Anti-FGFR2B antibodies and uses thereof

Abstract

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

Description

[Technical Field]

[0001] The present disclosure relates generally to novel anti-FGFR2b antibodies and antigen-binding fragments thereof that specifically bind to fibroblast growth factor receptor 2b (FGFR2IIIb or FGFR2b), as well as polynucleotides, vectors, cells, anti-FGFR2b compositions, and uses thereof.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of International Application No. PCT / CN2022 / 122986, filed September 30, 2022, which is incorporated herein by reference in its entirety.

[0003] Sequence Listing

[0001] This disclosure contains a Sequence Listing that has been submitted electronically as a file created on September 29, 2023 with the file name "9.29.2023 sequence listing anti-FGFR2B.xml" having a size of 385,412 bytes. The information contained in this Sequence Listing is incorporated herein by reference. [Background technology]

[0004] Fibroblast growth factor receptors (FGFRs) belong to a family of highly conserved transmembrane tyrosine kinase receptors consisting of an extracellular domain composed of distinct Ig-like domains (the α isoform contains all three Ig-like domains D1, D2, and D3, whereas the β isoform contains only the two Ig-like domains D2 and D3, but not D1), a transmembrane domain, and an intracellular tyrosine kinase domain. FGFRs are involved in various 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 important for ligand binding and specificity, whereas the D1 domain is absent in certain isoforms and is thought to have an autoinhibitory function. Alternative splicing of the carboxyl half of the D3 domain generates either the IIIb or IIIc isoforms of FGFR1-FGFR3 (Eswarakumar et al., Cytokine Growth Factor Rev 2005;16:139-49; Turner et al., Nat Rev Cancer 2010;10:116-29). These various isoforms of FGFRs exhibit tissue-specific expression and respond to a distinct spectrum of 18 mammalian fibroblast growth factors (FGFs) (Beenken et al., Nat Rev Drug Discov 2009;8:235-53). For FGFR2, alternative splicing of the exon encoding the D3 domain generates FGFR2IIIb and FGFR2IIIc (also written as FGFR2b and FGFR2c) splice forms, which have different ligand binding preferences. FGFR2IIIb, which is normally expressed on epithelial cells, is a specific receptor for keratinocyte growth factor (KGF) family members (FGF10, FGF22, especially FGF7), whereas FGFR2IIIc, which is expressed on mesenchymal tissues, responds to ligands secreted by epithelial cells and binds well to both 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] Ample evidence supports the important role of aberrant FGFR2 signaling in cancer, including overexpression of FGFR2 and its ligands, receptor mutation and amplification, and receptor isoform switching (Bai et al., Cancer Res; 70(19):7630-7639, October 1, 2010). Single nucleotide polymorphisms (SNPs) in FGFR2 are associated with an increased risk of breast cancer development, likely due to elevated FGFR2 expression (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). Potentially activating missense mutations in FGFR2 have been reported in multiple cancer types, including endometrial, ovarian, breast, lung, and gastric cancer (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 USA 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). Furthermore, the FGFR2 gene is amplified in a subset of gastric and breast cancers (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).Coexpression of FGFR2IIIb and its ligand, FGF7, in pancreatic and gastric cancers and lung adenocarcinomas is associated with poor prognosis, possibly due to aberrant receptor activation through the formation of an autocrine activation loop (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). Paradoxically, FGFR2 has also been implicated as 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). Decreased expression of FGFR2IIIb has been reported in several cancer types during tumor progression (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 USA 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 contrasting and context-dependent roles of FGFR2 signaling highlight the complexity of FGFR2 signaling.

[0007] Targeted therapy using anti-FGFR2b antibodies may be beneficial for patients with aberrantly activated / amplified FGFR2b signaling. There is a great need for novel anti-FGFR2b antibodies. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Katoh et al., Med Res Rev 2014;34:280-300 [Non-patent document 2] Eswarakumar et al. Cytokine Growth Factor Rev 2005;16:139-49 [Non-patent document 3] Turner et al., Nat Rev Cancer 2010;10:116-29 [Non-patent document 4] Beenken et al., Nat Rev Drug Discov 2009;8:235-53 [Non-patent document 5] Ornitz et al. J Biol Chem 1996;271:15292-7 [Non-patent document 6] Zhang et al. J Biol Chem 2006;281:15694-700 [Non-Patent Document 7] Bai et al., Cancer Res;70(19):7630-7639, October 1, 2010 [Non-patent document 8] Easton et al., Nature 2007;447:1087-93 [Non-Patent Document 9] Hunter et al., Nat Genet 2007;39:870-4; Meyer et al., PLoS Biol 2008;6:e108 [Non-Patent Document 10] Davies et al., Cancer Res 2005;65:7591-5 [Non-Patent Document 11] Ding et al., Nature 2008;455:1069-75 [Non-Patent Document 12] Dutt et al. Proc Natl Acad Sci USA 2008;105:8713-7 [Non-Patent Document 13] Greenman et al., Nature 2007;446:153-8 [Non-Patent Document 14] Pollock et al., Oncogene 2007;26:7158-62 [Non-Patent Document 15] Jang et al., Cancer Res 2001;61:3541-3 [Non-Patent Document 16] Heiskanen et al. Anal Cell Pathol 2001;22:229-34 [Non-Patent Document 17] Adnane et al., Oncogene 1991;6:659-63 [Non-Patent Document 18] Turner et al., Oncogene 2010;29:2013-23 [Non-Patent Document 19] Hara et al., Lab Invest 1998;78:1143-53 [Non-Patent Document 20] Mor et al. Cancer Genet Cytogenet 1993;65:111-4 [Non-Patent Document 21] Tsujimoto et al. Virchows Arch 1997;431:383-9 [Non-Patent Document 22] Yoshida et al. Semin Cancer Biol 1993;4:33-40 [Non-Patent Document 23] Yamayoshi et al. J Pathol 2004;204:110-8 [Non-Patent Document 24] Cho et al. Am J Pathol 2007;170:1964-74 [Non-Patent Document 25] Toyokawa et al. Oncol Rep 2009;21:875-80 [Non-Patent Document 26] Gartside et al. Mol Cancer Res 2009;7:41-54 [Non-Patent Document 27] Diez et al. Oncogene 1997;14:323-30 [Non-patent document 28] Giri et al. Clin Cancer Res 1999;5:1063-71 [Non-Patent Document 29] Ricol et al., Oncogene 1999;18:7234-43 [Non-Patent Document 30] Zhang et al., Proc Natl Acad Sci USA 2001;98:11336-40 [Non-Patent Document 31] Grose et al., EMBO J 2007;26:1268-78 [Non-Patent Document 32] Lin et al., Development 2007;134:723-34 Summary of the Invention [Problem to be solved by the invention]

[0009] The present disclosure provides novel anti-FGFR2b antibodies and antigen-binding fragments thereof, as well as polynucleotides, vectors, cells, anti-FGFR2b compositions, and uses thereof. [Means for solving the problem]

[0010] In one aspect, the disclosure provides an antibody comprising a heavy chain variable region, the heavy chain variable region comprising at least one complementarity determining region (CDR), wherein the CDR most N-terminally distant is selected from SEQ ID NO:61, SEQ ID NO:67, SEQ ID NO:73, SEQ ID NO:79, SEQ ID NO:85, SEQ ID NO:89, SEQ ID NO:95, SEQ ID NO:101, SEQ ID NO:104, SEQ ID NO:112, SEQ ID NO:116, SEQ ID NO:121, SEQ ID NO:125, SEQ ID NO:128, SEQ ID NO:131, SEQ ID NO:136, SEQ ID NO:138, SEQ ID NO:142, SEQ ID NO:144, SEQ ID NO:147, SEQ ID NO:151, SEQ ID NO:154, SEQ ID NO:, and SEQ ID NO:158.

[0011] In some embodiments, the heavy chain variable region comprises three CDRs, the three CDRs being, from N-terminus to C-terminus, hCDR1, hCDR2, and hCDR3, wherein hCDR1 is selected from SEQ ID NO:59, SEQ ID NO:65, SEQ ID NO:71, SEQ ID NO:77, SEQ ID NO:83, SEQ ID NO:88, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:110, SEQ ID NO:119, SEQ ID NO:135, SEQ ID NO:143, SEQ ID NO:146, SEQ ID NO:150, and SEQ ID NO:152; and hCDR2 is selected from SEQ ID NO:60, SEQ ID NO:66, SEQ ID NO:72, SEQ ID NO:78, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO: SEQ ID NO:111, SEQ ID NO:118, SEQ ID NO:120, SEQ ID NO:124, SEQ ID NO:141, SEQ ID NO:153, and hCDR3 is selected from SEQ ID NO:61, SEQ ID NO:67, SEQ ID NO:73, SEQ ID NO:79, SEQ ID NO:85, SEQ ID NO:89, SEQ ID NO:95, SEQ ID NO:101, SEQ ID NO:104, SEQ ID NO:112, SEQ ID NO:116, SEQ ID NO:121, SEQ ID NO:125, SEQ ID NO:128, SEQ ID NO:131, SEQ ID NO:136, SEQ ID NO:138, SEQ ID NO:142, SEQ ID NO:144, SEQ ID NO:147, SEQ ID NO:151, SEQ ID NO:154, and SEQ ID NO:158.

[0012] In some embodiments, hCDR1, hCDR2, and hCDR3 are 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. 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, q. SEQ ID NO: 119, SEQ ID NO: 124, SEQ ID NO: 125, 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, 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, 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, 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, or cc. SEQ ID NO: 88, SEQ ID NO: 94, SEQ ID NO: 158, respectively Includes.

[0013] In some embodiments, the heavy chain variable region comprises four framework regions (FR), the four FRs being, from N-terminus to C-terminus, hFR1, hFR2, hFR3, and hFR4, wherein hFR1 is selected from SEQ ID NO:160, SEQ ID NO:168, SEQ ID NO:175, SEQ ID NO:188, SEQ ID NO:194, SEQ ID NO:204, SEQ ID NO:210, SEQ ID NO:224, SEQ ID NO:233, SEQ ID NO:284, SEQ ID NO:259, SEQ ID NO:265, SEQ ID NO:268, SEQ ID NO:271, SEQ ID NO:274, SEQ ID NO:281, SEQ ID NO:295, and SEQ ID NO:305; and hFR2 is selected from SEQ ID NO:161, SEQ ID NO:169, SEQ ID NO:176, SEQ ID NO:183, SEQ ID NO:205, SEQ ID NO:221, SEQ ID NO:225, SEQ ID NO:237, SEQ ID NO:245, SEQ ID NO:251, SEQ ID NO:261, SEQ ID NO:266. , SEQ ID NO:275, SEQ ID NO:282, and SEQ ID NO:296; hFR3 is selected from SEQ ID NO:162, SEQ ID NO:170, SEQ ID NO:177, SEQ ID NO:184, SEQ ID NO:189, SEQ ID NO:195, SEQ ID NO:200, SEQ ID NO:206, SEQ ID NO:211, SEQ ID NO:216, SEQ ID NO:226, SEQ ID NO:231, SEQ ID NO:234, SEQ ID NO:239, SEQ ID NO:242, SEQ ID NO:246, SEQ ID NO:252, SEQ ID NO:254, SEQ ID NO:260, SEQ ID NO:262, SEQ ID NO:267, SEQ ID NO:272, SEQ ID NO:276, SEQ ID NO:297, and SEQ ID NO:306; and hFR4 is selected from SEQ ID NO:163, SEQ ID NO:178, SEQ ID NO:190, SEQ ID NO:196, SEQ ID NO:212, SEQ ID NO:217, SEQ ID NO:227, SEQ ID NO:255, SEQ ID NO:269, and SEQ ID NO:298.

[0014] In some embodiments, hFR1, hFR2, hFR3, and hFR4 are 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. SEQ ID NO:210, SEQ ID NO:169, SEQ ID NO:211, SEQ ID NO:212, respectively; j. SEQ ID NO:194, SEQ ID NO:169, SEQ ID NO:216, SEQ ID NO:217, respectively; k. SEQ ID NO:204, SEQ ID NO:221, SEQ ID NO:206, SEQ ID NO:178, respectively; l. SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, respectively; m. SEQ ID NO: 194, SEQ ID NO: 169, SEQ ID NO: 231, SEQ ID NO: 163, respectively n. SEQ ID NO: 233, SEQ ID NO: 169, SEQ ID NO: 234, SEQ ID NO: 178, respectively; o. SEQ ID NO:210, SEQ ID NO:237, SEQ ID NO:211, SEQ ID NO:212, respectively p. SEQ ID NO: 194, SEQ ID NO: 169, SEQ ID NO: 239, SEQ ID NO: 190, q. SEQ ID NO: 194, SEQ ID NO: 169, SEQ ID NO: 242, SEQ ID NO: 178, r. SEQ ID NO:284, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:163, s. SEQ ID NO: 194, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 163, t. SEQ ID NO: 188, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 163, u. SEQ ID NO: 188, SEQ ID NO: 169, SEQ ID NO: 254, SEQ ID NO: 255, respectively; v. SEQ ID NO: 259, SEQ ID NO: 169, SEQ ID NO: 260, SEQ ID NO: 190, respectively w. SEQ ID NO: 194, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 163, x. SEQ ID NO: 265, SEQ ID NO: 266, SEQ ID NO: 267, SEQ ID NO: 163, respectively y. SEQ ID NO: 268, SEQ ID NO: 169, SEQ ID NO: 239, SEQ ID NO: 269, z. SEQ ID NO: 194, SEQ ID NO: 169, SEQ ID NO: 200, SEQ ID NO: 190, respectively aa. SEQ ID NO: 271, SEQ ID NO: 169, SEQ ID NO: 272, SEQ ID NO: 190, bb. SEQ ID NO: 274, SEQ ID NO: 275, SEQ ID NO: 276, SEQ ID NO: 178, or cc. SEQ ID NO: 281, SEQ ID NO: 282, SEQ ID NO: 254, SEQ ID NO: 163, dd. SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, ee. SEQ ID NO: 305, SEQ ID NO: 296, SEQ ID NO: 306, SEQ ID NO: 298, ff. SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 306, SEQ ID NO: 298, gg. SEQ ID NO: 305, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, respectively Includes.

[0015] In some embodiments, the CDRs and FRs in the heavy chain variable region are operably linked in the order of hFR1-hCDR1-hFR2-hCDR2-hFR3-hCDR3-hFR4 from the N-terminus to the C-terminus.

[0016] In some embodiments, the antibody further comprises a heavy chain constant region, the heavy chain constant region comprising, from N-terminus to C-terminus, three domains, CH1, CH2, and CH3, wherein CH1, CH2, and CH3 are: SEQ ID NO: 307, SEQ ID NO: 309, and SEQ ID NO: 310, respectively; or SEQ ID NO: 307, SEQ ID NO: 312, and SEQ ID NO: 313, respectively is.

[0017] In some embodiments, the heavy chain variable region comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:285, SEQ ID NO:287, SEQ ID NO:290, and SEQ ID NO:291.

[0018] In some embodiments, the heavy chain variable region comprises the amino acid sequence of any one of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:285, SEQ ID NO:287, SEQ ID NO:290, and SEQ ID NO:291.

[0019] In some embodiments, the antibody further comprises a light chain variable region, wherein the light chain variable region comprises at least one CDR, wherein the CDR most N-terminally is selected from SEQ ID NO:64, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:82, SEQ ID NO:87, SEQ ID NO:92, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:115, SEQ ID NO:117, SEQ ID NO:123, SEQ ID NO:127, SEQ ID NO:130, SEQ ID NO:134, SEQ ID NO:137, SEQ ID NO:140, SEQ ID NO:145, SEQ ID NO:157, and SEQ ID NO:159.

[0020] In some embodiments, the light chain variable region comprises three CDRs, which are, from N-terminus to C-terminus, lCDR1, lCDR2, and lCDR3, wherein lCDR1 is selected from SEQ ID NO:62, SEQ ID NO:68, SEQ ID NO:74, SEQ ID NO:80, SEQ ID NO:86, SEQ ID NO:90, SEQ ID NO:96, SEQ ID NO:99, SEQ ID NO:105, SEQ ID NO:108, SEQ ID NO:113, SEQ ID NO:122, SEQ ID NO:126, SEQ ID NO:129, SEQ ID NO:132, SEQ ID NO:148, SEQ ID NO:149, and SEQ ID NO:155; and lCDR2 is selected from SEQ ID NO:63, SEQ ID NO:69, SEQ ID NO:75, SEQ ID NO: 81, SEQ ID NO:91, SEQ ID NO:97, SEQ ID NO:106, SEQ ID NO:114, SEQ ID NO:133, SEQ ID NO:139, and SEQ ID NO:156, and lCDR3 is selected from SEQ ID NO:64, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:82, SEQ ID NO:87, SEQ ID NO:92, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:115, SEQ ID NO:117, SEQ ID NO:123, SEQ ID NO:127, SEQ ID NO:130, SEQ ID NO:134, SEQ ID NO:137, SEQ ID NO:140, SEQ ID NO:145, SEQ ID NO:157, and SEQ ID NO:159.

