FGFR2b antibodies and uses thereof

Abstract

The present invention relates to novel anti-FGFR2b antibodies and antigen binding fragments thereof that specifically bind to the fibroblast growth factor receptor 2b (FGFR2IIIb, or FGFR2b), as well as polynucleotides encoding the anti-FGFR2b antibodies, related vectors, expression cells, compositions containing the anti-FGFR2b antibodies, and uses thereof.

Description

Technical Field

[0001] The present invention relates to novel FGFR2b antibodies and binding fragments thereof that can specifically bind to fibroblast growth factor receptor 2b (FGFR2Ⅲb or FGFR2b), including related nucleotides, vectors, cells, and uses thereof. Cross - Reference

[0002] The present invention claims the priority and benefits of the international application with the application number "PCT / CN2022 / 122986" filed on September 30, 2022. The entire content of the above PCT application is incorporated herein by reference. Sequence Listing

[0003] The present invention includes a sequence listing submitted electronically, with the name "9.29.2023 Sequence Listing anti - FGFR2B.xml", a size of 385,412 bytes, created on September 29, 2023. The content of the sequence listing is incorporated herein by reference. Background Art

[0004] Fibroblast growth factor receptors (FGFRs) belong to a highly conserved family of transmembrane tyrosine kinase receptors, which consist of an extracellular region, a transmembrane region, and an intracellular region containing a tyrosine kinase domain. The extracellular region is composed of different immunoglobulin - like domains. The α - type contains three immunoglobulin - like domains D1, D2, and D3, and the β - type contains only two immunoglobulin - like domains D2 and D3, without D1. FGFRs are involved in all aspects of cancer biology, including cell proliferation, differentiation, migration, angiogenesis, and carcinogenesis (Katoh et al., Med Res Rev 2014; 34:280 - 300).

[0005] The D2 and D3 domains are crucial for ligand binding and specificity, while the D1 domain is thought to have an auto-inhibitory function. Due to alternative splicing of the D3 domain, two different isoforms, namely IIIb and IIIc, are generated for FGFR1 to FGFR3 (Eswarakumar et al., Cytokine Growth Factor Rev 2005; 16:139-49; Turner et al., Nat Rev Cancer 2010; 10:116-29). The isoform expression of FGFR is tissue-specific and also differs in response to 18 mammalian fibroblast growth factors (FGFs) (Beenken et al., Nat Rev Drug Discov 2009; 8:235-53). For example, in FGFR2, alternative splicing of the exon encoding the D3 domain generates two isoforms, FGFR2IIIb and FGFR2IIIc (also written as FGFR2b and FGFR2c), which have different ligand-binding preferences. FGFR2IIIb is usually expressed on epithelial cells and is a specific receptor for members of the keratinocyte growth factor (KGF) family (FGF10, FGF22, especially FGF7), while FGFR2IIIc is mainly expressed on mesenchymal tissues and can bind to FGF1 and FGF2 but not to KGF family members (Ornitz et al., J Biol Chem 1996; 271:15292-7; Zhang et al., J Biol Chem 2006; 281:15694-700).

[0006] Numerous studies have confirmed the crucial role of aberrant FGFR2 signaling in cancer, including overexpression of FGFR2 and its ligands, mutations and amplifications of the receptor, and receptor subtype switching (Bai et al., Cancer Res; 70(19):7630-7639, October 1, 2010). Single nucleotide polymorphisms (SNPs) of FGFR2 are associated with an increased risk of breast cancer development, potentially due to FGFR2 overexpression (Easton et al., Nature 2007; 447:1087-93; Hunter et al., Nat Genet 2007; 39:870-4; Meyer et al., PLoS Biol 2008; 6:e108). Potential FGFR2 missense mutations are present in various cancer cells, including endometrial, ovarian, breast, lung, and gastric cancers (Turner et al., Nat Rev Cancer 2010; 10:116-29; Davies et al., Cancer Res 2005; 65:7591-5; Ding et al., Nature 2008; 455:1069-75; Dutt et al., Proc Natl Acad Sci U S A 2008; 105:8713-7; Greenman et al., Nature 2007; 446:153-8; Pollock et al., Oncogene 2007; 26:7158-62; Jang et al., Cancer Res 2001; 61:3541-3). In addition, overexpression of FGFR2 is also present in gastric and breast cancer cells (Heiskanen et al., Anal Cell Pathol 2001; 22:229-34; Adnane et al., Oncogene 1991; 6:659-63; Turner et al., Oncogene 2010; 29:2013-23; Hara et al., Lab Invest 1998; 78:1143-53; Mor et al., Cancer Genet Cytogenet 1993; 65:111-4; Tsujimoto et al., Virchows Arch 1997; 431:383-9; Yoshida et al., Semin Cancer Biol 1993; 4:33-40).Overexpression of FGFR2IIIb and its ligand FGF7 is associated with poor prognosis in pancreatic cancer, gastric cancer, and lung adenocarcinoma (Yamayoshi et al., J Pathol 2004; 204:110 - 8; Cho et al., Am J Pathol 2007; 170:1964 - 74; Toyokawa et al., Oncol Rep 2009; 21:875 - 80), which may be due to abnormal activation of the receptor by formation of an autocrine activation loop. Paradoxically, FGFR2 is also considered a tumor suppressor gene. For example, loss - of - function mutations have been detected in melanoma (Gartside et al., Mol Cancer Res 2009; 7:41 - 54). It has also been reported that during tumor progression, the expression of FGFR2IIIb is decreased in multiple cancer types (Diez et al., Oncogene 1997; 14:323 - 30; Giri et al., Clin Cancer Res 1999; 5:1063 - 71; Ricol et al., Oncogene 1999; 18:7234 - 43; Zhang et al., Proc Natl Acad Sci U S A 2001; 98:11336 - 40), which may reflect the physiological role of FGFR2 in regulating tissue homeostasis (Grose et al., EMBO J 2007; 26:1268 - 78; Lin et al., Development 2007; 134:723 - 34). These differences illustrate the complexity of FGFR2 signaling.

[0007] Targeted therapy with anti - FGFR2b antibodies may be effective for patients with abnormal activation or amplification of FGFR2b signaling. Therefore, there is a great need for novel anti - FGFR2b antibodies. Summary of the Invention

[0008] The present invention provides novel FGFR2b antibodies and binding fragments, including related nucleotides, vectors, cells, and uses.

[0009] In one aspect, the present invention provides an antibody comprising a heavy - chain variable region, wherein the heavy - chain variable region comprises at least one complementarity - determining region (CDR), and the complementarity - determining region farthest from the N - terminus of the antibody is selected from SEQ ID NOs: 61, 67, 73, 79, 85, 89, 95, 101, 104, 112, 116, 121, 125, 128, 131, 136, 138, 142, 144, 147, 151, 154, and 158.

[0010] In some embodiments, the heavy chain variable region provided herein comprises three complementarity determining regions: heavy chain complementarity determining region 1, heavy chain complementarity determining region 2, and heavy chain complementarity determining region 3, wherein heavy chain complementarity determining region 1 is selected from SEQ ID NOs: 59, 65, 71, 77, 83, 88, 93, 103, 110, 119, 135, 143, 146, 150, and 152; heavy chain complementarity determining region 2 is selected from SEQ ID NOs: 60, 66, 72, 78, 84, 94, 111, 118, 120, 124, 141, and 153; heavy chain complementarity determining region 3 is selected from SEQ ID NOs: NOs:61,67,73,79,85,89,95,101,104,112,116,121,125,128,131,136,138,142,144,147,151,154,and 158.

[0011] In some embodiments, the combinations of heavy chain complementarity determining region 1, heavy chain complementarity determining region 2, and heavy chain complementarity determining region 3 provided herein are as follows: a. SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61 respectively; b. SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, respectively; c. SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73 respectively; d. SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, respectively; e. SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, respectively; f. SEQ ID NO: 88, SEQ ID NO: 84, SEQ ID NO: 89, respectively; g. SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95 respectively; h. SEQ ID NO: 59, SEQ ID NO: 78, SEQ ID NO: 79, respectively; i. SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 101 respectively; j. SEQ ID NO: 103, SEQ ID NO: 94, SEQ ID NO: 104, respectively; k. are SEQ ID NO:59, SEQ ID NO:78, SEQ ID NO:79 respectively; l. are SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112 respectively; m. are SEQ ID NO:88, SEQ ID NO:84, SEQ ID NO:116 respectively; n. are SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:101 respectively; o. are SEQ ID NO:93, SEQ ID NO:118, SEQ ID NO:101 respectively; p. are SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121 respectively; q. are SEQ ID NO:119, SEQ ID NO:124, SEQ ID NO:125 respectively; r. are SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:128 respectively; s. are SEQ ID NO:83, SEQ ID NO:94, SEQ ID NO:131 respectively; t. are SEQ ID NO:135, SEQ ID NO:84, SEQ ID NO:136 respectively; u. are SEQ ID NO:88, SEQ ID NO:84, SEQ ID NO:138 respectively; v. are SEQ ID NO:83, SEQ ID NO:141, SEQ ID NO:142 respectively; w. are SEQ ID NO:143, SEQ ID NO:84, SEQ ID NO:144 respectively; x. are SEQ ID NO:146, SEQ ID NO:94, SEQ ID NO:147 respectively; y. are SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121 respectively; z. are SEQ ID NO:119, SEQ ID NO:124, SEQ ID NO:125 respectively; aa. are SEQ ID NO:150, SEQ ID NO:84, SEQ ID NO:151 respectively; bb. SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, respectively; or cc. SEQ ID NO:88, SEQ ID NO:94, SEQ ID NO:158, respectively.

[0012] In some embodiments, the heavy chain variable regions provided herein further comprise four framework regions: heavy chain framework region 1, heavy chain framework region 2, heavy chain framework region 3, and heavy chain framework region 4. Heavy chain framework region 1 is selected from SEQ ID NOs: 160, 168, 175, 188, 194, 204, 210, 224, 233, 284, 259, 265, 268, 271, 274, 281, 295, and 305; heavy chain framework region 2 is selected from SEQ ID NOs: 161, 169, 176, 183, 205, 221, 225, 237, 245, 251, 261, 266, 275, 282, and 296; heavy chain framework region 3 is selected from SEQ ID NOs: 162, 170, 177, 184, 189, 195, 200, 206, 211, 216, 226, 231, 234, 239, 242, 246, 252, 254, 260, 262, 267, 272, 276, 297, and 306; heavy chain framework region 4 is selected from SEQ ID NOs: 163, 178, 190, 196, 212, 217, 227, 255, 269, and 298.

[0013] In some embodiments, the compositions of heavy chain framework region 1, heavy chain framework region 2, heavy chain framework region 3, and heavy chain framework region 4 provided herein are as follows: a. SEQ ID NO:160, SEQ ID NO:161, SEQ ID NO:162, SEQ ID NO:163, respectively; b. SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:163, respectively; c. SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, respectively; d. SEQ ID NO:160, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:178, respectively; e. SEQ ID NO:188, SEQ ID NO:169, SEQ ID NO:189, SEQ ID NO:190, respectively; f. are SEQ ID NO:194, SEQ ID NO:169, SEQ ID NO:195, SEQ ID NO:196 respectively; g. are SEQ ID NO:194, SEQ ID NO:169, SEQ ID NO:200, SEQ ID NO:163 respectively; h. are SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:178 respectively; i. are SEQ ID NO:210, SEQ ID NO:169, SEQ ID NO:211, SEQ ID NO:212 respectively; j. are SEQ ID NO:194, SEQ ID NO:169, SEQ ID NO:216, SEQ ID NO:217 respectively; k. are SEQ ID NO:204, SEQ ID NO:221, SEQ ID NO:206, SEQ ID NO:178 respectively; l. are SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227 respectively; m. are SEQ ID NO:194, SEQ ID NO:169, SEQ ID NO:231, SEQ ID NO:163 respectively; n. are SEQ ID NO:233, SEQ ID NO:169, SEQ ID NO:234, SEQ ID NO:178 respectively; o. are SEQ ID NO:210, SEQ ID NO:237, SEQ ID NO:211, SEQ ID NO:212 respectively; p. are SEQ ID NO:194, SEQ ID NO:169, SEQ ID NO:239, SEQ ID NO:190 respectively; q. are SEQ ID NO:194, SEQ ID NO:169, SEQ ID NO:242, SEQ ID NO:178 respectively; r. are SEQ ID NO:284, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:163 respectively; s. are SEQ ID NO:194, SEQ ID NO:245, SEQ ID NO:246, SEQ ID NO:163 respectively; t. are SEQ ID NO:188, SEQ ID NO:251, SEQ ID NO:252, SEQ ID NO:163 respectively; u. are SEQ ID NO:188, SEQ ID NO:169, SEQ ID NO:254, SEQ ID NO:255 respectively; v. are SEQ ID NO:259, SEQ ID NO:169, SEQ ID NO:260, SEQ ID NO:190 respectively; w. are SEQ ID NO:194, SEQ ID NO:261, SEQ ID NO:262, SEQ ID NO:163 respectively; x. are SEQ ID NO:265, SEQ ID NO:266, SEQ ID NO:267, SEQ ID NO:163 respectively; y. are SEQ ID NO:268, SEQ ID NO:169, SEQ ID NO:239, SEQ ID NO:269 respectively; z. are SEQ ID NO:194, SEQ ID NO:169, SEQ ID NO:200, SEQ ID NO:190 respectively; aa. are SEQ ID NO:271, SEQ ID NO:169, SEQ ID NO:272, SEQ ID NO:190 respectively; bb. are SEQ ID NO:274, SEQ ID NO:275, SEQ ID NO:276, SEQ ID NO:178 respectively; cc. are SEQ ID NO:281, SEQ ID NO:282, SEQ ID NO:254, SEQ ID NO:163 respectively; dd. are SEQ ID NO:295, SEQ ID NO:296, SEQ ID NO:297, SEQ ID NO:298 respectively; ee. are SEQ ID NO:305, SEQ ID NO:296, SEQ ID NO:306, SEQ ID NO:298 respectively; ff. are SEQ ID NO:295, SEQ ID NO:296, SEQ ID NO:306, SEQ ID NO:298 respectively; or gg. are SEQ ID NO:305, SEQ ID NO:296, SEQ ID NO:297, SEQ ID NO:298 respectively.

[0014] In some embodiments, the complementarity-determining regions and framework regions of the heavy-chain variable regions provided herein are arranged in the following order from the N-terminus to the C-terminus of the sequence: heavy-chain framework region 1 - heavy-chain complementarity-determining region 1 - heavy-chain framework region 2 - heavy-chain complementarity-determining region 2 - heavy-chain framework region 3 - heavy-chain complementarity-determining region 3 - heavy-chain framework region 4.

[0015] In some embodiments, the antibody heavy chains provided herein comprise 3 constant regions: constant region 1, constant region 2, and constant region 3, which are respectively composed of:

[0016] SEQ ID NO.307, SEQ ID NO.309, and SEQ ID NO.310; or

[0017] SEQ ID NO:307, SEQ ID NO.312, and SEQ ID NO.313.

[0018] In some embodiments, the heavy-chain variable regions provided herein comprise SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 285, 287, 290, and 291 and their homologous sequences, and the homologous sequences have at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence homology with SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 3I, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 285, 287, 290, and 291.

[0019] In some embodiments, the heavy chain variable regions provided herein are selected from SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 285, 287, 290, and 291.

[0020] In some embodiments, the light chain variable regions provided herein comprise at least one complementarity determining region, and the light chain complementarity determining regions are selected from SEQ ID NOs: 64, 70, 76, 82, 87, 92, 98, 100, 102, 107, 109, 115, 117, 123, 127, 130, 134, 137, 140, 145, 157, and 159.

[0021] In some embodiments, the light chain variable region comprises 3 complementarity determining regions, Complementarity Determining Region 1 of the light chain, Complementarity Determining Region 2 of the light chain, and Complementarity Determining Region 3 of the light chain. Among them, Complementarity Determining Region 1 of the light chain is selected from SEQ ID NOs: 62, 68, 74, 80, 86, 90, 96, 99, 105, 108, 113, 122, 126, 129, 132, 148, 149 and 155; Complementarity Determining Region 2 of the light chain is selected from SEQ ID NOs: 63, 69, 75, 81, 91, 97, 106, 114, 133, 139, and 156; Complementarity Determining Region 3 of the light chain is selected from SEQ ID NOs: 64, 70, 76, 82, 87, 92, 98, 100, 102, 107, 109, 115, 117, 123, 127, 130, 134, 137, 140, 145, 157, and 159.

[0022] In some embodiments, the combinations of Complementarity Determining Region 1 of the light chain, Complementarity Determining Region 2 of the light chain, and Complementarity Determining Region 3 of the light chain provided herein are as follows: a. SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, respectively; b. SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, respectively; c. SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, respectively; d. SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, respectively; e. SEQ ID NO: 86, SEQ ID NO: 69, SEQ ID NO: 87, respectively; f. are SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92 respectively; g. are SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98 respectively; h. are SEQ ID NO:99, SEQ ID NO:69, SEQ ID NO:100 respectively; i. are SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:102 respectively; j. are SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107 respectively; k. are SEQ ID NO:108, SEQ ID NO:69, SEQ ID NO:109 respectively; l. are SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115 respectively; m. are SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:117 respectively; n. are SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:102 respectively; o. are SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:102 respectively; p. are SEQ ID NO:122, SEQ ID NO:69, SEQ ID NO:123 respectively; q. are SEQ ID NO:126, SEQ ID NO:69, SEQ ID NO:127 respectively; r. are SEQ ID NO:129, SEQ ID NO:69, SEQ ID NO:130 respectively; s. are SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134 respectively; t. are SEQ ID NO:126, SEQ ID NO:69, SEQ ID NO:137 respectively; u. are SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:140 respectively; v. are SEQ ID NO:122, SEQ ID NO:69, SEQ ID NO:123 respectively; w. are SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:145 respectively; x. are SEQ ID NO:148, SEQ ID NO:69, SEQ ID NO:109 respectively; y. are SEQ ID NO:149, SEQ ID NO:63, SEQ ID NO:109 respectively; z. are SEQ ID NO:122, SEQ ID NO:69, SEQ ID NO:123 respectively; aa. are SEQ ID NO:126, SEQ ID NO:69, SEQ ID NO:130 respectively; bb. are SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157 respectively; or cc. are SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:159 respectively.

[0023] In some embodiments, the light chain variable region provided herein contains 4 framework regions, light chain framework region 1, light chain framework region 2, light chain framework region 3, and light chain framework region 4. Among them, light chain framework region 1 is selected from SEQ ID NOs: 164, 171, 179, 185, 191, 197, 201, 207, 213, 218, 222, 228, 232, 247, 256, 263, 270, 277, 283, 299, and 303; light chain framework region 2 is selected from SEQ ID NOs: 165, 172, 180, 186, 192, 198, 202, 208, 214, 219, 223, 229, 235, 240, 243, 248, 257, 264, 278, 300, and 304; light chain framework region 3 is selected from SEQ ID NOs: 166, 173, 181, 187, 193, 199, 203, 209, 220, 230, 236, 238, 241, 244, 249, 253, 258, 273, 279, and 301; light chain framework region 4 is selected from SEQ ID NOs: 167, 174, 182, 215, 250, 280, and 302.

[0024] In some embodiments, the combinations of light chain framework region 1, light chain framework region 2, light chain framework region 3, and light chain framework region 4 provided herein are as follows: a. are SEQ ID NO:164, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:167 respectively; b. SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174 respectively; c. SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182 respectively; d. SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:174 respectively; e. SEQ ID NO:191, SEQ ID NO:192, SEQ ID NO:193, SEQ ID NO:174 respectively; f. SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:174 respectively; g. SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:167 respectively; h. SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:174 respectively; i. SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:203, SEQ ID NO:215 respectively; j. SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:174 respectively; k. SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:209, SEQ ID NO:174 respectively; l. SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:174 respectively; m. SEQ ID NO:232, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:167 respectively; n. SEQ ID NO:201, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:174 respectively; o. SEQ ID NO:201, SEQ ID NO:214, SEQ ID NO:238, SEQ ID NO:215 respectively; p. SEQ ID NO:171, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:174 respectively; q. SEQ ID NO:171, SEQ ID NO:243, SEQ ID NO:244, SEQ ID NO:174 respectively; r. SEQ ID NO:222, SEQ ID NO:165, SEQ ID NO:209, SEQ ID NO:174 respectively; s. SEQ ID NO:247, SEQ ID NO:248, SEQ ID NO:249, SEQ ID NO:250 respectively; t. SEQ ID NO:171, SEQ ID NO:243, SEQ ID NO:253, SEQ ID NO:167 respectively; u. SEQ ID NO:256, SEQ ID NO:257, SEQ ID NO:258, SEQ ID NO:174 respectively; v. SEQ ID NO:171, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:174 respectively; w. SEQ ID NO:263, SEQ ID NO:264, SEQ ID NO:199, SEQ ID NO:174 respectively; x. SEQ ID NO:222, SEQ ID NO:165, SEQ ID NO:209, SEQ ID NO:174 respectively; y. SEQ ID NO:270, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:174 respectively; z. SEQ ID NO:171, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:174 respectively; aa. SEQ ID NO:171, SEQ ID NO:243, SEQ ID NO:273, SEQ ID NO:174 respectively; bb. are SEQ ID NO:277, SEQ ID NO:278, SEQ ID NO:279, SEQ ID NO:280 respectively; cc. are SEQ ID NO:283, SEQ ID NO:278, SEQ ID NO:279, SEQ ID NO:174 respectively; dd. are SEQ ID NO:299, SEQ ID NO:300, SEQ ID NO:301, SEQ ID NO:302 respectively; ee. are SEQ ID NO:303, SEQ ID NO:304, SEQ ID NO:301, SEQ ID NO:302 respectively; or ff. are SEQ ID NO:299, SEQ ID NO:304, SEQ ID NO:301, SEQ ID NO:302 respectively.

