3 specificity.

[0105] Table 1. Binding characterization of hybridoma clones by ELISA assay (OD 450 )

[0106]

[0107]

[0108] Examples 1 - 5: Screening of hybridoma clones that specifically bind to HER3+ cancer cells by flow cytometry

[0109] Binding tests of hybridoma supernatants were performed on the HER3+ cell line T-47D (ATCC, HTB-133) and the HER3- cell line Jurkat E6.1 (ATCC, TIB-152) using flow cytometry analysis. Briefly, 50 μL of cells (2 × 10 6Cells / mL) were mixed with 50 μL of undiluted hybridoma supernatant. The mixture was incubated on ice for 20 min and then washed twice with ice-cold staining buffer. Subsequently, the cells were stained with 50 μL of PE-labeled secondary antibody (1:400 dilution, BioLegend, Cat#405307) for 20 min. After washing with staining buffer and fixing with 4% PFA, the cells were analyzed by flow cytometry. Purified anti-human HER3 antibody was used as a positive control. Purified mouse IgG1 antibody was used as an isotype control (R&D Systems, Cat#MAB3481). Figure 1 Shows an example of the selected cell binding signal measured by flow cytometry.

[0110] Example 1-6: Screening of Hybridoma Clones with Cell Internalization Activity by Indirect Killing Assay

[0111] The cell internalization activity of anti-HER3 antibodies from hybridoma supernatants was measured by using an indirect killing assay in CHO-K1-huHER3 cells (KYinno, cat#KC-1511). CHO-K1-huHER3 cells were seeded at 3000 cells / well in a 96-well plate and incubated overnight. Hybridoma supernatants from each hybridoma clone were diluted with hybridoma medium and mixed with a Fab anti-mouse IgG Fc-MMAF conjugate (Moradec, AM-202AF) with a cleavable linker, and then added to each well. The final concentrations of mouse IgG were approximately 10 nM, 2 nM, and 0.4 nM. The final concentration of Fab anti-mouse IgG Fc-MMAF conjugate in each well was 20 nM. In the presence of the second Fab-vc-MMAF, the internalized antibody / Fac-vc-MMAF conjugate complex would release the cytotoxic payload and kill the cells. After 3 days of incubation, the live cells in each well were detected by Cell Titer Glo 2.0 assay (Promega, G9243). Purified anti-human HER3 antibody was used as a positive control. Purified mouse IgG1 antibody was used as an isotype control (Biolegend, Cat#400102). As Figure 2 shown, the cells treated with the selected hybridoma supernatants showed reduced viability, indicating antibody internalization.

[0112] Example 2: Sequencing of Positive Hybridoma Clones

[0113] The process of cloning sequences from positive hybridomas is as follows. Hybridoma cells in the logarithmic growth phase are collected, RNA is extracted, reverse transcription is carried out, and then VDJ region amplification is performed. Next-generation sequencing is carried out on the cDNA libraries amplified from each clone. The amino acid sequences of the heavy-chain and light-chain variable region DNAs corresponding to the antibodies of the lead candidates are obtained. After manufacturability evaluation, several mutations are made in the FR region, and the amino acid sequences of each antibody heavy-chain variable region and light-chain variable region and the CDR sequences are shown in the following table. The amino acid residues of the CDRs in VH / VL are numbered and annotated according to the Kabat and Wu numbering systems.

[0114] Table 2. CDR sequences of the heavy-chain variable domain of HER3 hybridoma clones

[0115]

[0116]

[0117]

[0118] Table 3. CDR sequences of the light-chain variable domain of HER3 hybridoma clones

[0119]

[0120]

[0121] Table 4. Sequences of the heavy-chain and light-chain variable domains of HER3 hybridoma clones

[0122]

[0123]

[0124]

[0125]

[0126]

[0127] Example 3: Construction and expression of anti-HER3 recombinant antibodies

[0128] Example 3-1: Molecular cloning of recombinant antibodies

[0129] Directly synthesize the cDNA sequences encoding the selected VH and VL regions of the clone as DNA fragments with a 5'-terminal in-frame leader sequence (MGWSCIILFLVATATGVHS). Clone these DNA fragments into the selected vector using the NEBuilder DNA Assembly Cloning Kit (New England Biolabs). Clone the VH region into the pFUSE-CHIg_hG1 vector (InvivoGen #pfuse-hchg1) using the EcoRI and NheI sites, with the VH region in-frame with the hIgG1 heavy chain constant region in the vector. Clone the VL region into the pFUSE2-CLIg_hk vector (InvivoGen, #pfuse2-hclk) using the AgeI and BsiWI sites, with the VL region in-frame with the hIgκ light chain constant region in the vector.

[0130] The IgG form of the antibody is disclosed as the following full lengths of the heavy and light chains.

[0131] Table 5. Sequences of the recombinant antibody IgG constant regions

[0132]

[0133] Table 6. Full length sequences of the heavy and light chains of the anti-HER3 recombinant antibody

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147] Example 3-2: Expression and Purification of Recombinant Antibody

[0148] The heavy chain expression plasmid and the light chain plasmid were co-transfected into Expi293F cells (ThermoFisher, #A14527) using the ExpiFectamine 293 transfection kit (ThermoFisher, A14524), or co-transfected into ExpiCHO-S cells (ThermoFisher, #A29127) using the ExpiFectamine CHO transfection kit (ThermoFisher, A29129). Based on the manufacturer's instructions, the plasmid DNA concentration reached 1.0 μg per ml of suspended cells, and the LC:HC vector ratio was 1:1. The transfected cells were cultured on an orbital shaker at 37 °C and 8% CO2 for 5 to 7 days. The conditioned medium was collected, and the antibody was purified using a HiTrap MabSelect SuRe chromatography column (Cytiva, #17549112) on an AKTA Pure 25 machine (Cytiva). The eluted antibody was neutralized with Tris buffer (pH 9.0) and exchanged with PBS buffer. The product concentration was measured by UV absorption, and the quality was determined by SDS-PAGE and HPLC.