[0021] In some embodiments, lCDR1, lCDR2, and lCDR3 are 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, q. SEQ ID NO: 126, SEQ ID NO: 69, SEQ ID NO: 127, 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, t. SEQ ID NO: 126, SEQ ID NO: 69, SEQ ID NO: 137, 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, x. SEQ ID NO: 148, SEQ ID NO: 69, SEQ ID NO: 109, respectively; y. SEQ ID NO: 149, SEQ ID NO: 63, SEQ ID NO: 109, respectively; z. SEQ ID NO: 122, SEQ ID NO: 69, SEQ ID NO: 123, respectively; aa. SEQ ID NO: 126, SEQ ID NO: 69, SEQ ID NO: 130, respectively bb. SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 157, or cc. SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 159, respectively Includes.

[0022] In some embodiments, the light chain variable region comprises four framework regions, the four framework regions being, from N-terminus to C-terminus, lFR1, lFR2, lFR3, and lFR4, wherein lFR1 is selected from SEQ ID NO:164, SEQ ID NO:171, SEQ ID NO:179, SEQ ID NO:185, SEQ ID NO:191, SEQ ID NO:197, SEQ ID NO:201, SEQ ID NO:207, SEQ ID NO:213, SEQ ID NO:218, SEQ ID NO:222, SEQ ID NO:228, SEQ ID NO:232, SEQ ID NO:247, SEQ ID NO:256, SEQ ID NO:263, SEQ ID NO:270, SEQ ID NO:277, SEQ ID NO:283, SEQ ID NO:299, and SEQ ID NO:303; and lFR2 is selected from SEQ ID NO:165, SEQ ID NO:172, SEQ ID NO:180, SEQ ID NO:186, SEQ ID NO:192, SEQ ID NO:198, SEQ ID NO:202, SEQ ID NO:208, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:226, SEQ ID NO:228, SEQ ID NO:232, SEQ ID NO:247, SEQ ID NO:256, SEQ ID NO:263, SEQ ID NO:270, SEQ ID NO:277, SEQ ID NO:283, SEQ ID NO:299, and SEQ ID NO:303. IFR3 is selected from SEQ ID NO:166, SEQ ID NO:173, SEQ ID NO:181, SEQ ID NO:187, SEQ ID NO:193, SEQ ID NO:199, SEQ ID NO:203, SEQ ID NO:209, SEQ ID NO:220, SEQ ID NO:230, SEQ ID NO:236, SEQ ID NO:238, SEQ ID NO:241, SEQ ID NO:244, SEQ ID NO:249, SEQ ID NO:253, SEQ ID NO:258, SEQ ID NO:273, SEQ ID NO:279, and SEQ ID NO:301; and IFR4 is selected from SEQ ID NO:167, SEQ ID NO:174, SEQ ID NO:182, SEQ ID NO:215, SEQ ID NO:250, SEQ ID NO:280, and SEQ ID NO:302.

[0023] In some embodiments, lFR1, lFR2, lFR3, and lFR4 are 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, q. SEQ ID NO: 171, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 174, 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, t. SEQ ID NO: 171, SEQ ID NO: 243, SEQ ID NO: 253, SEQ ID NO: 167, 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, 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, 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, or cc. SEQ ID NO: 283, SEQ ID NO: 278, SEQ ID NO: 279, SEQ ID NO: 174, dd. SEQ ID NO: 299, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, ee. SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 301, SEQ ID NO: 302, ff. SEQ ID NO: 299, SEQ ID NO: 304, SEQ ID NO: 301, SEQ ID NO: 302, respectively Includes.

[0024] In some embodiments, the CDRs and FRs in the light chain variable region are operably linked from N-terminus to C-terminus in the order lFR1-lCDR1-lFR2-lCDR2-lFR3-lCDR3-lFR4.

[0025] In some embodiments, the antibody further comprises a light chain constant region (CL), wherein the CL is SEQ ID NO:311.

[0026] In some embodiments, the light chain variable region comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:286, SEQ ID NO:288, and SEQ ID NO:289.

[0027] In some embodiments, the light chain variable region comprises the amino acid sequence of any one of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:286, SEQ ID NO:288, and SEQ ID NO:289.

[0028] In another aspect, the disclosure provides an antibody comprising a light chain variable region, the light chain variable region comprising at least one CDR, wherein the CDR most N-terminally distant is selected from SEQ ID NO:64, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:82, SEQ ID NO:87, SEQ ID NO:92, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:115, SEQ ID NO:117, SEQ ID NO:123, SEQ ID NO:127, SEQ ID NO:130, SEQ ID NO:134, SEQ ID NO:137, SEQ ID NO:140, SEQ ID NO:145, SEQ ID NO:157, and SEQ ID NO:159.

[0029] In some embodiments, the light chain variable region comprises three CDRs, which are, from N-terminus to C-terminus, lCDR1, lCDR2, and lCDR3, wherein lCDR1 is selected from SEQ ID NO:62, SEQ ID NO:68, SEQ ID NO:74, SEQ ID NO:80, SEQ ID NO:86, SEQ ID NO:90, SEQ ID NO:96, SEQ ID NO:99, SEQ ID NO:105, SEQ ID NO:108, SEQ ID NO:113, SEQ ID NO:122, SEQ ID NO:126, SEQ ID NO:129, SEQ ID NO:132, SEQ ID NO:148, SEQ ID NO:149, and SEQ ID NO:155; and lCDR2 is selected from SEQ ID NO:63, SEQ ID NO:69, SEQ ID NO:75, SEQ ID NO: 81, SEQ ID NO:91, SEQ ID NO:97, SEQ ID NO:106, SEQ ID NO:114, SEQ ID NO:133, SEQ ID NO:139, and SEQ ID NO:156, and lCDR3 is selected from SEQ ID NO:64, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:82, SEQ ID NO:87, SEQ ID NO:92, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:115, SEQ ID NO:117, SEQ ID NO:123, SEQ ID NO:127, SEQ ID NO:130, SEQ ID NO:134, SEQ ID NO:137, SEQ ID NO:140, SEQ ID NO:145, SEQ ID NO:157, and SEQ ID NO:159.

[0030] In some embodiments, lCDR1, lCDR2, and lCDR3 are 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, q. SEQ ID NO: 126, SEQ ID NO: 69, SEQ ID NO: 127, 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, t. SEQ ID NO: 126, SEQ ID NO: 69, SEQ ID NO: 137, 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, x. SEQ ID NO: 148, SEQ ID NO: 69, SEQ ID NO: 109, respectively; y. SEQ ID NO: 149, SEQ ID NO: 63, SEQ ID NO: 109, respectively; z. SEQ ID NO: 122, SEQ ID NO: 69, SEQ ID NO: 123, respectively; aa. SEQ ID NO: 126, SEQ ID NO: 69, SEQ ID NO: 130, respectively bb. SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 157, or cc. SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 159, respectively Includes.

[0031] In some embodiments, the light chain variable region comprises four framework regions, the four framework regions being, from N-terminus to C-terminus, lFR1, lFR2, lFR3, and lFR4, wherein lFR1 is selected from SEQ ID NO:164, SEQ ID NO:171, SEQ ID NO:179, SEQ ID NO:185, SEQ ID NO:191, SEQ ID NO:197, SEQ ID NO:201, SEQ ID NO:207, SEQ ID NO:213, SEQ ID NO:218, SEQ ID NO:222, SEQ ID NO:228, SEQ ID NO:232, SEQ ID NO:247, SEQ ID NO:256, SEQ ID NO:263, SEQ ID NO:270, SEQ ID NO:277, SEQ ID NO:283, SEQ ID NO:299, and SEQ ID NO:303; and lFR2 is selected from SEQ ID NO:165, SEQ ID NO:172, SEQ ID NO:180, SEQ ID NO:186, SEQ ID NO:192, SEQ ID NO:198, SEQ ID NO:202, SEQ ID NO:208, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:226, SEQ ID NO:228, SEQ ID NO:232, SEQ ID NO:247, SEQ ID NO:256, SEQ ID NO:263, SEQ ID NO:270, SEQ ID NO:277, SEQ ID NO:283, SEQ ID NO:299, and SEQ ID NO:303. IFR3 is selected from SEQ ID NO:166, SEQ ID NO:173, SEQ ID NO:181, SEQ ID NO:187, SEQ ID NO:193, SEQ ID NO:199, SEQ ID NO:203, SEQ ID NO:209, SEQ ID NO:220, SEQ ID NO:230, SEQ ID NO:236, SEQ ID NO:238, SEQ ID NO:241, SEQ ID NO:244, SEQ ID NO:249, SEQ ID NO:253, SEQ ID NO:258, SEQ ID NO:273, SEQ ID NO:279, and SEQ ID NO:301; and IFR4 is selected from SEQ ID NO:167, SEQ ID NO:174, SEQ ID NO:182, SEQ ID NO:215, SEQ ID NO:250, SEQ ID NO:280, and SEQ ID NO:302.

[0032] In some embodiments, lFR1, lFR2, lFR3, and lFR4 are 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, q. SEQ ID NO: 171, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 174, 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, t. SEQ ID NO: 171, SEQ ID NO: 243, SEQ ID NO: 253, SEQ ID NO: 167, 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, 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, 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, or cc. SEQ ID NO: 283, SEQ ID NO: 278, SEQ ID NO: 279, SEQ ID NO: 174, dd. SEQ ID NO: 299, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, ee. SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 301, SEQ ID NO: 302, ff. SEQ ID NO: 299, SEQ ID NO: 304, SEQ ID NO: 301, SEQ ID NO: 302, gg. Includes.

[0033] In some embodiments, the CDRs and FRs in the light chain variable region are operably linked from N-terminus to C-terminus in the order lFR1-lCDR1-lFR2-lCDR2-lFR3-lCDR3-lFR4.

[0034] In some embodiments, the antibody further comprises a light chain constant region (CL), wherein the CL is SEQ ID NO:311.

[0035] In some embodiments, the light chain variable region comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:286, SEQ ID NO:288, and SEQ ID NO:289.

[0036] In some embodiments, the light chain variable region comprises the amino acid sequence of any one of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:286, SEQ ID NO:288, and SEQ ID NO:289.

[0037] In some embodiments, the heavy chain variable region and the light chain variable region are 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. 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; or cc. SEQ ID NO: 57 and SEQ ID NO: 58, respectively; dd. SEQ ID NO: 285 and SEQ ID NO: 286, respectively; ee. SEQ ID NO: 287 and SEQ ID NO: 288, respectively; ff. SEQ ID NO: 287 and SEQ ID NO: 289, respectively; gg. SEQ ID NO: 290 and SEQ ID NO: 288, respectively; hh. SEQ ID NO: 290 and SEQ ID NO: 286, respectively; ii. SEQ ID NO: 291 and SEQ ID NO: 286, respectively; jj. SEQ ID NO: 292 and SEQ ID NO: 293, respectively; kk. SEQ ID NO: 294 and SEQ ID NO: 293, respectively The amino acid sequence may have at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to

[0038] In some embodiments, the heavy chain variable region and the light chain variable region are 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. 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; or cc. SEQ ID NO: 57 and SEQ ID NO: 58, respectively; dd. SEQ ID NO: 285 and SEQ ID NO: 286, respectively; ee. SEQ ID NO: 287 and SEQ ID NO: 288, respectively; ff. SEQ ID NO: 287 and SEQ ID NO: 289, respectively; gg. SEQ ID NO: 290 and SEQ ID NO: 288, respectively; hh. SEQ ID NO: 290 and SEQ ID NO: 286, respectively; ii. SEQ ID NO: 291 and SEQ ID NO: 286, respectively; jj. SEQ ID NO: 292 and SEQ ID NO: 293, respectively; kk. SEQ ID NO: 294 and SEQ ID NO: 293, respectively Includes.

[0039] In some embodiments, the antibody specifically binds to fibroblast growth factor receptor 2b (FGFR2b).

[0040] In some embodiments, the FGFR2b is from a source selected from human, mouse, and cynomolgus monkey.

[0041] In some embodiments, the antibody has a K of about 10 nM or less. D It binds to FGFR2b.

[0042] In some embodiments, the antibody has a K of about 9 nM or less. D It binds to FGFR2b.

[0043] In some embodiments, the antibody has a K of about 5 nM or less. D It binds to FGFR2b.

[0044] In some embodiments, the antibody does not detectably bind to FGFR1b, FGFR1c, FGFR2c, FGFR3b, FGFR3c, or FGFR4.

[0045] In some embodiments, the antibody is a chimeric antibody.

[0046] In some embodiments, the antibody is a humanized or partially humanized antibody.

[0047] In some embodiments, the antibody is a monoclonal antibody.

[0048] In some embodiments, the antibody is an afucosylated antibody.

[0049] In some embodiments, the antibody is an Fc engineered antibody that has enhanced binding to activating Fc receptors and enhanced antibody-dependent cellular cytotoxicity (ADCC).

[0050] In some embodiments, the antibody is an ADCC enhancing antibody.

[0051] In some embodiments, the antibody is a bispecific antibody.

[0052] In some embodiments, the antibody is operably linked to a cytotoxic agent.

[0053] In another aspect, the disclosure provides a composition comprising an antibody described herein.

[0054] In another aspect, the present disclosure provides a pharmaceutical composition comprising an antibody described herein and a pharmaceutically acceptable carrier.

[0055] In another aspect, the disclosure provides polynucleotides encoding the antibodies described herein.

[0056] In another aspect, the disclosure provides a vector comprising a polynucleotide described herein.

[0057] In another aspect, the present disclosure provides cells capable of expressing the antibodies described herein.

[0058] In another aspect, the present disclosure provides a cell comprising a polynucleotide described herein and / or a vector described herein.

[0059] In another aspect, the disclosure provides a method of producing an antibody, comprising culturing a cell described herein and recovering the antibody from the cell.

[0060] In another aspect, the present disclosure provides a method for blocking FGFR2b from binding 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.

[0061] In some embodiments, the FGF is selected from FGF1, FGF3, FGF7, FGF10, and FGF22.

[0062] In another aspect, the disclosure provides a method of inhibiting cell proliferation, the method comprising administering to a subject an effective amount of an antibody described herein or a composition described herein.

[0063] In some embodiments, the cell proliferation is FGF-induced cell proliferation.

[0064] In some embodiments, the cells are cancer cells.

[0065] In another aspect, the present disclosure provides a method for inhibiting a signal transduction pathway stimulated by the binding of FGF to FGFR2b, the method comprising administering to a subject an effective amount of an antibody described herein or a composition described herein.

[0066] In another aspect, the present disclosure provides a method for inhibiting the growth of a tumor xenograft that overexpresses FGFR2b, the method comprising administering to a subject an effective amount of an antibody described herein or a composition described herein.

[0067] In another aspect, the present disclosure provides a method for detecting the presence of FGFR2b in a sample, comprising contacting the sample with an antibody described herein or a composition described herein, wherein detection of at least one bound antibody indicates the presence of FGFR2b. [Brief explanation of the drawings]

[0068] [Figure 1A] FIG. 1A shows the amino acid sequence of the entire mAb1 light chain, with the CDRs underlined. [Figure 1B] FIG. 1B shows the amino acid sequence of the entire mAb1 heavy chain, with the CDRs underlined. [Figure 2] FIG. 2 shows the BLI binding affinity of mAb1 to FGFR2b ECD from three species, using FPA144 as a control antibody for reference comparison. [Figure 3A] FIG. 3A shows the results from flow cytometry of the binding of mAb1 and the reference control FPA144 to FGFR2IIIb in FGFR2IIIb-HEK293 cells. [Figure 3B] FIG. 3B shows the results from flow cytometry of the binding of mAb1 and the reference control FPA144 to FGFR2IIIc in FGFR2IIIc-HEK293 cells. [Figure 4] FIG. 4 shows the binding selectivity of mAb1 to various family members of human FGFR. [Figure 5] FIG. 5 shows the level of inhibition of FGF7-induced cell proliferation of SNU16 cells by mAb1 and the reference control FPA144. [Figure 6] FIG. 6 shows the level of inhibition of FGF10-induced cell proliferation of SNU16 cells by mAb1 and the reference control FPA144. [Figure 7] FIG. 7 shows the level of inhibition of the FGFR2 signaling pathway by mAb1 and the reference control FPA144. [Figure 8] FIG. 8 shows the in vivo antitumor efficacy of mAb1 at 5 mg / kg ip administered twice weekly in an SNU16 gastric cancer xenograft model. [Figure 9A] FIG. 9A shows the amino acid sequence of the entire humAbA1 light chain, with the CDRs underlined. [Figure 9B] FIG. 9B shows the amino acid sequence of the entire humAbA1 heavy chain, with the CDRs underlined. [Figure 10] FIG. 10 shows the BLI binding Ka, Koff (represented as Kd in FIG. 10), and affinity KD of humAbA1 to the extracellular domain (ECD) of FGFR2b from three species. [Figure 11] FIG. 11 shows the results from flow cytometry of the binding of humAbA1 to FGFR2IIIb and FGFR2IIIc in FGFR2IIIb-HEK293 cells or FGFR2IIIc-HEK293 cells. [Figure 12] FIG. 12 shows the binding selectivity of humAbA1 for various family members of human FGFR. [Figure 13] FIG. 13 shows the level of inhibition of FGF7-induced cell proliferation of SNU16 cells by humAbA1 and the reference control bemarituzumab. [Figure 14] FIG. 14 shows the level of inhibition of FGFR2 phosphorylation in SNU-16 cells. [Figure 15A] FIG. 15A shows the ADCC activity of antibodies and bemarituzumab in the CD16aV158 cell line. [Figure 15B] FIG. 15B shows the ADCC activity of antibodies and bemarituzumab in the CD16aF158 cell line. [Figure 16] FIG. 16 shows the in vivo anti-tumor efficacy of the antibody at 10 mg / kg intraperitoneally (ip) administered twice weekly in a SNU-16 gastric cancer xenograft model. [Figure 17]FIG. 17 shows the in vivo anti-tumor efficacy of the antibody at 10 mg / kg ip administered twice weekly in an OCUM-2M gastric cancer xenograft model. DETAILED DESCRIPTION OF THE INVENTION

[0069] definition All publications, patent publications, patents, and patent applications mentioned in this specification are incorporated by reference in their entirety to the same extent as if each individual publication, patent publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

[0070] In this disclosure, unless otherwise specified, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice of this disclosure, preferred methods and materials are described herein. Accordingly, the terms defined herein are more fully described by reference to the specification as a whole.