[0025] In some embodiments, the complementarity determining regions and framework regions of the light chain variable regions provided herein are arranged in the following order from the N-terminus to the C-terminus of the sequence: light chain framework region 1 - light chain complementarity determining region 1 - light chain framework region 2 - light chain complementarity determining region 2 - light chain framework region 3 - light chain complementarity determining region 3 - light chain framework region 4.

[0026] In some embodiments, the antibody provided herein further comprises a light chain constant region SEQ ID NO:311.

[0027] In some embodiments, the light chain variable regions provided herein comprise SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 1, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 54, 56, 58, 286, 288 and 289 and their homologous sequences, and the homologous sequences have at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence homology with SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 54, 56, 58, 286, 288, and 289.

[0028] In some embodiments, the light chain variable regions provided herein are selected from SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 54, 56, 58, 286, 288, and 289.

[0029] In some embodiments, the light chain variable regions provided herein comprise at least one complementarity determining region, and the light chain complementarity determining regions are selected from SEQ ID NOs: 64, 70, 76, 82, 87, 92, 98, 100, 102, 107, 109, 115, 117, 123, 127, 130, 134, 137, 140, 145, 157, and 159.

[0030] In some embodiments, the light chain variable region comprises three complementarity determining regions, light chain complementarity determining region 1, light chain complementarity determining region 2, and light chain complementarity determining region 3. Light chain complementarity determining region 1 is selected from SEQ ID NOs: 62, 68, 74, 80, 86, 90, 96, 99, 105, 108, 113, 122, 126, 129, 132, 148, 149, and 155; light chain complementarity determining region 2 is selected from SEQ ID NOs: 63, 69, 75, 81, 91, 97, 106, 114, 133, 139, and 156; light chain complementarity determining region 3 is selected from SEQ ID NOs: 64, 70, 76, 82, 87, 92, 98, 100, 102, 107, 109, 115, 117, 123, 127, 130, 134, 137, 140, 145, 157, and 159.

[0031] In some embodiments, the combinations of light chain complementarity determining region 1, light chain complementarity determining region 2, and light chain complementarity determining region 3 are as follows: a. SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, respectively; b. SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, respectively; c. SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, respectively; d. SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, respectively; e. SEQ ID NO: 86, SEQ ID NO: 69, SEQ ID NO: 87, respectively; f. SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92 respectively; g. SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98 respectively; h. SEQ ID NO: 99, SEQ ID NO: 69, SEQ ID NO: 100, respectively; i. SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 102 respectively; j. SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, respectively; k. SEQ ID NO: 108, SEQ ID NO: 69, SEQ ID NO: 109, respectively; l. SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 115 respectively; m. SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 117, respectively; n. SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 102 respectively; o. SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 102, respectively; p. SEQ ID NO: 122, SEQ ID NO: 69, SEQ ID NO: 123, respectively; q. SEQ ID NO: 126, SEQ ID NO: 69, SEQ ID NO: 127, respectively; r. SEQ ID NO: 129, SEQ ID NO: 69, SEQ ID NO: 130, respectively; s. SEQ ID NO: 132, SEQ ID NO: 133, SEQ ID NO: 134, respectively; t. SEQ ID NO: 126, SEQ ID NO: 69, SEQ ID NO: 137, respectively; u. SEQ ID NO: 132, SEQ ID NO: 139, SEQ ID NO: 140, respectively; v. SEQ ID NO: 122, SEQ ID NO: 69, SEQ ID NO: 123, respectively; w. are SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:145 respectively; x. are SEQ ID NO:148, SEQ ID NO:69, SEQ ID NO:109 respectively; y. are SEQ ID NO:149, SEQ ID NO:63, SEQ ID NO:109 respectively; z. are SEQ ID NO:122, SEQ ID NO:69, SEQ ID NO:123 respectively; aa. are SEQ ID NO:126, SEQ ID NO:69, SEQ ID NO:130 respectively; bb. are SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157 respectively; or cc. are SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:159 respectively.

[0032] In some embodiments, the light chain variable region provided herein contains 4 framework regions, light chain framework region 1, light chain framework region 2, light chain framework region 3 and light chain framework region 4. Among them, light chain framework region 1 is selected from SEQ ID NOs: 164, 171, 179, 185, 191, 197, 201, 207, 213, 218, 222, 228, 232, 247, 256, 263, 270, 277, 283, 299, and 303; light chain framework region 2 is selected from SEQ ID NOs: 165, 172, 180, 186, 192, 198, 202, 208, 214, 219, 223, 229, 235, 240, 243, 248, 257, 264, 278, 300 and 304; light chain framework region 3 is selected from SEQ ID NOs: 166, 173, 181, 187, 193, 199, 203, 209, 220, 230, 236, 238, 241, 244, 249, 253, 258, 273, 279 and 301; light chain framework region 4 is selected from SEQ ID NOs: 167, 174, 182, 215, 250, 280 and 302.

[0033] In some embodiments, the combinations of light chain framework region 1, light chain framework region 2, light chain framework region 3 and light chain framework region 4 provided herein are as follows: a. are SEQ ID NO:164, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:167 respectively; b. SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174 respectively; c. SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182 respectively; d. SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:174 respectively; e. SEQ ID NO:191, SEQ ID NO:192, SEQ ID NO:193, SEQ ID NO:174 respectively; f. SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:174 respectively; g. SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:167 respectively; h. SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:174 respectively; i. SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:203, SEQ ID NO:215 respectively; j. SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:174 respectively; k. SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:209, SEQ ID NO:174 respectively; l. SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:174 respectively; m. SEQ ID NO:232, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:167 respectively; n. SEQ ID NO:201, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:174 respectively; o. SEQ ID NO:201, SEQ ID NO:214, SEQ ID NO:238, SEQ ID NO:215 respectively; p. SEQ ID NO:171, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:174 respectively; q. SEQ ID NO:171, SEQ ID NO:243, SEQ ID NO:244, SEQ ID NO:174 respectively; r. SEQ ID NO:222, SEQ ID NO:165, SEQ ID NO:209, SEQ ID NO:174 respectively; s. SEQ ID NO:247, SEQ ID NO:248, SEQ ID NO:249, SEQ ID NO:250 respectively; t. SEQ ID NO:171, SEQ ID NO:243, SEQ ID NO:253, SEQ ID NO:167 respectively; u. SEQ ID NO:256, SEQ ID NO:257, SEQ ID NO:258, SEQ ID NO:174 respectively; v. SEQ ID NO:171, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:174 respectively; w. SEQ ID NO:263, SEQ ID NO:264, SEQ ID NO:199, SEQ ID NO:174 respectively; x. SEQ ID NO:222, SEQ ID NO:165, SEQ ID NO:209, SEQ ID NO:174 respectively; y. SEQ ID NO:270, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:174 respectively; z. SEQ ID NO:171, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:174 respectively; aa. SEQ ID NO:171, SEQ ID NO:243, SEQ ID NO:273, SEQ ID NO:174 respectively; bb. are SEQ ID NO:277, SEQ ID NO:278, SEQ ID NO:279, SEQ ID NO:280 respectively; cc. are SEQ ID NO:283, SEQ ID NO:278, SEQ ID NO:279, SEQ ID NO:174 respectively; dd. are SEQ ID NO:299, SEQ ID NO:300, SEQ ID NO:301, SEQ ID NO:302 respectively; ee. are SEQ ID NO:303, SEQ ID NO:304, SEQ ID NO:301, SEQ ID NO:302 respectively; or ff. are SEQ ID NO:299, SEQ ID NO:304, SEQ ID NO:301, SEQ ID NO:302 respectively.

[0034] In some embodiments, the complementarity-determining regions and framework regions of the light chain variable regions provided herein are arranged in the following order from the N-terminus to the C-terminus of the sequence: light chain framework region 1 - light chain complementarity-determining region 1 - light chain framework region 2 - light chain complementarity-determining region 2 - light chain framework region 3 - light chain complementarity-determining region 3 - light chain framework region 4.

[0035] In some embodiments, the antibody provided herein further comprises a light chain constant region SEQ ID NO:311.

[0036] In some embodiments, the light chain variable regions provided herein comprise SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 54, 56, 58, 286, 288, and 289 and their homologous sequences, and the homologous sequences have at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence homology with SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 54, 56, 58, 286, 288, and 289.

[0037] In some embodiments, the light chain variable regions provided herein are selected from SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 54, 56, 58, 286, 288, and 289.

[0038] In some embodiments, the heavy chain variable regions and light chain variable regions provided herein comprise the following combinations and comprise sequences having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology with the following sequences and combinations thereof: a. SEQ ID NO: 1 and SEQ ID NO: 2, respectively; b. SEQ ID NO: 3 and SEQ ID NO: 4, respectively; c. SEQ ID NO: 5 and SEQ ID NO: 6, respectively; d. SEQ ID NO: 7 and SEQ ID NO: 8, respectively; e. SEQ ID NO: 9 and SEQ ID NO: 10, respectively; f. SEQ ID NO: 11 and SEQ ID NO: 12, respectively; g. SEQ ID NO: 13 and SEQ ID NO: 14, respectively; h. SEQ ID NO: 15 and SEQ ID NO: 16, respectively; i. SEQ ID NO: 17 and SEQ ID NO: 18, respectively; j. SEQ ID NO: 19 and SEQ ID NO: 20, respectively; k. SEQ ID NO: 21 and SEQ ID NO: 22, respectively; l. SEQ ID NO: 23 and SEQ ID NO: 24, respectively; m. SEQ ID NO: 25 and SEQ ID NO: 26, respectively; n. SEQ ID NO: 27 and SEQ ID NO: 28, respectively; o. SEQ ID NO: 29 and SEQ ID NO: 30, respectively; p. SEQ ID NO: 31 and SEQ ID NO: 32, respectively; q. SEQ ID NO: 33 and SEQ ID NO: 34, respectively; r. are SEQ ID NO:35 and SEQ ID NO:36 respectively; s. are SEQ ID NO:37 and SEQ ID NO:38 respectively; t. are SEQ ID NO:39 and SEQ ID NO:40 respectively; u. are SEQ ID NO:41 and SEQ ID NO:42 respectively; v. are SEQ ID NO:43 and SEQ ID NO:32 respectively; w. are SEQ ID NO:45 and SEQ ID NO:46 respectively; x. are SEQ ID NO:47 and SEQ ID NO:48 respectively; y. are SEQ ID NO:49 and SEQ ID NO:50 respectively; z. are SEQ ID NO:51 and SEQ ID NO:32 respectively; aa. are SEQ ID NO:53 and SEQ ID NO:54 respectively; bb. are SEQ ID NO:55 and SEQ ID NO:56 respectively; cc. are SEQ ID NO:57 and SEQ ID NO:58 respectively; dd. are SEQ ID NO:285 and SEQ ID NO:286 respectively; ee. are SEQ ID NO:287 and SEQ ID NO:288 respectively; ff. are SEQ ID NO:287 and SEQ ID NO:289 respectively; gg. are SEQ ID NO:290 and SEQ ID NO:288 respectively; hh. are SEQ ID NO:290 and SEQ ID NO:286 respectively; ii. are SEQ ID NO:291 and SEQ ID NO:286 respectively; jj. are SEQ ID NO:292 and SEQ ID NO:293 respectively; or kk. are SEQ ID NO:294 and SEQ ID NO:293 respectively.

[0039] In some embodiments, the heavy chain variable regions and light chain variable regions provided herein comprise the following combinations: a. SEQ ID NO:1 and SEQ ID NO:2 respectively; b. SEQ ID NO:3 and SEQ ID NO:4 respectively; c. SEQ ID NO:5 and SEQ ID NO:6 respectively; d. SEQ ID NO:7 and SEQ ID NO:8 respectively; e. SEQ ID NO:9 and SEQ ID NO:10 respectively; f. SEQ ID NO:11 and SEQ ID NO:12 respectively; g. SEQ ID NO:13 and SEQ ID NO:14 respectively; h. SEQ ID NO:15 and SEQ ID NO:16 respectively; i. SEQ ID NO:17 and SEQ ID NO:18 respectively; j. SEQ ID NO:19 and SEQ ID NO:20 respectively; k. SEQ ID NO:21 and SEQ ID NO:22 respectively; l. SEQ ID NO:23 and SEQ ID NO:24 respectively; m. SEQ ID NO:25 and SEQ ID NO:26 respectively; n. SEQ ID NO:27 and SEQ ID NO:28 respectively; o. SEQ ID NO:29 and SEQ ID NO:30 respectively; p. SEQ ID NO:31 and SEQ ID NO:32 respectively; q. SEQ ID NO:33 and SEQ ID NO:34 respectively; r. SEQ ID NO:35 and SEQ ID NO:36 respectively; s. SEQ ID NO:37 and SEQ ID NO:38 respectively; t. SEQ ID NO:39 and SEQ ID NO:40 respectively; u. SEQ ID NO:41 and SEQ ID NO:42 respectively; v. SEQ ID NO:43 and SEQ ID NO:32 respectively; w. are SEQ ID NO:45 and SEQ ID NO:46 respectively; x. are SEQ ID NO:47 and SEQ ID NO:48 respectively; y. are SEQ ID NO:49 and SEQ ID NO:50 respectively; z. are SEQ ID NO:51 and SEQ ID NO:32 respectively; aa. are SEQ ID NO:53 and SEQ ID NO:54 respectively; bb. are SEQ ID NO:55 and SEQ ID NO:56 respectively; cc. are SEQ ID NO:57 and SEQ ID NO:58 respectively; dd. are SEQ ID NO:285 and SEQ ID NO:286 respectively; ee. are SEQ ID NO:287 and SEQ ID NO:288 respectively; ff. are SEQ ID NO:287 and SEQ ID NO:289 respectively; gg. are SEQ ID NO:290 and SEQ ID NO:288 respectively; [[ID=ed]]hh. are SEQ ID NO:290 and SEQ ID NO:286 respectively; ii. are SEQ ID NO:291 and SEQ ID NO:286 respectively; jj. are SEQ ID NO:292 and SEQ ID NO:293 respectively; or kk. are SEQ ID NO:294 and SEQ ID NO:293 respectively.

[0040] In some embodiments, the antibodies provided herein specifically bind to fibroblast growth factor receptor 2b (FGFR2b).

[0041] In some embodiments, the fibroblast growth factor receptor 2b referred to herein is derived from humans, mice, and cynomolgus monkeys.

[0042] In some embodiments, the antibodies provided herein have an affinity for fibroblast growth factor receptor 2b of 10 nM or lower.

[0043] In some embodiments, the antibodies provided herein have an affinity for fibroblast growth factor receptor 2b of 9 nM or lower.

[0044] In some embodiments, the antibodies provided herein have an affinity for fibroblast growth factor receptor 2b of 5 nM or lower.

[0045] In some embodiments, the antibodies provided herein do not bind to fibroblast growth factor receptor 1b, 1c, 2c, 3b, 3c, or 4.

[0046] In some embodiments, the antibodies provided herein are human-mouse chimeric antibodies.

[0047] In some embodiments, the antibodies provided herein are fully humanized or partially humanized antibodies.

[0048] In some embodiments, the antibodies provided herein are monoclonal antibodies.

[0049] In some embodiments, the antibodies provided herein are afucosylated antibodies.

[0050] In some embodiments, the antibodies provided herein are Fc-engineered antibodies with enhanced ADCC function.

[0051] In some embodiments, the antibodies provided herein are ADCC-enhanced antibodies.

[0052] In some embodiments, the antibodies provided herein are bispecific antibodies.

[0053] In some embodiments, the antibodies provided herein can be conjugated to cytotoxins.

[0054] In another aspect, the present invention provides an antibody composition comprising the antibodies described herein.

[0055] In another aspect, the present invention provides a pharmaceutical composition comprising the antibodies described herein and a pharmaceutical carrier.

[0056] In another aspect, the present invention provides a nucleotide sequence encoding the antibodies described herein.

[0057] In another aspect, the present invention provides a vector comprising the nucleotide sequence described herein.

[0058] In another aspect, the present invention provides a cell capable of expressing the antibodies described herein.

[0059] In another aspect, the present invention provides a cell comprising the nucleotide sequence and vector described herein.

[0060] In another aspect, the present invention provides a method for culturing the cells described herein and preparing antibodies.

[0061] In yet another aspect, the present invention provides a method for using the antibodies or compositions described herein to block the binding of fibroblast growth factor (FGF) to its receptor FGFR2b.

[0062] In some embodiments, the fibroblast growth factor (FGF) is selected from FGF1, FGF3, FGF7, FGF10, and FGF22.

[0063] In another aspect, the present invention provides a method for inhibiting cell proliferation using the antibodies or compositions described herein.

[0064] In some embodiments, the cell proliferation described herein is FGF-induced proliferation.

[0065] In some embodiments, the cells described herein are cancer cells.

[0066] In another aspect, the present invention provides a method for inhibiting the activation and transduction of a signaling pathway caused by the binding of fibroblast growth factor ligand (FGF) to receptor (FGFR2b) using the antibodies or compositions described herein.

[0067] In another aspect, the present invention provides a method for inhibiting the growth of tumor xenografts overexpressing fibroblast growth factor receptor FGFR2b using the antibodies or compositions described herein.

[0068] In another aspect, the present invention provides a method for detecting fibroblast growth factor receptor (FGFR2b) using the antibodies or compositions described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1: Amino acid sequences of the complete mAb1 light chain ( Figure 1A ) and heavy chain ( Figure 1B ), with complementarity-determining regions (CDRs) underlined.

[0070] Figure 2 : Affinity of mAb1 for the extracellular region of FGFR2b in 3 species determined by BLI, with FPA144 as a control.

[0071] Figure 3: Binding ability of mAb1 to FGFR2b ( Figure 3A ) and FGFR2c ( Figure 3B ) at the cell level determined by flow cytometry, with FPA144 as a control.

[0072] Figure 4 : Selective binding ability of mAb1 to the human fibroblast growth factor family (FGFRs)

[0073] Figure 5 : Inhibitory effect of mAb1 on FGF7-induced proliferation of SNU16 cells, with FPA144 as a control

[0074] Figure 6: Inhibitory effect of mAb1 on the proliferation of SNU16 cells induced by FGF10, with FPA144 as a control

[0075] Figure 7 : Blocking effect of mAb1 on the FGFR2 signaling pathway, with FPA144 as a control

[0076] Figure 8 : In vivo anti-tumor effect of twice-weekly i.p. administration of 5 mg / kg in the SNU16 gastric cancer xenograft model

[0077] Figure 9: Amino acid sequences of the complete HumAbA1 light chain ( Figure 9A ) and heavy chain ( Figure 9B ), with complementarity-determining regions (CDRs) underlined.

[0078] Figure 10 : Affinity of humAbA1 for the extracellular domain of FGFR2b in 3 species determined by BLI

[0079] Figure 11 : Binding ability of mAb1 to FGFR2b and FGFR2c at the cellular level determined by flow cytometry

[0080] Figure 12 : Selective binding ability of humAbA1 to the human fibroblast growth factor family (FGFRs)

[0081] Figure 13 . Inhibitory effect of humAbA1 on the proliferation of SNU16 cells induced by FGF7, with Bemarituzumab as a control

[0082] Figure 14 : Inhibitory effect of humAbA1 on FGFR2 phosphorylation in SNU16 cells

[0083] Figure 15: ADCC activities of the antibodies provided herein and Bemarituzumab in the CD16aV158 cell line ( Figure 15A ), and in the CD16aF158 cell line ( Figure 15B )

[0084] Figure 16 : In vivo anti-tumor effect of twice-weekly i.p. administration of 10 mg / kg in the SNU16 gastric cancer xenograft model

[0085] Figure 17 : In vivo anti-tumor effect of twice-weekly i.p. administration of 10 mg / kg in the OCUM-2M gastric cancer xenograft model

[0086] Detailed description Definition

[0087] All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety as if each individual publication, patent, or patent application were specifically and individually incorporated by reference in its entirety.

[0088] In the present invention, unless otherwise specified, scientific and technical terms used herein have the ordinary meanings understood by those skilled in the art. Although methods and materials similar to those described herein can be used in the present invention, the preferred methods and materials are described herein. Accordingly, the terms defined herein are more fully described by reference to the entire specification.

[0089] As used herein, unless otherwise specified, the singular terms "a" and "the" include plural meanings.

[0090] As used herein, "and / or" means any and all possible combinations of one or more of the associated listed items, as well as combinations not listed when using "or". In addition, the present invention also contemplates that, in some embodiments of the present invention, any feature or combination of features set forth herein can be excluded or omitted.

[0091] The term "about" means, when describing measurable values such as sequence length, etc., includes variations of 5%, 1%, 0.5%, or even 0.1% of the specified amount.

[0092] Unless otherwise specified, the term "comprising" used herein means non-exclusive inclusion, such that the list of recited items includes not only those items stated or listed, but also other items not listed or stated.

[0093] Unless otherwise specified, nucleic acids are written from left to right in the 5' to 3' direction; amino acid sequences are written from left to right in the amino to carboxyl direction.

[0094] The present invention is not limited to the specific methods, protocols, and reagents described, as these may vary depending on how those skilled in the art use them.

[0095] As used herein, the terms "sequence homology" and "% homology", as applied to nucleic acid or nucleotide sequences, refer to the percentage of residue matches between at least two nucleic acid or nucleotide sequences aligned using a standardized algorithm. Such algorithms can insert gaps in the sequences being compared in a standardized and reproducible manner in order to optimize the alignment between the two sequences and thus achieve a more meaningful comparison of the two sequences.

[0096] The percent homology between nucleic acid or nucleotide sequences can be determined using a commonly used and freely available set of sequence comparison algorithms, the Basic Local Alignment Search Tool (BLAST) (Altschul, S.F. et al. (1990) J. Mol. Biol. 215:403-410), provided by the National Center for Biotechnology Information (NCBI). It can be obtained from several sources, including NCBI, Bethesda, MD, and the website http: / / www.ncbi.nlm.nih.gov / BLAST / .