[0149] Example 4: Binding Characterization of Anti-HER3 Recombinant Antibody to HER3 + Cell Lines by Flow Cytometry

[0150] The binding of hlgG1 mAb to cell surface HER3 was determined by FACS analysis using the HER3-expressing positive cancer cell line T-47D cells. The experimental procedure was referred to Example 1-5.

[0151] Table 7. K + Values of the Binding of Anti-HER3 Recombinant Antibody to HER3 D to T-47D Cells

[0152] antibody <![CDATA[K D (nM)]]> 16G6-1 3.25 17F11-1 0.35 17F11-2 0.18 17G3-1 0.18 22H4-1 3.76 22H4-2 3.66 23F6-1 0.30 12D8-1 0.14 18E11-1 0.14 18E11-2 0.13 20E1-1 0.27 20E1-3 0.30 21A7-1 1.64 21C3-1 0.72 15B9 1.12

[0153] Example 5: Characterization of the Cellular Internalization of Anti-HER3 Recombinant Antibody in HER3-Expressing Cells

[0154] The cellular internalization activity of anti-HER3 recombinant antibodies was measured using an indirect fluorescence internalization assay in CHO-K1-huHER3 cells (KYinno, cat# KC-1511). The CHO-K1-huHER3 cells were seeded at 20,000 cells / well in a 96-well plate and incubated overnight. The recombinant antibodies were diluted with cell culture medium and mixed with a Fab anti-human Fc-pHast conjugate (Advanced Targeting Systems, PH-01) with a pH-dependent fluorescent reporter gene pHast, and then added to each well. The final concentrations of the anti-HER3 recombinant antibodies were 1 nM, 3 nM, and 9 nM. The final concentration of the Fab anti-human Fc-pHast conjugate in each well was 35 nM. In the presence of the second Fab-pHast, the internalized antibody / Fac-pHast conjugate complex will show increased fluorescence in the acidic environment inside the cells. After 17 hours of incubation, the fluorescence from all wells was measured using a microplate reader. The purified anti-human HER3 antibody pertuzumab was used as a positive control. The purified human IgG1 antibody was used as a negative control. As Figure 3 shown, a strong internalization signal of the anti-HER3 antibody was observed in CHO-K1-huHER3 cells.

[0155] Example 6: Epitope Characterization of Anti-HER3 Recombinant Antibodies

[0156] Example 6-1: ELISA Binding to Human HER3 Subdomain Proteins

[0157] ELISA was performed using the DuoSet ELISA Ancillary Kit (R&D System, DY008). A 96-well ELISA plate was coated overnight at 4 °C with 1 μg / well of human HER3 protein (HER3-His) or human HER3 subdomains 1&2 (HER3 D1-2, amino acids 20-329), HER3 subdomain 2 (HER3 D2, amino acids 185-329), HER3 subdomains 3&4 (HER3 D3-4, amino acids 330-643), and HER3 subdomain 4 (HER3 D4, amino acids 496-643). Excess unbound protein was washed away by washing the plate three times with wash buffer using a plate washer, and then blocked for 1 hour at room temperature. 100 μl of 10 μg / mL HER3 recombinant antibody was added to the wells in duplicate and incubated for 1 hour at room temperature. Excess unbound antibody was washed away by the plate washer, and 100 μl of 1:5000 diluted secondary antibody goat anti-human IgG Fc-HRP (ab6858) was added to each well to incubate for 30 min at room temperature. According to the manufacturer's protocol, the plate was washed again by the plate washer, and then 100 μL of chemiluminescent reagent (TMB) was added. The reaction was stopped using 100 μL of 2N sulfuric acid. The optical density of the samples was measured at 450 nm using a microplate reader (PerkinElmer). All tested recombinant antibodies bound to the full-length human HER3 protein. Recombinant antibody 20B5-1 showed binding to human HER3 subdomains 3-4 and subdomain 4, indicating binding to subdomain 4. All remaining recombinant antibodies (see Table 8 below) showed binding to human HER3 subdomains 1-2 and subdomain 1, indicating binding to subdomain 1.

[0158] Table 8. Binding characterization of HER3 recombinant antibodies to human HER3 full-length or subdomain proteins by ELISA (OD 450 )

[0159]

[0160] Example 6-2: Octet binning

[0161] The epitopes of the first three clones (18E11-1, 20E1-3, 23F6-1) were binned and compared with the reference anti-HER3 antibody pertuzumab. Antibody epitope binning was performed using an Octet Red384 system equipped with a Ni-NTA biosensor from Pall Life Sciences (Menlo Park, CA). The experiment was conducted as a serial binning assay. The assay consisted of a five-step binding cycle: 1) establishing a buffer baseline for 30 seconds, 2) coupling 5 nM HER3 antigen (HER3-His) to the Ni-NTA octet sensor for 5 minutes using standard 1× assay buffer (PBS + 0.02% Tween 20, 0.1% BSA, 0.05% sodium azide) diluted from a 10× kinetic buffer stock solution (ForteBio), 3) loading 25 nM of each antibody (saturating mAb) to saturate the immobilized antigen for 10 minutes, 4) allowing 25 nM of each antibody (competitive mAb) to bind for 5 minutes, and 5) regenerating the capture sensor for 30 seconds. As shown in Tables 9 and 10, all four anti-HER3 antibodies could be divided into 2 different epitope bins. 118E11-1, 20E1-3, and 23F6-1 were in the same bin, while pertuzumab was in a different bin. After binding of 18E11-1, 20E1-3, or 23F6-1, pertuzumab could still bind to HER3 and had a good association curve, indicating different epitopes.

[0162] Table 9. Epitope binning of recombinant antibodies that bind to human HER3 protein determined by the Octet Red384 system.

