Claudin 18.2 binding moieties and uses thereof

Abstract

To provide additional Claudin 18.2 binding moieties and their chimeric antigen receptors with more desirable pharmaceutical properties.SOLUTION: The present invention relates to binding moieties, such as antibodies, that specifically bind to Claudin 18.2, and chimeric antigen receptors comprising such binding moieties. In addition, the present invention provides engineered immune cells (such as T cells) comprising anti-Claudin 18.2 chimeric antigen receptors. Moreover, the present invention discloses methods of treating Claudin 18.2-expressing tumor or cancers using the binding moieties, chimeric antigen receptors and engineered immune cells.SELECTED DRAWING: None

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to International Patent Application No. PCT / CN2018 / 125052, filed December 28, 2018, and International Patent Application No. PCT / CN2019 / 095827, filed July 12, 2019, the entire contents of which are incorporated by reference herein. [Technical Field]

[0002] The present invention relates to the fields of molecular biology, cell biology, and cancer biology, and in particular to antibodies, chimeric antigen receptors, and genetically engineered immune cells that target Claudin 18.2, and uses thereof. [Background technology]

[0003] Claudins are a family of cell surface proteins that establish intercellular barriers, regulate the flow of molecules between cells, and play important roles in cell signaling and maintaining epithelial cell polarity (Singh et al., (2010) J Oncol 2010:541-957). Each claudin molecule has four transmembrane segments with two extracellular loops and an N- and C-terminus located in the cytoplasm. Twenty-four claudin family members have been discovered and described in humans. These members are expressed in various tissues, and alterations in their function can lead to cancer formation. For example, altered expression levels of claudin-1, claudin-18, and claudin-10 have been associated with colon cancer, gastric cancer, and hepatocellular carcinoma, respectively, making claudins promising targets for therapeutic strategies (Swisshelm et al., (2005) Adv Drug Deliv Rev 57(6):919-928).

[0004] Claudin 18 (CLDN18) has two splice variants, claudin 18.1 (CLDN18.1) and claudin 18.2 (CLDN18.2), which differ in their N-terminal regions. There is no detectable expression of claudin 18.2 in normal tissues, except in the stomach, where it is expressed only in short-lived differentiated gastric epithelial cells. However, it is maintained during malignant transformation and is frequently displayed on the surface of human gastric cancer cells. Furthermore, this protein is ectopically activated at significant levels in esophageal, pancreatic, and lung adenocarcinomas (Niimi et al., (2001) Mol Cell Biol 21(21):7380-7390; Tanaka et al., (2011) J Histochem Cytochem 59(10):942-952; Micke et al., (2014) Int J Cancer 135(9):2206-2214; Shimobaba et al., (2016) Biochim Biophys Acta 1863(6 Pt A):1170-1178; Singh et al., (2017) J Hematol Oncol 10(1):105; Tokumitsu et al., (2017) Cytopathology 28(2):116-121).

[0005] Claudin 18.2, with its exposed extracellular loop and restricted expression pattern, has become a promising target for cancer immunotherapy. Anti-claudin 18.2 antibodies and CARs have been developed and studied for many years. For example, IMAB362 (Claudiximab, Zolbetuximab), a chimeric monoclonal IgG1 antibody, has been studied in numerous clinical trials to treat patients with advanced gastroesophageal cancer (Sahin et al., (2017) Journal of Hematology & Oncology 10:105). CARsgen's anti-claudin 18.2 chimeric antigen receptor T cell (CAR-T cell) therapy has also entered clinical trials.

[0006] Unlike antibody therapy, CAR-T cell therapy avoids the need for active immunization and has potential efficacy in immunologically impaired cancer patients. A new generation of CARs contains heavy and light chains derived from extracellular immunoglobulins, T cell activation domains (usually including the zeta chain of the CD3 complex), and one or more chimeric domains derived from costimulatory proteins. They recognize tumor antigens independently of HLA and, upon antigen binding, result in massive proliferation of CAR-T cells (Carl H. June, (2018) N Engl J Med, 379:64-73).

[0007] The FDA recently approved CD19 CAR-T cell therapy for the treatment of B-cell cancers, and there are hundreds of ongoing clinical trials involving CAR-T worldwide, most of which target blood cancers. Solid tumor trials are less dominated by CAR-T, with about half of cell therapy-based trials involving other platforms, such as NK cells.

[0008] Regarding claudin 18.2-associated solid tumors, gastric cancer is the fourth (men) and fifth (women) cause of cancer death in developed countries, and pancreatic cancer is usually diagnosed at an advanced stage, with a very poor prognosis for patients. There remains a need in the art for additional claudin 18.2-binding moieties and their CARs with more desirable pharmaceutical properties.

[0009] The present invention provides claudin 18.2-binding moieties, such as anti-claudin 18.2 antibodies or antigen-binding fragments thereof.