[0097] Due to the degeneracy of the genetic code, nucleic acid or nucleotide sequences that do not have a high degree of homology may encode similar amino acid sequences. Alterations in nucleic acid sequences can take advantage of this degeneracy to generate multiple nucleic acid sequences that all encode essentially the same protein. Specifically, degenerate codon substitution can be achieved by generating sequences in which the third position of one or more selected (or all) codons is replaced by a mixture of bases and / or deoxyinosine residues (Batzer et al. (1991) Nucleic Acid Res 19:5081; Ohtsuka et al. (1985) J Biol Chem 260:2605-2608; Rossolini et al. (1994) Mol Cell Probes 8:91-98).

[0098] The term "nucleic acid", which may be used interchangeably with gene, cDNA, and mRNA encoding the genes referred to herein, refers to deoxyribonucleotides or ribonucleotides in single- or double-stranded form, and polymers thereof. Unless otherwise indicated, the term includes nucleic acids containing known analogs of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides.

[0099] As used herein, "percent amino acid sequence homology (%)" with respect to a peptide, polypeptide, or protein sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in another peptide or polypeptide sequence. To achieve the maximum percent sequence homology, gaps may be introduced (if necessary) after aligning the sequences, and any conservative substitutions are not considered as part of sequence identity. The percent amino acid sequence homology in the present invention is measured using BLAST software. Those skilled in the art can determine the appropriate parameters for measuring the alignment, including any algorithms required to achieve the maximum alignment over the full length of the sequences being compared.

[0100] An amino acid substitution refers to the replacement of one amino acid in a polypeptide with another amino acid, as shown in Table 1. Amino acid substitutions can be introduced into a protein of interest, and the products with the desired activity can be screened, such as maintaining or enhancing biological activity.

[0101] Table 1 Amino acid residue Alternative example Ala(A) Val; Leu; Ile Arg(R) Lys; Gln; Asn Asn(N) Gln; His; Asp, Lys; Arg Asp(D) Glu; Asn Cys(C) Ser; Ala Gln(Q) Asn; Glu Glu(E) Asp; Gln Gly(G) Ala His(H) Asn; Gln; Lys; Arg Ile(I) Leu; Val; Met; Ala; Phe; Norleucine Leu(L) Norleucine; Ile; Val; Met; Ala; Phe Lys(K) Arg; Gln; Asn Met(M) Leu; Phe; Ile Phe(F) Trp; Leu; Val; Ile; Ala; Tyr Pro(P) Ala Ser(S) Thr Thr(T) Val; Ser Trp(W) Tyr; Phe Tyr(Y) Trp; Phe; Thr; Ser Val(V) Ile; Leu; Met; Phe; Ala; Norleucine

[0102] Amino acids can be grouped according to common side-chain properties:

[0103] (1) Hydrophobic amino acids: Norleucine, Met, Ala, Val, Leu, Ile, Pro, Trp, Phe;

[0104] (2) Neutral amino acids: Cys, Ser, Thr, Asn, Gln;

[0105] (3) Acidic amino acids: Asp, Glu;

[0106] (4) Basic amino acids: His, Lys, Arg;

[0107] (5) Amino acids that affect chain direction: Gly, Pro;

[0108] (6) Aromatic amino acids: Trp, Tyr, Phe.

[0109] Non-conservative substitutions would require the exchange of a member of one class for a member of another class. The term "corresponding" refers to the nucleotide or amino acid position of a sequence, as described in the sequence listing, that is identified based on a structural sequence alignment or when aligned with a target sequence using a standard alignment algorithm such as the GAP algorithm. For example, the corresponding residues of similar sequences (e.g., fragments or species variants) can be determined by aligning them with a reference sequence using a structural alignment method. By aligning sequences, one of ordinary skill in the art can identify the corresponding residues, for example, using conserved and identical amino acid residues as guides.

[0110] As used herein, a composition refers to any mixture of two or more products, matrices, or compounds, including cells.

[0111] As used herein, a "pharmaceutical composition" refers to a pharmaceutically or physiologically active pharmaceutical preparation that can be administered to cells or animals alone or in combination with one or more other therapeutic modalities. If desired, the compositions of the present invention can be administered in combination with other agents, such as cytokines, growth factors, hormones, small molecules, chemotherapeutic drugs, prodrug medications, antibodies, or other various pharmaceutically active agents. There are few limitations on other components that can also be included in the composition, provided that the additional reagents do not have an adverse effect on the expected pharmacodynamic effects of the composition. Some non-limiting examples of components that can be included in the composition are carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition facilitates the administration of the antibodies or cells described herein to a subject. There are a variety of administration techniques in the art, including but not limited to intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0112] As used herein, the term "pharmaceutically acceptable" refers to a substance, such as a carrier or diluent, which does not abrogate the biological activity or properties of a therapeutic agent and is relatively non-toxic, i.e., the substance can be administered to a subject without causing undesirable biological effects or interacting in a harmful manner with any component of the composition containing the substance. Pharmaceutically acceptable ingredients include those compounds, substances, compositions, and / or dosage forms that are suitable, within the scope of reasonable medical judgment, for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications and commensurate with a reasonable benefit / risk ratio.

[0113] As used herein, "effective amount" means an amount of a pharmaceutical composition sufficient to significantly and positively alter the symptoms and / or condition to be treated (e.g., provide a positive clinical response). The effective amount of a pharmaceutical composition will vary with the particular disorder being treated, the severity of the disorder, the duration of the treatment, the nature of concurrent treatments, the particular composition employed, the particular pharmaceutically acceptable excipient and / or carrier used, and like factors relevant to the medical judgment of the attending physician.

[0114] As used herein, the terms "individual" and "subject" are used interchangeably herein to refer to an animal. For example, in some embodiments, the animal is a mammal. In some embodiments, the animal is a human, rodent, ape, feline, canine, horse, cow, porcupine, sheep, goat, laboratory mammal, farm mammal, sport mammal, or pet mammal. The animal can be male or female and can be at any suitable age, including infant, juvenile, adolescent, adult, and elderly. In some embodiments, the "individual" or "subject" refers to an animal in need of treatment for a disease or disorder. In some embodiments, the animal being treated can be a "patient", indicating that the animal has been determined to have a disease relevant to the treatment or is at sufficient risk of contracting the disease. In certain embodiments, the animal is a human, such as a human patient.

[0115] As used herein, an "epitope" refers to the portion of an antigen that is recognized and bound by an antibody. An antigen has multiple epitopes that can be recognized by antibodies. Epitopes are typically composed of the chemically active surface components of a molecule, such as amino acids or sugar side chains, and have specific three-dimensional structural features as well as specific charge characteristics.

[0116] As used herein, the terms "FGFR2IIIb" and "FGFR2b" are used interchangeably to refer to the subtype IIIb splice form of FGFR2. Exemplary FGFR2b sequences include Homo sapiens (human) FGFR2b protein (e.g., precursor sequence with a signal peptide, Genbank number: NP 075259.4); Mus musculus FGFR2b protein (e.g., full sequence, Genbank number: NP_963895.2).

[0117] As used herein, the terms "FGFR2IIIc" and "FGFR2c" are used interchangeably to refer to the isoform IIIc splice form of FGFR2. Exemplary FGFR2c sequences include human FGFR2c protein (eg, precursor sequence, Genbank No. NP000132.3).

[0118] As used herein, the term "anti-FGFR2b antibody" refers to an antibody that specifically binds to FGFR2b. In some embodiments, the anti-FGFR2b antibodies provided herein specifically bind only to FGFR2b, but do not have detectable binding affinity to FGFR1b, FGFR1c, FGFR2c, FGFR3b, FGFR3c, or FGFR4.

[0119] As used herein, the term "specific binding" or "binding to" a specific antigen refers to binding that is significantly different from non-specific interactions. For example, in some embodiments, when a binding molecule (antibody) reacts with a specific target molecule (antigen) more frequently, faster, longer lasting, and / or with higher affinity than with alternative molecules. A binding molecule, such as an antibody, "specifically binds" to a targeting molecule if it binds to the targeting molecule with a stronger affinity, easier, and / or longer lasting than with other molecules. A specifically binding molecule, such as an antibody, will not necessarily specifically bind to a second targeting molecule, so specific binding does not require exclusivity. In some embodiments, specific binding can be detected, for example, by comparing whether a specific antibody binds to the antigen. Specific binding can also be shown by a KD value (the dissociation rate of the antibody / antigen interaction). For example, when the KD of an antibody to an antigen is at most about 10 -4 M, up to about 10 -5 M, up to about 10 -6 M, at least about 10 -7 M, up to about 10 -8 M, up to about 10 -9At time M, specific binding to a specific antigen can be shown. In some embodiments, the KD of an antibody that specifically binds an antigen is at least 20, 50, 100, 500, 1000, 5000, 10000-fold or more than the KD of an antibody that does not bind the antigen. In some embodiments, the binding between an antibody and a specific antigen can be shown by an EC50 value, which is measured using a suitable method known in the art, such as flow cytometry. Specific binding is a non-random binding reaction between two molecules, such as the binding reaction between an antibody and an antigen. The binding affinity of the antibodies and antigen-binding fragments provided herein can be represented by a KD value, which represents the ratio of the dissociation rate to the binding rate (Koff / Kon) when the binding between an antigen and an antigen-binding molecule (such as an antibody and an antigen-binding fragment) reaches equilibrium. Antigen-binding affinity (e.g., KD) can be appropriately measured using suitable methods known in the art, including, for example, Biacore (based on surface plasmon resonance technology) and Octet (biomolecular layer interferometry).

[0120] As used herein, "affinity" refers to the strength of non-covalent interactions between a molecule (such as a receptor) and its binding partner (such as a ligand). The affinity of a molecule for its partner can generally be represented by the equilibrium dissociation constant (KD) (or its inverse equilibrium association constant KA). Affinity can be measured by common methods known in the art, such as the methods described herein (See e.g., Pope et al., J. Immunol. Methods. 2009; 341(1-2):86-96). antibody

[0121] Antibodies can be widely used in biotherapy. The complementarity-determining regions of antibodies determine that antibodies have high specificity and high affinity and have the potential for treating a variety of diseases. (Liu J.K.H., Ann. Med. Surg., 3, 113-116 (2014)).

[0122] "Antibody" refers to a glycoprotein or antigen-binding fragment containing at least two heavy chains (H) and two light chains (L) linked to each other by disulfide bonds. "Antibody" also refers to IgA, IgD, IgE, IgG or IgM antibody subtypes or antigen-binding fragments. Each heavy chain consists of a heavy-chain variable region (VH) and a heavy-chain constant region (CH). The heavy-chain constant region typically consists of three domains, namely CH1, CH2 and CH3. Each light chain consists of a light-chain variable region (VL) and a light-chain constant region. The light-chain constant region consists of one domain CL. 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 (N-terminus) to the carboxyl terminus (C-terminus): FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant region of the antibody can mediate the binding of immunoglobulins to host tissues or factors. The six CDRs in the variable domains of the antibody fold together in three-dimensional space to form the binding site of the actual antibody on the target antigen (Chothia et al., J Mol Biol, 1978; 196, 901-17; Chothia et al., Nature, 1989; 342(6252), 877-883; Kabat et al., Sequences of Proteins of Immunological Interest. 5th edn. National Institutes of Health Publication No. 91-3242. National Institutes of Health, Bethesda, MD (1991); Al-Lazikani et al., J. Mol. Bio., 1997; 273(4), 927-948; Lefranc er al., Developmental & Comparative Immunology, 2003; 27(1), 55-77).

[0123] The "CDR" of a variable domain is an amino acid residue within the variable region annotated according to CDR coding methods and / or annotation methods known in the art, including but not limited to Kabat, Chothia, Kabat and Chothia, AbM, Contact, and conformational annotation methods. Antibody CDRs can be considered to be the hypervariable regions originally defined in the article published by Kabat et al. (Kabat et al., Sequences of Proteins of Immunological Interest. (1991) 5th edn. National Institutes of Health Publication No. 91-3242. National Institutes of Health, Bethesda, MD). The positions of CDRs can also be recognized as loop domains, as described in (Chothia et al., Nature 342.6252 (1989): 877-883.). Other methods for CDR identification include the "IMGT definition" (Lefranc, M.-P. et al., 1999, Nucleic Acids Res. 27: 209-212); the "AbM definition," which is a compromise between Kabat and Chothia and is derived using the AbM antibody modeling software from Oxford Molecular; the "contact definition" in view of the amino acid residues observed to be in direct contact with the antigen, (MacCallum et al., 1996, J. Mol. Biol. 262: 732-745.). Another "conformational definition method" defines the positions of CDRs as the amino acid residues that make an enthalpic contribution to antigen binding. (Makabe et al., 2008, J. Biol. Chem. 283: 1156-1166). As used herein, CDR refers to a CDR defined by any method known in the art, including combinations of methods.

[0124] As used herein, the term "antigen-binding portion" or "antigen-binding fragment" (or simply "antibody portion") refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. Fragments of full-length antibodies have been shown to also possess the antigen-binding function of the antibody. Examples of binding fragments included within the term "antigen-binding fragment" of an antibody include, but are not limited to, (i) Fab fragments, monovalent fragments consisting of the VL, VH, CL, and CH1 domains; (ii) F(ab’)2 fragments, divalent fragments comprising two Fab fragments linked by disulfide bonds in the hinge region; (iii) Fd fragments consisting of the VH and CH1 domains; (iv) Fv fragments consisting of the VL and VH domains of a single arm of an antibody, (v) dAb fragments consisting of a single VH or a single VL domain (Ward et al., 1989, Nature 341:544-546); (vi) an isolated complementarity-determining region. Furthermore, 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 so that they can form a single protein chain in which the VL and VH pair to form a monovalent molecule, called single-chain Fv (scFv) (e.g., Bird et al., 1988, Science 242:423-426; Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single-chain antibodies are also included within the term "antigen-binding portion" of an antibody. These antibody fragments are obtained using conventional techniques known to those of skill in the art and are screened in the same manner as intact antibodies.

[0125] For the purposes of the present disclosure, the term "antibody" includes full-length antibodies and any fragment or single-chain thereof that can bind to an antigen. The term "antibody" includes, but is not limited to, monoclonal antibodies, polyclonal antibodies, chimeric antibodies, recombinant antibodies, single-chain variable fragments (ScFv), heavy-chain antibodies, single-domain antibodies, humanized antibodies, human antibodies, and antibodies from other sources such as mice and rabbits.

[0126] As used herein, "isotype" refers to the class or isotype of an antibody determined by the constant domain of the heavy chain (e.g., IgA, IgD, IgE, IgG, and IgM). In humans and most mammals, an antibody typically consists of four polypeptide chains: two identical heavy chains and two identical light chains linked by disulfide bonds. A light chain consists of a variable domain VL and a constant domain CL, while a heavy chain contains a variable domain VH and three to four constant domains, such as CH1, CH2, and CH3. Immunoglobulins can be classified into five major classes, namely IgA, IgD, IgE, IgG, and IgM, based on the amino acid sequence of the heavy chain constant domain. IgA and IgG are typically further subdivided into IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The antibody light chains of vertebrates can be divided into two different types based on the amino acid sequence of their constant domains, namely kappa (κ) and lambda (λ).

[0127] As used herein, the term "antigen" has the same meaning as "immunogen".

[0128] As used herein, the term "Fc" refers to the antibody fragment composed of the second and third constant regions of the first heavy chain bound to the second and third constant regions of the second heavy chain by disulfide bonds. The Fc portion of an antibody is responsible for various effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), but does not play a role in antigen binding.

[0129] In one aspect, the present invention provides an antibody comprising a heavy chain variable region, wherein the heavy chain variable region comprises at least one complementarity determining region (CDR), and the heavy chain complementarity determining regions are selected from SEQ ID NOs:: 61, 67, 73, 79, 85, 89, 95, 101, 104, 112, 116, 121, 125, 128, 131, 136, 138, 142, 144, 147, 151, 154, and 158. In some embodiments, the CDR farthest from the N-terminus is CDR3. The heavy chain CDR3 is conformationally located at the center of the antigen-binding site and is thus considered to make the most contacts with the antigen and provide the most free energy for the affinity of the antibody for the antigen. It can also be considered that the heavy chain CDR3 is the most diverse CDR in terms of length, amino acid composition, and conformation in the antigen-binding site to date (Tonegawa, S., Nature, 1983; 302(5909), 575-581). The diversity of the heavy chain CDR3 is sufficient to generate the specificity of most antibodies and the desired antigen-binding affinity (Xu et al., Immunity, 2000; 13(1), 37-45; Schier et al., Journal of molecular biology, 1996; 263(4), 551-567).

[0130] In some embodiments, the heavy chain variable region provided herein comprises three complementarity determining regions: heavy chain complementarity determining region 1, heavy chain complementarity determining region 2, and heavy chain complementarity determining region 3, wherein heavy chain complementarity determining region 1 is selected from SEQ ID NOs: 59, 65, 71, 77, 83, 88, 93, 103, 110, 119, 135, 143, 146, 150, and 152; heavy chain complementarity determining region 2 is selected from SEQ ID NOs: 60, 66, 72, 78, 84, 94, 111, 118, 120, 124, 141, and 153; heavy chain complementarity determining region 3 is selected from SEQ ID NOs: 61, 67, 73, 79, 85, 89, 95, 101, 104, 112, 116, 121, 125, 128, 131, 136, 138, 142, 144, 147, 151, 154, and 158.

[0131] In some embodiments, the combinations of heavy chain complementarity determining region 1, heavy chain complementarity determining region 2, and heavy chain complementarity determining region 3 provided herein are as follows: a. SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, respectively; b. SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, respectively; c. SEQ ID NO:71, SEQ ID NO:72, and SEQ ID NO:73 respectively; d. SEQ ID NO:77, SEQ ID NO:78, and SEQ ID NO:79 respectively; e. SEQ ID NO:83, SEQ ID NO:84, and SEQ ID NO:85 respectively; f. SEQ ID NO:88, SEQ ID NO:84, and SEQ ID NO:89 respectively; g. SEQ ID NO:93, SEQ ID NO:94, and SEQ ID NO:95 respectively; h. SEQ ID NO:59, SEQ ID NO:78, and SEQ ID NO:79 respectively; i. SEQ ID NO:93, SEQ ID NO:94, and SEQ ID NO:101 respectively; j. SEQ ID NO:103, SEQ ID NO:94, and SEQ ID NO:104 respectively; k. SEQ ID NO:59, SEQ ID NO:78, and SEQ ID NO:79 respectively; l. SEQ ID NO:110, SEQ ID NO:111, and SEQ ID NO:112 respectively; m. SEQ ID NO:88, SEQ ID NO:84, and SEQ ID NO:116 respectively; n. SEQ ID NO:93, SEQ ID NO:94, and SEQ ID NO:101 respectively; o. SEQ ID NO:93, SEQ ID NO:118, and SEQ ID NO:101 respectively; p. SEQ ID NO:119, SEQ ID NO:120, and SEQ ID NO:121 respectively; q. SEQ ID NO:119, SEQ ID NO:124, and SEQ ID NO:125 respectively; r. SEQ ID NO:77, SEQ ID NO:78, and SEQ ID NO:128 respectively; s. SEQ ID NO:83, SEQ ID NO:94, and SEQ ID NO:131 respectively; t. are SEQ ID NO:135, SEQ ID NO:84, SEQ ID NO:136 respectively; u. are SEQ ID NO:88, SEQ ID NO:84, SEQ ID NO:138 respectively; v. are SEQ ID NO:83, SEQ ID NO:141, SEQ ID NO:142 respectively; w. are SEQ ID NO:143, SEQ ID NO:84, SEQ ID NO:144 respectively; x. are SEQ ID NO:146, SEQ ID NO:94, SEQ ID NO:147 respectively; y. are SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121 respectively; z. are SEQ ID NO:119, SEQ ID NO:124, SEQ ID NO:125 respectively; aa. are SEQ ID NO:150, SEQ ID NO:84, SEQ ID NO:151 respectively; bb. are SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154 respectively; or cc. are SEQ ID NO:88, SEQ ID NO:94, SEQ ID NO:158 respectively.

[0132] In some embodiments, the heavy chain variable regions provided herein further comprise four framework regions: heavy chain framework region 1, heavy chain framework region 2, heavy chain framework region 3, and heavy chain framework region 4. Heavy chain framework region 1 is selected from SEQ ID NOs: 160, 168, 175, 188, 194, 204, 210, 224, 233, 284, 259, 265, 268, 271, 274, 281, 295, and 305; heavy chain framework region 2 is selected from SEQ ID NOs: 161, 169, 176, 183, 205, 221, 225, 237, 245, 251, 261, 266, 275, 282, and 296; heavy chain framework region 3 is selected from SEQ ID NOs: 162, 170, 177, 184, 189, 195, 200, 206, 211, 216, 226, 231, 234, 239, 242, 246, 252, 254, 260, 262, 267, 272, 276, 297, and 306; heavy chain framework region 4 is selected from SEQ ID NOs: 163, 178, 190, 196, 212, 217, 227, 255, 269, and 298.