[0163] antibody pertuzumab 18E11-1 20E1-3 23F6-1 buffer pertuzumab 0.7419 4.5329 4.7621 5.5602 8.7259 18E11-1 1.0099 1.1638 1.2956 1.9913 4.9593 20E1-3 0.9782 1.0697 1.2728 1.8363 5.064 23F6-1 0.8579 0.912 0.9653 1.2834 3.617 buffer 0.3294 0.4415 0.4635 0.4384 -0.0202

[0164] Signal shift unit: nm

[0165] Table 10. Epitope bins of anti-HER3 recombinant antibodies against human HER3

[0166] epitope bin anti - HER3 antibody 1 pertuzumab 2 18E11 - 1, 20E1 - 3, 23F6 - 1

[0167] Example 7: Effect of NRG1 on binding to SKBr3 cells

[0168] NRG1 has been shown to have a high affinity for HER3 as a natural ligand ([Kd] < 100 pM) (Am J Respir Cell Mol Biol. April 2000; 22(4):432-40), and it is difficult for antibodies to compete with it. However, antibodies can bind to the antigen at different epitopes, which can be different from the epitopes to which NRG1 can bind. Then we tested our antibodies on SKBr3 cells.

[0169] In SKBr3 (HER3+, EGFR+ and HER2+) cells, in the presence of NRG1, the in vitro cellular binding of HER3 recombinant antibodies to the HER3+ cell line by flow cytometry was inhibited. However, some HER3 recombinant antibodies (18E11-1, 20E1-3 and 23F6-1) were not affected by NRG1 and still showed binding to HER3+ SKBr3 (HER3+, EGFR+ and HER2+) cells in the presence of NRG1. The binding of the HER3 recombinant antibody 20B5-1 was only slightly inhibited by equimolar concentrations of NRG1 molecules, while the binding of pertuzumab was significantly affected.

Claims

1. An anti-HER3 antibody or an antigen-binding fragment thereof, comprising: a variable region of the heavy chain of the antibody comprising HCDR1, HCDR2, and HCDR3 regions, and a variable region of the light chain of the antibody comprising LCDR1, LCDR2, and LCDR3 regions, wherein: The variable region sequence of the heavy chain comprises: HCDR1 as shown in SEQ ID NO: 08, HCDR2 as shown in SEQ ID NO: 27, and HCDR3 as shown in SEQ ID NO: 46; or HCDR1 as shown in SEQ ID NO: 09, HCDR2 as shown in SEQ ID NO: 28, and HCDR3 as shown in SEQ ID NO: 47; or HCDR1 as shown in SEQ ID NO: 10, HCDR2 as shown in SEQ ID NO: 29, and HCDR3 as shown in SEQ ID NO: 48; or HCDR1 as shown in SEQ ID NO: 11, HCDR2 as shown in SEQ ID NO: 30, and HCDR3 as shown in SEQ ID NO: 49; or HCDR1 as shown in SEQ ID NO: 12, HCDR2 as shown in SEQ ID NO: 31, and HCDR3 as shown in SEQ ID NO: 50; or HCDR1 as shown in SEQ ID NO: 01, HCDR2 as shown in SEQ ID NO: 21, and HCDR3 as shown in SEQ ID NO: 51; or HCDR1 as shown in SEQ ID NO: 06, HCDR2 as shown in SEQ ID NO: 32, and HCDR3 as shown in SEQ ID NO: 52; or HCDR1 as shown in SEQ ID NO: 13, HCDR2 as shown in SEQ ID NO: 33, and HCDR3 as shown in SEQ ID NO: 53; or HCDR1 as shown in SEQ ID NO: 14, HCDR2 as shown in SEQ ID NO: 33, and HCDR3 as shown in SEQ ID NO: 54; or HCDR1 as shown in SEQ ID NO: 15, HCDR2 as shown in SEQ ID NO: 34, and HCDR3 as shown in SEQ ID NO: 55; or HCDR1 as shown in SEQ ID NO: 16, HCDR2 as shown in SEQ ID NO: 35, and HCDR3 as shown in SEQ ID NO: 56; or HCDR1 as shown in SEQ ID NO: 17, HCDR2 as shown in SEQ ID NO: 36, and HCDR3 as shown in SEQ ID NO: 57; or HCDR1 as shown in SEQ ID NO: 06, HCDR2 as shown in SEQ ID NO: 32, and HCDR3 as shown in SEQ ID NO: 58; or HCDR1 as shown in SEQ ID NO: 01, HCDR2 as shown in SEQ ID NO: 18, and HCDR3 as shown in SEQ ID NO: 37; or HCDR1 as shown in SEQ ID NO: 02, HCDR2 as shown in SEQ ID NO: 19, and HCDR3 as shown in SEQ ID NO: 38; or HCDR1 as shown