[0071] As used herein, the singular terms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0072] As used herein, "and / or" refers to and includes any and all possible combinations of one or more of the associated listed items, as well as the absence of a combination when interpreted in the alternative ("or"). Furthermore, the present invention contemplates that in some embodiments of the invention, any feature or combination of features described herein may be excluded or omitted.

[0073] The term "about," as used herein when referring to a measurable value such as a sequence length, is meant to encompass variations of 5%, 1%, 0.5%, or even 0.1% of the specified amount.

[0074] Unless contradictory to the context, the terms "comprise," "comprises," and "comprising," or similar terms, are intended to mean a non-exclusive inclusion, such that an enumerated list of elements or features not only includes the elements described or listed, but may also include other elements or features not listed or described.

[0075] Unless otherwise indicated, nucleic acids are written left to right in 5' to 3' orientation; amino acid sequences are written left to right in amino to carboxy orientation.

[0076] It will be understood that this disclosure is not limited to the particular methodology, protocols, and reagents described, as these may vary depending on the context in which they are used by those of skill in the art.

[0077] As used herein, the terms "percent identity" and "% identity" as applied to nucleic acid or polynucleotide sequences refer to the percentage of residue matches between at least two nucleic acid or polynucleotide sequences aligned using a standardized algorithm. Such algorithms may insert gaps in a standardized and reproducible manner between the sequences being compared to optimize the alignment between the two sequences and thus achieve a more meaningful comparison of the two sequences.

[0078] Percent identity between nucleic acid or polynucleotide sequences may be determined using the Basic Local Alignment Search Tool (BLAST), a commonly used, freely available suite of sequence comparison algorithms provided by the National Center for Biotechnology Information (NCBI) (Altschul, S.F. et al. (1990) J. Mol. Biol. 215:403-410), which is available from several sources, including NCBI, Bethesda, MD, and on the Internet at http: / / www.ncbi.nlm.nih.gov / BLAST / .

[0079] Nucleic acid or polynucleotide sequences that do not show a high degree of identity may nevertheless encode similar amino acid sequences due to the degeneracy of the genetic code. It is understood that alterations to nucleic acid sequences can be made to take advantage of this degeneracy to generate multiple nucleic acid sequences that all encode substantially the same protein. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base 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).

[0080] The term "nucleic acid" refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double-stranded form. Unless otherwise specified, the term encompasses nucleic acids containing known analogues of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. The term nucleic acid is used interchangeably with polynucleotide and (in appropriate context) gene, cDNA, and mRNA encoded by a gene.

[0081] As used herein, "percent (%) amino acid sequence identity" 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 with amino acid residues in another peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering conservative substitutions as part of the sequence identity. Percent amino acid sequence identity in this disclosure is measured using BLAST software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0082] Amino acid substitution refers to the replacement of one amino acid in a polypeptide with another amino acid. Exemplary substitutions are shown in Table 1. Amino acid substitutions may be introduced into a protein of interest and the products screened for a desired activity, e.g., retained / improved biological activity.

[0083] [Table 1]

[0084] Amino acids can be grouped according to common side chain properties. (1) Hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile, (2) Neutral hydrophilicity: Cys, Ser, Thr, Asn, Gln, (3) Acidic: Asp, Glu, (4) Basic: His, Lys, Arg, (5) Residues that affect chain orientation: Gly, Pro, (6) Aromatic: Trp, Tyr, Phe.

[0085] Non-conservative substitutions involve exchanging a member of one of these classes for another. The term "corresponding" with respect to a nucleotide or amino acid position of a sequence as set forth in the sequence listing refers to the nucleotide or amino acid position identified when aligned with a target sequence based on structural sequence alignment or using a standard alignment algorithm such as the GAP algorithm. For example, corresponding residues of a similar sequence (e.g., a fragment or species variant) can be determined by alignment to a reference sequence using structural alignment methods. By aligning the sequences, one skilled in the art can identify corresponding residues, for example, using conserved and identical amino acid residues as a guide.

[0086] As used herein, a composition refers to any mixture of two or more products, substances, or compounds, including cells.

[0087] As used herein, a "pharmaceutical composition" refers to an active pharmaceutical agent formulated in a pharmaceutically or physiologically acceptable solution for administration to a cell or an animal, either alone or in combination with one or more other therapeutic modalities. It will also be understood that, if desired, the compositions of the present disclosure may be administered in combination with other agents, such as, for example, cytokines, growth factors, hormones, small molecules, chemotherapeutic agents, prodrugs, drugs, antibodies, or various other pharmaceutically active agents. There is virtually no limit to other components that may also be included in the composition, provided that the additional agents do not adversely affect the ability of the composition to deliver the intended therapy. Some non-limiting examples of components that may be included in the composition are carriers, stabilizers, diluents, dispersing agents, suspending agents, thickeners, and / or excipients. The pharmaceutical composition facilitates administration of the antibodies or cells described herein to a subject. Multiple administration techniques exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0088] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of a therapeutic compound and that is relatively non-toxic, i.e., the material can be administered to a subject without causing undesired biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. Pharmaceutically acceptable ingredients include compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment.

[0089] As used herein, "effective amount" refers to that amount of a pharmaceutical composition sufficient to significantly and desirably modify the symptoms and / or condition being treated (e.g., provide a clinical response in a desirable direction). The effective amount of a pharmaceutical composition will vary depending on factors such as the particular condition being treated, the severity of the condition, the duration of treatment, the nature of any concurrent therapy, the particular composition used, the particular pharmaceutically acceptable excipients and / or carriers employed, and the knowledge and expertise of the attending physician.

[0090] 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, monkey, cat, dog, horse, cow, pig, sheep, goat, mammalian laboratory animal, mammalian farm animal, mammalian sport animal, or mammalian pet. The animal may be male or female and may be of any appropriate age, including infant, juvenile, adolescent, adult, and geriatric. In some instances, "individual" or "subject" refers to an animal in need of treatment for a disease or disorder. In some embodiments, an animal receiving treatment may be a "patient," which refers to the fact that the animal has been identified as having a disorder relevant to the treatment or at sufficient risk of developing such a disorder. In certain embodiments, the animal is a human, e.g., a human patient.

[0091] As used herein, "epitope" refers to the portion of an antigen that is recognized and bound by an antibody. An antigen may have multiple epitopes recognized by an antibody. Epitopes often consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and have specific three-dimensional structural characteristics as well as specific charge characteristics.

[0092] As used herein, the terms "FGFR2IIIb" and "FGFR2b" are used interchangeably to refer to the subtype IIIb splice form of FGFR2. Exemplary sequences of FGFR2b include the Homo sapiens (human) FGFR2b protein (e.g., precursor sequence with signal peptide, Genbank accession number: NP 075259.4); the Mus musculus (mouse) FGFR2b protein (e.g., complete sequence, Genbank accession number: NP_963895.2).

[0093] As used herein, the terms "FGFR2IIIc" and "FGFR2c" are used interchangeably to refer to the subtype IIIc splice form of FGFR2. Exemplary sequences of FGFR2c include human FGFR2c protein (e.g., precursor sequence, Genbank Accession Number: NP 000132.3).

[0094] As used herein, the term "anti-FGFR2b antibody" refers to an antibody that can specifically bind to FGFR2b. In some embodiments, the anti-FGFR2b antibody provided herein specifically binds to both FGFR2b, but does not have detectable binding affinity for FGFR1b, FGFR1c, FGFR2c, FGFR3b, FGFR3c, or FGFR4.

[0095] As used herein, the terms "specifically bind" or "bind" to a particular antigen refer to binding that is measurably different from non-specific interactions. For example, in some embodiments, a binding molecule such as an antibody specifically binds to a particular target molecule such as an antigen if the binding molecule reacts or associates with that target molecule more frequently, more rapidly, with a longer duration, and / or with greater affinity than with alternative molecules. A binding molecule such as an antibody "specifically binds" to a target molecule if it binds with greater affinity, avidity, more readily, and / or with a longer duration than it binds to other molecules. It is understood that a binding molecule such as an antibody that specifically binds to a first target may or may not specifically bind to a second target. Thus, "specific binding" does not necessarily require exclusive binding (although specific binding may include exclusive binding). In some embodiments, specific binding can be determined, for example, by comparing the binding of a particular antibody to the binding of an antibody that does not bind to the particular antigen. Specific binding to a particular antigen can occur, for example, when an antibody binds to a target molecule up to about 10 -4 M, maximum approx. 10 -5 M, maximum approx. 10 -6 M, at least about 10 -7 M, maximum approx. 10 -8 M, maximum approx. 10 -9 K against antigens of M D and K D refers to the off-rate of an antibody / antigen interaction. In some embodiments, an antibody that specifically binds to an antigen has a K that is lower than that of an antibody that does not bind to the same antigen. D 20, 50, 100, 500, 1000, 5,000, 10,000 or even smaller K D In some embodiments, the binding between an antibody and a particular antigen is measured using an EC200 antibody, which is determined using a suitable method known in the art, including, for example, a flow cytometry assay. 50Specific binding is a non-random binding reaction between two molecules, such as between an antibody and an antigen. The binding affinity of the antibodies and antigen-binding fragments provided herein can be expressed as the ratio of the dissociation rate to the association rate (K ) when the binding between an antigen and an antigen-binding molecule (e.g., an antibody or antigen-binding fragment) reaches equilibrium. off / K on ) represents K D The antigen binding affinity (e.g., K D ) can be suitably determined using suitable methods known in the art, including, for example, Biacore (based on surface plasmon resonance technology) and Octet® BLI Label-Free Detection Systems.

[0096] As used herein, "affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., a receptor) and its binding partner (e.g., a ligand). The affinity of a molecule for its partner is generally determined by the equilibrium dissociation constant (K D ) (or its reciprocal, the equilibrium association constant, K A Affinity can be measured by common methods known in the art, including those described herein (see, e.g., Pope et al., J. Immunol. Methods 2009;341(1-2):86-96).

[0097] antibody Antibodies are widely used in biological therapy. The potential and use of antibodies as therapeutic agents for a wide range of diseases is due to their high specificity and affinity of binding, which is facilitated by the variability of their complementarity-determining regions (CDRs) (Liu JKH Ann. Med. Surg., 3, 113-116 (2014)).

[0098] "Antibody" refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or an antigen-binding fragment thereof. "Antibody" also refers to IgA, IgD, IgE, IgG, or IgM antibody subtypes, or an antigen-binding fragment thereof. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region typically consists of three domains, CH1, CH2, and CH3. Each light chain is composed 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), surrounded by more conserved regions called framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs arranged from the amino terminus (N-terminus) to the carboxy terminus (C-terminus) in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant region of the antibody may mediate the binding of the immunoglobulin to host tissues or factors. The six CDRs in an antibody variable domain fold together in 3D space to form the actual antibody binding site that locks onto 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 ed., National Institutes of Health Publication No. 91-3242. National Institutes of Health, Bethesda, MD (1991); Al-Lazikani et al., J. Mol. Biol., 1997; 273(4), 927-948; Lefranc et al., Developmental & Comparative Immunology, 2003; 27(1), 55-77).

[0099] "CDRs" of a variable domain are amino acid residues within the variable region identified according to any CDR determination method and / or definition known in the art, including, but not limited to, the Kabat definition, the Chothia definition, a combination of both the Kabat and Chothia definitions, the AbM definition, the contact definition, and the conformational definition. Antibody CDRs may be identified as hypervariable regions as originally defined in Kabat et al., Sequences of Proteins of Immunological Interest (1991) 5th ed. National Institutes of Health Publication No. 91-3242. National Institutes of Health, Bethesda, MD. The locations of CDRs may also be identified as structural loop structures as described in Chothia et al., Nature 342.6252(1989):877-883. Other approaches to CDR identification include the "IMGT definition" (Lefranc, M.-P. et al., 1999, Nucleic Acids Res. 27:209-212), the "AbM definition," a compromise between Kabat and Chothia, derived using Oxford Molecular's AbM antibody modeling software, and the "contact definition" of CDRs based on observed antigen contacts, as described in MacCallum et al., 1996, J. Mol. Biol. 262:732-745. In another approach, referred to herein as the "conformational definition" of CDRs, the positions of CDRs may be identified as residues that contribute enthalpic values ​​to antigen binding (Makabe et al., 2008, J. Biol. Chem. 283:1156-1166). As used herein, CDR refers to CDRs defined by any approach known in the art, including a combination of approaches.

[0100] The term "antigen-binding portion" or "antigen-binding fragment" of an antibody (or simply "antibody portion"), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term "antigen-binding fragment" of an antibody include, but are not limited to, (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) an F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment consisting of a single VH domain or a single VL domain (see Ward et al., 1989, Nature 341:544-546); and (vi) an isolated complementarity-determining region. Furthermore, although the two domains of an Fv fragment, VL and VH, are encoded by separate genes, they can be joined using recombinant methods by a synthetic linker that allows them to be produced as a single protein chain in which the pair of VL and VH domains form a monovalent molecule (known as a single-chain Fv (scFv)) (see, 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 intended to be encompassed 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 the fragments are screened for utility in the same manner as intact antibodies.

[0101] For the purposes of this disclosure, the term "antibody" includes whole antibodies and any antigen-binding fragments or single chains thereof. The term "antibody" includes, but is not limited to, monoclonal antibodies, polyclonal antibodies, chimeric antibodies, recombinant antibodies, single-chain variable fragments (ScFvs), heavy chain antibodies, single domain antibodies, humanized antibodies, human antibodies, and antibodies from other sources such as mouse and rabbit.

[0102] As used herein, "isotype" refers to the class or subtype of an antibody (e.g., IgA, IgD, IgE, IgG, and IgM) determined by the heavy chain constant domain. In humans and most mammals, an antibody unit typically consists of four polypeptide chains: two identical heavy chains and two identical light chains linked by disulfide bonds. The light chain consists of one variable domain (VL) and one constant domain (CL), while the heavy chain contains one variable domain (VH) and three to four constant domains, e.g., CH1, CH2, and CH3. Immunoglobulins can be assigned to five major classes, namely, IgA, IgD, IgE, IgG, and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are typically further subdivided into IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Antibody light chains of any vertebrate species can be assigned to one of two different types, namely kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains.

[0103] As used herein, the term "antigen" has the same meaning as "immunogen."

[0104] As used herein, the term "Fc" refers to the portion of an antibody consisting of the second and third constant regions of a first heavy chain linked via disulfide bonds to the second and third constant regions of a second heavy chain. 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 function in antigen binding.

[0105] In one aspect, the disclosure provides an antibody comprising a heavy chain variable region, the heavy chain variable region comprising at least one complementarity determining region (CDR), wherein the CDR furthest from the N-terminus is selected from SEQ ID NO:61, SEQ ID NO:67, SEQ ID NO:73, SEQ ID NO:79, SEQ ID NO:85, SEQ ID NO:89, SEQ ID NO:95, SEQ ID NO:101, SEQ ID NO:104, SEQ ID NO:112, SEQ ID NO:116, SEQ ID NO:121, SEQ ID NO:125, SEQ ID NO:128, SEQ ID NO:131, SEQ ID NO:136, SEQ ID NO:138, SEQ ID NO:142, SEQ ID NO:144, SEQ ID NO:147, SEQ ID NO:151, SEQ ID NO:154, and SEQ ID NO:158. In some embodiments, the CDR furthest from the N-terminus is CDR3. Heavy chain CDR3 is conformationally located at the center of the antigen-binding site and is therefore thought to make the most contact with the antigen and provide the most free energy for the affinity of the antibody for the antigen. Heavy chain CDR3 is also considered to be by far the most diverse CDR of the antigen-binding site in terms of length, amino acid composition, and conformation, due to multiple diversification mechanisms (Tonegawa, S., Nature, 1983; 302(5909), 575-581). The diversity of heavy chain CDR3 is sufficient to generate most antibody specificities and desirable antigen-binding affinities (Xu et al., Immunity, 2000; 13(1), 37-45; Schier et al., Journal of molecular biology, 1996; 263(4), 551-567).