[0133] In some embodiments, the compositions of heavy chain framework region 1, heavy chain framework region 2, heavy chain framework region 3, and heavy chain framework region 4 provided herein are as follows: a. SEQ ID NO: 160, SEQ ID NO: 161, SEQ ID NO: 162, SEQ ID NO: 163, respectively; b. SEQ ID NO: 168, SEQ ID NO: 169, SEQ ID NO: 170, SEQ ID NO: 163, respectively; c. SEQ ID NO: 175, SEQ ID NO: 176, SEQ ID NO: 177, SEQ ID NO: 178, respectively; d. SEQ ID NO: 160, SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 178, respectively; e. SEQ ID NO: 188, SEQ ID NO: 169, SEQ ID NO: 189, SEQ ID NO: 190, respectively; f. SEQ ID NO: 194, SEQ ID NO: 169, SEQ ID NO: 195, SEQ ID NO: 196, respectively; g. SEQ ID NO: 194, SEQ ID NO: 169, SEQ ID NO: 200, SEQ ID NO: 163, respectively; h. are SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:178 respectively; i. are SEQ ID NO:210, SEQ ID NO:169, SEQ ID NO:211, SEQ ID NO:212 respectively; j. are SEQ ID NO:194, SEQ ID NO:169, SEQ ID NO:216, SEQ ID NO:217 respectively; k. are SEQ ID NO:204, SEQ ID NO:221, SEQ ID NO:206, SEQ ID NO:178 respectively; l. are SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227 respectively; m. are SEQ ID NO:194, SEQ ID NO:169, SEQ ID NO:231, SEQ ID NO:163 respectively; n. are SEQ ID NO:233, SEQ ID NO:169, SEQ ID NO:234, SEQ ID NO:178 respectively; o. are SEQ ID NO:210, SEQ ID NO:237, SEQ ID NO:211, SEQ ID NO:212 respectively; p. are SEQ ID NO:194, SEQ ID NO:169, SEQ ID NO:239, SEQ ID NO:190 respectively; q. are SEQ ID NO:194, SEQ ID NO:169, SEQ ID NO:242, SEQ ID NO:178 respectively; r. are SEQ ID NO:284, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:163 respectively; s. are SEQ ID NO:194, SEQ ID NO:245, SEQ ID NO:246, SEQ ID NO:163 respectively; t. are SEQ ID NO:188, SEQ ID NO:251, SEQ ID NO:252, SEQ ID NO:163 respectively; u. are SEQ ID NO:188, SEQ ID NO:169, SEQ ID NO:254, SEQ ID NO:255 respectively; v. are SEQ ID NO:259, SEQ ID NO:169, SEQ ID NO:260, SEQ ID NO:190 respectively; w. are SEQ ID NO:194, SEQ ID NO:261, SEQ ID NO:262, SEQ ID NO:163 respectively; x. are SEQ ID NO:265, SEQ ID NO:266, SEQ ID NO:267, SEQ ID NO:163 respectively; y. are SEQ ID NO:268, SEQ ID NO:169, SEQ ID NO:239, SEQ ID NO:269 respectively; z. are SEQ ID NO:194, SEQ ID NO:169, SEQ ID NO:200, SEQ ID NO:190 respectively; aa. are SEQ ID NO:271, SEQ ID NO:169, SEQ ID NO:272, SEQ ID NO:190 respectively; bb. are SEQ ID NO:274, SEQ ID NO:275, SEQ ID NO:276, SEQ ID NO:178 respectively; cc. are SEQ ID NO:281, SEQ ID NO:282, SEQ ID NO:254, SEQ ID NO:163 respectively; dd. are SEQ ID NO:295, SEQ ID NO:296, SEQ ID NO:297, SEQ ID NO:298 respectively; ee. are SEQ ID NO:305, SEQ ID NO:296, SEQ ID NO:306, SEQ ID NO:298 respectively; ff. are SEQ ID NO:295, SEQ ID NO:296, SEQ ID NO:306, SEQ ID NO:298 respectively; or gg. are SEQ ID NO:305, SEQ ID NO:296, SEQ ID NO:297, SEQ ID NO:298 respectively.

[0134] In some embodiments, the antigen - complementary determining regions and framework regions of the heavy - chain variable region provided herein are arranged in the following order from the N - terminus to the C - terminus: heavy - chain framework region 1 - heavy - chain antigen - complementary determining region 1 - heavy - chain framework region 2 - heavy - chain antigen - complementary determining region 2 - heavy - chain framework region 3 - heavy - chain antigen - complementary determining region 3 - heavy - chain framework region 4.

[0135] In some embodiments, the antibody comprises a heavy - chain constant region, wherein the heavy - chain constant region comprises three domains CH1, CH2, and CH3 from the N - terminus to the C - terminus, and wherein the CH1, CH2, and CH3 are as follows:

[0136] SEQ ID NO.307, SEQ ID NO.309, and SEQ ID NO.310, respectively; or

[0137] SEQ ID NO:307, SEQ ID NO.312, and SEQ ID NO.313, respectively.

[0138] In some embodiments, the heavy - chain variable region provided herein comprises SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 285, 287, 290, and 291 and their homologous sequences, and the homologous sequences have at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence homology with SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 285, 287, 290, and 291.

[0139] In some embodiments, the heavy - chain variable region provided herein is selected from SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 285, 287, 290, and 291.

[0140] In some embodiments, the light - chain variable region provided herein comprises at least one antigen - complementary determining region, and the light - chain antigen - complementary determining regions are selected from SEQ ID NOs: 64, 70, 76, 82, 87, 92, 98, 100, 102, 107, 109, 115, 117, 123, 127, 130, 134, 137, 140, 145, 157, and 159.

[0141] In some embodiments, the light chain variable region comprises three antigen complementarity determining regions, light chain antigen complementarity determining region 1, light chain antigen complementarity determining region 2, and light chain antigen complementarity determining region 3. wherein the light chain antigen complementary determining region 1 is selected from SEQ ID NOs: 62, 68, 74, 80, 86, 90, 96, 99, 105, 108, 113, 122, 126, 129, 132, 148, 149, and 155; the light chain antigen complementary determining region 2 is selected from SEQ ID NOs: 63, 69, 75, 81, 91, 97, 106, 114, 133, 139, and 156; and the light chain antigen complementary determining region 3 is selected from SEQ ID NOs: 64, 70, 76, 82, 87, 92, 98, 100, 102, 107, 109, 115, 117, 123, 127, 130, 134, 137, 140, 145, 157, and 159.

[0142] In some embodiments, the combinations of light chain antigen complementary determining region 1, light chain antigen complementary determining region 2, and light chain antigen complementary determining region 3 provided herein are as follows: a. SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64 respectively; b. SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70 respectively; c. SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76 respectively; d. SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, respectively; e. SEQ ID NO: 86, SEQ ID NO: 69, SEQ ID NO: 87, respectively; f. SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92 respectively; g. SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98 respectively; h. SEQ ID NO: 99, SEQ ID NO: 69, SEQ ID NO: 100, respectively; i. SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 102 respectively; j. SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, respectively; k. are SEQ ID NO:108, SEQ ID NO:69, SEQ ID NO:109 respectively; l. are SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115 respectively; m. are SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:117 respectively; n. are SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:102 respectively; o. are SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:102 respectively; p. are SEQ ID NO:122, SEQ ID NO:69, SEQ ID NO:123 respectively; q. are SEQ ID NO:126, SEQ ID NO:69, SEQ ID NO:127 respectively; r. are SEQ ID NO:129, SEQ ID NO:69, SEQ ID NO:130 respectively; s. are SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134 respectively; t. are SEQ ID NO:126, SEQ ID NO:69, SEQ ID NO:137 respectively; u. are SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:140 respectively; v. are SEQ ID NO:122, SEQ ID NO:69, SEQ ID NO:123 respectively; w. are SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:145 respectively; x. are SEQ ID NO:148, SEQ ID NO:69, SEQ ID NO:109 respectively; y. are SEQ ID NO:149, SEQ ID NO:63, SEQ ID NO:109 respectively; z. are SEQ ID NO:122, SEQ ID NO:69, SEQ ID NO:123 respectively; aa. are SEQ ID NO:126, SEQ ID NO:69, SEQ ID NO:130 respectively; bb. are SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157 respectively; or cc. are SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:159 respectively.

[0143] In some embodiments, the light chain variable region provided herein comprises 4 framework regions, light chain framework region 1, light chain framework region 2, light chain framework region 3 and light chain framework region 4. Among them, light chain framework region 1 is selected from SEQ ID NOs: 164, 171, 179, 185, 191, 197, 201, 207, 213, 218, 222, 228, 232, 247, 256, 263, 270, 277, 283, 299, and 303; light chain framework region 2 is selected from SEQ ID NOs: 165, 172, 180, 186, 192, 198, 202, 208, 214, 219, 223, 229, 235, 240, 243, 248, 257, 264, 278, 300 and 304; light chain framework region 3 is selected from SEQ ID NOs: 166, 173, 181, 187, 193, 199, 203, 209, 220, 230, 236, 238, 241, 244, 249, 253, 258, 273, 279 and 301; light chain framework region 4 is selected from SEQ ID NOs: 167, 174, 182, 215, 250, 280 and 302.

[0144] In some embodiments, the combinations of light chain framework region 1, light chain framework region 2, light chain framework region 3 and light chain framework region 4 provided herein are as follows: a. are SEQ ID NO:164, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:167 respectively; b. are SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174 respectively; c. are SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182 respectively; d. are SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:174 respectively; e. SEQ ID NO:191, SEQ ID NO:192, SEQ ID NO:193, SEQ ID NO:174 respectively; f. SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:174 respectively; g. SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:167 respectively; h. SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:174 respectively; i. SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:203, SEQ ID NO:215 respectively; j. SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:174 respectively; k. SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:209, SEQ ID NO:174 respectively; l. SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:174 respectively; m. SEQ ID NO:232, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:167 respectively; n. SEQ ID NO:201, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:174 respectively; o. SEQ ID NO:201, SEQ ID NO:214, SEQ ID NO:238, SEQ ID NO:215 respectively; p. SEQ ID NO:171, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:174 respectively; q. SEQ ID NO:171, SEQ ID NO:243, SEQ ID NO:244, SEQ ID NO:174 respectively; r. are SEQ ID NO:222, SEQ ID NO:165, SEQ ID NO:209, SEQ ID NO:174 respectively; s. are SEQ ID NO:247, SEQ ID NO:248, SEQ ID NO:249, SEQ ID NO:250 respectively; t. are SEQ ID NO:171, SEQ ID NO:243, SEQ ID NO:253, SEQ ID NO:167 respectively; u. are SEQ ID NO:256, SEQ ID NO:257, SEQ ID NO:258, SEQ ID NO:174 respectively; v. are SEQ ID NO:171, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:174 respectively; w. are SEQ ID NO:263, SEQ ID NO:264, SEQ ID NO:199, SEQ ID NO:174 respectively; x. are SEQ ID NO:222, SEQ ID NO:165, SEQ ID NO:209, SEQ ID NO:174 respectively; y. are SEQ ID NO:270, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:174 respectively; z. are SEQ ID NO:171, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:174 respectively; aa. are SEQ ID NO:171, SEQ ID NO:243, SEQ ID NO:273, SEQ ID NO:174 respectively; bb. are SEQ ID NO:277, SEQ ID NO:278, SEQ ID NO:279, SEQ ID NO:280 respectively; cc. are SEQ ID NO:283, SEQ ID NO:278, SEQ ID NO:279, SEQ ID NO:174 respectively; dd. are SEQ ID NO:299, SEQ ID NO:300, SEQ ID NO:301, SEQ ID NO:302 respectively; ee. are SEQ ID NO:303, SEQ ID NO:304, SEQ ID NO:301, SEQ ID NO:302 respectively; or ff. are SEQ ID NO:299, SEQ ID NO:304, SEQ ID NO:301, SEQ ID NO:302 respectively.

[0145] In some embodiments, the antigen - complementary determining regions and framework regions of the light - chain variable region provided herein are arranged in the following order from the N - terminus to the C - terminus: light - chain framework region 1 - light - chain antigen - complementary determining region 1 - light - chain framework region 2 - light - chain antigen - complementary determining region 2 - light - chain framework region 3 - light - chain antigen - complementary determining region 3 - light - chain framework region 4.

[0146] In some embodiments, the antibody provided herein further comprises a light - chain constant region SEQ ID NO:311.

[0147] In some embodiments, the light - chain variable region provided herein comprises SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 54, 56, 58, 286, 288 and 289 and their homologous sequences, and the homologous sequences have at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence homology with SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 54, 56, 58, 286, 288, and 289.

[0148] In some embodiments, the light - chain variable region provided herein is selected from SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 54, 56, 58, 286, 288 and 289.

[0149] In some embodiments, the heavy - chain variable region and the light - chain variable region provided herein comprise the following combinations and comprise sequences having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology with the following sequences and their combinations: a. are SEQ ID NO:1, and SEQ ID NO:2 respectively; b. are SEQ ID NO:3, and SEQ ID NO:4 respectively; c. SEQ ID NO:5 and SEQ ID NO:6 respectively; d. SEQ ID NO:7 and SEQ ID NO:8 respectively; e. SEQ ID NO:9 and SEQ ID NO:10 respectively; f. SEQ ID NO:11 and SEQ ID NO:12 respectively; g. SEQ ID NO:13 and SEQ ID NO:14 respectively; h. SEQ ID NO:15 and SEQ ID NO:16 respectively; i. SEQ ID NO:17 and SEQ ID NO:18 respectively; j. SEQ ID NO:19 and SEQ ID NO:20 respectively; k. SEQ ID NO:21 and SEQ ID NO:22 respectively; l. SEQ ID NO:23 and SEQ ID NO:24 respectively; m. SEQ ID NO:25 and SEQ ID NO:26 respectively; n. SEQ ID NO:27 and SEQ ID NO:28 respectively; o. SEQ ID NO:29 and SEQ ID NO:30 respectively; p. SEQ ID NO:31 and SEQ ID NO:32 respectively; q. SEQ ID NO:33 and SEQ ID NO:34 respectively; r. SEQ ID NO:35 and SEQ ID NO:36 respectively; s. SEQ ID NO:37 and SEQ ID NO:38 respectively; t. SEQ ID NO:39 and SEQ ID NO:40 respectively; u. SEQ ID NO:41 and SEQ ID NO:42 respectively; v. SEQ ID NO:43 and SEQ ID NO:32 respectively; w. SEQ ID NO:45 and SEQ ID NO:46 respectively; x. SEQ ID NO:47 and SEQ ID NO:48 respectively; y. are SEQ ID NO:49 and SEQ ID NO:50 respectively; z. are SEQ ID NO:51 and SEQ ID NO:32 respectively; aa. are SEQ ID NO:53 and SEQ ID NO:54 respectively; bb. are SEQ ID NO:55 and SEQ ID NO:56 respectively; cc. are SEQ ID NO:57 and SEQ ID NO:58 respectively; dd. are SEQ ID NO:285 and SEQ ID NO:286 respectively; ee. are SEQ ID NO:287 and SEQ ID NO:288 respectively; ff. are SEQ ID NO:287 and SEQ ID NO:289 respectively; gg. are SEQ ID NO:290 and SEQ ID NO:288 respectively; hh. are SEQ ID NO:290 and SEQ ID NO:286 respectively; ii. are SEQ ID NO:291 and SEQ ID NO:286 respectively; jj. are SEQ ID NO:292 and SEQ ID NO:293 respectively; or kk. are SEQ ID NO:294 and SEQ ID NO:293 respectively.

[0150] In some embodiments, the heavy chain variable regions and light chain variable regions provided herein include the following combinations: a. are SEQ ID NO:1 and SEQ ID NO:2 respectively; b. are SEQ ID NO:3 and SEQ ID NO:4 respectively; c. are SEQ ID NO:5 and SEQ ID NO:6 respectively; d. are SEQ ID NO:7 and SEQ ID NO:8 respectively; e. are SEQ ID NO:9 and SEQ ID NO:10 respectively; f. are SEQ ID NO:11 and SEQ ID NO:12 respectively; g. are SEQ ID NO:13 and SEQ ID NO:14 respectively; h. SEQ ID NO:15 and SEQ ID NO:16 respectively; i. SEQ ID NO:17 and SEQ ID NO:18 respectively; j. SEQ ID NO:19 and SEQ ID NO:20 respectively; k. SEQ ID NO:21 and SEQ ID NO:22 respectively; l. SEQ ID NO:23 and SEQ ID NO:24 respectively; m. SEQ ID NO:25 and SEQ ID NO:26 respectively; n. SEQ ID NO:27 and SEQ ID NO:28 respectively; o. SEQ ID NO:29 and SEQ ID NO:30 respectively; p. SEQ ID NO:31 and SEQ ID NO:32 respectively; q. SEQ ID NO:33 and SEQ ID NO:34 respectively; r. SEQ ID NO:35 and SEQ ID NO:36 respectively; s. SEQ ID NO:37 and SEQ ID NO:38 respectively; t. SEQ ID NO:39 and SEQ ID NO:40 respectively; u. SEQ ID NO:41 and SEQ ID NO:42 respectively; v. SEQ ID NO:43 and SEQ ID NO:32 respectively; w. SEQ ID NO:45 and SEQ ID NO:46 respectively; x. SEQ ID NO:47 and SEQ ID NO:48 respectively; y. SEQ ID NO:49 and SEQ ID NO:50 respectively; z. SEQ ID NO:51 and SEQ ID NO:32 respectively; aa. SEQ ID NO:53 and SEQ ID NO:54 respectively; bb. SEQ ID NO:55 and SEQ ID NO:56 respectively; cc. SEQ ID NO:57 and SEQ ID NO:58 respectively; dd. are SEQ ID NO:285 and SEQ ID NO:286 respectively; ee. are SEQ ID NO:287 and SEQ ID NO:288 respectively; ff. are SEQ ID NO:287 and SEQ ID NO:289 respectively; gg. are SEQ ID NO:290 and SEQ ID NO:288 respectively; hh. are SEQ ID NO:290 and SEQ ID NO:286 respectively; ii. are SEQ ID NO:291 and SEQ ID NO:286 respectively; jj. are SEQ ID NO:292 and SEQ ID NO:293 respectively; or kk. are SEQ ID NO:294 and SEQ ID NO:293 respectively.

[0151] In some embodiments, the light chain variable region provided herein comprises at least one antigen - complementary determining region, and the light chain antigen - complementary determining regions are selected from SEQ ID NOs: 64, 70, 76, 82, 87, 92, 98, 100, 102, 107, 109, 115, 117, 123, 127, 130, 134, 137, 140, 145, 157 and 159.

[0152] In some embodiments, the light chain variable region comprises 3 antigen - complementary determining regions, namely light chain antigen - complementary determining region 1, light chain antigen - complementary determining region 2 and light chain antigen - complementary determining region 3. Among them, light chain antigen - complementary determining region 1 is selected from SEQ ID NOs: 62, 68, 74, 80, 86, 90, 96, 99, 105, 108, 113, 122, 126, 129, 132, 148, 149, and 155; light chain antigen - complementary determining region 2 is selected from SEQ ID NOs: 63, 69, 75, 81, 91, 97, 106, 114, 133, 139, and 156; light chain antigen - complementary determining region 3 is selected from SEQ ID NOs: 64, 70, 76, 82, 87, 92, 98, 100, 102, 107, 109, 115, 117, 123, 127, 130, 134, 137, 140, 145, 157, and 159.

[0153] In some embodiments, the combinations of light chain antigen - complementary determining region 1, light chain antigen - complementary determining region 2 and light chain antigen - complementary determining region 3 provided herein are as follows: a. SEQ ID NO:62, SEQ ID NO:63, and SEQ ID NO:64 respectively; b. SEQ ID NO:68, SEQ ID NO:69, and SEQ ID NO:70 respectively; c. SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76 respectively; d. SEQ ID NO:80, SEQ ID NO:81, and SEQ ID NO:82 respectively; e. SEQ ID NO:86, SEQ ID NO:69, and SEQ ID NO:87 respectively; f. SEQ ID NO:90, SEQ ID NO:91, and SEQ ID NO:92 respectively; g. SEQ ID NO:96, SEQ ID NO:97, and SEQ ID NO:98 respectively; h. SEQ ID NO:99, SEQ ID NO:69, and SEQ ID NO:100 respectively; i. SEQ ID NO:96, SEQ ID NO:97, and SEQ ID NO:102 respectively; j. SEQ ID NO:105, SEQ ID NO:106, and SEQ ID NO:107 respectively; k. SEQ ID NO:108, SEQ ID NO:69, and SEQ ID NO:109 respectively; l. SEQ ID NO:113, SEQ ID NO:114, and SEQ ID NO:115 respectively; m. SEQ ID NO:105, SEQ ID NO:106, and SEQ ID NO:117 respectively; n. SEQ ID NO:96, SEQ ID NO:97, and SEQ ID NO:102 respectively; o. SEQ ID NO:96, SEQ ID NO:97, and SEQ ID NO:102 respectively; p. SEQ ID NO:122, SEQ ID NO:69, and SEQ ID NO:123 respectively; q. SEQ ID NO:126, SEQ ID NO:69, and SEQ ID NO:127 respectively; r. are SEQ ID NO:129, SEQ ID NO:69, SEQ ID NO:130 respectively; s. are SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134 respectively; t. are SEQ ID NO:126, SEQ ID NO:69, SEQ ID NO:137 respectively; u. are SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:140 respectively; v. are SEQ ID NO:122, SEQ ID NO:69, SEQ ID NO:123 respectively; w. are SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:145 respectively; x. are SEQ ID NO:148, SEQ ID NO:69, SEQ ID NO:109 respectively; y. are SEQ ID NO:149, SEQ ID NO:63, SEQ ID NO:109 respectively; z. are SEQ ID NO:122, SEQ ID NO:69, SEQ ID NO:123 respectively; aa. are SEQ ID NO:126, SEQ ID NO:69, SEQ ID NO:130 respectively; bb. are SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157 respectively; or cc. are SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:159 respectively.

[0154] In some embodiments, the light chain variable regions provided herein include 4 framework regions, light chain framework region 1, light chain framework region 2, light chain framework region 3, and light chain framework region 4. Among them, light chain framework region 1 is selected from SEQ ID NOs: 164, 171, 179, 185, 191, 197, 201, 207, 213, 218, 222, 228, 232, 247, 256, 263, 270, 277, 283, 299, and 303; light chain framework region 2 is selected from SEQ ID NOs: 165, 172, 180, 186, 192, 198, 202, 208, 214, 219, 223, 229, 235, 240, 243, 248, 257, 264, 278, 300, and 304; light chain framework region 3 is selected from SEQ ID NOs: 166, 173, 181, 187, 193, 199, 203, 209, 220, 230, 236, 238, 241, 244, 249, 253, 258, 273, 279, and 301; light chain framework region 4 is selected from SEQ ID NOs: 167, 174, 182, 215, 250, 280, and 302.