in SEQ ID NO: 03, HCDR2 as shown in SEQ ID NO: 20, and HCDR3 as shown in SEQ ID NO: 39; or HCDR1 as shown in SEQ ID NO: 04, HCDR2 as shown in SEQ ID NO: 21, and HCDR3 as shown in SEQ ID NO: 40; or HCDR1 as shown in SEQ ID NO: 05, HCDR2 as shown in SEQ ID NO: 22, and HCDR3 as shown in SEQ ID NO: 41; or HCDR1 as shown in SEQ ID NO: 06, HCDR2 as shown in SEQ ID NO: 23, and HCDR3 as shown in SEQ ID NO: 42; or HCDR1 as shown in SEQ ID NO: 07, HCDR2 as shown in SEQ ID NO: 24, and HCDR3 as shown in SEQ ID NO: 43; or HCDR1 as shown in SEQ ID NO: 06, HCDR2 as shown in SEQ ID NO: 25, and HCDR3 as shown in SEQ ID NO: 44; or HCDR1 as shown in SEQ ID NO: 06, HCDR2 as shown in SEQ ID NO: 26, and HCDR3 as shown in SEQ ID NO: 45; and / or The variable region of the antibody light chain comprises: LCDR1 as shown in SEQ ID NO: 66, LCDR2 as shown in SEQ ID NO: 83, and LCDR3 as shown in SEQ ID NO: 96; or LCDR1 as shown in SEQ ID NO: 67, LCDR2 as shown in SEQ ID NO: 79, and LCDR3 as shown in SEQ ID NO: 97; or LCDR1 as shown in SEQ ID NO: 68, LCDR2 as shown in SEQ ID NO: 77, and LCDR3 as shown in SEQ ID NO: 98; or LCDR1 as shown in SEQ ID NO: 69, LCDR2 as shown in SEQ ID NO: 84, and LCDR3 as shown in SEQ ID NO: 99; or LCDR1 as shown in SEQ ID NO: 70, LCDR2 as shown in SEQ ID NO: 85, and LCDR3 as shown in SEQ ID NO: 100; or LCDR1 as shown in SEQ ID NO: 71, LCDR2 as shown in SEQ ID NO: 85, and LCDR3 as shown in SEQ ID NO: 100; or LCDR1 as shown in SEQ ID NO: 61, LCDR2 as shown in SEQ ID NO: 77, and LCDR3 as shown in SEQ ID NO: 90; or LCDR1 as shown in SEQ ID NO: 72, LCDR2 as shown in SEQ ID NO: 86, and LCDR3 as shown in SEQ ID NO: 101; or LCDR1 as shown in SEQ ID NO: 73, LCDR2 as shown in SEQ ID NO: 82, and LCDR3 as shown in SEQ ID NO: 103; or LCDR1 as shown in SEQ ID NO: 64, LCDR2 as shown in SEQ ID NO: 82, and LCDR3 as shown in SEQ ID NO: 103; or LCDR1 as shown in SEQ ID NO: 74, LCDR2 as shown in SEQ ID NO: 79, and LCDR3 as shown in SEQ ID NO: 92; or LCDR1 as shown in SEQ ID NO: 75, LCDR2 as shown in SEQ ID NO: 82, and LCDR3 as shown in SEQ ID NO: 104; or LCDR1 as shown in SEQ ID NO: 65, LCDR2 as shown in SEQ ID NO: 82, and LCDR3 as shown in SEQ ID NO: 95; or LCDR1 as shown in SEQ ID NO: 76, LCDR2 as shown in SEQ ID NO: 85, and LCDR3 as shown in SEQ ID NO: 100; or LCDR1 as shown in SEQ ID NO: 66, LCDR2 as shown in SEQ ID NO: 83, and LCDR3 as shown in SEQ ID NO: 96; or LCDR1 as shown in SEQ ID NO: 59, LCDR2 as shown in SEQ ID NO: 77, and LCDR3 as shown in SEQ ID NO: 58; or LCDR1 as shown in SEQ ID NO: 60, LCDR2 as shown in SEQ ID NO: 78, and LCDR3 as shown in SEQ ID NO: 89; or LCDR1 as shown in SEQ ID NO: 61, LCDR2 as shown in SEQ ID NO: 77, and LCDR3 as shown in SEQ ID NO: 90; or LCDR1 as shown in SEQ ID NO: 59, LCDR2 as shown in SEQ ID NO: 77, and LCDR3 as shown in SEQ ID NO: 90; or LCDR1 as shown in SEQ ID NO: 62, LCDR2 as shown in SEQ ID NO: 77, and LCDR3 as shown in SEQ ID NO: 91; or LCDR1 as shown in SEQ ID NO: 63, LCDR2 as shown in SEQ ID NO: 79, and LCDR3 as shown in SEQ ID NO: 92; or LCDR1 as shown in SEQ ID NO: 60, LCDR2 as shown in SEQ ID NO: 80, and LCDR3 as shown in SEQ ID NO: 93; or LCDR1 as shown in SEQ ID NO: 64, LCDR2 as shown in SEQ ID NO: 81, and LCDR3 as shown in SEQ ID NO: 94; or LCDR1 as shown in SEQ ID NO: 65, LCDR2 as shown in SEQ ID NO: 82, and LCDR3 as shown in SEQ ID NO: 95; or LCDR1 as shown in SEQ ID NO: 60, LCDR2 as shown in SEQ ID NO: 80, and LCDR3 as shown in SEQ ID NO:

89.

2. The anti-HER3 antibody or antigen-binding fragment thereof according to claim 1, wherein: a) The heavy chain variable region sequence comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 08, SEQ ID NO: 27, and SEQ ID NO: 46, respectively; and the light chain variable region sequence comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 66, SEQ ID NO: 83, and SEQ ID NO: 96, respectively; or b) The heavy chain variable region sequence comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 09, SEQ ID NO: 28, and SEQ ID NO: 47, respectively; and the light chain variable region sequence comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 67, SEQ ID NO: 79, and SEQ ID NO: 97, respectively; or c) The heavy chain variable region sequence comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 10, SEQ ID NO: 29, and SEQ ID NO: 48, respectively; and the light chain variable region sequence comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 68, SEQ ID NO: 77, and SEQ ID NO: 98, respectively; or d) The heavy chain variable region sequence comprises HCDR1, HCDR2 and HCDR3 shown as SEQ ID NO: 11, SEQ ID NO: 30 and SEQ ID NO: 49 respectively; and the light chain variable region sequence comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO: 69, SEQ ID NO: 84 and SEQ ID NO: 99 respectively; or e) The heavy chain variable region sequence comprises HCDR1, HCDR2 and HCDR3 shown as SEQ ID NO: 12, SEQ ID NO: 31 and SEQ ID NO: 50 respectively; and the light chain variable region sequence comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO: 70, SEQ ID NO: 85 and SEQ ID NO: 100 respectively; or f) The heavy chain variable region sequence comprises HCDR1, HCDR2 and HCDR3 shown as SEQ ID NO: 12, SEQ ID NO: 31 and SEQ ID NO: 50 respectively; and the light chain variable region sequence comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO: 71, SEQ ID NO: 85 and SEQ ID NO: 100 respectively; or g) The heavy chain variable region sequence comprises HCDR1, HCDR2 and HCDR3 shown as SEQ ID NO: 01, SEQ ID NO: 21 and SEQ ID NO: 51 respectively; and the light chain variable region sequence comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO: 61, SEQ ID NO: 77 and SEQ ID NO: 90 respectively; or h) The heavy chain variable region sequence comprises HCDR1, HCDR2 and HCDR3 shown as SEQ ID NO: 06, SEQ ID NO: 32 and SEQ ID NO: 52 respectively; and the light chain variable region sequence comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO: 72, SEQ ID NO: 86 and SEQ ID NO: 101 respectively; or i) The heavy chain variable region sequence comprises HCDR1, HCDR2 and HCDR3 shown as SEQ ID NO: 06, SEQ ID NO: 32 and SEQ ID NO: 52 respectively; and the light chain variable region sequence comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO: 73, SEQ ID NO: 87 and SEQ ID NO: 102 respectively; or j) The heavy chain variable region sequence comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 13, SEQ ID NO: 33, and SEQ ID NO: 53, respectively; and the light chain variable region sequence comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 73, SEQ ID NO: 82, and SEQ ID NO: 103, respectively; or k) The heavy chain variable region sequence comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 14, SEQ ID NO: 33, and SEQ ID NO: 54, respectively; and the light chain variable region sequence comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 64, SEQ ID NO: 82, and SEQ ID NO: 103, respectively; or l) The heavy chain variable region sequence comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 15, SEQ ID NO: 34, and SEQ ID NO: 55, respectively; and the light chain variable region sequence comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 74, SEQ ID NO: 79, and SEQ ID NO: 92, respectively; or m) The heavy chain variable region sequence comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 16, SEQ ID NO: 35, and SEQ ID NO: 56, respectively; and the light chain variable region sequence comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 75, SEQ ID NO: 82, and SEQ ID NO: 104, respectively; or n) The heavy chain variable region sequence comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 16, SEQ ID NO: 35, and SEQ ID NO: 56, respectively; and the light chain variable region sequence comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 65, SEQ ID NO: 82, and SEQ ID NO: 95, respectively; or o) The heavy chain variable region sequence comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 17, SEQ ID NO: 36, and SEQ ID NO: 57, respectively; and the light chain variable region sequence comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 76, SEQ ID NO: 85, and SEQ ID NO: 100, respectively; or p) The heavy chain variable region sequence comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 06, SEQ ID NO: 32 and SEQ ID NO: 58 respectively; and the light chain variable region sequence comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 66, SEQ ID NO: 83 and SEQ ID NO: 96 respectively; or q) The heavy chain variable region sequence comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 01, SEQ ID NO: 18 and SEQ ID NO: 37 respectively; and the light chain variable region sequence comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 59, SEQ ID NO: 77 and SEQ ID NO: 88 respectively; or r) The heavy chain variable region sequence comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 02, SEQ ID NO: 19 and SEQ ID NO: 38 respectively; and the light chain variable region sequence comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 60, SEQ ID NO: 78 and SEQ ID NO: 89 respectively; or s) The heavy chain variable region sequence comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 03, SEQ ID NO: 20 and SEQ ID NO: 39 respectively; and the light chain variable region sequence comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 61, SEQ ID NO: 77 and SEQ ID NO: 90 respectively; or t) The heavy chain variable region sequence comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 04, SEQ ID NO: 21 and SEQ ID NO: 40 respectively; and the light chain variable region sequence comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 59, SEQ ID NO: 77 and SEQ ID NO: 90 respectively; or u) The heavy chain variable region sequence comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 05, SEQ ID NO: 22 and SEQ ID NO: 41 respectively; and the light chain variable region sequence comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 62, SEQ ID NO: 77 and SEQ ID NO: 91 respectively; or v) The heavy chain variable region sequence comprises HCDR1, HCDR2 and HCDR3 shown as SEQ ID NO: 06, SEQ ID NO: 23 and SEQ ID NO: 42 respectively; and the light chain variable region sequence comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO: 63, SEQ ID NO: 79 and SEQ ID NO: 92 respectively; or w) The heavy chain variable region sequence comprises HCDR1, HCDR2 and HCDR3 shown as SEQ ID NO: 07, SEQ ID NO: 24 and SEQ ID NO: 43 respectively; and the light chain variable region sequence comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO: 60, SEQ ID NO: 80 and SEQ ID NO: 93 respectively; or x) The heavy chain variable region sequence comprises HCDR1, HCDR2 and HCDR3 shown as SEQ ID NO: 06, SEQ ID NO: 25 and SEQ ID NO: 44 respectively; and the light chain variable region sequence comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO: 64, SEQ ID NO: 81 and SEQ ID NO: 94 respectively; or y) The heavy chain variable region sequence comprises HCDR1, HCDR2 and HCDR3 shown as SEQ ID NO: 06, SEQ ID NO: 26 and SEQ ID NO: 45 respectively; and the light chain variable region sequence comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO: 65, SEQ ID NO: 82 and SEQ ID NO: 95 respectively; or z) The heavy chain variable region sequence comprises HCDR1, HCDR2 and HCDR3 shown as SEQ ID NO: 08, SEQ ID NO: 27 and SEQ ID NO: 46 respectively; and the light chain variable region sequence comprises LCDR1, LCDR2 and LCDR3 shown as SEQ ID NO: 60, SEQ ID NO: 80 and SEQ ID NO: 89 respectively.

3. The anti-HER3 antibody or antigen-binding fragment thereof according to any one of claims 1 to 2, wherein the antibody or antigen-binding fragment thereof is selected from murine antibodies, chimeric antibodies, humanized antibodies, human antibodies or antigen-binding fragments thereof.

4. The anti-HER3 antibody or antigen-binding fragment thereof according to claim 3, wherein the antibody or antigen-binding fragment thereof comprises: A heavy chain variable region comprising an amino acid sequence selected from SEQ ID NO: 127, 129, 131, 133, 135, 137, 139, 141, 144, 145, 147, 149, 151, 153, 155, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, and 125, or having at least 80%, 85%, 90%, 95%, or 99% sequence identity thereto; and / or A light chain variable region comprising an amino acid sequence selected from SEQ ID NO: 128, 130, 132, 134, 136, 138, 140, 142, 143, 146, 148, 150, 152, 154, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, and 126, or having at least 80%, 85%, 90%, 95%, or 99% sequence identity thereto.