[0106] In some embodiments, the heavy chain variable region comprises three CDRs, the three CDRs being, from N-terminus to C-terminus, hCDR1, hCDR2, and hCDR3, wherein hCDR1 is selected from SEQ ID NO:59, SEQ ID NO:65, SEQ ID NO:71, SEQ ID NO:77, SEQ ID NO:83, SEQ ID NO:88, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:110, SEQ ID NO:119, SEQ ID NO:135, SEQ ID NO:143, SEQ ID NO:146, SEQ ID NO:150, and SEQ ID NO:152; and hCDR2 is selected from SEQ ID NO:60, SEQ ID NO:66, SEQ ID NO:72, SEQ ID NO:78, SEQ ID NO:84, SEQ ID NO:94, hCDR3 is selected from SEQ ID NO:111, SEQ ID NO:118, SEQ ID NO:120, SEQ ID NO:124, SEQ ID NO:141, and SEQ ID NO:153, and hCDR4 is selected from SEQ ID NO:61, SEQ ID NO:67, SEQ ID NO:73, SEQ ID NO:79, SEQ ID NO:85, SEQ ID NO:89, SEQ ID NO:95, SEQ ID NO:101, SEQ ID NO:104, SEQ ID NO:112, SEQ ID NO:116, SEQ ID NO:121, SEQ ID NO:125, SEQ ID NO:128, SEQ ID NO:131, SEQ ID NO:136, SEQ ID NO:138, SEQ ID NO:142, SEQ ID NO:144, SEQ ID NO:147, SEQ ID NO:151, SEQ ID NO:154, and SEQ ID NO:158.

[0107] In some embodiments, hCDR1, hCDR2, and hCDR3 are 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. 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, q. SEQ ID NO: 119, SEQ ID NO: 124, SEQ ID NO: 125, 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, 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, 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, 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, or cc. SEQ ID NO: 88, SEQ ID NO: 94, SEQ ID NO: 158, respectively Includes.

[0108] In some embodiments, the heavy chain variable region comprises four framework regions (FR), the four FRs being, from N-terminus to C-terminus, hFR1, hFR2, hFR3, and hFR4, wherein hFR1 is selected from SEQ ID NO:160, SEQ ID NO:168, SEQ ID NO:175, SEQ ID NO:188, SEQ ID NO:194, SEQ ID NO:204, SEQ ID NO:210, SEQ ID NO:224, SEQ ID NO:233, SEQ ID NO:284, SEQ ID NO:259, SEQ ID NO:265, SEQ ID NO:268, SEQ ID NO:271, SEQ ID NO:274, SEQ ID NO:281, SEQ ID NO:295, and SEQ ID NO:305; and hFR2 is selected from SEQ ID NO:161, SEQ ID NO:169, SEQ ID NO:176, SEQ ID NO:183, SEQ ID NO:205, SEQ ID NO:221, SEQ ID NO:225, SEQ ID NO:237, SEQ ID NO:245, SEQ ID NO:251, SEQ ID NO:261, SEQ ID NO:266. , SEQ ID NO:275, SEQ ID NO:282, and SEQ ID NO:296; hFR3 is selected from SEQ ID NO:162, SEQ ID NO:170, SEQ ID NO:177, SEQ ID NO:184, SEQ ID NO:189, SEQ ID NO:195, SEQ ID NO:200, SEQ ID NO:206, SEQ ID NO:211, SEQ ID NO:216, SEQ ID NO:226, SEQ ID NO:231, SEQ ID NO:234, SEQ ID NO:239, SEQ ID NO:242, SEQ ID NO:246, SEQ ID NO:252, SEQ ID NO:254, SEQ ID NO:260, SEQ ID NO:262, SEQ ID NO:267, SEQ ID NO:272, SEQ ID NO:276, SEQ ID NO:297, and SEQ ID NO:306; and hFR4 is selected from SEQ ID NO:163, SEQ ID NO:178, SEQ ID NO:190, SEQ ID NO:196, SEQ ID NO:212, SEQ ID NO:217, SEQ ID NO:227, SEQ ID NO:255, SEQ ID NO:269, and SEQ ID NO:298.

[0109] In some embodiments, hFR1, hFR2, hFR3, and hFR4 are 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. SEQ ID NO:210, SEQ ID NO:169, SEQ ID NO:211, SEQ ID NO:212, respectively; j. SEQ ID NO:194, SEQ ID NO:169, SEQ ID NO:216, SEQ ID NO:217, respectively; k. SEQ ID NO:204, SEQ ID NO:221, SEQ ID NO:206, SEQ ID NO:178, respectively; l. SEQ ID NO:224, SEQ ID NO:225, SEQ ID NO:226, SEQ ID NO:227, respectively; m. SEQ ID NO: 194, SEQ ID NO: 169, SEQ ID NO: 231, SEQ ID NO: 163, respectively n. SEQ ID NO: 233, SEQ ID NO: 169, SEQ ID NO: 234, SEQ ID NO: 178, respectively; o. SEQ ID NO:210, SEQ ID NO:237, SEQ ID NO:211, SEQ ID NO:212, respectively p. SEQ ID NO: 194, SEQ ID NO: 169, SEQ ID NO: 239, SEQ ID NO: 190, q. SEQ ID NO: 194, SEQ ID NO: 169, SEQ ID NO: 242, SEQ ID NO: 178, r. SEQ ID NO:284, SEQ ID NO:183, SEQ ID NO:184, SEQ ID NO:163, s. SEQ ID NO: 194, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 163, t. SEQ ID NO: 188, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 163, u. SEQ ID NO: 188, SEQ ID NO: 169, SEQ ID NO: 254, SEQ ID NO: 255, respectively; v. SEQ ID NO: 259, SEQ ID NO: 169, SEQ ID NO: 260, SEQ ID NO: 190, respectively w. SEQ ID NO: 194, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 163, x. SEQ ID NO: 265, SEQ ID NO: 266, SEQ ID NO: 267, SEQ ID NO: 163, respectively y. SEQ ID NO: 268, SEQ ID NO: 169, SEQ ID NO: 239, SEQ ID NO: 269, z. SEQ ID NO: 194, SEQ ID NO: 169, SEQ ID NO: 200, SEQ ID NO: 190, respectively aa. SEQ ID NO: 271, SEQ ID NO: 169, SEQ ID NO: 272, SEQ ID NO: 190, bb. SEQ ID NO: 274, SEQ ID NO: 275, SEQ ID NO: 276, SEQ ID NO: 178, or cc. SEQ ID NO: 281, SEQ ID NO: 282, SEQ ID NO: 254, SEQ ID NO: 163, dd. SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, ee. SEQ ID NO: 305, SEQ ID NO: 296, SEQ ID NO: 306, SEQ ID NO: 298, ff. SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 306, SEQ ID NO: 298, gg. SEQ ID NO: 305, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, respectively Includes.

[0110] In some embodiments, the CDRs and FRs in the heavy chain variable region are operably linked in the order of hFR1-hCDR1-hFR2-hCDR2-hFR3-hCDR3-hFR4 from the N-terminus to the C-terminus.

[0111] In some embodiments, the antibody further comprises a heavy chain constant region, the heavy chain constant region comprising, from N-terminus to C-terminus, three domains, CH1, CH2, and CH3, wherein CH1, CH2, and CH3 are: SEQ ID NO: 307, SEQ ID NO: 309, and SEQ ID NO: 310, respectively; or SEQ ID NO: 307, SEQ ID NO: 312 and SEQ ID NO: 313, respectively is.

[0112] In some embodiments, the heavy chain variable region comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:285, SEQ ID NO:287, SEQ ID NO:290, and SEQ ID NO:291.

[0113] In some embodiments, the heavy chain variable region comprises the amino acid sequence of any one of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:285, SEQ ID NO:287, SEQ ID NO:290, and SEQ ID NO:291.

[0114] In some embodiments, the antibodies described herein further comprise a light chain variable region, wherein the light chain variable region comprises at least one CDR, wherein the CDR most N-terminally distant from the N-terminus is selected from SEQ ID NO:64, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:82, SEQ ID NO:87, SEQ ID NO:92, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:115, SEQ ID NO:117, SEQ ID NO:123, SEQ ID NO:127, SEQ ID NO:130, SEQ ID NO:134, SEQ ID NO:137, SEQ ID NO:140, SEQ ID NO:145, SEQ ID NO:157, and SEQ ID NO:159.

[0115] In some embodiments, the light chain variable region comprises three CDRs, which are, from N-terminus to C-terminus, lCDR1, lCDR2, and lCDR3, wherein lCDR1 is selected from SEQ ID NO:62, SEQ ID NO:68, SEQ ID NO:74, SEQ ID NO:80, SEQ ID NO:86, SEQ ID NO:90, SEQ ID NO:96, SEQ ID NO:99, SEQ ID NO:105, SEQ ID NO:108, SEQ ID NO:113, SEQ ID NO:122, SEQ ID NO:126, SEQ ID NO:129, SEQ ID NO:132, SEQ ID NO:148, SEQ ID NO:149, and SEQ ID NO:155; and lCDR2 is selected from SEQ ID NO:63, SEQ ID NO:69, SEQ ID NO:75, SEQ ID NO: 81, SEQ ID NO:91, SEQ ID NO:97, SEQ ID NO:106, SEQ ID NO:114, SEQ ID NO:133, SEQ ID NO:139, and SEQ ID NO:156, and lCDR3 is selected from SEQ ID NO:64, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:82, SEQ ID NO:87, SEQ ID NO:92, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:115, SEQ ID NO:117, SEQ ID NO:123, SEQ ID NO:127, SEQ ID NO:130, SEQ ID NO:134, SEQ ID NO:137, SEQ ID NO:140, SEQ ID NO:145, SEQ ID NO:157, and SEQ ID NO:159.

[0116] In some embodiments, lCDR1, lCDR2, and lCDR3 are 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, q. SEQ ID NO: 126, SEQ ID NO: 69, SEQ ID NO: 127, 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, t. SEQ ID NO: 126, SEQ ID NO: 69, SEQ ID NO: 137, 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, x. SEQ ID NO: 148, SEQ ID NO: 69, SEQ ID NO: 109, respectively; y. SEQ ID NO: 149, SEQ ID NO: 63, SEQ ID NO: 109, respectively; z. SEQ ID NO: 122, SEQ ID NO: 69, SEQ ID NO: 123, respectively; aa. SEQ ID NO: 126, SEQ ID NO: 69, SEQ ID NO: 130, respectively bb. SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 157, or cc. SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 159, respectively Includes.

[0117] In some embodiments, the light chain variable region comprises four framework regions, the four framework regions being, from N-terminus to C-terminus, lFR1, lFR2, lFR3, and lFR4, wherein lFR1 is selected from SEQ ID NO:164, SEQ ID NO:171, SEQ ID NO:179, SEQ ID NO:185, SEQ ID NO:191, SEQ ID NO:197, SEQ ID NO:201, SEQ ID NO:207, SEQ ID NO:213, SEQ ID NO:218, SEQ ID NO:222, SEQ ID NO:228, SEQ ID NO:232, SEQ ID NO:247, SEQ ID NO:256, SEQ ID NO:263, SEQ ID NO:270, SEQ ID NO:277, SEQ ID NO:283, SEQ ID NO:299, and SEQ ID NO:303; and lFR2 is selected from SEQ ID NO:165, SEQ ID NO:172, SEQ ID NO:180, SEQ ID NO:186, SEQ ID NO:192, SEQ ID NO:198, SEQ ID NO:202, SEQ ID NO:208, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:226, SEQ ID NO:228, SEQ ID NO:232, SEQ ID NO:247, SEQ ID NO:256, SEQ ID NO:263, SEQ ID NO:270, SEQ ID NO:277, SEQ ID NO:283, SEQ ID NO:299, and SEQ ID NO:303. IFR3 is selected from SEQ ID NO:166, SEQ ID NO:173, SEQ ID NO:181, SEQ ID NO:187, SEQ ID NO:193, SEQ ID NO:199, SEQ ID NO:203, SEQ ID NO:209, SEQ ID NO:220, SEQ ID NO:230, SEQ ID NO:236, SEQ ID NO:238, SEQ ID NO:241, SEQ ID NO:244, SEQ ID NO:249, SEQ ID NO:253, SEQ ID NO:258, SEQ ID NO:273, SEQ ID NO:279, and SEQ ID NO:301; and IFR4 is selected from SEQ ID NO:167, SEQ ID NO:174, SEQ ID NO:182, SEQ ID NO:215, SEQ ID NO:250, SEQ ID NO:280, and SEQ ID NO:302.

[0118] In some embodiments, lFR1, lFR2, lFR3, and lFR4 are 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, q. SEQ ID NO: 171, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 174, 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, t. SEQ ID NO: 171, SEQ ID NO: 243, SEQ ID NO: 253, SEQ ID NO: 167, 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, 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, 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, or cc. SEQ ID NO: 283, SEQ ID NO: 278, SEQ ID NO: 279, SEQ ID NO: 174, dd. SEQ ID NO: 299, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, ee. SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 301, SEQ ID NO: 302, ff. SEQ ID NO: 299, SEQ ID NO: 304, SEQ ID NO: 301, SEQ ID NO: 302, respectively Includes.

[0119] In some embodiments, the CDRs and FRs in the light chain variable region are operably linked from N-terminus to C-terminus in the order lFR1-lCDR1-lFR2-lCDR2-lFR3-lCDR3-lFR4.

[0120] In some embodiments, the antibody further comprises a light chain constant region (CL), wherein the CL is SEQ ID NO:311.

[0121] In some embodiments, the light chain variable region comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:286, SEQ ID NO:288, and SEQ ID NO:289.

[0122] In some embodiments, the light chain variable region comprises the amino acid sequence of any one of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:286, SEQ ID NO:288, and SEQ ID NO:289.

[0123] In some embodiments, the heavy chain variable region and the light chain variable region are 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. 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; or cc. SEQ ID NO: 57 and SEQ ID NO: 58, respectively; dd. SEQ ID NO: 285 and SEQ ID NO: 286, respectively; ee. SEQ ID NO: 287 and SEQ ID NO: 288, respectively; ff. SEQ ID NO: 287 and SEQ ID NO: 289, respectively; gg. SEQ ID NO: 290 and SEQ ID NO: 288, respectively; hh. SEQ ID NO: 290 and SEQ ID NO: 286, respectively; ii. SEQ ID NO: 291 and SEQ ID NO: 286, respectively; jj. SEQ ID NO: 292 and SEQ ID NO: 293, respectively; kk. SEQ ID NO: 294 and SEQ ID NO: 293, respectively The amino acid sequence may have at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to

[0124] In some embodiments, the heavy chain variable region and the light chain variable region are 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. 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; or cc. SEQ ID NO: 57 and SEQ ID NO: 58, respectively; dd. SEQ ID NO: 285 and SEQ ID NO: 286, respectively; ee. SEQ ID NO: 287 and SEQ ID NO: 288, respectively; ff. SEQ ID NO: 287 and SEQ ID NO: 289, respectively; gg. SEQ ID NO: 290 and SEQ ID NO: 288, respectively; hh. SEQ ID NO: 290 and SEQ ID NO: 286, respectively; ii. SEQ ID NO: 291 and SEQ ID NO: 286, respectively; jj. SEQ ID NO: 292 and SEQ ID NO: 293, respectively; kk. SEQ ID NO: 294 and SEQ ID NO: 293, respectively Includes.

[0125] In another aspect, the disclosure provides an antibody comprising a light chain variable region, the light chain variable region comprising at least one CDR, wherein the CDR most N-terminally distant is selected from SEQ ID NO:64, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:82, SEQ ID NO:87, SEQ ID NO:92, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:115, SEQ ID NO:117, SEQ ID NO:123, SEQ ID NO:127, SEQ ID NO:130, SEQ ID NO:134, SEQ ID NO:137, SEQ ID NO:140, SEQ ID NO:145, SEQ ID NO:157, and SEQ ID NO:159.