[0155] In some embodiments, the combinations of light chain framework region 1, light chain framework region 2, light chain framework region 3, and light chain framework region 4 provided herein are as follows: a. SEQ ID NO: 164, SEQ ID NO: 165, SEQ ID NO: 166, SEQ ID NO: 167, respectively; b. SEQ ID NO: 171, SEQ ID NO: 172, SEQ ID NO: 173, SEQ ID NO: 174, respectively; c. SEQ ID NO: 179, SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 182, respectively; [[ID=##ID=11]]d. SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 174, respectively; e. SEQ ID NO: 191, SEQ ID NO: 192, SEQ ID NO: 193, SEQ ID NO: 174, respectively; f. SEQ ID NO: 197, SEQ ID NO: 198, SEQ ID NO: 199, SEQ ID NO: 174, respectively; g. SEQ ID NO: 201, SEQ ID NO: 202, SEQ ID NO: 203, SEQ ID NO: 167, respectively; h. are SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:174 respectively; i. are SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:203, SEQ ID NO:215 respectively; j. are SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:174 respectively; k. are SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:209, SEQ ID NO:174 respectively; l. are SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:174 respectively; m. are SEQ ID NO:232, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:167 respectively; n. are SEQ ID NO:201, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:174 respectively; o. are SEQ ID NO:201, SEQ ID NO:214, SEQ ID NO:238, SEQ ID NO:215 respectively; p. are SEQ ID NO:171, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:174 respectively; q. are SEQ ID NO:171, SEQ ID NO:243, SEQ ID NO:244, SEQ ID NO:174 respectively; r. are SEQ ID NO:222, SEQ ID NO:165, SEQ ID NO:209, SEQ ID NO:174 respectively; s. are SEQ ID NO:247, SEQ ID NO:248, SEQ ID NO:249, SEQ ID NO:250 respectively; t. are SEQ ID NO:171, SEQ ID NO:243, SEQ ID NO:XX3, SEQ ID NO:167 respectively; It should be noted that in the original text, there may be a typo in the "SEQ ID NO:XX3" in item t. It is recommended to check and correct it according to the actual situation. Here, it is translated as "XX3" for the purpose of maintaining the consistency of the translation.u. are SEQ ID NO:256, SEQ ID NO:257, SEQ ID NO:258, SEQ ID NO:174 respectively; v. are SEQ ID NO:171, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:174 respectively; w. are SEQ ID NO:263, SEQ ID NO:264, SEQ ID NO:199, SEQ ID NO:174 respectively; x. are SEQ ID NO:222, SEQ ID NO:165, SEQ ID NO:209, SEQ ID NO:174 respectively; y. are SEQ ID NO:270, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:174 respectively; z. are SEQ ID NO:171, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:174 respectively; aa. are SEQ ID NO:171, SEQ ID NO:243, SEQ ID NO:273, SEQ ID NO:174 respectively; bb. are SEQ ID NO:277, SEQ ID NO:278, SEQ ID NO:279, SEQ ID NO:280 respectively; cc. are SEQ ID NO:283, SEQ ID NO:278, SEQ ID NO:279, SEQ ID NO:174 respectively; dd. are SEQ ID NO:299, SEQ ID NO:300, SEQ ID NO:301, SEQ ID NO:302 respectively; ee. are SEQ ID NO:303, SEQ ID NO:304, SEQ ID NO:301, SEQ ID NO:302 respectively; or ff. are SEQ ID NO:299, SEQ ID NO:304, SEQ ID NO:301, SEQ ID NO:302 respectively.

[0156] In some embodiments, the antigen - complementary determining regions and framework regions of the light - chain variable regions provided herein are arranged in the following order from the N - terminus to the C - terminus of the sequence: light - chain framework region 1 - light - chain antigen - complementary determining region 1 - light - chain framework region 2 - light - chain antigen - complementary determining region 2 - light - chain framework region 3 - light - chain antigen - complementary determining region 3 - light - chain framework region 4.

[0157] In some embodiments, the antibody provided herein further comprises a light - chain constant region SEQ ID NO:311.

[0158] In some embodiments, the light - chain variable regions provided herein comprise SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 54, 56, 58, 286, 288, and 289 and their homologous sequences, and the homologous sequences have at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence homology with SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 54, 56, 58, 286, 288, and 289.

[0159] In some embodiments, the light - chain variable regions provided herein are selected from SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 54, 56, 58, 286, 288, and 289.

[0160] In some embodiments, the antibody described herein is a chimeric antibody. In some embodiments, the chimeric antibody is derived from a murine antibody and / or a humanized antibody. As used herein, a "chimeric antibody" refers to an antibody having a portion of a heavy chain and / or a light chain derived from one species and the remaining portion of the heavy chain and / or heavy chain derived from a different species. In some embodiments, the chimeric antibody comprises a constant region derived from a human and a variable region derived from a non - human animal such as a mouse. In some embodiments, the non - human animal refers to a mammal, such as a mouse, a rat, or a rabbit. The chimeric antibody can also comprise variable domains and constant domains derived from two different antibodies of the same species.

[0161] In some embodiments, the antibodies described herein are humanized or partially humanized antibodies. As used herein, a "humanized antibody" refers to an antibody that has been modified to reduce its immunogenicity in humans. Humanization can be performed using conventional methods known in the art. In some embodiments, humanization is performed by grafting CDR sequences of non-human origin onto human framework sequences. In some embodiments, additional framework region modifications can be made within the human framework sequences. In some embodiments, humanization can be performed by enhanced binary substitution (Townsend et al., Proceedings of the National Academy of Sciences 112.50(2015):15354-15359). As used herein, "partially humanized" means that a portion of the antibody has been modified to reduce its immunogenicity in humans. For example, in some embodiments, a pair of heavy and light chains are modified to reduce immunogenicity in humans.

[0162] In some embodiments, the antibodies described herein are monoclonal antibodies. As used herein, a "monoclonal antibody (mAb)" refers to an antibody molecule composed of a single molecule. Monoclonal antibody compositions exhibit a single binding specificity and affinity for a particular epitope. In some embodiments, monoclonal antibodies are present in a homogeneous or substantially homogeneous population.

[0163] In some embodiments, the antibodies described herein are polyclonal antibodies. As used herein, a "polyclonal antibody" refers to a combination of antibodies composed of multiple different molecules that can recognize multiple epitopes on an antigen.

[0164] In some embodiments, the antibodies described herein are multispecific antibodies. In some embodiments, the antibodies described herein are bispecific antibodies. As used herein, a "multispecific antibody" refers to an antibody that can specifically bind to more than one epitope. A "bispecific antibody" refers to an antibody that can specifically bind to two distinct epitopes.

[0165] In some embodiments, the antibodies described herein are recombinant antibodies. As used herein, "recombinant antibodies" include all antibodies prepared, expressed, produced, or isolated by recombinant means, such as, but not limited to, antibodies isolated from host cells transformed to express the antibody, antibodies isolated from recombinant, combinatorial antibody libraries, and antibodies produced or isolated by other means such as gene recombination.

[0166] In some embodiments, the antibodies described herein are heavy chain antibodies. As used herein, a "heavy chain antibody" refers to an antibody composed of two heavy chains without a light chain.

[0167] In some embodiments, the antibodies described herein are single-domain antibodies. As used herein, "single-domain antibody (sdAb)" or "nanobody", which are used interchangeably, refers to an antibody fragment consisting of a single monomeric variable antibody domain.

[0168] In some embodiments, the antibodies described herein can be conjugated to a cytotoxic molecule. In some embodiments, the antibody is conjugated to the cytotoxic molecule via a short peptide. In some embodiments, the antibody is directly fused to the cytotoxic molecule by recombinant means. As used herein, "cytotoxic agent", "cytotoxic substance" or "cytotoxic drug" refers to a substance that is toxic to cells and / or capable of killing cells, including cancer cells. Some exemplary cytotoxic agents are actinomycin, all-trans retinoic acid, azacitidine, azathioprine, bleomycin, bortezomib, carboplatin, capecitabine, cisplatin, clozapine, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, teniposide, thioguanine, topotecan, valrubicin, vemurafenib, vinblastine, vincristine and vindesine.

[0169] In some embodiments, the antibodies described herein are ADCC-enhanced antibodies. In some embodiments, the antibody is a non-fucosylated antibody. In some embodiments, the antibody comprises an Fc region that is engineered to enhance ADCC.

[0170] "Antibody-dependent cell-mediated cytotoxicity" and "ADCC" refer to a cell-mediated reaction in which effector cells expressing Fc receptors (FcRs) recognize an antibody or antigen-binding fragment bound to a target cell, followed by lysis of the target cell. "ADCC activity" refers to the ability of an antibody or antigen-binding fragment bound to a target cell to initiate an ADCC reaction.

[0171] As described in Example 9, ADCC activity is measured using an in vivo assay. ADCC activity is determined by calculating the EC50 and maximum potency of the antibody. In some embodiments, the ADCC activity of the antibody is enhanced by making the antibody non-fucosylated (fucose-fucosylation). In some embodiments, the ADCC activity of the antibody is enhanced by engineering its Fc region to increase its affinity for Fc receptors on NK cells. Example 7 further discloses the details of these two methods for enhancing the ADCC activity of antibodies. Table 2 Specifically bind

[0172] The anti-FGFR2b antibody provided by the present invention can specifically bind to fibroblast growth factor receptor 2b (FGFR2b).

[0173] In some embodiments, the antibodies described herein specifically bind to fibroblast growth factor receptor 2b (FGFR2b).

[0174] [[ID=�1]]In some embodiments, the antibodies described herein bind to FGFR2b with a KD of about 10 nM or lower. In some embodiments, the antibodies described herein bind to FGFR2b with a KD of about 9 nM or lower. In some embodiments, the antibodies described herein bind to FGFR2b with a KD of about 5 nM or lower. In some embodiments, the antibodies described herein bind to FGFR2b with a KD of about 4 nM, 3 nM, 2 nM, 1 nM, 0.1 nM or lower.

[0175] In some embodiments, FGFR2b is human FGFR2b. In some embodiments, FGFR2b is mouse FGFR2b or cynomolgus monkey FGFR2b.

[0176] In some embodiments, the antibodies provided herein have a specific binding affinity for human FGFR2b that is sufficient for diagnostic and / or therapeutic uses. For example, by contacting the antibodies or their compositions described herein with a sample, the antibodies described herein can be used to detect the presence of FGFR2 in the sample, and the detection of binding to at least one antibody indicates the presence of FGFR2b. By quantifying the bound antibodies, this method can also be used to detect overexpression of the FGFR2 gene, which is closely related to abnormal FGFR2 signaling and cancer.

[0177] In some embodiments, the antibodies described herein can be used to block FGFR2b, particularly human FGFR2b, from binding to its ligand. Thus, the antibodies described herein can provide biological activities such as inhibiting the proliferation of FGFR2b overexpressing cells.

[0178] In some embodiments, the antibodies described herein do not bind to FGFR1b, FGFR1c, FGFR2c, FGFR 3b, FGFR3c, or FGFR4. In some embodiments, the antibodies described herein do not have a detectable binding ability to FGFR1b, FGFR1c, FGFR2c, FGFR 3b, FGFR3c, or FGFR4. As used herein, the phrase "detectable binding" means that the Response value measured by biolayer interferometry (BLI) using Octet at the KD value is not less than 0.1, or the OD450 value measured by ELISA at 50 nM is not less than 1.0. The protocols for BLI and ELISA are described in Example 3 below.

[0179] The antibodies described herein have nanomolar equilibrium dissociation constants (KDs) with the extracellular domains (ECDs) of mouse, cynomolgus monkey, and human FGFR2b, indicating that the antibodies described herein have good cross-species affinity. Thus, mice and cynomolgus monkeys are considered suitable species for toxicology studies with the antibodies described herein. Pharmaceutical Compositions

[0180] In another aspect, the present invention provides a composition comprising the antibodies described herein.

[0181] In another aspect, the present invention provides a pharmaceutical composition comprising the antibodies described herein and a pharmaceutically acceptable carrier.

[0182] The compositions or pharmaceutical compositions described herein may comprise a pharmaceutically acceptable carrier, diluent, or excipient. As used herein, "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, thickening agent, diluent, preservative, dye / colorant, flavorant, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent approved by the US Food and Drug Administration for use in humans or livestock. Exemplary pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; Huanggang; malt; gelatin; talc; cocoa butter; waxes; animal and vegetable fats; paraffin; silicone; bentonite; silicic acid; zinc oxide; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; diols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solution; and any other compatible substances used in pharmaceutical formulations.

[0183] Liquid pharmaceutical compositions, whether in solution, suspension, or other similar form, may include one or more of the following: sterile diluents such as water for injection, saline solutions, preferably physiological saline; Ringer's solution; isotonic sodium chloride; fixed oils that can serve as solvents or suspending media, such as synthetic monoglycerides or diglycerides; polyethylene glycol; glycerol, propylene glycol, or other solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffering agents such as acetate, citrate, or phosphate; and agents for adjusting tonicity such as sodium chloride or glucose. Parenteral formulations may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. Injectable pharmaceutical compositions must be sterile.

[0184] The compositions may be suitable for intravenous, intratumoral, oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, oral, ophthalmic, or other routes of administration. Polynucleotide

[0185] Polynucleotide In another aspect, the present disclosure provides polynucleotides encoding the antibodies described herein.

[0186] ​ vector

[0187] In another aspect, the present invention provides a vector comprising the polynucleotide described herein. Such a vector can be a plasmid vector, a viral vector, a vector for baculovirus expression, a transposon-based vector, or any other vector suitable for introducing the polynucleotide of the present invention into a given organism or genetic background by any means. For example, the polynucleotide encoding the antibody described herein can be inserted into an expression vector. The DNA fragment encoding the antibody can be ligated to regulatory elements in the expression vector to ensure the expression of the immunoglobulin polypeptide. Such regulatory elements include signal peptides, promoters (e.g., native or heterologous promoters), enhancer elements, and transcription terminators, and are compatible with the host cell selected for expressing the antibody. After the vector is introduced into a suitable host, the host is cultured under conditions that select for high-level expression.

[0188] Suitable expression vectors typically replicate in the host organism either as episomes or as an integral part of the host chromosomal DNA. Usually, the expression vector contains a selectable marker, such as ampicillin resistance, hygromycin resistance, tetracycline resistance, kanamycin resistance, or neomycin resistance, to permit the detection of those cells transformed with the desired DNA sequence. Vectors, promoters, and enhancer elements are mostly known in the art and can be purchased from commercial suppliers.

[0189] The term "host cell" refers to a cell into which a vector has been introduced. The term "host" refers not only to the particular subject cell but also to the progeny of such a cell. Due to mutations or environmental influences, certain modifications may occur in the progeny, and thus such progeny may not be identical to the parental cell, but are still included within the scope of the term "host cell" as used herein. Such host cells can be eukaryotic cells, prokaryotic cells, plant cells, or archaeal cells. Escherichia coli, bacilli (such as Bacillus subtilis), and other Enterobacteriaceae (such as Salmonella, Serratia, and various Pseudomonas species) are examples of prokaryotic host cells. Other microorganisms, such as yeast, can also be used for expression. Saccharomyces cerevisiae and Pichia pastoris are examples of suitable yeast host cells. Exemplary eukaryotic cells can be of mammalian, insect, avian, or other animal origin. cell

[0190] In another aspect, the present invention provides a cell capable of expressing the antibody described herein.

[0191] In another aspect, the present invention provides a cell comprising the polynucleotide described herein and / or the vector described herein.

[0192] The cells described herein include, but are not limited to, eukaryotic cells, prokaryotic cells, plant cells, or archaeal cells. Exemplary eukaryotic cells include, but are not limited to, those of mammalian, insect, avian, or other animal origin.

[0193] Exemplary prokaryotic cells include, but are not limited to, Escherichia coli, Bacilli such as Bacillus subtilis, and other Enterobacteriaceae such as Salmonella, Serratia, and various Pseudomonas. Other microorganisms such as yeast can also be used for expression. Saccharomyces cerevisiae and Pichia pastoris are examples of suitable yeast host cells.

[0194] The cells described herein include various cells derived from an individual animal, passage cells, primary cultured cells, cell lines, recombinant cells, and microbial cells.

[0195] In some embodiments, the cells are hybridoma cells. In some embodiments, the hybridoma cells are obtained by fusing myeloma cells with cells that produce the antibodies described herein. In some embodiments, the cells that produce the antibodies described herein are spleen cells. Methods of Use

[0196] In another aspect, the present invention provides a method for producing an antibody, comprising culturing the cells described herein and recovering the antibody from the cells.

[0197] The antibodies described herein can be obtained by methods known in the art. For example, monoclonal antibodies can be obtained by the following steps: (1) preparing an antigen; (2) immunizing; (3) preparing spleen cells; (4) preparing myeloma cells; (5) fusing the spleen cells with the myeloma cells; (6) screening for hybridomas that produce the antibody; and (7) obtaining a single cell clone.

[0198] Exemplary methods for producing the monoclonal antibodies described herein are provided. First, an animal such as a rat or a mouse is immunized with a recombinant human FGFR2b-Fc protein or a soluble form thereof according to the method of Kohler and Milstein ( et al., Nature, 1975; 256(5517), 495-497; Kennet, R.H., T.J. McKeam, and K.B. Bechtol. "Methods for production and characterization of monoclonal antibodies." Monoclonal Antibodies (Appendix), R.H. Kennet, T.J. McKeam, and K.B. Bechtol, eds., Plenum, New York, 1980). The recombinant human FGFR2b antigen is available from a distributor. Then, the cells that produce the antibodies described herein are isolated from the spleen of the immunized animal. These cells are then fused with myeloma cells to establish hybridomas. The monoclonal antibodies described herein can be obtained from the cultures of these hybridomas.

[0199] The genus and species of the mouse or rat are not restricted. In the case of mice, for example, BALB / c, C57BL / 6, CD1, SJL can be used. These mice can be obtained from laboratory animal breeders or distributors. The BALB / c mouse strain is preferred. The mice are preferably 5 to 12 weeks old, more preferably 6 to 8 weeks old, when immunized.

[0200] Exemplary methods for determining antibody titers include, but are not limited to, immunoassays such as ELISA.

[0201] Cells capable of producing the antibodies described herein can be prepared according to methods known in the art. These cells are derived from splenocytes or lymphocytes of immunized animals. The myeloma cells used for cell fusion are not particularly restricted and can be appropriately selected from cell lines known in the art. According to methods known in the art, the antibody-producing cells can be fused with myeloma cells under conditions that prevent excessive reduction of cell viability.

[0202] The screening of hybridomas includes, but is not limited to, binding and blocking at the protein level, binding and blocking at the cell level, determination of signal pathway blockade, and determination of cell proliferation inhibition. Hybridomas can be cloned using the limiting dilution method.

[0203] The antibodies described herein can also be produced by recombinant expression. The desired antibodies can be expressed in any organism suitable for producing the desired amount and form of the antibody. Expression hosts include prokaryotes and eukaryotes such as Escherichia coli, yeast, plants, insect cells, mammalian cells, including human cell lines and transgenic animals. The protein expression levels of the expression hosts and the types of post-translational modifications of the expressed proteins may vary. The expression host can be selected based on factors such as regulatory and safety considerations, production costs, and the need and method for purification.

[0204] Many expression vectors are available and known to those skilled in the art and can be used for protein expression. The choice of expression vector will be influenced by the choice of host expression system. Generally, an expression vector can include a transcriptional promoter and optionally an enhancer, translation signals, and transcriptional and translational termination signals. Expression vectors for stable transformation usually have selectable markers that allow the selection and maintenance of transformed cells. In some cases, an origin of replication can be used to amplify the copy number of the vector.

[0205] The expression vector can be introduced into the host cell by methods such as transformation, transfection, transduction, infection, electroporation, and sonication. Those skilled in the art are able to select the methods and conditions suitable for introducing the expression vector into the host cell.

[0206] After introducing a vector containing a selectable marker, cells can be allowed to grow in enriched medium for 1-2 days and then switched to selective medium. The purpose of the selectable marker is to confer resistance to selection, and its presence allows only the growth and recovery of cells that have successfully incorporated the expression sequence. The transformed resistant cells can be stably propagated by tissue culture techniques. In some embodiments, the antibodies described herein are expressed in mammalian expression systems. The expression construct can be transferred into mammalian cells by viral infection (such as an adenoviral construct) or direct DNA transfer (such as liposomes, calcium phosphate, DEAE dextran) and by physical means (such as electroporation and microinjection). In some embodiments, the antibodies described herein are delivered using viral transduction, such as with a vector.

[0207] After the vector is introduced into a suitable host cell, the host cell will be cultured under conditions suitable for high expression of the target protein. Those skilled in the art can select conditions suitable for expressing the antibodies described herein.

[0208] The antibodies described herein can be purified according to any known method in the art, such as protein A chromatography, anion exchange chromatography, and cation exchange chromatography. Those skilled in the art can select appropriate methods and conditions to purify the antibodies described herein.

[0209] The present invention provides a method for inhibiting the growth of FGFR2b-positive cancer cells and the progression of tumor diseases by providing novel anti-FGFR2b antibodies. The anti-FGFR2b antibodies of the present invention bind only to FGFR2IIIb and not to FGFR2IIIc and can partially or completely inhibit one or more biological activities of FGFR2b. The first important activity of FGFR2b that can be inhibited by the anti-FGFR2b antibodies described herein is the ability of FGFR2b to bind one or more or all of its FGF ligands, such as but not limited to FGF1, FGF3, FGF7, FGF10, and FGF22. The second activity of FGFR2b that can be inhibited by the anti-FGFR2b antibodies described herein is the cell proliferation of cells overexpressing FGFR2b (such as cancer cells). Other functions of FGFR2b that can be inhibited by the anti-FGFR2b antibodies described herein include but are not limited to signal transduction pathways stimulated by the binding of FGF ligands to FGFR2b, such as FGFR2b phosphorylation. In some embodiments, the anti-FGFR2b antibodies described herein inhibit these activities induced by one or more of the above FGFs.

[0210] The anti-FGFR2b antibodies described herein can also inhibit the growth of tumor xenografts overexpressing FGFR2b, such as SNU-16 or OCUM-2M xenografts.