5. The anti-HER3 antibody or antigen-binding fragment thereof according to claim 4, wherein the antibody or antigen-binding fragment thereof comprises: a-1) A heavy chain variable region as shown in SEQ ID NO: 127 or having at least 80%, 85%, 90%, 95%, or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 128 or having at least 80%, 85%, 90%, 95%, or 99% sequence identity thereto; or a-2) A heavy chain variable region as shown in SEQ ID NO: 127 or having at least 80%, 85%, 90%, 95%, or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 126 or having at least 80%, 85%, 90%, 95%, or 99% sequence identity thereto; or b) A heavy chain variable region as shown in SEQ ID NO: 129 or having at least 80%, 85%, 90%, 95%, or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 130 or having at least 80%, 85%, 90%, 95%, or 99% sequence identity thereto; or c) A heavy chain variable region as shown in SEQ ID NO: 131 or having at least 80%, 85%, 90%, 95%, or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 132 or having at least 80%, 85%, 90%, 95%, or 99% sequence identity thereto; or d) A heavy chain variable region as shown in SEQ ID NO: 133 or having at least 80%, 85%, 90%, 95%, or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 134 or having at least 80%, 85%, 90%, 95%, or 99% sequence identity thereto; or e-1) A heavy chain variable region as shown in SEQ ID NO: 135 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 136 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or e-2) A heavy chain variable region as shown in SEQ ID NO: 137 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 138 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or f) A heavy chain variable region as shown in SEQ ID NO: 139 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 140 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or g-1) A heavy chain variable region as shown in SEQ ID NO: 141 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 142 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or g-2) A heavy chain variable region as shown in SEQ ID NO: 141 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 143 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or g-3) A heavy chain variable region as shown in SEQ ID NO: 144 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 142 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or h) A heavy chain variable region as shown in SEQ ID NO: 145 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 146 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or i) A heavy chain variable region as shown in SEQ ID NO: 147 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 148 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or j) a heavy chain variable region as shown in SEQ ID NO: 149 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 150 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or k-1) a heavy chain variable region as shown in SEQ ID NO: 151 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 152 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or k-2) a heavy chain variable region as shown in SEQ ID NO: 151 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 122 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or l) a heavy chain variable region as shown in SEQ ID NO: 153 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 154 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or m) a heavy chain variable region as shown in SEQ ID NO: 155 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 126 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or n) a heavy chain variable region as shown in SEQ ID NO: 105 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 106 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or o) a heavy chain variable region as shown in SEQ ID NO: 107 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 108 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or p) a heavy chain variable region as shown in SEQ ID NO: 109 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 110 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or q) A heavy chain variable region as shown in SEQ ID NO: 111 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 112 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or r) A heavy chain variable region as shown in SEQ ID NO: 113 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 114 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or s) A heavy chain variable region as shown in SEQ ID NO: 115 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 116 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or t) A heavy chain variable region as shown in SEQ ID NO: 117 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 118 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or u) A heavy chain variable region as shown in SEQ ID NO: 119 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 120 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or v) A heavy chain variable region as shown in SEQ ID NO: 121 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 122 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or w-1) A heavy chain variable region as shown in SEQ ID NO: 123 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 124 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or w-2) A heavy chain variable region as shown in SEQ ID NO: 125 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 126 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; or x) a heavy chain variable region as shown in SEQ ID NO: 123 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto; and / or a light chain variable region as shown in SEQ ID NO: 126 or having at least 80%, 85%, 90%, 95% or 99% sequence identity thereto.

6. The anti-HER3 antibody or antigen-binding fragment thereof according to claim 5, wherein the antibody or antigen-binding fragment thereof comprises: a-1) a heavy chain variable region as shown in SEQ ID NO: 127; and / or a light chain variable region as shown in SEQ ID NO: 128; a-2) a heavy chain variable region as shown in SEQ ID NO: 127; and / or a light chain variable region as shown in SEQ ID NO: 126; b) a heavy chain variable region as shown in SEQ ID NO: 129; and / or a light chain variable region as shown in SEQ ID NO: 130; c) a heavy chain variable region as shown in SEQ ID NO: 131; and / or a light chain variable region as shown in SEQ ID NO: 132; d) a heavy chain variable region as shown in SEQ ID NO: 133; and / or a light chain variable region as shown in SEQ ID NO: 134; e-1) a heavy chain variable region as shown in SEQ ID NO: 135; and / or a light chain variable region as shown in SEQ ID NO: 136; e-2) a heavy chain variable region as shown in SEQ ID NO: 137; and / or a light chain variable region as shown in SEQ ID NO: 138; f) a heavy chain variable region as shown in SEQ ID NO: 139; and / or a light chain variable region as shown in SEQ ID NO: 140; g-1) a heavy chain variable region as shown in SEQ ID NO: 141; and / or a light chain variable region as shown in SEQ ID NO: 142; g-2) a heavy chain variable region as shown in SEQ ID NO: 141; and / or a light chain variable region as shown in SEQ ID NO: 143; g-3) a heavy chain variable region as shown in SEQ ID NO: 144; and / or a light chain variable region as shown in SEQ ID NO: 142; h) a heavy chain variable region as shown in SEQ ID NO: 145; and / or a light chain variable region as shown in SEQ ID NO: 146; i) a heavy chain variable region as shown in SEQ ID NO: 147; and / or a light chain variable region as shown in SEQ ID NO: 148; j) a heavy chain variable region as shown in SEQ ID NO: 149; and / or a light chain variable region as shown in SEQ ID NO: 150; k-1) a heavy chain variable region as shown in SEQ ID NO: 151; and / or a light chain variable region as shown in SEQ ID NO: 152; k-2) a heavy chain variable region as shown in SEQ ID NO: 151; and / or a light chain variable region as shown in SEQ ID NO: 122; l) The heavy chain variable region as shown in SEQ ID NO: 153; and / or the light chain variable region as shown in SEQ ID NO: 154; m) The heavy chain variable region as shown in SEQ ID NO: 155; and / or the light chain variable region as shown in SEQ ID NO: 126; n) The heavy chain variable region as shown in SEQ ID NO: 105; and / or the light chain variable region as shown in SEQ ID NO: 106; o) The heavy chain variable region as shown in SEQ ID NO: 107; and / or the light chain variable region as shown in SEQ ID NO: 108; p) The heavy chain variable region as shown in SEQ ID NO: 109; and / or the light chain variable region as shown in SEQ ID NO: 110; q) The heavy chain variable region as shown in SEQ ID NO: 111; and / or the light chain variable region as shown in SEQ ID NO: 112; r) The heavy chain variable region as shown in SEQ ID NO: 113; and / or the light chain variable region as shown in SEQ ID NO: 114; s) The heavy chain variable region as shown in SEQ ID NO: 115; and / or the light chain variable region as shown in SEQ ID NO: 116; t) The heavy chain variable region as shown in SEQ ID NO: 117; and / or the light chain variable region as shown in SEQ ID NO: 118; u) The heavy chain variable region as shown in SEQ ID NO: 119; and / or the light chain variable region as shown in SEQ ID NO: 120; v) The heavy chain variable region as shown in SEQ ID NO: 121; and / or the light chain variable region as shown in SEQ ID NO: 122; w-1) The heavy chain variable region as shown in SEQ ID NO: 123; and / or the light chain variable region as shown in SEQ ID NO: 124; w-2) The heavy chain variable region as shown in SEQ ID NO: 125; and / or the light chain variable region as shown in SEQ ID NO: 126; x) The heavy chain variable region as shown in SEQ ID NO: 123; and / or the light chain variable region as shown in SEQ ID NO:

126.

7. The anti-HER3 antibody or antigen-binding fragment thereof according to claim 6, wherein the antibody or antigen-binding fragment thereof comprises: a-1) The heavy chain variable region as shown in SEQ ID NO: 127 and the light chain variable region as shown in SEQ ID NO: 128; a-2) The heavy chain variable region as shown in SEQ ID NO: 127 and the light chain variable region as shown in SEQ ID NO: 126; b) The heavy chain variable region as shown in SEQ ID NO: 129 and the light chain variable region as shown in SEQ ID NO: 130; c) The heavy chain variable region as shown in SEQ ID NO: 131 and the light chain variable region as shown in SEQ ID NO: 132; d) The heavy chain variable region as shown in SEQ ID NO: 133 and the light chain variable region as shown in SEQ ID NO: 134; e-1) The heavy chain variable region as shown in SEQ ID NO: 135 and the light chain variable region as shown in SEQ ID NO: 136; e-2) The heavy chain variable region as shown in SEQ ID NO: 137 and the light chain variable region as shown in SEQ ID NO: 138; f) The heavy chain variable region as shown in SEQ ID NO: 139 and the light chain variable region as shown in SEQ ID NO: 140; g-1) The heavy chain variable region as shown in SEQ ID NO: 141 and the light chain variable region as shown in SEQ ID NO: 142; g-2) The heavy chain variable region as shown in SEQ ID NO: 141 and the light chain variable region as shown in SEQ ID NO: 143; g-3) The heavy chain variable region as shown in SEQ ID NO: 144 and the light chain variable region as shown in SEQ ID NO: 142; h) The heavy chain variable region as shown in SEQ ID NO: 145 and the light chain variable region as shown in SEQ ID NO: 146; i) The heavy chain variable region as shown in SEQ ID NO: 147 and the light chain variable region as shown in SEQ ID NO: 148; j) The heavy chain variable region as shown in SEQ ID NO: 149 and the light chain variable region as shown in SEQ ID NO: 150; k-1) The heavy chain variable region as shown in SEQ ID NO: 151 and the light chain variable region as shown in SEQ ID NO: 152; k-2) The heavy chain variable region as shown in SEQ ID NO: 151 and the light chain variable region as shown in SEQ ID NO: 122; l) The heavy chain variable region as shown in SEQ ID NO: 153 and the light chain variable region as shown in SEQ ID NO: 154; m) The heavy chain variable region as shown in SEQ ID NO: 155 and the light chain variable region as shown in SEQ ID NO: 126; n) The heavy chain variable region as shown in SEQ ID NO: 105 and the light chain variable region as shown in SEQ ID NO: 106; o) The heavy chain variable region as shown in SEQ ID NO: 107 and the light chain variable region as shown in SEQ ID NO: 108; p) The heavy chain variable region as shown in SEQ ID NO: 109 and the light chain variable region as shown in SEQ ID NO: 110; q) The heavy chain variable region as shown in SEQ ID NO: 111 and the light chain variable region as shown in SEQ ID NO: 112; r) The heavy chain variable region as shown in SEQ ID NO: 113 and the light chain variable region as shown in SEQ ID NO: 114; s) The heavy chain variable region as shown in SEQ ID NO: 115 and the light chain variable region as shown in SEQ ID NO: 116; t) A heavy chain variable region as shown in SEQ ID NO: 117 and a light chain variable region as shown in SEQ ID NO: 118; u) A heavy chain variable region as shown in SEQ ID NO: 119 and a light chain variable region as shown in SEQ ID NO: 120; v) A heavy chain variable region as shown in SEQ ID NO: 121 and a light chain variable region as shown in SEQ ID NO: 122; w-1) A heavy chain variable region as shown in SEQ ID NO: 123 and a light chain variable region as shown in SEQ ID NO: 124; w-2) A heavy chain variable region as shown in SEQ ID NO: 125 and a light chain variable region as shown in SEQ ID NO: 126; x) A heavy chain variable region as shown in SEQ ID NO: 123 and a light chain variable region as shown in SEQ ID NO:

126.

8. The anti-HER3 antibody or antigen-binding fragment thereof according to any one of claims 1 to 7, wherein the antibody is a full-length antibody, which further comprises a human antibody constant region; Preferably, the heavy chain constant region of the human antibody constant region is selected from the constant regions of human IgG1, IgG2, IgG3, and IgG4 and their conservative variants, and the light chain constant region of the human antibody constant region is selected from the kappa chain constant region and lambda chain constant region of human antibodies and their conservative variants; More preferably, the full-length antibody comprises the human heavy chain constant region of SEQ ID NO: 156 and the human light chain constant region of SEQ ID NO:

157.