[0126] In some embodiments, the light chain variable region comprises three CDRs, which are, from N-terminus to C-terminus, lCDR1, lCDR2, and lCDR3, wherein lCDR1 is selected from SEQ ID NO:62, SEQ ID NO:68, SEQ ID NO:74, SEQ ID NO:80, SEQ ID NO:86, SEQ ID NO:90, SEQ ID NO:96, SEQ ID NO:99, SEQ ID NO:105, SEQ ID NO:108, SEQ ID NO:113, SEQ ID NO:122, SEQ ID NO:126, SEQ ID NO:129, SEQ ID NO:132, SEQ ID NO:148, SEQ ID NO:149, and SEQ ID NO:155; and lCDR2 is selected from SEQ ID NO:63, SEQ ID NO:69, SEQ ID NO:75, SEQ ID NO: 81, SEQ ID NO:91, SEQ ID NO:97, SEQ ID NO:106, SEQ ID NO:114, SEQ ID NO:133, SEQ ID NO:139, and SEQ ID NO:156, and lCDR3 is selected from SEQ ID NO:64, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:82, SEQ ID NO:87, SEQ ID NO:92, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:115, SEQ ID NO:117, SEQ ID NO:123, SEQ ID NO:127, SEQ ID NO:130, SEQ ID NO:134, SEQ ID NO:137, SEQ ID NO:140, SEQ ID NO:145, SEQ ID NO:157, and SEQ ID NO:159.

[0127] In some embodiments, lCDR1, lCDR2, and lCDR3 are 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, q. SEQ ID NO: 126, SEQ ID NO: 69, SEQ ID NO: 127, 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, t. SEQ ID NO: 126, SEQ ID NO: 69, SEQ ID NO: 137, 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, x. SEQ ID NO: 148, SEQ ID NO: 69, SEQ ID NO: 109, respectively; y. SEQ ID NO: 149, SEQ ID NO: 63, SEQ ID NO: 109, respectively; z. SEQ ID NO: 122, SEQ ID NO: 69, SEQ ID NO: 123, respectively; aa. SEQ ID NO: 126, SEQ ID NO: 69, SEQ ID NO: 130, respectively bb. SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 157, or cc. SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 159, respectively Includes.

[0128] In some embodiments, the light chain variable region comprises four framework regions, the four framework regions being, from N-terminus to C-terminus, lFR1, lFR2, lFR3, and lFR4, wherein lFR1 is selected from SEQ ID NO:164, SEQ ID NO:171, SEQ ID NO:179, SEQ ID NO:185, SEQ ID NO:191, SEQ ID NO:197, SEQ ID NO:201, SEQ ID NO:207, SEQ ID NO:213, SEQ ID NO:218, SEQ ID NO:222, SEQ ID NO:228, SEQ ID NO:232, SEQ ID NO:247, SEQ ID NO:256, SEQ ID NO:263, SEQ ID NO:270, SEQ ID NO:277, SEQ ID NO:283, SEQ ID NO:299, and SEQ ID NO:303; and lFR2 is selected from SEQ ID NO:165, SEQ ID NO:172, SEQ ID NO:180, SEQ ID NO:186, SEQ ID NO:192, SEQ ID NO:198, SEQ ID NO:202, SEQ ID NO:208, SEQ ID NO:214, SEQ ID NO:215, SEQ ID NO:226, SEQ ID NO:228, SEQ ID NO:232, SEQ ID NO:247, SEQ ID NO:256, SEQ ID NO:263, SEQ ID NO:270, SEQ ID NO:277, SEQ ID NO:283, SEQ ID NO:299, and SEQ ID NO:303. IFR3 is selected from SEQ ID NO:166, SEQ ID NO:173, SEQ ID NO:181, SEQ ID NO:187, SEQ ID NO:193, SEQ ID NO:199, SEQ ID NO:203, SEQ ID NO:209, SEQ ID NO:220, SEQ ID NO:230, SEQ ID NO:236, SEQ ID NO:238, SEQ ID NO:241, SEQ ID NO:244, SEQ ID NO:249, SEQ ID NO:253, SEQ ID NO:258, SEQ ID NO:273, SEQ ID NO:279, and SEQ ID NO:301; and IFR4 is selected from SEQ ID NO:167, SEQ ID NO:174, SEQ ID NO:182, SEQ ID NO:215, SEQ ID NO:250, SEQ ID NO:280, and SEQ ID NO:302.

[0129] In some embodiments, lFR1, lFR2, lFR3, and lFR4 are 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, q. SEQ ID NO: 171, SEQ ID NO: 243, SEQ ID NO: 244, SEQ ID NO: 174, 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, t. SEQ ID NO: 171, SEQ ID NO: 243, SEQ ID NO: 253, SEQ ID NO: 167, 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, 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, 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, or cc. SEQ ID NO: 283, SEQ ID NO: 278, SEQ ID NO: 279, SEQ ID NO: 174, dd. SEQ ID NO: 299, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, ee. SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 301, SEQ ID NO: 302, ff. SEQ ID NO: 299, SEQ ID NO: 304, SEQ ID NO: 301, SEQ ID NO: 302, respectively Includes.

[0130] In some embodiments, the CDRs and FRs in the light chain variable region are operably linked from N-terminus to C-terminus in the order lFR1-lCDR1-lFR2-lCDR2-lFR3-lCDR3-lFR4.

[0131] In some embodiments, the antibody further comprises a light chain constant region (CL), wherein the CL is SEQ ID NO:311.

[0132] In some embodiments, the light chain variable region comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:286, SEQ ID NO:288, and SEQ ID NO:289.

[0133] In some embodiments, the light chain variable region comprises the amino acid sequence of any one of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:286, SEQ ID NO:288, and SEQ ID NO:289.

[0134] In some embodiments, the antibodies described herein are chimeric antibodies. In some embodiments, chimeric antibodies are derived from murine and / or humanized antibodies. As used herein, "chimeric antibody" refers to an antibody in which a portion of the heavy and / or light chain is derived from one species, and the remainder of the heavy and / or light chain is derived from a different species. In some embodiments, a 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 is a mammal, such as a mouse, rat, or rabbit. Chimeric antibodies may also include antibodies in which the variable and constant domains are derived from two different sources, even if both are derived from the same species.

[0135] In some embodiments, the antibodies described herein are humanized or partially humanized antibodies. As used herein, "humanized antibody" refers to an antibody that has been modified to reduce immunogenicity in humans. Humanization can be performed by any method known in the art. In some embodiments, humanization is performed by grafting CDR sequences of non-human origin into human framework sequences. In some embodiments, additional framework region modifications may be made within the human framework sequences. In some embodiments, humanization is performed by augmented binary substitution (Townsend et al., Proceedings of the National Academy of Sciences 112.50(2015):15354-15359). As used herein, "partially humanized" or "partially humanized" means that a portion of an antibody has been modified to reduce its immunogenicity in humans. For example, in some embodiments, a heavy and light chain pair is modified to reduce immunogenicity in humans.

[0136] In some embodiments, the antibodies described herein are monoclonal antibodies. As used herein, "monoclonal antibody (mAb)" refers to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope. In some embodiments, monoclonal antibodies exist in a homogeneous or substantially homogeneous population.

[0137] In some embodiments, the antibodies described herein are polyclonal antibodies. As used herein, "polyclonal antibody" refers to a preparation of antibody molecules of different molecular composition that recognize different epitopes on an antigen.

[0138] In some embodiments, the antibodies described herein are multispecific antibodies. In some embodiments, the antibodies described herein are bispecific antibodies. As used herein, "multispecific antibodies" refer to antibodies that can specifically bind to multiple epitopes. "Bispecific antibodies" refer to antibodies that can specifically bind to two distinct epitopes.

[0139] In some embodiments, the antibodies described herein are recombinant antibodies. As used herein, "recombinant antibody" includes all antibodies that are prepared, expressed, produced, or isolated by recombinant means, including, but not limited to, antibodies isolated from host cells transformed to express the antibody, antibodies isolated from recombinant combinatorial antibody libraries, and antibodies prepared, expressed, produced, or isolated by any other means, including splicing of immunoglobulin gene sequences into other DNA sequences.

[0140] In some embodiments, the antibodies described herein are heavy chain antibodies. As used herein, "heavy chain antibody" refers to an antibody that consists of two heavy chains and no light chains.

[0141] In some embodiments, the antibodies described herein are single domain antibodies. As used herein, "single domain antibody (sdAb)" or "nanobody" are used interchangeably and refer to antibody fragments consisting of a single monomeric variable antibody domain.

[0142] In some embodiments, the antibodies described herein are operably linked to a cytotoxic agent. In some embodiments, the antibodies are linked to the cytotoxic agent by a short peptide. In some embodiments, the antibodies are directly fused to the cytotoxic agent by recombinant means. As used herein, "cytotoxic agent," "cytotoxic agent," or "cytotoxic drug" refers to a substance that is toxic to cells and / or can kill cells, including cancer cells. Some exemplary cytotoxic agents are actinomycin, all-trans retinoic acid, azacitidine, azathioprine, bleomycin, bortezomib, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, irinotecan, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, teniposide, thioguanine, topotecan, valrubicin, vemurafenib, vinblastine, vincristine, and vindesine.

[0143] In some embodiments, the antibodies described herein are ADCC-enhancing antibodies. In some embodiments, the antibodies are afucosylated antibodies. In some embodiments, the antibodies comprise an engineered Fc region to enhance ADCC.

[0144] "Antibody-dependent cell-mediated cytotoxicity" and "ADCC" refer to a cell-mediated reaction in which effector cells expressing Fc receptors (FcRs) recognize bound antibodies or antigen-binding fragments on target cells and subsequently cause lysis of the target cells. "ADCC activity" refers to the ability of an antibody or antigen-binding fragment bound to a target cell to elicit an ADCC response.

[0145] ADCC activity is measured in an in vivo assay as described in Example 9. ADCC activity was determined by calculating the EC50 of the antibody response and the maximum response potency. In some embodiments, the ADCC activity of an antibody is enhanced by rendering the antibody fucose-free (afucosylated). In some embodiments, the ADCC activity of an antibody is enhanced by engineering its Fc region to enhance its affinity for Fc receptors on target cells. Example 7 further discloses details of these two methods of enhancing the ADCC activity of an antibody.

[0146] [Table 2(1)] [Table 2(2)] [Table 2(3)] [Table 2(4)] [Table 2(5)] [Table 2(6)] [Table 2(7)] [Table 2(8)] [Table 2(9)] [Table 2 (10)] [Table 2(11)] [Table 2 (12)] [Table 2(13)] [Table 2(14)] [Table 2(15)] [Table 2(16)] [Table 2(17)] [Table 2(18)] [Table 2(19)] [Table 2(20)] [Table 2(21)] [Table 2(22)] [Table 2(23)] [Table 2(24)]

[0147] specific binding The anti-FGFR2b antibodies provided herein are capable of specifically binding to FGFR2b.

[0148] In some embodiments, the antibodies described herein specifically bind to fibroblast growth factor receptor 2b (FGFR2b).

[0149] In some embodiments, the antibodies described herein have a K of about 10 nM or less. DIn some embodiments, the antibodies described herein bind to FGFR2b with a K of about 9 nM or less. D In some embodiments, the antibodies described herein bind to FGFR2b with a K of about 5 nM or less. D In some embodiments, the antibodies described herein bind to FGFR2b with a K of about 4 nM, 3 nM, 2 nM, 1 nM, 0.1 nM or lower. D It binds to FGFR2b.

[0150] In some embodiments, the FGFR2b is human FGFR2b, hi some embodiments, the FGFR2b is mouse FGFR2b or cynomolgus monkey FGFR2b.

[0151] In certain embodiments, the antibody provided herein has sufficient specific binding affinity for human FGFR2b to provide diagnostic and / or therapeutic use.For example, the antibody described herein can be used to detect the presence of FGFR2 in a sample by contacting the antibody described herein or a composition thereof with the sample, and detecting at least one bound antibody indicates the presence of FGFR2b.By quantifying the bound antibody, this method can also be used to detect the overexpression of the FGFR2 gene, which is closely related to abnormal FGFR2 signal transduction and cancer.

[0152] 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, including, for example, inhibiting the proliferation of FGFR2b-overexpressing cells.

[0153] In some embodiments, the antibodies described herein do not bind to FGFR1b, FGFR1c, FGFR2c, FGFR3b, FGFR3c, or FGFR4. In some embodiments, the antibodies described herein do not detectably bind to FGFR1b, FGFR1c, FGFR2c, FGFR3b, FGFR3c, or FGFR4. As used herein, the phrase "detectably binding" or "detectably binds" refers to K as measured by Bio-layer interferometry (BLI) using Octet® BLI Label-Free Detection Systems. D Values ​​greater than 0.1 or OD measured at 50 nM by ELISA 450 A value of 1.0 or greater is considered to be a positive value. Protocols for BLI and ELISA are described in Example 3 below.

[0154] The antibodies described herein have subnanomolar equilibrium dissociation constants (K) for mouse, cynomolgus monkey, and human FGFR2b extracellular domain (ECD). D ) and the association and dissociation constants (K on and K. off ) are comparable. The antibodies described herein have good interspecies affinity. Therefore, mice and cynomolgus monkeys are considered to be suitable species for conducting toxicological studies using the antibodies described herein.

[0155] composition In another aspect, the disclosure provides a composition comprising an antibody described herein.

[0156] In another aspect, the present disclosure provides a pharmaceutical composition comprising an antibody described herein and a pharmaceutically acceptable carrier.

[0157] 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, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, surface active agent, or emulsifier approved by the United States Food and Drug Administration as acceptable for human or veterinary use. 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 cellulose derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth; malt; gelatin; talc; cocoa butter; waxes; animal and vegetable fats; paraffin; silicones; bentonite; silicic acid; zinc oxide; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and any other compatible substance used in pharmaceutical formulations.

[0158] Liquid pharmaceutical compositions, whether in solution, suspension, or other similar form, may contain one or more of the following: sterile diluents such as water for injection, saline, preferably physiological saline; Ringer's solution; isotonic sodium chloride; fixed oils such as synthetic mono- or diglycerides that can serve as solvents or suspending media; polyethylene glycol; glycerin; propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates; and agents for adjusting tonicity such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic. Pharmaceutical compositions for injection are preferably sterile.

[0159] The compositions may be suitably formulated for intravenous, intratumoral, oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, ocular, or another route of administration.

[0160] Polynucleotides In another aspect, the disclosure provides polynucleotides encoding the antibodies described herein.

[0161] The polynucleotide sequences encoding the antibodies described herein can be operably linked to one or more regulatory elements, such as promoters and enhancers, that allow expression of the nucleotide sequence in the intended host cell. The polynucleotide may be DNA or RNA, e.g., cDNA or mRNA. The polynucleotides described herein can be obtained by methods readily available in the art.

[0162] vector In another aspect, the present disclosure provides vectors comprising the polynucleotides described herein. Such vectors may be plasmid vectors, viral vectors, vectors for baculovirus expression, transposon-based vectors, or any other vector suitable for introducing the polynucleotides of the present disclosure into a given organism or genetic background by any means. For example, a polynucleotide encoding an antibody described herein may be inserted into an expression vector. The DNA segment encoding the antibody may be operably linked to control sequences in the expression vector that ensure expression of immunoglobulin polypeptides. Such control sequences include a signal sequence, a promoter (e.g., a naturally associated or heterologous promoter), an enhancer element, and a transcription termination sequence, and are selected to be compatible with the host cell selected to express the antibody. Once the vector is incorporated into an appropriate host, the host is maintained under conditions suitable for high-level expression of the protein encoded by the incorporated polynucleotide.

[0163] Suitable expression vectors are typically replicable in host organisms either as episomes or as an integral part of the host chromosomal DNA. Expression vectors usually contain a selection marker, such as ampicillin resistance, hygromycin resistance, tetracycline resistance, kanamycin resistance, or neomycin resistance, to allow detection of cells transformed with the desired DNA sequence. Suitable vectors, promoters, and enhancer elements are known in the art, and many are commercially available for generating the subject recombinant constructs.

[0164] The term "host cell" refers to a cell into which a vector has been introduced. It is understood that the term host cell is intended to refer not only to the particular subject cell but also to the progeny of such a cell. Because certain modifications may occur in subsequent generations due to either mutation or environmental influences, such progeny may not be identical to the parent cell but are still included within the scope of the term "host cell" as used herein. Such host cells may be eukaryotic, prokaryotic, plant, or archaeal cells. Bacillus species, such as Escherichia coli and Bacillus subtilis, and other Enterobacteriaceae, such as Salmonella, Serratia, and various Pseudomonas species, are examples of prokaryotic host cells. Other microorganisms, such as yeast, are also useful for expression. Saccharomyces (e.g., S. cerevisiae) and Pichia are examples of suitable yeast host cells. Exemplary eukaryotic cells may be of mammalian, insect, avian, or other animal origin.

[0165] cell In another aspect, the present disclosure provides cells capable of expressing the antibodies described herein.

[0166] In another aspect, the present disclosure provides a cell comprising a polynucleotide described herein and / or a vector described herein.

[0167] 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, cells of mammalian, insect, avian, or other animal origin.

[0168] Exemplary prokaryotic cells include, but are not limited to, E. coli, bacilli such as Bacillus subtilis, and other Enterobacteriaceae such as Salmonella, Serratia, and various Pseudomonas species. Other microbes, such as yeast, are also useful for expression. Saccharomyces (e.g., S. cerevisiae) and Pichia are examples of suitable yeast host cells.