[0211] In another aspect, the present invention provides a method of blocking the binding of FGFR2b to at least one fibroblast growth factor (FGF), comprising administering to a subject an effective amount of an antibody described herein or a composition described herein. In some embodiments, the FGF is selected from FGF1, FGF3, FGF7, FGF10, and FGF22. Fibroblast growth factors (FGFs) are a family of cell-signaling proteins produced by macrophages; they are involved in a wide variety of processes, especially as key elements in the normal development of animal cells. Any abnormality in their function can lead to a series of developmental defects. These growth factors typically act as systemic or locally circulating molecules from an extracellular source to activate cell surface receptors.

[0212] In another aspect, the present invention provides a method of inhibiting cell proliferation, comprising administering to a subject an effective amount of an antibody described herein or a composition described herein. In some embodiments, the cell proliferation is FGF-induced cell proliferation. In some embodiments, the cells are cancer cells.

[0213] In another aspect, the present invention provides a method of inhibiting a signal transduction pathway stimulated by the binding of FGF to FGFR2b, comprising administering to a subject an effective amount of an antibody described herein or a composition described herein.

[0214] In another aspect, the present invention provides a method of inhibiting the growth of tumor xenografts overexpressing FGFR2b, comprising administering to a subject an effective amount of an antibody described herein or a composition described herein.

[0215] In another aspect, the present invention provides a method of detecting the presence of FGFR2b in a sample, comprising mixing an antibody described herein or a composition described herein with the sample, and detecting the binding to the antibody indicates the presence of FGFR2b. Examples

[0216] The present invention can be further described by the following non-limiting examples, in which, where appropriate, standard techniques known to those skilled in the art and techniques similar to those described in these examples can be used. Those skilled in the art will envision additional examples consistent with the disclosure provided herein.

[0217] The following examples are provided to better illustrate the claimed invention and should not be construed as limiting the scope of the invention. The examples do not represent all of the experiments conducted or that only these experiments were conducted. Example 1 Cells and Reagents

[0218] The human gastric cancer cell line KATO III and the tool cell line HEK 293 were purchased from the Chinese Academy of Sciences. The human gastric cancer cell line SNU16 was purchased from Suzhou Bena Creation Biotechnology Co., Ltd. (BNCC). The above human cell lines were cultured according to the suppliers' recommendations.

[0219] To establish cell-based assays for antibody screening during antibody production, HEK293 cells were engineered to express FGFR2b or FGFR2c. HEK293 cells were transfected with FGFR2b or FGFR2c isoform plasmids encoding human FGFR2. After screening with puromycin, monoclonal cells highly expressing FGFR2b or FGFR2c were isolated.

[0220] Human FGFR2 alpha(IIIb)-Fc (Cat.16485-H02H) and human FGFR1alpha(IIIb)-His (Cat.16482-H08H) were purchased from Beijing Sino Biological Inc. Human FGFR1 / CD331-His (Cat.FG1-H5223) and human FGFR4 / CD334-His (Cat.FG4-H5228) were purchased from Beijing Protein Innovation Co., Ltd. Human FGFR2alpha(IIIb)-His (Cat.FGR-HM1BD), human FGFR2 alpha(IIIc)-His (Cat.FGR-HM2CD), human FGFR3alpha(IIIb)-His (Cat.FGF-HM43B) and human FGFR3 alpha(IIIc)-His (Cat.FGF-HM43C) were purchased from Kaikai Biotech Co., Ltd. (Shanghai). Mouse FGFR2 (canonical)-Fc (Cat.51128-M02H) was purchased from Beijing Sino Biological Inc. Cynomolgus monkey FGFR2 (beta IIIb)-His (Cat.FGF-CM1BB) was purchased from Kaikai Biotech Co., Ltd. (Shanghai). Human KGF / FGF-7 recombinant protein (His Tag) (Cat.10210-H07E) was purchased from Beijing Sino Biological Inc. Human FGF10 protein (Cat.FGF-HE010) was purchased from Kaikai Biotech Co., Ltd. (Shanghai).

[0221] Express the clinical-stage anti-human FGFR2b specific antibody FPA144 according to the relevant patent application WO 2015 / 017600Al. Example 2 Generation of anti-FGFR monoclonal antibodies

[0222] Balb / c mice, CD1 mice or SJL mice were subcutaneously immunized with Freund's adjuvant, SAS or CpG containing human FGFR2b(alpha)-Fc at an initial dose of 50 μg per mouse and then at a dose of 25 μg per mouse every three weeks. Serum titers of anti-human FGFR2b-Fc were measured by ELISA. In the last booster immunization cycle, intravenous injection was performed continuously for 3 days at 4 μg, 3 μg, 3 μg. Four days later, mouse spleen cells were extracted and fused with mouse myeloma cells. Seven days after fusion, FGFR2b(β)-His binding in the hybridoma culture supernatant was first screened by ELISA. Hybridomas passing the primary screening were subjected to secondary screening, including binding to KATO III cells determined by FACS. Hybridomas passing the secondary screening were screened and subcloned, and the obtained mouse monoclonal antibody was named mAb1.

[0223] The variable region (VH, VL) sequences of the heavy and light chains of mAb1 were determined using standard RACE technology. Total RNA was extracted from the selected hybridoma cell line. Then, using the SMART RACE cDNA amplification kit (Clontech), full-length first-strand cDNA containing the 5' end was amplified by PCR according to the instructions. The PCR product was isolated and purified, and then cloned and sequenced.

[0224] Then, a chimeric antibody mAb1 was generated by transplanting the VH and VL of mouse Ab 1 into human Fc. The amino acid sequences of the entire mAb1 light and heavy chains are shown in Figure 1. Example 3. Binding characteristics of the antibody

[0225] The binding of the antibody to human FGFR2b antigen was measured by Biolayer Interferometry (BLI) (OCET). Briefly, the Protein A biosensor was first pre-wetted with PBST (0.05% Tween 20) for 10 minutes. The antibody was diluted with PBST (0.05% Tween), and the biosensor after immobilizing the antibody was immersed in antigens of serial concentrations (0, 1.56, 3.12, 6.25, 12.5, 25, 50 nM) to detect binding, including surface regeneration of the Protein A biosensor surface in each run cycle. The binding constant and dissociation constant were calculated using OCETRED384 evaluation software (version 1.0). As Figure 2 shown, mAb1 showed strong binding affinity (nanomolar) for human, mouse and cynomolgus monkey FGFR2b, superior to or similar to the competitor antibody FPA144.

[0226] To confirm that the selected antibody can bind to endogenous FGFR2b on the cell membrane, flow cytometry was performed using HEK293 cells transfected with human FGFR2IIIc and FGFR2IIIb genes. FGFR2IIIb-HEK293 or FGFR2IIIc-HEK293 monoclonal cells were cultured in DMEM medium containing 10% FBS, then seeded at 100,000 cells per well and washed with PBS + 0.5% FBS. Then, antibodies at different concentrations were added and incubated for 30 min, followed by incubation with a fluorescently conjugated anti-human IgG-Fc secondary antibody for 30 min. The fluorescence signal was detected using Cytoflex. The binding activity data of mAb1 were processed using Graphpad Prism, and the data are shown in Figure 3. As Figure 3B shown, as expected, mAb1 binds to cells transfected with FGFR2IIIb but not to cells transfected with FGFR2IIIc.

[0227] The specific binding of mAb1 to each FGFR family member, FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, FGFR3c, and FGFR4, was determined by ELISA. 50 ng / well of FGFR1 alpha(IIIb)-His, human FGFR1 / CD331 protein-His, human FGFR2 alpha(IIIb)Protein, human FGFR2 alpha(IIIc)Protein, human FGFR3 alpha(IIIb)-His, human FGFR3 alpha(IIIc)-His, and human FGFR4 / CD334-His were added to 96-well plates and incubated overnight. Then, they were blocked with PBST containing 2% BSA (PBS containing 0.05% Tween20), and then antibody samples were added and incubated at room temperature for 60 min. Then, they were washed once with PBST and incubated with mAb1 at room temperature. Then, they were washed with PBST and incubated with a peroxidase-conjugated AffiniPure F(AB’)2 fragment goat anti-human IgG (Jackson Immuno Researchech, #109-036-098) conjugate for 30 min. The HRP activity was detected using a TMB substrate (Solarbio, #PR1200), and the reaction was stopped with a stop solution (Solarbio, #C1058). The plate was read at 450 nm. The data are shown in Figure 4 Figure 7. According to the results of ELISA analysis, mAb1 specifically binds only to FGFR2b and does not bind to any other FGFR family members. Example 4. In vitro inhibitory activity

[0228] The inhibitory activity of the antibody against ligand-induced cell proliferation was determined using SNU 16 cells. Cells were seeded in 96-well plates at 5000 cells / well in RPMI 1640 medium containing 0.5% fetal bovine serum. The cells were starved for 16 hours / overnight. SNU-16 cells were treated with different concentrations of the antibody diluted in RPMI medium containing 0.5% FBS for 30 minutes. Then, the cells were treated with 100 ng / mL FGF7 or FGF10 and 1 μg / mL heparin (final concentration), and incubated at 37 °C and 5% CO2 for 4 days. 50 μL of CTG was added, and the absorbance was read. The data of the proliferation inhibitory activity of mAb1 were processed using Graphpad Prism, and the data are as Figure 5 and Figure 6 shown. As the concentration of mAb1 increased, the proliferation of FGF7-induced ( Figure 5 ) and FGF10-induced ( Figure 6 ) SNU-16 cells was inhibited in a concentration-dependent manner, and the potency of mAb1 was superior to that of FPA144.

[0229] The inhibitory effect of the FGFR2b antibody on the FGFR2 signaling pathway was determined using the SRE reporter gene method. The HEK293 cell line stably expressed a luciferase reporter gene driven by the serum response element (SRE) and human fibroblast growth factor receptor (FGFR2) IIIb. FGFR2IIIb-SRE-HEK293 monoclonal cells were grown in DMEM medium containing 10% FBS, plated at 40000 / well, and starved overnight in DMEM + 0.5%. Then, different concentrations of mAb1 were added for 30 min, and then incubated with FGF7 protein for 4 h. The luciferase signal was detected by TECAN. The data were processed using Graphpad Prism, as Figure 7 shown. In FGFR2b-overexpressing cells, mAb1 inhibited the FGFR2 signaling pathway in a concentration-dependent manner. Example 5. In vivo tumor inhibitory activity of the antibody in a tumor mouse model

[0230] A cell line-derived xenograft (CDX) mouse model was established by first culturing SNU16 cells in vitro and then subcutaneously inoculating SNU16 cells mixed with 50% Matrigel into the dorsal side of mice at a dose of 3x106 cells / 100 μL per mouse.

[0231] The tumor nodules were measured two-dimensionally with calipers, and the tumor volume was calculated using the following formula: Tumor volume = (length x width x width) x 0.52. When the tumor volume reached 150 - 200 mm3, the mice were randomly divided into treatment groups. Then, the mice were treated twice a week with a control (e.g., IgG1) or a test antibody (e.g., FPA144, mAb1). The tumor volume and body weight of the mice were measured twice a week, and the raw data were recorded. Tumor growth inhibition from the start of treatment was evaluated by comparing the mean change in tumor volume between the control group and the treatment groups. The geometric or arithmetic mean of the relative tumor volume (RTV) of each group was calculated. RTV was calculated by dividing the tumor volume on the treatment day by the initial tumor volume. The tumor growth curve of SNU16 cells is as Figure 8 shown, and mAb1 showed better anti-tumor activity. Example 6. Humanization of mAb1

[0232] The humanized mAb 1 was designed, constructed, and expressed using standard methods of molecular biology. That is, the murine CDR regions of mAb 1 were transplanted into the homologous human germline antibody framework regions. Then, a library of back-mutations at key sites in the framework regions was generated with the help of computer simulation, and the human amino acids at framework positions that significantly affected antibody affinity were back-mutated to the original murine framework amino acid residues (using Kabat numbering) by screening the library. The humanized mAb 1 antibody was named humAb 1. The amino acid NG in CDR2 of the heavy chain of humAb 1 may be further substituted. Example 7. Enhancement of the ADCC effect of the antibody

[0233] Antibody-dependent cell cytotoxicity (ADCC), also known as antibody-dependent mediated cytotoxicity, is an immune mechanism by which effector cells expressing Fc receptors recognize and kill target cells expressing tumor-derived or pathogen-derived antigens on their surface. Given that increased IgG binding affinity due to CD16A polymorphism can enhance ADCC and improve clinical outcomes, a strategy has emerged to improve the therapeutic mAb function by using 1,6-fucosyltransferase knockout (FUT8- / -) CHOK1 cells (Wuxi Biological Products Co., Ltd., Shanghai, China) as the host cell line to produce afucosylated antibodies. The humAb 1 with enhanced ADCC is called humAbA1. Another strategy is to modify the Fc portion of the tumor-targeting antibody by amino acid mutation in the Fc region of the antibody to enhance the affinity for Fc-related receptors and thereby improve the ADCC function of the therapeutic mAb.

[0234] The afucosylated antibody was purified by Protein A, replaced into the formulation buffer, and stored at -80 °C. The purified afucosylated antibody was analyzed by LC-MS. The results showed that the afucosylated antibody was almost 100% non-fucosylated. It is expected that the non-fucosylated antibody will provide comparable in vitro or in vivo activity compared to the fucosylated control antibody.

[0235] The amino acid sequences of the complete humAbA1 light and heavy chains with human IgG1 are shown in Figure 9. Example 8. Binding Characteristics of Antibodies

[0236] The binding of the antibody to human FGFR2b antigen was determined by Biolayer Interferometry (BLI) (OCET). Briefly, the Protein A biosensor was first pre-wetted with PBST (0.05% Tween 20) for 10 minutes. The antibody was diluted with PBST (0.05% Tween), and the biosensor after immobilizing the antibody was immersed in wells containing serial concentrations (0, 1.56, 3.12, 6.25, 12.5, 25, 50 nM) of antigen to detect binding, with surface regeneration of the Protein A biosensor included in each run cycle. The binding and dissociation constants were calculated using the OCETRED384 evaluation software (version 1.0). As Figure 10 shown, humAbA1 showed strong binding affinity to human, mouse, and cynomolgus monkey FGFR2b. Therefore, toxicology studies of humAbA1 can be conducted in rats and cynomolgus monkeys.

[0237] To confirm that the selected antibody could bind to endogenous FGFR2b on the cell membrane, flow cytometry was performed using HEK293 cells transfected with human FGFR2IIIc and FGFR2IIIb genes. FGFR2IIIb-HEK293 or FGFR2IIIc-HEK293 monoclonals were cultured in DMEM medium containing 10% FBS, then seeded at 100,000 / well and washed with PBS + 0.5% FBS. Then different concentrations of the antibody were added and incubated for 30 min, followed by incubation with a fluorescently conjugated anti-human IgG-Fc secondary antibody for 30 min. The fluorescence signal was then detected using Cytoflex. The binding activity data of humAbA1 were processed using Graphpad Prism, and the data are as Figure 11 shown. As Figure 11 shown, as expected, humAbA1 bound to cells transfected with FGFR2IIIb, but not to cells transfected with FGFR2IIIc.

[0238] The specific binding of humAbA1 to each FGFR family member, FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, FGFR3c, and FGFR4, was determined by ELISA. 50 ng / well of 0.5 mg / ml FGFR1 alpha(IIIb)-His, human FGFR1 / CD331 protein-His, human FGFR2 alpha(IIIb)Protein, human FGFR2 alpha(IIIc)Protein, human FGFR3 alpha(IIIb)-His, human FGFR3 alpha(IIIc)-His, and human FGFR4 / CD334-His were added to 96-well plates and incubated overnight. Then, they were blocked with PBST (PBS containing 0.05% Tween 20) containing 2% BSA, and then antibody samples were added and incubated at room temperature for 60 minutes. Then, they were washed once with PBST, and then incubated with mAb1 at room temperature. Then, they were washed with PBST, and then incubated with a peroxidase-conjugated AffiniPure F(ab’)2 fragment goat anti-human IgG (Jackson Immuno Researchech, #109-036-098) conjugate for 30 minutes. HRP activity was detected using a TMB substrate (Solarbio, #PR1200), and the reaction was stopped with a stop solution (Solarbio, #C1058). The plate was read at 450 nm. The data is as Figure 12 shown. According to the results of ELISA analysis, humAbA1 specifically binds only to FGFR2b and does not bind to any other FGFR family members. Example 9. In vitro activity

[0239] The inhibitory activity of the antibody against ligand-induced cell proliferation was determined using SNU 16 cells. Cells were seeded in a 96-well plate at 5000 cells / well in RPMI1640 medium containing 0.5% fetal bovine serum. The cells were starved for 16 hours / overnight. SNU-16 cells were treated with different concentrations of the antibody diluted in RPMI medium containing 0.5% FBS for 30 minutes. Then, the cells were treated with 100 ng / mL FGF7 or FGF10 and 1 μg / mL heparin (final concentration) and incubated at 37 °C and 5% CO2 for 4 days. 50 μL of CTG was added, and the absorbance was read. The inhibitory activity data of mAb1 was processed using Graphpad Prism, and the data is as Figure 13 shown. As the concentration of mAb1 increased, the FGF7-induced cell proliferation of SNU-16 cells was inhibited in a concentration-dependent manner, and the potency of humAbA1 was superior to that of Bemarituzumab.

[0240] The inhibitory effect of the antibody on FGFR2 phosphorylation was evaluated in the SNU-16 human gastric cancer cell line. As the concentration of the monoclonal antibody increased, FGF7-induced FGFR2 phosphorylation in SNU-16 cells was inhibited in a concentration-dependent manner( Figure 14 ).

[0241] In vitro assays were performed to determine the ADCC activity of the antibody. The ADCC reporter cell lines Jurkat-Luc NFAT-CD16a-V158 and Jurkat-Ruc NFAT-CD16a-F158 were developed based on Jurkat cells and the luciferase gene stably integrated under the control of the NFAT (nuclear factor of activated T cells) response element with high-affinity CD16a (V158 allotype) or low-affinity CD16 (F158), respectively. The reporter cells were seeded in 96-well plates at a density of 1E5 cells per well, and then serial dilutions of the monoclonal antibody were added and incubated at 37 °C for 30 min. The cell line KATOⅢ overexpressing FGFR2b was used as the target cell and co-incubated with the effector cells Jurkat-Luc NFAT-CD16a-V158 or Jurkat-Ruc NFAT-CD16a-F158 at an E:T ratio of 5:1 for 6 h. The absorbance was measured using a microplate reader after incubation with the substrate Nano-glo for 5 - 30 min. The fitted curve was plotted as RLU versus Log10[antibody] using GraphPad software. The ADCC activity was determined by calculating the EC50 and the maximum response potency of the antibody response, as shown in Figure 15. humAbA1 exhibited superior ADCC activity compared to Bemarituzumab. Example 10. In Vivo Tumor Inhibitory Activity of the Antibody in a Tumor Mouse Model

[0242] Cell line-derived xenograft (CDX) mouse models were established by first culturing SNU-16 or OCUM-2M cells in vitro and then subcutaneously inoculating SNU16 cells or OCUM-2M cells mixed with 50% Matrigel into the dorsal side of mice at a dose of 3x10 6 ~5x10 6 cells / 100 μL per mouse.