9. The anti-HER3 antibody or antigen-binding fragment thereof according to claims 1 to 8, wherein the antibody or antigen-binding fragment thereof comprises: a-1) A heavy chain as shown in SEQ ID NO: 180 and a light chain as shown in SEQ ID NO: 181; a-2) A heavy chain as shown in SEQ ID NO: 180 and a light chain as shown in SEQ ID NO: 179; b) A heavy chain as shown in SEQ ID NO: 182 and a light chain as shown in SEQ ID NO: 183; c) A heavy chain as shown in SEQ ID NO: 184 and a light chain as shown in SEQ ID NO: 185; g) A heavy chain as shown in SEQ ID NO: 186 and a light chain as shown in SEQ ID NO: 187; e-1) A heavy chain as shown in SEQ ID NO: 188 and a light chain as shown in SEQ ID NO: 189; e-2) A heavy chain as shown in SEQ ID NO: 190 and a light chain as shown in SEQ ID NO: 191; f) A heavy chain as shown in SEQ ID NO: 192 and a light chain as shown in SEQ ID NO: 193; g-1) A heavy chain as shown in SEQ ID NO: 194 and a light chain as shown in SEQ ID NO: 195; g-2) A heavy chain as shown in SEQ ID NO: 194 and a light chain as shown in SEQ ID NO: 196; g-3) A heavy chain as shown in SEQ ID NO: 197 and a light chain as shown in SEQ ID NO: 195; h) A heavy chain as shown in SEQ ID NO: 198 and a light chain as shown in SEQ ID NO: 199; i) A heavy chain as shown in SEQ ID NO: 200 and a light chain as shown in SEQ ID NO: 201; j) A heavy chain as shown in SEQ ID NO: 202 and a light chain as shown in SEQ ID NO: 203; k-1) A heavy chain as shown in SEQ ID NO: 204 and a light chain as shown in SEQ ID NO: 205; k-2) A heavy chain as shown in SEQ ID NO: 204 and a light chain as shown in SEQ ID NO: 175; l) A heavy chain as shown in SEQ ID NO: 206 and a light chain as shown in SEQ ID NO: 207; m) A heavy chain as shown in SEQ ID NO: 208 and a light chain as shown in SEQ ID NO: 179; n) A heavy chain as shown in SEQ ID NO: 158 and a light chain as shown in SEQ ID NO: 159; o) A heavy chain as shown in SEQ ID NO: 160 and a light chain as shown in SEQ ID NO: 161; p) A heavy chain as shown in SEQ ID NO: 162 and a light chain as shown in SEQ ID NO: 163; q) A heavy chain as shown in SEQ ID NO: 164 and a light chain as shown in SEQ ID NO: 165; r) A heavy chain as shown in SEQ ID NO: 166 and a light chain as shown in SEQ ID NO: 167; s) A heavy chain as shown in SEQ ID NO: 168 and a light chain as shown in SEQ ID NO: 169; t) A heavy chain as shown in SEQ ID NO: 170 and a light chain as shown in SEQ ID NO: 171; u) A heavy chain as shown in SEQ ID NO: 172 and a light chain as shown in SEQ ID NO: 173; v) A heavy chain as shown in SEQ ID NO: 174 and a light chain as shown in SEQ ID NO: 175; w-1) A heavy chain as shown in SEQ ID NO: 176 and a light chain as shown in SEQ ID NO: 177; w-2) A heavy chain as shown in SEQ ID NO: 178 and a light chain as shown in SEQ ID NO: 179; x) A heavy chain as shown in SEQ ID NO: 176 and a light chain as shown in SEQ ID NO:

179.

10. The anti-HER3 antibody or antigen-binding fragment thereof according to any one of claims 1 to 7, wherein the antigen-binding fragment is selected from: Fab, Fab', F(ab')2, variable fragment (Fv), single-chain variable fragment (scFv), dimeric domain V (diabody), disulfide-stabilized Fv (dsFv), and CDR-containing peptides.

11. A bispecific or multispecific binding molecule comprising an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 10.

12. An immunoconjugate comprising an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 10.

13. A chimeric antigen receptor comprising an antigen-binding domain of an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 10.

14. An isolated nucleic acid molecule encoding an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 10.

15. A recombinant vector comprising the isolated nucleic acid molecule according to claim 14.

16. A host cell comprising the recombinant vector according to claim 15, wherein the host cell is selected from prokaryotic cells and eukaryotic cells, preferably eukaryotic cells, more preferably mammalian cells.

17. A method for generating an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 10, wherein the method comprises: Culturing the host cell according to claim 16 in a medium to produce and accumulate an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 10, and harvesting the antibody or the antigen-binding fragment thereof from the culture.

18. A method for immunodetection or measurement of HER3, wherein the method comprises: Detecting HER3 by contacting an anti-HER3 antibody or an antigen-binding fragment thereof according to any one of claims 1 to 10.

19. A method for diagnosing a disease associated with human HER3-positive cells, wherein the method comprises: Detecting or measuring HER3 or HER3-positive cells by contacting an anti-HER3 antibody or an antigen-binding fragment thereof according to any one of claims 1 to 10.

20. A pharmaceutical composition comprising a therapeutically effective amount of an anti-HER3 antibody or an antigen-binding fragment thereof according to any one of claims 1 to 10, and one or more pharmaceutically acceptable carriers, diluents or excipients.

21. Use of an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 10, or the pharmaceutical composition according to claim 20, in the manufacture of a medicament for the treatment or prevention of a disease associated with human HER3.

22. The use according to claim 21, characterized in that It is used in the manufacture of a medicament for the treatment or prevention of a cancer having HER3 expression; preferably, the cancer is breast cancer, colorectal cancer, lung cancer, multiple myeloma, ovarian cancer, liver cancer, gastric cancer, pancreatic cancer, prostate cancer, acute myeloid leukemia, chronic myeloid leukemia, osteosarcoma, squamous cell carcinoma, peripheral nerve sheath tumor, schwannoma, head and neck cancer, bladder cancer, esophageal cancer, glioblastoma, soft tissue clear cell sarcoma, malignant mesothelioma, neurofibromatosis, renal cancer and melanoma.

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