[0169] The cells described herein include various cells derived from individual animals, subcultured cells, primary cultured cells, cell lines, recombinant cells, and microbial cells.

[0170] In some embodiments, the cell is a hybridoma cell. In some embodiments, the hybridoma cell is obtained by fusing a myeloma cell with a cell that produces an antibody described herein. In some embodiments, the cell that produces an antibody described herein is a splenocyte.

[0171] method In another aspect, the disclosure provides a method of producing an antibody, the method comprising culturing a cell described herein and recovering the antibody from the cell.

[0172] The antibodies described herein can be obtained by any method 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 antibody-producing hybridomas, and (7) obtaining single-cell clones.

[0173] An exemplary method for producing the monoclonal antibodies described herein is provided. First, an animal such as a rat or mouse is immunized with recombinant human FGFR2b-FC protein or its soluble form according to the method of Kohler and Milstein (Kohler et al., Nature, 1975; 256(5517), 495-497; Kennet, RH, TJ McKeam, and KB Bechtol, "Methods for production and characterization of monoclonal antibodies." Monoclonal Antibodies (Appendix), RH Kennet, TJ McKeam, and KB Bechtol, eds., Plenum, New York, 1980). Recombinant human FGFR2b antigen is available from commercial distributors. Cells producing the antibodies described herein are then isolated from the spleen of the immunized animal. These cells are then fused with myeloma cells, thereby establishing hybridomas. The monoclonal antibodies described herein can be obtained from cultures of these hybridomas.

[0174] The strain of mouse or rat is not limited. In the case of mice, for example, BALB / c, C57BL, CD1, or SJL can be used. These mice are available 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, at the time of immunization.

[0175] Exemplary methods for determining antibody titers include, but are not limited to, immunoassays such as ELISA.

[0176] Antibody-producing cells derived from spleen cells or lymphocytes isolated from immunized animals can be prepared according to methods known in the art. The myeloma cells used for cell fusion are not particularly limited and can be appropriately selected for use in cell lines known in the art. Antibody-producing cells can be fused with myeloma cells according to any method known in the art under conditions that prevent excessive reduction in cell viability.

[0177] Screening of hybridomas includes, but is not limited to, protein level binding and blocking, cell binding and blocking, signal transduction pathway blocking assays, and cell growth inhibition assays. Hybridomas can be cloned using limiting dilution methods.

[0178] The antibodies described herein can also be produced by recombinant expression. The desired antibody can be expressed in any organism suitable for producing the required amount and form of antibody. Expression hosts include prokaryotic and eukaryotic organisms, such as E. coli, yeast, plants, insect cells, mammalian cells, including human cell lines and transgenic animals. Expression hosts can differ in their protein production levels and the types of post-translational modifications present on the expressed protein. The choice of expression host can be based on these and other factors, such as regulatory and safety considerations, production costs, and purification needs and methods.

[0179] Many expression vectors are available and known to those skilled in the art and can be used to express proteins. The selection of an expression vector is influenced by the selection of a host expression system. In general, an expression vector can include a transcription promoter and optionally an enhancer, a translation signal, and a transcription and translation termination signal. Expression vectors used for stable transformation typically have a selection marker that allows 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.

[0180] The expression vector can be introduced into the host cell via, for example, transformation, transfection, transduction, infection, electroporation, and sonoporation. Those skilled in the art can select suitable methods and conditions for introducing the expression vector into the host cell.

[0181] After introduction of the vector containing a selectable marker, cells can be grown in enriched media for 1-2 days before switching them to selective media. The purpose of the selectable marker is to confer resistance to selection; its presence allows growth and recovery of cells that successfully express the introduced sequences. Resistant cells of stably transformed cells can be propagated using tissue culture techniques appropriate to the cell type. In some embodiments, the antibodies described herein are expressed in mammalian expression systems. Expression constructs can be introduced into mammalian cells by viral infection, e.g., adenoviral constructs, or by direct DNA transfer, e.g., liposomes, calcium phosphate, DEAE-dextran, and physical means, e.g., electroporation and microinjection. In some embodiments, the antibodies described herein are delivered using viral transduction, e.g., with vectors.

[0182] Once the vector has been incorporated into a suitable host cell, the host cell is maintained under conditions suitable for expression of the antibody encoded by the incorporated polynucleotide. Those skilled in the art can select suitable conditions for expression of the antibodies described herein.

[0183] The antibodies described herein can be purified according to any method known in the art, such as protein A chromatography, anion exchange chromatography, and cation exchange chromatography. It is understood that a person skilled in the art can select appropriate methods and conditions for purifying the antibodies described herein.

[0184] The present disclosure provides a novel anti-FGFR2b antibody, thereby providing a method for inhibiting the proliferation of FGFR2b-positive cancer cells and the progression of neoplastic diseases. The anti-FGFR2b antibody of the present disclosure, which binds to FGFR2IIIb but does not detectably bind to FGFR2IIIc, 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 antibody described herein is its ability to bind to 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 antibody described herein is the stimulation of cell proliferation, for example, cancer cells that overexpress FGFR2b. Other functions of FGFR2b that can be inhibited by anti-FGFR2b antibody described herein include, but are not limited to, the signal transduction pathway stimulated by the binding of FGF ligand to FGFR2b, such as the phosphorylation of FGFR2b.In some embodiments, anti-FGFR2b antibody described herein inhibits these activities induced by one or more of the FGFs listed above.

[0185] The anti-FGFR2b antibodies described herein may also inhibit the growth of tumor xenografts that overexpress FGFR2b, such as SNU-16 or OCUM-2M xenografts.

[0186] In another aspect, the present disclosure provides a method for inhibiting FGFR2b from binding to at least one fibroblast growth factor (FGF), comprising administering an effective amount of an antibody described herein or a composition described herein to a subject. 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 that are involved in a wide variety of processes, most notably as key elements for normal development in animal cells. Any irregularities in their function result in various developmental defects. These growth factors typically act as systemic or local circulating molecules of extracellular origin that activate cell surface receptors.

[0187] In another aspect, the disclosure 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 cell is a cancer cell.

[0188] In another aspect, the present disclosure provides a method for inhibiting a signal transduction pathway stimulated by the binding of FGF to FGFR2b, the method comprising administering to a subject an effective amount of an antibody described herein or a composition described herein.

[0189] In another aspect, the present disclosure provides a method for inhibiting the growth of a tumor xenograft that overexpresses FGFR2b, the method comprising administering to a subject an effective amount of an antibody described herein or a composition described herein.

[0190] In another aspect, the present disclosure provides a method for detecting the presence of FGFR2b in a sample, comprising contacting the sample with an antibody described herein or a composition described herein, wherein detection of at least one bound antibody indicates the presence of FGFR2b. [Example]

[0191] The present disclosure may be further illustrated by the following non-limiting examples, in which standard techniques known to those of skill in the art and similar to those described in these examples may be used, where appropriate, It is understood that those skilled in the art will envision additional embodiments consistent with the disclosure provided herein.

[0192] The examples discussed below are intended to be purely illustrative of the present invention and should not be construed as limiting the present invention in any way. The examples are not intended to represent that the following experiments are all or the only experiments performed.

[0193] Example 1 Cells and Reagents The human gastric cancer cell line KATO III and tool cell line HEK 293 were purchased from the Chinese Academy of Sciences. The human gastric cancer cell line SNU16 was purchased from BeNa Culture Collection (BNCC). The above human cell lines were cultured according to the supplier's recommendations.

[0194] To establish a cell-based assay for antibody screening during antibody generation, HEK293 cells were engineered to express FGFR2b or FGFR2c. HEK293 cells were transfected with plasmids encoding the FGFR2b or FGFR2c isoform of human FGFR2. After selection with puromycin, single clones with high expression of FGFR2b or FGFR2c were isolated.

[0195] Human FGFR2α(IIIb)-Fc (catalog no. 16485-H02H) and human FGFR1α(IIIb)-His (catalog no. 16482-H08H) were purchased from Sino Biological, China. Human FGFR1 / CD331-His (catalog no. FG1-H5223) and human FGFR4 / CD334-His (catalog no. FG4-H5228) were purchased from ACRO Biosystems, China. Human FGFR2α(IIIb)-His (catalog number FGR-HM1BD), human FGFR2α(IIIc)-His (catalog number FGR-HM2CD), human FGFR3α(IIIb)-His (catalog number FGF-HM43B), and human FGFR3α(IIIc)-His (catalog number FGF-HM43C) were purchased from Kactus Biosystems, China. Mouse FGFR2 (canonical)-Fc (catalog number 51128-M02H) was purchased from Sino Biological, China. Cynomolgus monkey FGFR2(βIIIb)-His (catalog number FGF-CM1BB) was purchased from Kactus Biosystems, China. KGF / FGF-7 protein, human, recombinant (His tag) (catalog number 10210-H07E) was purchased from Sino Biological, China. Human FGF10 protein (catalog number FGF-HE010) was purchased from Kactus Biosystems, China.

[0196] The clinical stage anti-human FGFR2b specific antibody FPA144 was developed according to related patent application WO 2015 / 017600 A1.

[0197] Example 2. Generation of anti-FGFR monoclonal Abs BALB / c, CD1, or SJL mice were immunized with human FGFR2b(α)-Fc in SAS / CpG SC at an initial dose of 50 μg / mouse, followed by 25 μg / mouse three weeks later and 25 μg / mouse three weeks later. Serum titers against human FGFR2b-Fc were determined by ELISA. Four days after the final injection, spleen cells were extracted and fused with mouse myeloma cells. Seven days after fusion, hybridoma culture supernatants were first screened for FGFR2b(β)-His binding by ELISA. Hybridomas that passed the primary screening were subjected to a secondary screening panel, including binding to KATO III cells by FACS. Hybridomas that passed the second screening round were selected and subcloned. The resulting monoclonal mouse antibody is mAb1.

[0198] The sequences of the heavy and light chain variable (VH, VL) regions of mAb1 were determined using standard RACE techniques. Total RNA was extracted from selected hybridoma cell lines. Full-length first-strand cDNA, including the 5' end, was then generated and amplified by PCR using the SMART RACE cDNA Amplification Kit (Clontech) according to the manufacturer's instructions. The PCR product was isolated, purified, and then TA cloned and sequenced.

[0199] The chimeric antibody mAb1 was then generated by grafting the VH and VL of murine Ab1 onto human Fc. The entire amino acid sequences of the mAb1 light and heavy chains are shown in Figure 1.

[0200] Example 3. Antibody binding properties Antibody binding to the human FGFR2b antigen was determined by biolayer interferometry (BLI) (OCTET). Briefly, the Protein A biosensor was first prewetted with a 10-minute injection of PBST (0.05% Tween 20). The antibody was diluted in PBST-BSA (0.05% Tween, 0.1% BSA) and injected at serial concentrations (0, 1.56, 3.12, 6.25, 12.5, 25, and 50 nM). Protein A biosensor surface regeneration was included in each run cycle. Association and dissociation constants were calculated using OCTET RED384 evaluation software (version 1.0). As shown in Figure 2, mAb1 exhibited strong binding affinity (nanomolar concentrations) for human, mouse, and cynomolgus monkey FGFR2b, superior to or similar to the competing antibody FPA144.

[0201] To confirm that the selected antibodies could bind to the endogenous form of FGFR2b on the cell membrane, flow cytometry was performed using human HEK293 cells transfected with the FGFR2IIIc and FGFR2IIIb genes. FGFR2IIIb-HEK293 monoclones or FGFR2IIIc-HEK293 monoclones were grown in DMEM medium containing 10% FBS, then seeded at 100,000 / well and washed with PBS + 0.5% FBS. Various concentrations of mAb were then added for 30 minutes, followed by incubation with a fluorescently conjugated anti-human IgG Fc secondary antibody for 30 minutes. Fluorescent signals were detected using Cytoflex. The binding activity data for mAb1 was processed using Graphpad Prism, and the data are shown in Figure 3. As can be seen in Figure 3B, mAb1 binds to cells transfected with FGFR2IIIb, but fails to bind to cells transfected with FGFR2IIIc, as expected from their epitopes.

[0202] The binding specificity of mAb1 to various FGFR family members, FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, FGFR3c, and FGFR4, was characterized by ELISA assay. Briefly, 96-well ELISA plates were coated overnight with approximately 50 ng / well of 0.5 mg / ml human FGFR1α(IIIb)-His, human FGFR1 / CD331 protein-His, human FGFR2α(IIIb) protein, human FGFR2α(IIIc) protein, human FGFR3α(IIIb)-His, human FGFR3α(IIIc)-His, and human FGFR4 / CD334-His in a pH 9.6 carbonate buffer solution. The plates were then blocked with 2% BSA in PBST (PBS containing 0.05% Tween 20) and incubated with the antibody sample for 60 min at room temperature. They were then washed once in PBST and subsequently incubated with mAb1 (0.2 µm first well, 3-fold reduction in seven steps, 10-fold reduction in the final step) at room temperature. They were then washed once in PBST and subsequently incubated with peroxidase-conjugated AffiniPure F(AB')2 fragment goat anti-human IgG (Jackson ImmunoResearch, no. 109-036-098) conjugate for 30 min. HRP activity was detected with TMB substrate (Solarbio, no. PR1200), and the reaction was stopped with stop solution (Solarbio, no. C1058). The plates were read at 450 nm. The data are shown in Figure 4. The results of ELISA analysis show that mAb1 specifically binds to FGFR2b and not to any other FGFR family members.

[0203] Example 4. In vitro inhibitory activity The inhibitory activity of antibodies against ligand-induced cell proliferation was examined in SNU16 cell clones. Cells were seeded in 96-well plates at 5,000 cells / well in RPMI 1640 medium containing 0.5% fetal bovine serum. Cells were starved for 16 hours or overnight. SNU-16 cells were treated with various concentrations of antibodies diluted in RPMI medium containing 0.5% FBS for 30 minutes. SNU-16 cells were then treated with 100 ng / mL FGF7 or FGF10 containing 1 μg / mL heparin (final concentration) diluted in RPMI medium containing 0% FBS and incubated at 37°C and 5% CO2 for 4 days. 50 μL of CTG was added, and luminescence was read as T144H. The inhibitory activity data of mAb1 was processed using Graphpad Prism, and the data are shown in Figures 5 and 6. In the presence of increasing concentrations of mAB1, FGF7-induced (FIG. 5) and FGF10-induced (FIG. 6) cell proliferation was inhibited in a concentration-dependent manner in SNU-16 cells, with the potency of mAB1 being better than that of FPA144.

[0204] Inhibition of the FGFR2 signaling pathway by antibodies was investigated using an anti-FGFR2b antibody against human FGFR2IIIb in an SRE reporter assay. HEK293 cell lines stably expressed a luciferase reporter driven by the serum response element (SRE) and human fibroblast growth factor receptor (FGFR2) IIIb. FGFR2IIIb-SRE-HEK293 monoclones were grown in DMEM medium containing 10% FBS, then seeded at 40,000 cells / well and cultured overnight in DMEM + 0.5% FBS. Various concentrations of mAb1 were then added for 30 minutes, followed by incubation with FGF7 protein for 4 hours. Luciferase signals were detected using a TECAN probe. The inhibition data of mAb1 were processed using Graphpad Prism, and the data are shown in Figure 7. The FGFR2 signaling pathway was inhibited by mAb1 in a concentration-dependent manner in FGFR2b-overexpressing cells.

[0205] Example 5. In vivo antitumor activity of antibodies in tumor mouse models The cell line-derived xenograft (CDX) mouse model was developed by first culturing SNU16 cells in vitro and then culturing 3 × 10 cells mixed with 50% Matrigel / mouse. 6 The tumor was established by subcutaneous inoculation of SNU16 cells into the dorsal flank of mice at 100 μL / cell.

[0206] Tumor nodules were measured in two dimensions with calipers, and tumor volume = (length × width) 2 Tumor volume was calculated using the formula: ∑ × 0.52. When tumor volumes reached 150–200 mm3, tumor-bearing mice were randomized into treatment groups. Mice were then treated with either an isotype control (e.g., IgG1) or a test antibody (e.g., FPA144, mAb1) twice weekly from the day after randomization. Tumor volume and body weight of mice were measured twice weekly, and raw data were recorded. Tumor growth inhibition from the start of treatment was assessed by comparing the mean change in tumor volume between the control and treatment groups. Calculations were based on the geometric or arithmetic mean of relative tumor volume (RTV) in each group. RTV was calculated by dividing the tumor volume on the day of treatment by the initial tumor volume. Figure 8 shows the in vivo tumor growth curves of SNU16 cells treated with mAb1, demonstrating better antitumor activity with mAb1.

[0207] Example 6. Humanization of mAb1 A humanized version of mAb1 was designed, constructed, and expressed using standard molecular biology methods. Briefly, the CDRs of mAb1 were grafted onto a human acceptor framework. Then, at framework positions where computer modeling suggested significant contact with the CDRs, amino acid residues from the murine antibody were replaced with human framework amino acid residues, including M48I and V68A in the heavy chain and 49F in the light chain, using Kabat numbering. This provided a humanized antibody of mAb1 designated humAb1. An additional amino acid substitution was made for NG in CDR2 of the heavy chain of humAb1.