[0243] Tumor nodules were measured two-dimensionally with calipers, and the tumor volume was calculated using the following formula: Tumor volume = (length x width x width) x 0.52. When the tumor volume reached 150 - 200 mm 3At that time, the mice were randomly divided into treatment groups. Then, the mice were treated twice a week with a control (such as IgG1) or a test antibody (such as FPA144, mAb1). The tumor volume and body weight of the mice were measured twice a week, and the original data were recorded. Tumor growth inhibition from the start of treatment was evaluated by comparing the average change in tumor volume between the control group and the treatment group. The geometric or arithmetic mean based on the relative tumor volume (RTV) of each group was calculated. RTV was calculated by dividing the tumor volume on the treatment day by the initial tumor volume. The tumor growth curve of SNU-16 cells is as Figure 16 shown, and the tumor growth curve of OCUM-2M cells is as Figure 17 shown. Both humAbA1 and humAbA2 showed better anti-tumor activity. List of references 1 Katoh M and Nakagama H.FGF receptors: cancer biology and therapeutics.Med Res Rev 2014;34:280-300. 2 Eswarakumar VP, Lax I, Schlessinger J.Cellular signaling by fibroblast growth factor receptors.Cytokine Growth Factor Rev 2005;16:139-49. 3 Turner N, Grose R.Fibroblast growth factor signalling: from development to cancer.Nat Rev Cancer 2010;10:116-29. 4 Beenken A, Mohammadi M.The FGF family: biology, pathophysiology and therapy.Nat Rev Drug Discov 2009;8:235-53. 5 Ornitz DM, Xu J, Colvin JS, et al.Receptor specificity of the fibroblast growth factor family.J Biol Chem 1996;271:15292-7. 6 Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem 2006;281:15694 - 700. 7 Bai, Ailin, et al. "GP369, an FGFR2-IIIb-Specific Antibody, Exhibits Potent Antitumor Activity against Human Cancers Driven by Activated FGFR2 Signaling In vivo Efficacy of GP369 in FGFR2-Amplified Tumors." Cancer research 70.19(2010):7630 - 7639. Easton DF, Pooley KA, Dunning AM, et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 2007;447:1087 - 93. 8 Hunter DJ, Kraft P, Jacobs KB, et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 2007;39:870 - 4. 9 Meyer KB, Maia AT, O'Reilly M, et al. Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer. PLoS Biol 2008;6:e108. 10 Davies H,Hunter C,Smith R,et al.Somatic mutations of the proteinkinase gene family in human lung cancer.Cancer Res 2005;65:7591-5. 11 Ding L,Getz G,Wheeler DA,et al.Somatic mutations affect keypathways in lung adenocarcinoma.Nature 2008;455:1069-75. 12 Dutt A,Salvesen HB,Chen TH,et al.Drug-sensitive FGFR2 mutations inendometrial carcinoma.Proc Natl Acad Sci U S A 2008;105:8713-7. 13 Greenman C,Stephens P,Smith R,et al.Patterns of somatic mutationin human cancer genomes.Nature 2007;446:153-8. 14 Pollock PM,Gartside MG,Dejeza LC,et al.Frequent activating FGFR2mutations in endometrial carcinomas parallel germline mutations associatedwith craniosynostosis and skeletal dysplasia syndromes.Oncogene 2007;26:7158-62. 15 Jang JH,Shin KH,Park JG.Mutations in fibroblast growth factorreceptor 2and fibroblast growth factor receptor 3genes associated with humangastric and colorectal cancers.Cancer Res 2001;61:3541-3. 16 Heiskanen M, Kononen J, Barlund M, et al. CGH, cDNA and tissue microarray analyses implicate FGFR2 amplification in a small subset of breast tumors. Anal Cell Pathol 2001;22:229-34. 17 Adnane J, Gaudray P, Dionne CA, et al. BEK and FLG, two receptors to members of the FGF family, are amplified in subsets of human breast cancers. Oncogene 1991;6:659-63. 18 Turner N, Lambros MB, Horlings HM, et al. Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets. Oncogene 2010;29:2013-23. 19 Hara T, Ooi A, Kobayashi M, Mai M, Yanagihara K, Nakanishi I. Amplification of c-myc, K-sam, and c-met in gastric cancers: detection by fluorescence in situ hybridization. Lab Invest 1998;78:1143-53. 20 Mor O, Ranzani GN, Ravia Y, et al. DNA amplification in human gastric carcinomas. Cancer Genet Cytogenet 1993;65:111-4. 21 Tsujimoto H,Sugihara H,Hagiwara A,Hattori T.Amplification of growth factor receptor genes and DNA ploidy pattern in the progression of gastric cancer.Virchows Arch 1997;431:383-9. 22 Yoshida T,Sakamoto H,Terada M.Amplified genes in cancer in upper digestive tract.Semin Cancer Biol 1993;4:33-40. 23 Yamayoshi T,Nagayasu T,Matsumoto K,Abo T,Hishikawa Y,Koji T.Expression of keratinocyte growth factor / fibroblast growth factor-7 and its receptor in human lung cancer:correlation with tumour proliferative activity and patient prognosis.J Pathol 2004;204:110-8. 24 Cho K,Ishiwata T,Uchida E,et al.Enhanced expression of keratinocyte growth factor and its receptor correlates with venous invasion in pancreatic cancer.Am J Pathol 2007;170:1964-74. 25 Toyokawa T,Yashiro M,Hirakawa K.Co-expression of keratinocyte growth factor and K-sam is an independent prognostic factor in gastric carcinoma.Oncol Rep 2009;21:875-80. 26 Gartside MG, Chen H, Ibrahimi OA, et al. Loss-of-function fibroblast growth factor receptor-2 mutations in melanoma. Mol Cancer Res 2009;7:41-54. 27 Diez de Medina SG, Chopin D, El Marjou A, et al. Decreased expression of keratinocyte growth factor receptor in a subset of human transitional cell bladder carcinomas. Oncogene 1997;14:323-30. 28 Giri D, Ropiquet F, Ittmann M. Alterations in expression of basic fibroblast growth factor (FGF) 2 and its receptor FGFR-1 in human prostate cancer. Clin Cancer Res 1999;5:1063-71. 29 Ricol D, Cappellen D, El Marjou A, et al. Tumour suppressive properties of fibroblast growth factor receptor 2-IIIb in human bladder cancer. Oncogene 1999;18:7234-43. 30 Zhang Y, Wang H, Toratani S, et al. Growth inhibition by keratinocyte growth factor receptor of human salivary adenocarcinoma cells through induction of differentiation and apoptosis. Proc Natl Acad Sci U S A 2001;98:11336-40. 31 Grose R,Fantl V,Werner S,et al.The role of fibroblast growthfactor receptor 2b in skin homeostasis and cancer development.EMBO J 2007;26:1268-78. 32 Lin Y,Liu G,Zhang Y,et al.Fibroblast growth factor receptor 2tyrosine kinase is required for prostatic morphogenesis and the acquisitionof strict androgen dependency for adult tissue homeostasis.Development 2007;134:723-34. 33 Grilo A.L.,Mantalaris A.(2019)The increasingly human andprofitable monoclonal antibody market.Trends Biotechnol.,37,9-16. 34 Liu J.K.H.(2014)The history of monoclonal antibody development-progress,remaining challenges and future innovations.Ann.Med.Surg.,3,113-116. 35 Chothia,C.,&Lesk,A.M.(1987).Canonical structures for thehypervariable regions of T cellαβreceptors.J Mol Biol,196,901-17. 36 Chothia,C.,Lesk,A.M.,Tramontano,A.,Levitt,M.,Smith-Gill,S.J.,Air,G.,...&Poljak,R.J.(1989).Conformations of immunoglobulin hypervariableregions.Nature,342(6252),877-883. 37 Kabat, E.A., Wu, T.T., Perry, H.M., Gottesmann, K.S., & Foeller, C. (1991). Sequences of Proteins of Immunological Interest. 5th edn. National Institutes of Health Publication No. 91 - 3242. National Institutes of Health, Bethesda, MD. 38 Al - Lazikani, B., Lesk, A.M., & Chothia, C. (1997). Standard conformations for the canonical structures of immunoglobulins. Journal of molecular biology, 273(4), 927 - 948. 39 Lefranc, M.P., Pommié, C., Ruiz, M., Giudicelli, V., Foulquier, E., Truong, L.,... & Lefranc, G. (2003). IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V - like domains. Developmental & Comparative Immunology, 27(1), 55 - 77. 40 Tonegawa, S. (1983). Somatic generation of antibody diversity. Nature, 302(5909), 575 - 581. 41 Xu, J.L., & Davis, M.M. (2000). Diversity in the CDR3 region of VH is sufficient for most antibody specificities. Immunity, 13(1), 37 - 45. 42 Schier, R., McCall, A., Adams, G. P., Marshall, K. W., Merritt, H., Yim, M.,... & Marks, J. D. (1996). Isolation of picomolar affinity anti-c-erbB-2 single-chain Fv by molecular evolution of the complementarity determining regions in the center of the antibody binding site. Journal of molecular biology, 263(4), 551-567. 43 G., & Milstein, C. (1975). Continuous cultures of fused cells secreting antibody of predefined specificity. nature, 256(5517), 495-497. 44 Kennet, R. H., McKeam, T. J., & Bechtol, K. B. (1980). Methods for production and characterization of monoclonal antibodies. Monoclonal Antibodies (Appendix), RH Kennet, TJ McKeam, and KB Bechtol, eds., Plenum, New York. 45 Batzer, M. A., Arcot, S. S., Phinney, J. W., Alegria-Hartman, M., Kass, D. H., & Milligan, S. M., et al. (1996). Genetic variation of recent alu insertions in human populations. Journal of Molecular Evolution, 42(1), 22-29. 46 Ohtsuka, E., Matsuki, S., Ikehara, M., Takahashi, Y., & Matsubara, K. (1985). An alternative approach to deoxyoligonucleotides as hybridation probes by insertion of deoxyinosine at ambiguous codon positions. Journal of Biological Chemistry, 260(5), 2605 - 2608. 47 Cassol, S. A., Lapointe, N., Salas, T., Hankins, C., & Charest, J. (1992). Diagnosis of vertical hiv-1 transmission using the polymerase chain reaction and dried blood spot specimens. J Acquir Immune Defic Syndr, 5(2), 113 - 119. 48 Rossolini, G. M., Cresti, S., Ingianni, A., Cattani, P., & Satta, G. (1994). Use of deoxyinosine-containing primers vs degenerate primers for polymerase chain reaction based on ambiguous sequence information. Molecular & Cellular Probes, 8(2), 91. 49 “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme), 50 Al-Lazikani et al., (1997) JMB 273, 927 - 948 (“Chothia” numbering scheme); 51 MacCallum et al., J.Mol.Biol. 262:732-745(1996), “Antibody-antigen interactions: Contact analysis and binding site topography,” J.Mol.Biol. 262, 732-745.”(“Contact” numbering scheme); 52 Lefranc MP et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Dev Comp Immunol, 2003 Jan; 27(1):55-77(“IMGT” numbering scheme); 53 Honegger A and Plückthun A, “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool,” J Mol Biol, 2001 Jun 8; 309(3):657-70, (“Aho” numbering scheme); 54 Martin et al., “Modeling antibody hypervariable loops: a combined algorithm,” PNAS, 1989, 86(23):9268-9272, (“AbM” numbering scheme). 55 Ward, E. Sally, et al. "Binding activities of a repertoire of single immunoglobulin variable domains secreted from Escherichia coli." Nature 341.6242(1989):544-546. 56 Bird, Robert E., et al. "Single-chain antigen-binding proteins." Science 242.4877(1988): 423-426. 57 Pope, Matthew E., et al. "Anti-peptide antibody screening: selection of high affinity monoclonal reagents by a refined surface plasmon resonance technique." Journal of immunological methods 341.1-2(2009): 86-96.

Claims

1. An antibody comprising a heavy chain variable region, wherein the heavy chain variable region comprises at least one complementarity determining region (CDR), and the heavy chain complementarity determining region that is furthest from the N-terminus of the antibody is selected from SEQ ID NOs: 61, 67, 73, 79, 85, 89, 95, 101, 104, 112, 116, 121, 125, 128, 131, 136, 138, 142, 144, 147, 151, 154, and 158.

2. The antibody according to claim 1, wherein the heavy chain variable region comprises three complementarity determining regions: heavy chain complementarity determining region 1, heavy chain complementarity determining region 2, and heavy chain complementarity determining region 3, in order from the N-terminus to the C-terminus, wherein heavy chain antigen complementarity determining region 1 is selected from SEQ ID NOs: 59, 65, 71, 77, 83, 88, 93, 103, 110, 119, 135, 143, 146, 150, and 152; heavy chain antigen complementarity determining region 2 is selected from SEQ ID NOs: 60, 66, 72, 78, 84, 94, 111, 118, 120, 124, 141, and 153; and heavy chain antigen complementarity determining region 3 is selected from SEQ ID NOs: 61, 67, 73, 79, 85, 89, 95, 101, 104, 112, 116, 121, 125, 128, 131, 136, 138, 142, 144, 147, 151, 154, and 158.

3. The antibody according to claim 2, wherein the combination of heavy chain complementarity determining region 1, heavy chain complementarity determining region 2, and heavy chain complementarity determining region 3 is as follows: a. SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, respectively; b. SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, respectively; c. SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, respectively; d. SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, respectively; e. SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, respectively; f. SEQ ID NO: 88, SEQ ID NO: 84, SEQ ID NO: 89, respectively; g. SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, respectively; h. SEQ ID NO: 59, SEQ ID NO: 78, SEQ ID NO: 79, respectively; i. SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 101, respectively; j. SEQ ID NO: 103, SEQ ID NO: �4, SEQ ID NO: 104, respectively; k. SEQ ID NO: 59, SEQ ID NO: 78, SEQ ID NO: 79, respectively; l. SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 112 respectively; m. SEQ ID NO: 88, SEQ ID NO: 84, SEQ ID NO: 116, respectively; n. SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 101 respectively; o. SEQ ID NO:93, SEQ ID NO:118, SEQ ID NO:101, respectively; p. SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121, respectively; q. SEQ ID NO: 119, SEQ ID NO: 124, SEQ ID NO: 125, respectively; r. SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 128, respectively; s. SEQ ID NO:83, SEQ ID NO:94, SEQ ID NO:131, respectively; t. SEQ ID NO: 135, SEQ ID NO: 84, SEQ ID NO: 136, respectively; u. SEQ ID NO: 88, SEQ ID NO: 84, SEQ ID NO: 138 respectively; v. SEQ ID NO:83, SEQ ID NO:141, SEQ ID NO:142, respectively; w. SEQ ID NO: 143, SEQ ID NO: 84, SEQ ID NO: 144, respectively; x. SEQ ID NO: 146, SEQ ID NO: 94, SEQ ID NO: 147, respectively; y. SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121, respectively; z. SEQ ID NO: 119, SEQ ID NO: 124, SEQ ID NO: 125, respectively; aa. SEQ ID NO: 150, SEQ ID NO: 84, SEQ ID NO: 151, respectively; bb. SEQ ID NO: 152, SEQ ID NO: 153, SEQ ID NO: 154, respectively; or cc. SEQ ID NO:88, SEQ ID NO:94, SEQ ID NO:158 respectively.

4. The heavy chain variable region of the antibody according to any one of the preceding claims further comprises four framework regions: heavy chain framework region 1, heavy chain framework region 2, heavy chain framework region 3, and heavy chain framework region 4. Heavy chain framework region 1 is selected from SEQ ID NOs: 160, 168, 175, 188, 194, 204, 210, 224, 233, 284, 259, 265, 268, 271, 274, 281, 295, and 305; heavy chain framework region 2 is selected from SEQ ID NOs: 161, 169, 176, 183, 205, 221, 225, 237, 245, 251, 261, 266, 275, 282, and 296; heavy chain framework region 3 is selected from SEQ ID NOs: 162, 170, 177, 184, 189, 195, 200, 206, 211, 216, 226, 231, 234, 239, 242, 246, 252, 254, 260, 262, 267, 272, 276, 297, and 306; heavy chain framework region 4 is selected from SEQ ID NOs: 163, 178, 190, 196, 212, 217, 227, 255, 269, and 298.

5. For the antibody according to claim 4, the compositions of heavy chain framework region 1, heavy chain framework region 2, heavy chain framework region 3, and heavy chain framework region 4 are as follows: a. SEQ ID NO: 160, SEQ ID NO: 161, SEQ ID NO: 162, SEQ ID NO: 163, respectively; b. SEQ ID NO: 168, SEQ ID NO: 169, SEQ ID NO: 170, SEQ ID NO: 163, respectively; c. SEQ ID NO: 175, SEQ ID NO: 176, SEQ ID NO: 177, SEQ ID NO: 178, respectively; d. SEQ ID NO: 160, SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 178, respectively; e. SEQ ID NO: 188, SEQ ID NO: 169, SEQ ID NO: 189, SEQ ID NO: 190, respectively; f. SEQ ID NO: 194, SEQ ID NO: 169, SEQ ID NO: 195, SEQ ID NO: 196, respectively; g. SEQ ID NO: 194, SEQ ID NO: 169, SEQ ID NO: 200, SEQ ID NO: 163, respectively; h. SEQ ID NO: 204, SEQ ID NO: 205, SEQ ID NO: 206, SEQ ID NO: 178, respectively; i. are SEQ ID NO:210, SEQ ID NO:169, SEQ ID NO:211, SEQ ID NO:212 respectively; j. are SEQ ID NO:194, SEQ ID NO:169, SEQ ID NO:216, SEQ ID NO:217 respectively; k. are SEQ ID NO:204, SEQ ID NO:221, SEQ ID NO:206, SEQ ID NO:178 respectively; l. are SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227 respectively; m. are SEQ ID NO:194, SEQ ID NO:169, SEQ ID NO:231, SEQ ID NO:163 respectively; n. are SEQ ID NO:233, SEQ ID NO:169, SEQ ID NO:234, SEQ ID NO:178 respectively; o. are SEQ ID NO:210, SEQ ID NO:237, SEQ ID NO:211, SEQ ID NO:212 respectively; p. are SEQ ID NO:194, SEQ ID NO:169, SEQ ID NO:239, SEQ ID NO:190 respectively; q. are SEQ ID NO:194, SEQ ID NO:169, SEQ ID NO:242, SEQ ID NO:178 respectively; r. are SEQ ID NO:284, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:163 respectively; s. are SEQ ID NO:194, SEQ ID NO:245, SEQ ID NO:246, SEQ ID NO:163 respectively; t. are SEQ ID NO:188, SEQ ID NO:251, SEQ ID NO:252, SEQ ID NO:163 respectively; u. are SEQ ID NO:188, SEQ ID NO:169, SEQ ID NO:254, SEQ ID NO:255 respectively; v. are SEQ ID NO:259, SEQ ID NO:169, SEQ ID NO:260, SEQ ID NO:190 respectively; w. are SEQ ID NO:194, SEQ ID NO:261, SEQ ID NO:262, SEQ ID NO:163 respectively; x. are SEQ ID NO:265, SEQ ID NO:266, SEQ ID NO:267, SEQ ID NO:163 respectively; y. are SEQ ID NO:268, SEQ ID NO:169, SEQ ID NO:239, SEQ ID NO:269 respectively; z. are SEQ ID NO:194, SEQ ID NO:169, SEQ ID NO:200, SEQ ID NO:190 respectively; aa. are SEQ ID NO:271, SEQ ID NO:169, SEQ ID NO:272, SEQ ID NO:190 respectively; bb. are SEQ ID NO:274, SEQ ID NO:275, SEQ ID NO:276, SEQ ID NO:178 respectively; cc. are SEQ ID NO:281, SEQ ID NO:282, SEQ ID NO:254, SEQ ID NO:163 respectively; dd. are SEQ ID NO:295, SEQ ID NO:296, SEQ ID NO:297, SEQ ID NO:298 respectively; ee. are SEQ ID NO:305, SEQ ID NO:296, SEQ ID NO:306, SEQ ID NO:298 respectively; ff. are SEQ ID NO:295, SEQ ID NO:296, SEQ ID NO:306, SEQ ID NO:298 respectively; or gg. are SEQ ID NO:305, SEQ ID NO:296, SEQ ID NO:297, SEQ ID NO:298 respectively.

6. The antibody according to any one of claims 4 and 5, wherein the complementarity determining regions and framework regions of the heavy chain variable region are arranged in the following order from the N-terminal to the C-terminal of the sequence: heavy chain framework region 1 - heavy chain complementarity determining region 1 - heavy chain framework region 2 - heavy chain complementarity determining region 2 - heavy chain framework region 3 - heavy chain complementarity determining region 3 - heavy chain framework region 4.

7. The antibody according to any one of the foregoing claims, wherein the heavy chain further comprises three constant regions: constant region 1, constant region 2 and constant region 3, which are composed of: SEQ ID NO.307, SEQ ID NO.309 and SEQ ID NO.310 or SEQ ID NO:307, SEQ ID NO.312 and SEQ ID NO.

313.

8. The antibody according to any one of the preceding claims, wherein the heavy chain variable region comprises SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 285, 287, 290, and 291 and their homologous sequences, and the homologous sequences have at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence homology with SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 285, 287, 290, and 291.

9. The antibody according to any one of the preceding claims, wherein the heavy chain variable region is selected from SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 285, 287, 290 and 291.

10. An antibody comprising a light chain variable region, wherein the light chain variable region comprises at least one complementarity determining region (CDR), and the light chain complementarity determining region farthest from the N-terminus of the antibody is selected from SEQ ID NOs: 64, 70, 76, 82, 87, 92, 98, 100, 102, 107, 109, 115, 117, 123, 127, 130, 134, 137, 140, 145, 157 and 159.

11. The antibody according to claim 10, wherein the light chain variable region comprises 3 complementarity determining regions, light chain complementarity determining region 1, light chain complementarity determining region 2 and light chain complementarity determining region 3. Among them, light chain complementarity determining region 1 is selected from SEQ ID NOs: 62, 68, 74, 80, 86, 90, 96, 99, 105, 108, 113, 122, 126, 129, 132, 148, 149, and 155; light chain complementarity determining region 2 is selected from SEQ ID NOs: 63, 69, 75, 81, 91, 97, 106, 114, 133, 139, and 156; light chain complementarity determining region 3 is selected from SEQ ID NOs: 64, 70, 76, 82, 87, 92, 98, 100, 102, 107, 109, 115, 117, 123, 127, 130, 134, 137, 140, 145, 157, and 159.

12. The antibody according to claim 11, wherein the combination of light chain complementarity determining region 1, light chain complementarity determining region 2 and light chain complementarity determining region 3 is as follows: a. SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64 respectively; b. SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70 respectively; c. SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76 respectively; d. SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82 respectively; e. SEQ ID NO:86, SEQ ID NO:69, SEQ ID NO:87 respectively; f. SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92 respectively; g. SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98 respectively; h. SEQ ID NO:99, SEQ ID NO:69, SEQ ID NO:100 respectively; i. SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:102 respectively; j. SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107 respectively; k. SEQ ID NO:108, SEQ ID NO:69, SEQ ID NO:109 respectively; l. SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115 respectively; m. SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:117 respectively; n. SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:102 respectively; o. SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:102 respectively; p. SEQ ID NO:122, SEQ ID NO:69, SEQ ID NO:123 respectively; q. SEQ ID NO:126, SEQ ID NO:69, SEQ ID NO:127 respectively; r. SEQ ID NO:129, SEQ ID NO:69, SEQ ID NO:130 respectively; s. SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134 respectively; t. SEQ ID NO:126, SEQ ID NO:69, SEQ ID NO:137 respectively; u. SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:140 respectively; v. SEQ ID NO:122, SEQ ID NO:69, SEQ ID NO:123 respectively; w. SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:145 respectively; x. are SEQ ID NO:148, SEQ ID NO:69, SEQ ID NO:109 respectively; y. are SEQ ID NO:149, SEQ ID NO:63, SEQ ID NO:109 respectively; z. are SEQ ID NO:122, SEQ ID NO:69, SEQ ID NO:123 respectively; aa. are SEQ ID NO:126, SEQ ID NO:69, SEQ ID NO:130 respectively; bb. are SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157 respectively; or cc. are SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:159 respectively.

13. The light chain variable region of the antibody according to any one of the preceding claims 10 to 12 further comprises 4 framework regions, which are, in sequence from the N-terminus to the C-terminus, light chain framework region 1, light chain framework region 2, light chain framework region 3 and light chain framework region 4. Among them, light chain framework region 1 is selected from SEQ ID NOs: 164, 171, 179, 185, 191, 197, 201, 207, 213, 218, 222, 228, 232, 247, 256, 263, 270, 277, 283, 299, and 303; light chain framework region 2 is selected from SEQ ID NOs: 165, 172, 180, 186, 192, 198, 202, 208, 214, 219, 223, 229, 235, 240, 243, 248, 257, 264, 278, 300 and 304; light chain framework region 3 is selected from SEQ ID NOs: 166, 173, 181, 187, 193, 199, 203, 209, 220, 230, 236, 238, 241, 244, 249, 253, 258, 273, 279 and 301; light chain framework region 4 is selected from SEQ ID NOs: 167, 174, 182, 215, 250, 280 and 302.

14. For the antibody according to claim 13, the combinations of light chain framework region 1, light chain framework region 2, light chain framework region 3 and light chain framework region 4 are as follows: a. are SEQ ID NO:164, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:167 respectively; b. are SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174 respectively; c. are SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, SEQ ID NO:182 respectively; d. SEQ ID NO:185, SEQ ID NO:186, SEQ ID NO:187, SEQ ID NO:174, respectively; e. SEQ ID NO:191, SEQ ID NO:192, SEQ ID NO:193, SEQ ID NO:174, respectively; f. SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:174, respectively; g. SEQ ID NO:201, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:167, respectively; h. SEQ ID NO:207, SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:174, respectively; i. SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:203, SEQ ID NO:215 respectively; j. SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:174 respectively; k. SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:209, SEQ ID NO:174 respectively; l. SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:174 respectively; m. SEQ ID NO:232, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:167 respectively; n. SEQ ID NO:201, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:174 respectively; o. SEQ ID NO:201, SEQ ID NO:214, SEQ ID NO:238, SEQ ID NO:215 respectively; p. SEQ ID NO:171, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:174 respectively; q. SEQ ID NO:171, SEQ ID NO:243, SEQ ID NO:244, SEQ ID NO:174 respectively; r. SEQ ID NO:222, SEQ ID NO:165, SEQ ID NO:209, SEQ ID NO:174 respectively; s. SEQ ID NO:247, SEQ ID NO:248, SEQ ID NO:249, SEQ ID NO:250 respectively; t. SEQ ID NO:171, SEQ ID NO:243, SEQ ID NO:253, SEQ ID NO:167 respectively; u. SEQ ID NO:256, SEQ ID NO:257, SEQ ID NO:258, SEQ ID NO:174 respectively; v. SEQ ID NO:171, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:174 respectively; w. SEQ ID NO:263, SEQ ID NO:264, SEQ ID NO:199, SEQ ID NO:174 respectively; x. SEQ ID NO:222, SEQ ID NO:165, SEQ ID NO:209, SEQ ID NO:174 respectively; y.SEQ ID NO: 270, SEQ ID NO: 165, SEQ ID NO: 166, SEQ ID NO: 174 respectively; z. SEQ ID NO: 171, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 174 respectively; aa. SEQ ID NO: 171, SEQ ID NO: 243, SEQ ID NO: 273, SEQ ID NO: 174 respectively; bb. SEQ ID NO: 277, SEQ ID NO: 278, SEQ ID NO: 279, SEQ ID NO: 280 respectively; cc. SEQ ID NO: 283, SEQ ID NO: 278, SEQ ID NO: 279, SEQ ID NO: 174 respectively; dd. SEQ ID NO: 299, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302 respectively; ee. SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 301, SEQ ID NO: 302 respectively; or ff. SEQ ID NO: 299, SEQ ID NO: 304, SEQ ID NO: 301, SEQ ID NO: 302 respectively.

15. For the antibody according to any one of the preceding claims 13 and 14, the complementarity determining regions and framework regions of the light chain variable region are arranged in the following order from the N-terminus to the C-terminus: light chain framework region 1 - light chain complementarity determining region 1 - light chain framework region 2 - light chain complementarity determining region 2 - light chain framework region 3 - light chain complementarity determining region 3 - light chain framework region 4.

16. For the antibody according to any one of the preceding claims 10 to 15, the light chain further comprises a light chain constant region SEQ ID NO:

311.

17. For the antibody according to any one of the preceding claims 10 to 16, the light chain variable region comprises SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 54, 56, 58, 286, 288 and 289 and their homologous sequences, and the homologous sequences have at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence homology with SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 54, 56, ​ 19. The antibody according to any one of claims 1 to 9 above, comprising a light chain variable region, wherein the light chain variable region comprises at least one complementarity determining region (CDR), and the light chain complementarity determining region farthest from the N-terminus of the antibody is selected from SEQ ID NOs: 64, 70, 76, 82, 87, 92, 98, 100, 102, 107, 109, 115, 117, 123, 127, 130, 134, 137, 140, 145, 157 and 159.

20. The antibody according to claim 18, wherein the light chain variable region comprises 3 complementarity determining regions, light chain complementarity determining region 1, light chain complementarity determining region 2 and light chain complementarity determining region 3. Among them, light chain complementarity determining region 1 is selected from SEQ ID NOs: 62, 68, 74, 80, 86, 90, 96, 99, 105, 108, 113, 122, 126, 129, 132, 148, 149, and 155; light chain complementarity determining region 2 is selected from SEQ ID NOs: 63, 69, 75, 81, 91, 97, 106, 114, 133, 139, and 156; light chain complementarity determining region 3 is selected from SEQ ID NOs: 64, 70, 76, 82, 87, 92, 98, 100, 102, 107, 109, 115, 117, 123, 127, 130, 134, 137, 140, 145, 157, and 159.

21. For the antibody according to claim 20, the combinations of light chain complementarity determining region 1, light chain complementarity determining region 2 and light chain complementarity determining region 3 are as follows: a. SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64 respectively; b. SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70 respectively; c. SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76 respectively; d. SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82 respectively; e. SEQ ID NO: 86, SEQ ID NO: 69, SEQ ID NO: 87 respectively; f. SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92 respectively; g. SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98 respectively; h. SEQ ID NO: 99, SEQ ID NO: 69, SEQ ID NO: 100 respectively; i. SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 102 respectively; j. SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107 respectively; k. are SEQ ID NO:108, SEQ ID NO:69, SEQ ID NO:109 respectively; l. are SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115 respectively; m. are SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:117 respectively; n. are SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:102 respectively; o. are SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:102 respectively; p. are SEQ ID NO:122, SEQ ID NO:69, SEQ ID NO:123 respectively; q. are SEQ ID NO:126, SEQ ID NO:69, SEQ ID NO:127 respectively; r. are SEQ ID NO:129, SEQ ID NO:69, SEQ ID NO:130 respectively; s. are SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134 respectively; t. are SEQ ID NO:126, SEQ ID NO:69, SEQ ID NO:137 respectively; u. are SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:140 respectively; v. are SEQ ID NO:122, SEQ ID NO:69, SEQ ID NO:123 respectively; w. are SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:145 respectively; x. are SEQ ID NO:148, SEQ ID NO:69, SEQ ID NO:109 respectively; y. are SEQ ID NO:149, SEQ ID NO:63, SEQ ID NO:109 respectively; z. are SEQ ID NO:122, SEQ ID NO:69, SEQ ID NO:123 respectively; aa. are SEQ ID NO:126, SEQ ID NO:69, SEQ ID NO:130 respectively; bb. are SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:157 respectively; or cc. are SEQ ID NO:155, SEQ ID NO:156, SEQ ID NO:159 respectively.

22. The light chain variable region of the antibody according to any one of claims 19-21 above further comprises 4 framework regions, which are, in sequence from the N-terminus to the C-terminus, light chain framework region 1, light chain framework region 2, light chain framework region 3, and light chain framework region 4. Among them, light chain framework region 1 is selected from SEQ ID NOs: 164, 171, 179, 185, 191, 197, 201, 207, 213, 218, 222, 228, 232, 247, 256, 263, 270, 277, 283, 299, and 303; light chain framework region 2 is selected from SEQ ID NOs: 165, 172, 180, 186, 192, 198, 202, 208, 214, 219, 223, 229, 235, 240, 243, 248, 257, 264, 278, 300, and 304; light chain framework region 3 is selected from SEQ ID NOs: 166, 173, 181, 187, 193, 199, 203, 209, 220, 230, 236, 238, 241, 244, 249, 253, 258, 273, 279, and 301; light chain framework region 4 is selected from SEQ ID NOs: 167, 174, 182, 215, 250, 280, and 302.

23. The combination of light chain framework region 1, light chain framework region 2, light chain framework region 3, and light chain framework region 4 of the antibody according to claim 22 is as follows: a. SEQ ID NO: 164, SEQ ID NO: 165, SEQ ID NO: 166, SEQ ID NO: 167, respectively; b. SEQ ID NO: 171, SEQ ID NO: 172, SEQ ID NO: 173, SEQ ID NO: 174, respectively; c. SEQ ID NO: 179, SEQ ID NO: 180, SEQ ID NO: 181, SEQ ID NO: 182, respectively; d. SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, SEQ ID NO: 174, respectively; e. SEQ ID NO: 191, SEQ ID NO: 192, SEQ ID NO: 193, SEQ ID NO: 174, respectively; f. SEQ ID NO: 197, SEQ ID NO: 198, SEQ ID NO: 199, SEQ ID NO: 174, respectively; g. SEQ ID NO: 201, SEQ ID NO: 202, SEQ ID NO: 203, SEQ ID NO: 167, respectively; h. SEQ ID NO: 207, SEQ ID NO: 208, SEQ ID NO: 209, SEQ ID NO: 174, respectively; i. SEQ ID NO:213, SEQ ID NO:214, SEQ ID NO:203, SEQ ID NO:215 respectively; j. SEQ ID NO:218, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:174 respectively; k. SEQ ID NO:222, SEQ ID NO:223, SEQ ID NO:209, SEQ ID NO:174 respectively; l. SEQ ID NO:228, SEQ ID NO:229, SEQ ID NO:230, SEQ ID NO:174 respectively; m. SEQ ID NO:232, SEQ ID NO:219, SEQ ID NO:220, SEQ ID NO:167 respectively; n. SEQ ID NO:201, SEQ ID NO:235, SEQ ID NO:236, SEQ ID NO:174 respectively; o. SEQ ID NO:201, SEQ ID NO:214, SEQ ID NO:238, SEQ ID NO:215 respectively; p. SEQ ID NO:171, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:174 respectively; q. SEQ ID NO:171, SEQ ID NO:243, SEQ ID NO:244, SEQ ID NO:174 respectively; r. SEQ ID NO:222, SEQ ID NO:165, SEQ ID NO:209, SEQ ID NO:174 respectively; s. SEQ ID NO:247, SEQ ID NO:248, SEQ ID NO:249, SEQ ID NO:250 respectively; t. SEQ ID NO:171, SEQ ID NO:243, SEQ ID NO:253, SEQ ID NO:167 respectively; u. SEQ ID NO:256, SEQ ID NO:257, SEQ ID NO:258, SEQ ID NO:174 respectively; v. SEQ ID NO:171, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:174 respectively; w. SEQ ID NO:263, SEQ ID NO:264, SEQ ID NO:199, SEQ ID NO:174 respectively; x. SEQ ID NO:222, SEQ ID NO:165, SEQ ID NO:209, SEQ ID NO:174 respectively; y. are SEQ ID NO:270, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:174 respectively; z. are SEQ ID NO:171, SEQ ID NO:240, SEQ ID NO:241, SEQ ID NO:174 respectively; aa. are SEQ ID NO:171, SEQ ID NO:243, SEQ ID NO:273, SEQ ID NO:174 respectively; bb. are SEQ ID NO:277, SEQ ID NO:278, SEQ ID NO:279, SEQ ID NO:280 respectively; cc. are SEQ ID NO:283, SEQ ID NO:278, SEQ ID NO:279, SEQ ID NO:174 respectively; dd. are SEQ ID NO:299, SEQ ID NO:300, SEQ ID NO:301, SEQ ID NO:302 respectively; ee. are SEQ ID NO:303, SEQ ID NO:304, SEQ ID NO:301, SEQ ID NO:302 respectively; or ff. are SEQ ID NO:299, SEQ ID NO:304, SEQ ID NO:301, SEQ ID NO:302 respectively.

24. The antibody according to any one of the preceding claims 20 and 21, the complementarity determining regions and framework regions of the light chain variable region are arranged in the following order from the N-terminus to the C-terminus: light chain framework region 1 - light chain complementarity determining region 1 - light chain framework region 2 - light chain complementarity determining region 2 - light chain framework region 3 - light chain complementarity determining region 3 - light chain framework region 4.

25. The antibody according to any one of the preceding claims 19 to 24, the light chain further comprises a light chain constant region SEQ ID NO:

311.

26. The antibody according to any one of the preceding claims 19 to 25, the light chain variable region comprises SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 54, 56, 58, 286, 288 and 289 and their homologous sequences, the homologous sequences have at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence homology with SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 54, 56, 58, 286, 288, and 289.

27. The light chain variable region of the antibody according to any one of the preceding claims 19 to 26 is selected from: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 54, 56, 58, 286, 288 and 289.

28. The antibody according to any one of the preceding claims, wherein the heavy chain variable region and the light chain variable region comprise the following combinations and comprise sequences having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% homology with the following sequences and their combinations: a. SEQ ID NO:1 and SEQ ID NO:2, respectively; b. SEQ ID NO:3 and SEQ ID NO:4, respectively; c. SEQ ID NO:5 and SEQ ID NO:6, respectively; d. SEQ ID NO:7 and SEQ ID NO:8, respectively; e. SEQ ID NO:9 and SEQ ID NO:10, respectively; f. SEQ ID NO:11 and SEQ ID NO:12, respectively; g. SEQ ID NO:13 and SEQ ID NO:14, respectively; h. SEQ ID NO:15 and SEQ ID NO:16, respectively; i. SEQ ID NO:17 and SEQ ID NO:18, respectively; j. SEQ ID NO:19 and SEQ ID NO:20, respectively; k. SEQ ID NO:21 and SEQ ID NO:22, respectively; l. SEQ ID NO:23 and SEQ ID NO:24, respectively; m. SEQ ID NO:25 and SEQ ID NO:26, respectively; n. SEQ ID NO:27 and SEQ ID NO:28, respectively; o. SEQ ID NO:29 and SEQ ID NO:30, respectively; p. SEQ ID NO:31 and SEQ ID NO:32, respectively; q. SEQ ID NO:33 and SEQ ID NO:34, respectively; r. SEQ ID NO:35 and SEQ ID NO:36, respectively; s. SEQ ID NO:37 and SEQ ID NO:38, respectively; t. SEQ ID NO:39 and SEQ ID NO:40, respectively; u. SEQ ID NO:41 and SEQ ID NO:42, respectively; v. SEQ ID NO:43 and SEQ ID NO:32, respectively; w. SEQ ID NO:45 and SEQ ID NO:46, respectively; x. SEQ ID NO:47 and SEQ ID NO:48, respectively; y. are SEQ ID NO:49 and SEQ ID NO:50 respectively; z. are SEQ ID NO:51 and SEQ ID NO:32 respectively; aa. are SEQ ID NO:53 and SEQ ID NO:54 respectively; bb. are SEQ ID NO:55 and SEQ ID NO:56 respectively; cc. are SEQ ID NO:57 and SEQ ID NO:58 respectively; dd. are SEQ ID NO:285 and SEQ ID NO:286 respectively; ee. are SEQ ID NO:287 and SEQ ID NO:288 respectively; ff. are SEQ ID NO:287 and SEQ ID NO:289 respectively; gg. are SEQ ID NO:290 and SEQ ID NO:288 respectively; hh. are SEQ ID NO:290 and SEQ ID NO:286 respectively; ii. are SEQ ID NO:291 and SEQ ID NO:286 respectively; jj. are SEQ ID NO:292 and SEQ ID NO:293 respectively; or kk. are SEQ ID NO:294 and SEQ ID NO:293 respectively.

29. The antibody according to any one of the preceding claims, wherein the heavy chain variable region and the light chain variable region comprise the following combinations: a. are SEQ ID NO:1 and SEQ ID NO:2 respectively; b. are SEQ ID NO:3 and SEQ ID NO:4 respectively; c. are SEQ ID NO:5 and SEQ ID NO:6 respectively; d. are SEQ ID NO:7 and SEQ ID NO:8 respectively; e. are SEQ ID NO:9 and SEQ ID NO:10 respectively; f. are SEQ ID NO:11 and SEQ ID NO:12 respectively; g. are SEQ ID NO:13 and SEQ ID NO:14 respectively; h. are SEQ ID NO:15 and SEQ ID NO:16 respectively; i. are SEQ ID NO:17 and SEQ ID NO:18 respectively; j. are SEQ ID NO:19 and SEQ ID NO:20 respectively; k. are SEQ ID NO:21 and SEQ ID NO:22 respectively; l. are SEQ ID NO:23 and SEQ ID NO:24 respectively; m. are SEQ ID NO:25 and SEQ ID NO:26 respectively; n. are SEQ ID NO:27 and SEQ ID NO:28 respectively; o. are SEQ ID NO:29 and SEQ ID NO:30 respectively; p. are SEQ ID NO:31 and SEQ ID NO:32 respectively; q. are SEQ ID NO:33 and SEQ ID NO:34 respectively; r. are SEQ ID NO:35 and SEQ ID NO:36 respectively; s. are SEQ ID NO:37 and SEQ ID NO:38 respectively; t. are SEQ ID NO:39 and SEQ ID NO:40 respectively; u. are SEQ ID NO:41 and SEQ ID NO:42 respectively; v. are SEQ ID NO:43 and SEQ ID NO:32 respectively; w. are SEQ ID NO:45 and SEQ ID NO:46 respectively; x. are SEQ ID NO:47 and SEQ ID NO:48 respectively; y. are SEQ ID NO:51 and SEQ ID NO:32 respectively; z. are SEQ ID NO:53 and SEQ ID NO:54 respectively; aa. are SEQ ID NO:55 and SEQ ID NO:56 respectively; bb. are SEQ ID NO:57 and SEQ ID NO:58 respectively; cc. are SEQ ID NO:285 and SEQ ID NO:286 respectively; dd. are SEQ ID NO:287 and SEQ ID NO:288 respectively; ee. are SEQ ID NO:287 and SEQ ID NO:289 respectively; ff. are SEQ ID NO:290 and SEQ ID NO:288 respectively; gg. are SEQ ID NO:290 and SEQ ID NO:286 respectively; hh. are SEQ ID NO:291 and SEQ ID NO:286 respectively; ii. are SEQ ID NO:292 and SEQ ID NO:293 respectively; or jj. are SEQ ID NO:294 and SEQ ID NO:293 respectively.

30. The antibody according to any one of the preceding claims 1-29, wherein the antibody specifically binds to fibroblast growth factor receptor 2b (FGFR2b).

31. The antibody according to claim 30, wherein the fibroblast growth factor receptor 2b (FGFR2b) can be from any species of human, mouse and cynomolgus monkey.

32. The antibody according to any one of the preceding claims 1-31, wherein the affinity of the antibody for FGFR2b is about 10 nM or lower.

33. The antibody according to any one of the preceding claims 1-32, wherein the affinity of the antibody for FGFR2b is about 9 nM or lower.

34. The antibody according to any one of the preceding claims 1-33, wherein the affinity of the antibody for FGFR2b is about 5 nM or lower.

35. The antibody according to any one of the preceding claims 1-34, wherein the antibody does not bind to FGFR1b, FGFR1c, FGFR2c, FGFR3b, FGFR3c or FGFR4.

36. The antibody according to any one of the preceding claims 1-35, wherein the antibody is a chimeric antibody.

37. The antibody according to any one of the preceding claims 1-36, wherein the antibody is a humanized or partially humanized antibody.

38. The antibody according to any one of the preceding claims 1-37, wherein the antibody is a monoclonal antibody.

39. The antibody according to any one of the preceding claims 1-38, wherein the antibody is a bispecific antibody.

40. The antibody according to any one of the preceding claims 1-39, wherein the antibody is capable of conjugating to a cytotoxic agent.

41. The antibody according to any one of the preceding claims 1-40, wherein the antibody is a defucosylated antibody.

42. The antibody according to any one of the preceding claims 1-41, wherein the antibody comprises an Fc portion, and the Fc region is engineered to enhance antibody-dependent cell-mediated cytotoxicity (ADCC).

43. The antibody according to any one of the preceding claims 1-42, wherein the antibody is an antibody-dependent cell-mediated cytotoxicity (ADCC)-enhanced antibody.

44. A composition comprising the antibody according to any one of the preceding claims 1-43.

45. A pharmaceutical composition comprising the antibody according to any one of the preceding claims 1-43 and a pharmaceutically acceptable carrier.

46. A polynucleotide encoding the antibody according to any one of the preceding claims 1-43.

47. A vector comprising the polynucleotide of claim 46.

48. A cell capable of expressing the antibody according to any one of the preceding claims 1-43.

49. A cell comprising the polynucleotide of claim 40 and / or the vector of claim 47.

50. A method for preparing an antibody, comprising culturing the cell of claim 48 or 49 and recovering the antibody.

51. A method for blocking the binding of FGFR2b to at least one fibroblast growth factor (FGF), comprising administering to a subject an effective amount of the antibody according to any one of the preceding claims 1-43 or the composition of claim 44 or 45.

52. The method according to claim 51, wherein the FGF is selected from FGF1, FGF3, FGF7, FGF10, and FGF22.

53. A method for inhibiting cell proliferation, comprising administering to a subject an effective amount of the antibody according to any one of the preceding claims 1-43 or the composition of claim 44 or 45.

54. The method according to claim 53, wherein the cell proliferation is FGF-induced cell proliferation.

55. The method according to claim 53 or 54, wherein the cell is a cancer cell.

56. A method for inhibiting a signal transduction pathway stimulated by the binding of FGF to FGFR2b, comprising administering to a subject an effective amount of the antibody according to any one of the preceding claims 1-43 or the composition of claim 44 or 45.

57. A method for inhibiting the growth of tumor xenografts overexpressing FGFR2b, comprising administering to a subject an effective amount of the antibody according to any one of claims 1-43 or the composition according to claim 44 or 45.

58. A method for detecting whether FGFR2b is contained in a sample, comprising contacting the antibody according to any one of claims 1-43 or the composition according to claim 44 or 45 with the sample to be tested, and if binding to the antibody is detected, it indicates that FGFR2b is contained in the sample.

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