[0208] Example 7. Antibody ADCC enhancement Antibody-dependent cellular cytotoxicity (ADCC), also known as antibody-dependent cell-mediated cytotoxicity, is an immune mechanism in which effector cells expressing Fc receptors recognize and kill target cells expressing tumor- 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 to improve therapeutic mAb function has emerged by producing fucose-free antibodies (afucosylated antibodies) using 1,6-fucosyltransferase knockout (FUT8- / -) CHOK1 cells (Wuxi Biologies, Shanghai, China) as a host cell line. This provided enhanced ADCC for humAb1, designated humAbA1. Another strategy to improve therapeutic mAb function has emerged by modifying the Fc portion of tumor-targeting antibodies. This has been achieved through amino acid substitution. This provided enhanced ADCC for humAb1, designated humAbA2.

[0209] The afucosylated antibodies were purified by Protein A and SEC-HPLC and dialysis, exchanged into formulation buffer, and stored at -80°C. The glycans of the purified afucosylated antibodies were analyzed using LC-MS. The mass of each peak was determined and used to identify each glycan, and the results show that each of the afucosylated antibodies is nearly 100% afucosylated. The afucosylated antibodies are expected to provide at least equivalent in vitro or in vivo activity compared to their fucosylated counterparts.

[0210] The amino acid sequences of the entire mature humAbA1 light and heavy chains with human IgG1 are shown in FIG.

[0211] Example 8. Antibody binding properties Antibody binding to the human FGFR2b antigen was determined by biolayer interferometry (BLI) (OCTET). Briefly, the Protein A biosensor was first prewetted with a 10-minute injection of PBST (0.05% Tween 20). The antibody was diluted in PBST-BSA (0.05% Tween, 0.1% BSA) and injected at serial concentrations (0, 1.56, 3.12, 6.25, 12.5, 25, and 50 nM). Protein A biosensor surface regeneration was included in each run cycle. Association and dissociation constants were calculated using OCTET RED384 evaluation software (version 1.0). As shown in Figure 10, humAbA1 exhibited subnanomolar equilibrium dissociation constants (KD) for rat, cynomolgus monkey, and human FGFR2b ECDs, and the association and dissociation constants (Kon and Koff) were similar. Based on these data, rats and cynomolgus monkeys were considered appropriate species for conducting toxicity studies with humAbA1.

[0212] To confirm that the selected antibodies could bind to the endogenous form of FGFR2b on the cell membrane, flow cytometry was performed using human HEK293 cells transfected with the FGFR2IIIc and FGFR2IIIb genes. FGFR2IIIb-HEK293 monoclones or FGFR2IIIc-HEK293 monoclones were grown in DMEM medium containing 10% FBS, then seeded at 100,000 / well and washed with PBS + 0.5% FBS. Various concentrations of mAb were then added for 30 minutes, followed by incubation with a fluorescently conjugated anti-human IgG Fc secondary antibody for 30 minutes. Fluorescent signals were detected using Cytoflex. The binding activity data for mAb1 was processed using Graphpad Prism, and the data are shown in Figure 11. As can be seen in Figure 11, humAbA1 binds to cells transfected with FGFR2IIIb, but fails to bind to cells transfected with FGFR2IIIc, as expected from their epitopes.

[0213] The binding specificity of humAbA1 to various FGFR family members, FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, FGFR3c, and FGFR4, was characterized by ELISA assay. Briefly, 96-well ELISA plates were coated overnight with approximately 50 ng / well of human FGFR1α(IIIb)-His, human FGFR1 / CD331 protein-His, human FGFR2α(IIIb) protein, human FGFR2α(IIIc) protein, human FGFR3α(IIIb)-His, human FGFR3α(IIIc)-His, and human FGFR4 / CD334-His in a pH 9.6 carbonate buffer solution (0.5 mg / ml). The plates were then blocked with 2% BSA in PBST (PBS containing 0.05% Tween 20) and incubated with the antibody sample for 60 minutes at room temperature. They were then washed once in PBST and subsequently incubated with mAb1 (0.2 μm first well, 3-fold reduction in seven steps, 10-fold reduction in the final step) at room temperature. The plates were then washed once in PBST and subsequently incubated with peroxidase-conjugated AffiniPure F(AB')2 fragment goat anti-human IgG (Jackson Immuno Research, no. 109-036-098) conjugate for 30 minutes. HRP activity was detected with TMB substrate (Solarbio, no. PR1200), and the reaction was stopped with stop solution (Solarbio, no. C1058). The plates were read at 450 nm. The data are shown in Figure 12. ELISA analysis showed that humAbA1 specifically binds to FGFR2b but not to any other FGFR family members.

[0214] Example 9. In vitro activity The inhibitory activity of antibodies against ligand-induced cell proliferation was examined in SNU16 cell clones. Cells were seeded in 96-well plates at 5,000 cells / well in RPMI 1640 medium containing 0.5% fetal bovine serum. Cells were starved for 16 hours or overnight. SNU-16 cells were treated with various concentrations of antibodies diluted in RPMI medium containing 0.5% FBS for 30 minutes. SNU-16 cells were then treated with 100 ng / mL FGF7 containing 1 μg / mL heparin (final concentration) diluted in RPMI medium containing 0% FBS and incubated at 37°C and 5% CO2 for 4 days. 50 μL of CTG was added, and luminescence was read as T144H. The inhibitory activity data of humAbA1 was processed using Graphpad Prism, and the data is shown in Figure 13. In the presence of increasing concentrations of humAbA1, FGF7-induced (FIG. 5) cell proliferation was inhibited in a concentration-dependent manner in SNU-16 cells, and the efficacy of humAbA1 was better than that of Bemarituzumab.

[0215] The antibody inhibition of FGFR2 phosphorylation was evaluated in the SNU-16 human gastric cancer cell line. In the presence of increasing concentrations of mAb, FGF7-induced FGFR2 phosphorylation was inhibited in a concentration-dependent manner in SNU-16 cells (Figure 14).

[0216] An in vitro assay was performed to determine the ADCC activity of the antibodies. The ADCC reporter cell lines, Jurkat-Luc NFAT-CD16a-V158 and Jurkat-Luc NFAT-CD16a-F158, were developed based on Jurkat cells stably incorporating high-affinity CD16a (V158 allotype) or low-affinity CD16 (F158), respectively, and a luciferase gene under the control of the NFAT (nuclear factor of activated T cells) response element. The reporter cells were plated at 1E5 cells per well in a 96-well plate, followed by the addition of serially diluted mAbs for 30 minutes at 37°C. The FGFR2b-expressing cell line, KATOIII, as target cells was co-incubated with the effector cells, Jurkat-Luc NFAT-CD16a-V158 or Jurkat-Luc NFAT-CD16a-F158, at an E:T ratio of 5:1 for 6 hours. After incubation with the substrate Nano-glo for 5 to 30 minutes, luminescence was measured using a microplate reader. The fitting curves were graphed as RLU vs. Log10 [antibody] using GraphPad Prism® software. ADCC activity was determined by calculating the EC50 and maximum response potency of the antibody response, as shown in Figure 15. humAbA1 exhibits superior ADCC activity compared to bemarituzumab.

[0217] Example 10. In vivo antitumor activity of antibodies in tumor mouse models Cell line-derived xenograft (CDX) mouse models were developed by first culturing SNU-16 or OCUM-2M cells in vitro and then adding 3 × 10 cells mixed with 50% Matrigel / mouse. 6 ~5×10 6 The cells were established by subcutaneous inoculation of SNU-16 / OCUM-2M cells into the dorsal flank of mice at 100 cells / 100 mL.

[0218] Tumor nodules were measured in two dimensions with calipers, and tumor volume = (length × width) 2Tumor volume was calculated using the formula: ∑ × 0.52. When tumor volumes reached 150–200 mm3, tumor-bearing mice were randomized into treatment groups. Mice were then treated twice weekly from the day after randomization with either an isotype control (e.g., IgG1) or a test antibody (e.g., bemarituzumab, humAbA1, or humAbA2). Tumor volume and body weight of mice were measured twice weekly, and raw data were recorded. Tumor growth inhibition from the start of treatment was assessed by comparing the mean change in tumor volume between the control and treatment groups. Calculations were based on the geometric or arithmetic mean of relative tumor volume (RTV) in each group. RTV was calculated by dividing the tumor volume on the day of treatment by the initial tumor volume. Figure 16 shows the in vivo tumor growth curves of SNU-16 cells treated with antibodies. humAbA1 and humAbA2 demonstrate better antitumor activity than bemarituzumab. The in vivo tumor growth curves of antibody-treated OCUM-2M cells are shown in Figure 17. humAbA1 and humAbA2 show better antitumor activity than bemarituzumab.

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Continuous cultures of fused cells secreting antibody of predefined specificity. nature、256(5517)、495-497. 44 Kennet , RH , McKeam , TJ , and Bechtol , KB ( 1980 ). Methods for production and characterization of monoclonal antibodies. Monoclonal Antibodies (Appendix) RH Kennet, TJ McKeam, and KB Bechtol Antibodies, Plenum. 45 Batzer, MA, Arcot, SS, Phinney, JW, Alegria-Hartman, M., Kass, DH, and Milligan, SM (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., and Matsubara, K. (1985). An alternative approach to deoxyoligonucleotides as hybridization probes by insertion of deoxyinosine at ambiguous codon positions. Journal of Biological Chemistry, 260(5), 2605-2608. 47 Cassol, SA, Lapointe, N., Salas, T., Hankins, C., and Charest, J. (1992). Diagnosis of vertical HIV-1 transmission using the polymerase chain reaction and dried blood spot specimens. 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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 CDR furthest from the N-terminus is selected from SEQ ID NO:61, SEQ ID NO:67, SEQ ID NO:73, SEQ ID NO:79, SEQ ID NO:85, SEQ ID NO:89, SEQ ID NO:95, SEQ ID NO:101, SEQ ID NO:104, SEQ ID NO:112, SEQ ID NO:116, SEQ ID NO:121, SEQ ID NO:125, SEQ ID NO:128, SEQ ID NO:131, SEQ ID NO:136, SEQ ID NO:138, SEQ ID NO:142, SEQ ID NO:144, SEQ ID NO:147, SEQ ID NO:151, SEQ ID NO:154, and SEQ ID NO:

158.

2. The heavy chain variable region comprises three CDRs, the three CDRs being, from N-terminus to C-terminus, hCDR1, hCDR2, and hCDR3, wherein the hCDR1 is selected from SEQ ID NO:59, SEQ ID NO:65, SEQ ID NO:71, SEQ ID NO:77, SEQ ID NO:83, SEQ ID NO:88, SEQ ID NO:93, SEQ ID NO:103, SEQ ID NO:110, SEQ ID NO:119, SEQ ID NO:135, SEQ ID NO:143, SEQ ID NO:146, SEQ ID NO:150, and SEQ ID NO:152; and the hCDR2 is selected from SEQ ID NO:60, SEQ ID NO:66, SEQ ID NO:72, SEQ ID NO:78, SEQ ID NO:84, SEQ ID NO:94, SEQ ID NO:111, SEQ ID NO:

152. 118, SEQ ID NO: 120, SEQ ID NO: 124, SEQ ID NO: 141, and SEQ ID NO: 153, and the hCDR3 is selected from SEQ ID NO: 61, SEQ ID NO: 67, SEQ ID NO: 73, SEQ ID NO: 79, SEQ ID NO: 85, SEQ ID NO: 89, SEQ ID NO: 95, SEQ ID NO: 101, SEQ ID NO: 104, SEQ ID NO: 112, SEQ ID NO: 116, SEQ ID NO: 121, SEQ ID NO: 125, SEQ ID NO: 128, SEQ ID NO: 131, SEQ ID NO: 136, SEQ ID NO: 138, SEQ ID NO: 142, SEQ ID NO: 144, SEQ ID NO: 147, SEQ ID NO: 151, SEQ ID NO: 154, and SEQ ID NO:

158.

3. The hCDR1, hCDR2, and hCDR3 are 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. 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, 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, 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, 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, bb. SEQ ID NO: 152, SEQ ID NO: 153, SEQ ID NO: 154, or cc. SEQ ID NO: 88, SEQ ID NO: 94, SEQ ID NO: 158, respectively The antibody of claim 2, comprising:

4. The heavy chain variable region comprises four framework regions (FR), the four FRs being, from N-terminus to C-terminus, hFR1, hFR2, hFR3, and hFR4, wherein the hFR1 is selected from SEQ ID NO:160, SEQ ID NO:168, SEQ ID NO:175, SEQ ID NO:188, SEQ ID NO:194, SEQ ID NO:204, SEQ ID NO:210, SEQ ID NO:224, SEQ ID NO:233, SEQ ID NO:284, SEQ ID NO:259, SEQ ID NO:265, SEQ ID NO:268, SEQ ID NO:271, SEQ ID NO:274, SEQ ID NO:281, SEQ ID NO:295, and SEQ ID NO:305; and the hFR2 is selected from SEQ ID NO:161, SEQ ID NO:169, SEQ ID NO:176, SEQ ID NO:183, SEQ ID NO:205, SEQ ID NO:221, SEQ ID NO:225, SEQ ID NO:237, SEQ ID NO:245, SEQ ID NO:251, SEQ ID NO:261, SEQ ID NO:266, SEQ ID NO:275, SEQ ID NO:282, and SEQ ID NO:296; the hFR3 is selected from SEQ ID NO:162, SEQ ID NO:170, SEQ ID NO:177, SEQ ID NO:184, SEQ ID NO:189, SEQ ID NO:195, SEQ ID NO:200, SEQ ID NO:206, SEQ ID NO:211, SEQ ID NO:216, SEQ ID NO:226, SEQ ID NO:231, SEQ ID NO:234, SEQ ID NO:239, SEQ ID NO:242, SEQ ID NO:246, SEQ ID NO:252, SEQ ID NO:254, SEQ ID NO:260, SEQ ID NO:262, SEQ ID NO:267, SEQ ID NO:272, SEQ ID NO:276, SEQ ID NO:297, and SEQ ID NO:306; and the hFR4 is selected from SEQ ID NO:163, SEQ ID NO:178, SEQ ID NO:190, SEQ ID NO:196, SEQ ID NO:212, SEQ ID NO:217, SEQ ID NO:227, SEQ ID NO:255, SEQ ID NO:269, and SEQ ID NO:

298.

5. The hFR1, hFR2, hFR3, and hFR4 are 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. SEQ ID NO:210, SEQ ID NO:169, SEQ ID NO:211, SEQ ID NO:212, respectively; j. SEQ ID NO: 194, SEQ ID NO: 169, SEQ ID NO: 216, SEQ ID NO: 217, respectively; k. SEQ ID NO: 204, SEQ ID NO: 221, SEQ ID NO: 206, SEQ ID NO: 178, respectively; l. SEQ ID NO: 224, SEQ ID NO: 225, SEQ ID NO: 226, SEQ ID NO: 227, respectively; m. SEQ ID NO: 194, SEQ ID NO: 169, SEQ ID NO: 231, SEQ ID NO: 163, n. SEQ ID NO: 233, SEQ ID NO: 169, SEQ ID NO: 234, SEQ ID NO: 178, o. SEQ ID NO:210, SEQ ID NO:237, SEQ ID NO:211, SEQ ID NO:212, respectively p. SEQ ID NO: 194, SEQ ID NO: 169, SEQ ID NO: 239, SEQ ID NO: 190, q. SEQ ID NO: 194, SEQ ID NO: 169, SEQ ID NO: 242, SEQ ID NO: 178, r. SEQ ID NO: 284, SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 163, respectively s. SEQ ID NO: 194, SEQ ID NO: 245, SEQ ID NO: 246, SEQ ID NO: 163, respectively t. SEQ ID NO: 188, SEQ ID NO: 251, SEQ ID NO: 252, SEQ ID NO: 163, SEQ ID NO: 188, SEQ ID NO: 169, SEQ ID NO: 254, SEQ ID NO: 255, respectively; v. SEQ ID NO: 259, SEQ ID NO: 169, SEQ ID NO: 260, SEQ ID NO: 190, respectively; w. SEQ ID NO: 194, SEQ ID NO: 261, SEQ ID NO: 262, SEQ ID NO: 163, x. SEQ ID NO: 265, SEQ ID NO: 266, SEQ ID NO: 267, SEQ ID NO: 163, y. SEQ ID NO: 268, SEQ ID NO: 169, SEQ ID NO: 239, SEQ ID NO: 269, z. SEQ ID NO: 194, SEQ ID NO: 169, SEQ ID NO: 200, SEQ ID NO: 190, respectively aa. SEQ ID NO: 271, SEQ ID NO: 169, SEQ ID NO: 272, SEQ ID NO: 190, bb. SEQ ID NO: 274, SEQ ID NO: 275, SEQ ID NO: 276, SEQ ID NO: 178, or cc. SEQ ID NO: 281, SEQ ID NO: 282, SEQ ID NO: 254, SEQ ID NO: 163, dd. SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, ee. SEQ ID NO: 305, SEQ ID NO: 296, SEQ ID NO: 306, SEQ ID NO: 298, ff. SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 306, SEQ ID NO: 298, gg. SEQ ID NO: 305, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, respectively The antibody of claim 4, comprising:

6. The antibody of claim 4 or claim 5, wherein the CDRs and FRs in the heavy chain variable region are operably linked in the order of hFR1-hCDR1-hFR2-hCDR2-hFR3-hCDR3-hFR4 from the N-terminus to the C-terminus.

7. The heavy chain constant region further comprises, from N-terminus to C-terminus, three domains, CH1, CH2, and CH3, wherein the CH1, CH2, and CH3 are: a. SEQ ID NO: 307, SEQ ID NO: 309, and SEQ ID NO: 310, respectively; or b. SEQ ID NO: 307, SEQ ID NO: 312, and SEQ ID NO: 313, respectively The antibody according to any one of claims 1 to 6,

8. 8. The antibody of claim 1, wherein the heavy chain variable region comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:285, SEQ ID NO:287, SEQ ID NO:290, and SEQ ID NO:

291.

9. The antibody of any one of claims 1 to 8, wherein the heavy chain variable region comprises any one of the amino acid sequences of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:285, SEQ ID NO:287, SEQ ID NO:290, and SEQ ID NO:

291.

10. An antibody comprising a light chain variable region, wherein the light chain variable region comprises at least one CDR, and the CDR furthest from the N-terminus is selected from SEQ ID NO:64, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:82, SEQ ID NO:87, SEQ ID NO:92, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:115, SEQ ID NO:117, SEQ ID NO:123, SEQ ID NO:127, SEQ ID NO:130, SEQ ID NO:134, SEQ ID NO:137, SEQ ID NO:140, SEQ ID NO:145, SEQ ID NO:157, and SEQ ID NO:

159.

11. The light chain variable region comprises three CDRs, the three CDRs being, from N-terminus to C-terminus, CDR1, CDR2, and CDR3, wherein CDR1 is selected from SEQ ID NO:62, SEQ ID NO:68, SEQ ID NO:74, SEQ ID NO:80, SEQ ID NO:86, SEQ ID NO:90, SEQ ID NO:96, SEQ ID NO:99, SEQ ID NO:105, SEQ ID NO:108, SEQ ID NO:113, SEQ ID NO:122, SEQ ID NO:126, SEQ ID NO:129, SEQ ID NO:132, SEQ ID NO:148, SEQ ID NO:149, and SEQ ID NO:155, and CDR2 is selected from SEQ ID NO:63, SEQ ID NO:69, SEQ ID NO:75, SEQ ID NO:81, SEQ ID NO:9 11. The antibody of claim 10, wherein the lCDR3 is selected from SEQ ID NO:64, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:82, SEQ ID NO:87, SEQ ID NO:92, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:115, SEQ ID NO:117, SEQ ID NO:123, SEQ ID NO:127, SEQ ID NO:130, SEQ ID NO:134, SEQ ID NO:137, SEQ ID NO:140, SEQ ID NO:145, SEQ ID NO:157, and SEQ ID NO:

159.

12. The lCDR1, lCDR2, and lCDR3 are 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, 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, 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, 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, x. SEQ ID NO: 148, SEQ ID NO: 69, SEQ ID NO: 109, respectively; y. SEQ ID NO: 149, SEQ ID NO: 63, SEQ ID NO: 109, respectively; z. SEQ ID NO: 122, SEQ ID NO: 69, SEQ ID NO: 123, respectively; aa. SEQ ID NO: 126, SEQ ID NO: 69, SEQ ID NO: 130, bb. SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 157, or cc. SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 159, respectively The antibody of claim 11, comprising:

13. The light chain variable region comprises four framework regions, the four framework regions being, from N-terminus to C-terminus, lFR1, lFR2, lFR3, and lFR4, wherein lFR1 is selected from SEQ ID NO:164, SEQ ID NO:171, SEQ ID NO:179, SEQ ID NO:185, SEQ ID NO:191, SEQ ID NO:197, SEQ ID NO:201, SEQ ID NO:207, SEQ ID NO:213, SEQ ID NO:218, SEQ ID NO:222, SEQ ID NO:228, SEQ ID NO:232, SEQ ID NO:247, SEQ ID NO:256, SEQ ID NO:263, SEQ ID NO:270, SEQ ID NO:277, SEQ ID NO:283, SEQ ID NO:299, and SEQ ID NO:303, and lFR2 is selected from SEQ ID NO:165, SEQ ID NO:172, SEQ ID NO:180, SEQ ID NO:186, SEQ ID NO:192, SEQ ID NO:198, SEQ ID NO:202, SEQ ID NO:208, SEQ ID NO:214, SEQ ID NO:219, SEQ ID NO:223, SEQ ID NO: 229, SEQ ID NO:235, SEQ ID NO:240, SEQ ID NO:243, SEQ ID NO:248, SEQ ID NO:257, SEQ ID NO:264, SEQ ID NO:278, SEQ ID NO:300, and SEQ ID NO:304; IFR3 is selected from SEQ ID NO:166, SEQ ID NO:173, SEQ ID NO:181, SEQ ID NO:187, SEQ ID NO:193, SEQ ID NO:199, SEQ ID NO:203, SEQ ID NO:209, SEQ ID NO:220, SEQ ID NO:230, SEQ ID NO:236, SEQ ID NO:238, SEQ ID NO:241, SEQ ID NO:244, SEQ ID NO:249, SEQ ID NO:253, SEQ ID NO:258, SEQ ID NO:273, SEQ ID NO:279, and SEQ ID NO:301; and IFR4 is selected from SEQ ID NO:167, SEQ ID NO:174, SEQ ID NO:182, SEQ ID NO:215, SEQ ID NO:250, SEQ ID NO:280, and SEQ ID NO:

302.

14. The lFR1, lFR2, lFR3, and lFR4 are 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, t. SEQ ID NO: 171, SEQ ID NO: 243, SEQ ID NO: 253, SEQ ID NO: 167, 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, 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, or cc. SEQ ID NO: 283, SEQ ID NO: 278, SEQ ID NO: 279, SEQ ID NO: 174, dd. SEQ ID NO: 299, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, ee. SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 301, SEQ ID NO: 302, ff. SEQ ID NO: 299, SEQ ID NO: 304, SEQ ID NO: 301, SEQ ID NO: 302, respectively The antibody of claim 13, comprising:

15. The antibody of claim 13 or claim 14, wherein the CDRs and FRs in the light chain variable region are operably linked in the order of lFR1-lCDR1-lFR2-lCDR2-lFR3-lCDR3-lFR4 from the N-terminus to the C-terminus.

16. 16. The antibody of any one of claims 10 to 15, further comprising a light chain constant region (CL), wherein the CL is SEQ ID NO:

311.

17. 17. The antibody of any one of claims 10-16, wherein the light chain variable region comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:286, SEQ ID NO:288, and SEQ ID NO:

289.

18. 18. The antibody of any one of claims 10 to 17, wherein the light chain variable region comprises any one of the amino acid sequences of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:286, SEQ ID NO:288, and SEQ ID NO:

289.

19. 10. The antibody of claim 1, further comprising a light chain variable region, wherein the light chain variable region comprises at least one CDR, and the CDR furthest from the N-terminus is selected from SEQ ID NO:64, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:82, SEQ ID NO:87, SEQ ID NO:92, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:115, SEQ ID NO:117, SEQ ID NO:123, SEQ ID NO:127, SEQ ID NO:130, SEQ ID NO:134, SEQ ID NO:137, SEQ ID NO:140, SEQ ID NO:145, SEQ ID NO:157, and SEQ ID NO:

159.

20. The light chain variable region comprises three CDRs, the three CDRs being, from N-terminus to C-terminus, CDR1, CDR2, and CDR3, wherein CDR1 is selected from SEQ ID NO:62, SEQ ID NO:68, SEQ ID NO:74, SEQ ID NO:80, SEQ ID NO:86, SEQ ID NO:90, SEQ ID NO:96, SEQ ID NO:99, SEQ ID NO:105, SEQ ID NO:108, SEQ ID NO:113, SEQ ID NO:122, SEQ ID NO:126, SEQ ID NO:129, SEQ ID NO:132, SEQ ID NO:148, SEQ ID NO:149, and SEQ ID NO:155; and CDR2 is selected from SEQ ID NO:63, SEQ ID NO:69, SEQ ID NO:75, SEQ ID NO:81, SEQ ID NO: 91, SEQ ID NO:97, SEQ ID NO:106, SEQ ID NO:114, SEQ ID NO:133, SEQ ID NO:139, and SEQ ID NO:156, and the lCDR3 is selected from SEQ ID NO:64, SEQ ID NO:70, SEQ ID NO:76, SEQ ID NO:82, SEQ ID NO:87, SEQ ID NO:92, SEQ ID NO:98, SEQ ID NO:100, SEQ ID NO:102, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:115, SEQ ID NO:117, SEQ ID NO:123, SEQ ID NO:127, SEQ ID NO:130, SEQ ID NO:134, SEQ ID NO:137, SEQ ID NO:140, SEQ ID NO:145, SEQ ID NO:157, and SEQ ID NO:

159.

21. The lCDR1, lCDR2, and lCDR3 are 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, n. SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 102, 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, 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, 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, x. SEQ ID NO: 148, SEQ ID NO: 69, SEQ ID NO: 109, respectively; y. SEQ ID NO: 149, SEQ ID NO: 63, SEQ ID NO: 109, respectively; z. SEQ ID NO: 122, SEQ ID NO: 69, SEQ ID NO: 123, respectively; aa. SEQ ID NO: 126, SEQ ID NO: 69, SEQ ID NO: 130, bb. SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 157, or cc. SEQ ID NO: 155, SEQ ID NO: 156, SEQ ID NO: 159, respectively The antibody of claim 20, comprising:

22. The light chain variable region comprises four framework regions, the four framework regions being, from N-terminus to C-terminus, lFR1, lFR2, lFR3, and lFR4, wherein lFR1 is selected from SEQ ID NO:164, SEQ ID NO:171, SEQ ID NO:179, SEQ ID NO:185, SEQ ID NO:191, SEQ ID NO:197, SEQ ID NO:201, SEQ ID NO:207, SEQ ID NO:213, SEQ ID NO:218, SEQ ID NO:222, SEQ ID NO:228, SEQ ID NO:232, SEQ ID NO:247, SEQ ID NO:256, SEQ ID NO:263, SEQ ID NO:270, SEQ ID NO:277, SEQ ID NO:283, SEQ ID NO:299, and SEQ ID NO:303, and lFR2 is selected from SEQ ID NO:165, SEQ ID NO:172, SEQ ID NO:180, SEQ ID NO:186, SEQ ID NO:192, SEQ ID NO:198, SEQ ID NO:202, SEQ ID NO:208, SEQ ID NO:214, SEQ ID NO:219, SEQ ID NO:223, SEQ ID NO: 229, SEQ ID NO:235, SEQ ID NO:240, SEQ ID NO:243, SEQ ID NO:248, SEQ ID NO:257, SEQ ID NO:264, SEQ ID NO:278, SEQ ID NO:300, and SEQ ID NO:304; IFR3 is selected from SEQ ID NO:166, SEQ ID NO:173, SEQ ID NO:181, SEQ ID NO:187, SEQ ID NO:193, SEQ ID NO:199, SEQ ID NO:203, SEQ ID NO:209, SEQ ID NO:220, SEQ ID NO:230, SEQ ID NO:236, SEQ ID NO:238, SEQ ID NO:241, SEQ ID NO:244, SEQ ID NO:249, SEQ ID NO:253, SEQ ID NO:258, SEQ ID NO:273, SEQ ID NO:279, and SEQ ID NO:301; and IFR4 is selected from SEQ ID NO:167, SEQ ID NO:174, SEQ ID NO:182, SEQ ID NO:215, SEQ ID NO:250, SEQ ID NO:280, and SEQ ID NO:

302.

23. The lFR1, lFR2, lFR3, and lFR4 are 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, t. SEQ ID NO: 171, SEQ ID NO: 243, SEQ ID NO: 253, SEQ ID NO: 167, 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, 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, or cc. SEQ ID NO: 283, SEQ ID NO: 278, SEQ ID NO: 279, SEQ ID NO: 174, dd. SEQ ID NO: 299, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, ee. SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 301, SEQ ID NO: 302, ff. SEQ ID NO: 299, SEQ ID NO: 304, SEQ ID NO: 301, SEQ ID NO: 302, respectively 23. The antibody of claim 22, comprising:

24. The antibody of claim 20 or claim 21, wherein the CDRs and FRs in the light chain variable region are operably linked in the order of lFR1-lCDR1-lFR2-lCDR2-lFR3-lCDR3-lFR4 from the N-terminus to the C-terminus.

25. 25. The antibody of any one of claims 19 to 24, further comprising a light chain constant region (CL), wherein the CL is SEQ ID NO:

311.

26. 26. The antibody of any one of claims 19-25, wherein the light chain variable region comprises an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:286, SEQ ID NO:288, and SEQ ID NO:

289.

27. 27. The antibody of any one of claims 19 to 26, wherein the light chain variable region comprises the amino acid sequence of any one of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:286, SEQ ID NO:288, and SEQ ID NO:

289.

28. The heavy chain variable region and the light chain variable region are 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. 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; or cc. SEQ ID NO: 57 and SEQ ID NO: 58, respectively; dd. SEQ ID NO: 285 and SEQ ID NO: 286, respectively; ee. SEQ ID NO: 287 and SEQ ID NO: 288, respectively; ff. SEQ ID NO: 287 and SEQ ID NO: 289, respectively; gg. SEQ ID NO: 290 and SEQ ID NO: 288, respectively; hh. SEQ ID NO: 290 and SEQ ID NO: 286, respectively; ii. SEQ ID NO: 291 and SEQ ID NO: 286, respectively; jj. SEQ ID NO: 292 and SEQ ID NO: 293, respectively; kk. SEQ ID NO: 294 and SEQ ID NO: 293, respectively 28. The antibody of any one of claims 19 to 27, comprising an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to

29. The heavy chain variable region and the light chain variable region are 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. 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; or cc. SEQ ID NO: 57 and SEQ ID NO: 58, respectively; dd. SEQ ID NO: 285 and SEQ ID NO: 286, respectively; ee. SEQ ID NO: 287 and SEQ ID NO: 288, respectively; ff. SEQ ID NO: 287 and SEQ ID NO: 289, respectively; gg. SEQ ID NO: 290 and SEQ ID NO: 288, respectively; hh. SEQ ID NO: 290 and SEQ ID NO: 286, respectively; ii. SEQ ID NO: 291 and SEQ ID NO: 286, respectively; jj. SEQ ID NO: 292 and SEQ ID NO: 293, respectively; kk. SEQ ID NO: 294 and SEQ ID NO: 293, respectively 29. The antibody of any one of claims 19 to 28, comprising:

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

31. 31. The antibody of claim 30, wherein the FGFR2b is from a source selected from human, mouse, and cynomolgus monkey.

32. The antibody has a K Ｄ 32. The antibody of any one of claims 1 to 31, which binds to FGFR2b at

33. The antibody has a K Ｄ 33. The antibody of any one of claims 1 to 32, which binds to FGFR2b at

34. The antibody has a K Ｄ 34. The antibody of any one of claims 1 to 33, which binds to FGFR2b at

35. 35. The antibody of any one of claims 1 to 34, wherein the antibody does not detectably bind to FGFRlb, FGFRlc, FGFR2c, FGFR3b, FGFR3c, or FGFR4.

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

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

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

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

40. 40. The antibody of any one of claims 1 to 39, wherein the antibody is operably linked to a cytotoxic agent.

41. 41. The antibody of any one of claims 1 to 40, wherein the antibody is an afucosylated antibody.

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

43. 43. The antibody of any one of claims 1 to 42, wherein the antibody is an ADCC-enhancing antibody.

44. 44. A composition comprising an antibody according to any one of claims 1 to 43.

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

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

47. A vector comprising the polynucleotide of claim 46.

48. A cell capable of expressing an antibody according to any one of claims 1 to 43.

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

50. 50. A method of producing an antibody, comprising culturing a cell of claim 48 or claim 49 and recovering the antibody from the cell.

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

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

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

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

55. 55. The method of claim 53 or claim 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 an antibody described in any one of claims 1 to 43 or a composition described in claim 44 or claim 45.

57. A method for inhibiting the growth of a tumor xenograft that overexpresses FGFR2b, comprising administering to a subject an effective amount of an antibody described in any one of claims 1 to 43 or a composition described in claim 44 or claim 45.

58. 46. ​​A method for detecting the presence of FGFR2b in a sample, comprising contacting the sample with an antibody described in any one of claims 1 to 43 or a composition described in claim 44 or claim 45, wherein detection of at least one bound antibody indicates the presence of FGFR2b.

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