[0010] The present invention provides a method for the preparation of a VH comprising administering to a patient a vaccine ... 10 X 11 YNX 12 X 13 FX 14 X15 (X6 is Y or W, X7 is Y or F, X8 is N or D, X9 is G, R, or N, X 10 is T, N, or S, X 11 is K, N, or Y, X 12 is Q, E, X 13 is K, N, or X 14 is T, K, or X 15 (3) a heavy chain CDR2 (VH CDR2) comprising X 16 YYGNSFX 17 X 18 (X 16 is D, F, or X 17 is A or V, X 18 is Y or N, SEQ ID NO: 176), and the light chain variable region (VL) comprises: (1) KSSQSLX 19 NSGNQKNYLT(X 19 (2) a light chain CDR1 (VL CDR1) comprising a WAX 20 TRES(X 20 is S or A, SEQ ID NO: 187); and (3) QNX 21 X 22 X 23 X 24 PX 25 X 26 (X 21 is D, G, or N, X 22 is Y or F, X 23 is M, R, S, W, Y, or F, X 24 is F or Y, X 25 is F or L, X 26 and a light chain CDR3 (VL CDR3) comprising:

[0011] In some embodiments, a binding moiety that specifically binds to claudin 18.2 comprises (a) a VH and / or (b) a VL. The VH comprises (1) a VH CDR1 comprising SHNMH (SEQ ID NO: 69), (2) a VH CDR2 comprising YIYPGNGGTNYNQKFKG (SEQ ID NO: 90), and (3) a VH CDR3 comprising DYYGNSFAY (SEQ ID NO: 117), or a variant thereof with up to about five amino acid substitutions in the CDRs. The VL comprises (1) a VL CDR1 comprising KSSQSLLNSGNQKNYLT (SEQ ID NO: 136), (2) a VL CDR2 comprising WASTRES (SEQ ID NO: 143), and (3) a VL CDR3 comprising QNDYRYPFT (SEQ ID NO: 151), or a variant thereof with up to about five amino acid substitutions in the CDRs.

[0012] In some embodiments, the binding moiety that specifically binds to claudin 18.2 is (a) (1) the amino acid sequences of SEQ ID NOs: 69, 89, and 117, respectively; (2) the amino acid sequences of SEQ ID NOs: 69, 90, and 117, respectively; (3) the amino acid sequences of SEQ ID NOs: 70, 90, and 117, respectively; (4) the amino acid sequences of SEQ ID NOs: 69, 91, and 117, respectively; (5) the amino acid sequences of SEQ ID NOs: 71, 92, and 117, respectively; (6) the amino acid sequences of SEQ ID NOs: 72, 93, and 117, respectively; (7) the amino acid sequences of SEQ ID NOs: 69, 94, and 117, respectively; (8) the amino acid sequences of SEQ ID NOs: 73, 95, and 117, respectively; (9) the amino acid sequences of SEQ ID NOs: 74, 96, and 119, respectively; (10) the amino acid sequences of SEQ ID NOs: 74, 96, and 130, respectively; (11) the amino acid sequences of SEQ ID NOs: 69, 202, and 118, respectively; (12) the amino acid sequences of SEQ ID NOs: 72, 90, and 117, respectively; or (13) the amino acid sequences of SEQ ID NOs: 69, 390, and 118, respectively, or variants thereof having up to about five amino acid substitutions in the CDRs. a VH comprising CDR1, CDR2, and CDR3, and / or (b) (1) the amino acid sequences of SEQ ID NOs: 136, 143, and 150, respectively; (2) the amino acid sequences of SEQ ID NOs: 137, 143, and 151, respectively; (3) the amino acid sequences of SEQ ID NOs: 136, 143, and 152, respectively; (4) the amino acid sequences of SEQ ID NOs: 137, 143, and 153, respectively; (5) the amino acid sequences of SEQ ID NOs: 136, 143, and 154, respectively; or (6) the amino acid sequences of SEQ ID NOs: 136 and 143, respectively. and 155, (7) the amino acid sequences of SEQ ID NOs: 136, 143, and 156, respectively, (8) the amino acid sequences of SEQ ID NOs: 137, 143, and 157, respectively, (9) the amino acid sequences of SEQ ID NOs: 136, 144, and 158, respectively, (10) the amino acid sequences of SEQ ID NOs: 136, 143, and 455, respectively, or (11) the amino acid sequences of SEQ ID NOs: 136, 143, and 249, respectively, or variants thereof with up to about five amino acid substitutions in the CDRs.

[0013] In some embodiments, the binding moiety that specifically binds to claudin 18.2 comprises (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 89, and 117, respectively, and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 150, respectively.

[0014] In some embodiments, the binding moiety that specifically binds to claudin 18.2 comprises (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 90, and 117, respectively, and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 137, 143, and 151, respectively.

[0015] In some embodiments, the binding moiety that specifically binds to claudin 18.2 comprises (a) a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 70, 90, and 117, respectively, and / or (b) a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 152, respectively.

[0016] In some embodiments, the binding moiety that specifically binds to claudin 18.2 comprises (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 91, and 117, respectively, and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 137, 143, and 153, respectively.

[0017] In some embodiments, the binding moiety that specifically binds to claudin 18.2 comprises (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 71, 92, and 117, respectively, and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 154, respectively.

[0018] In some embodiments, the binding moiety that specifically binds to claudin 18.2 comprises (a) a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 72, 93, and 117, respectively, and / or (b) a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 155, respectively.

[0019] In some embodiments, a binding moiety that specifically binds to claudin 18.2 comprises (a) a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 94, and 118, respectively, and / or (b) a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 156, respectively.

[0020] In some embodiments, the binding moiety that specifically binds to claudin 18.2 comprises (a) a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 73, 95, and 117, respectively, and / or (b) a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 137, 143, and 157, respectively.

[0021] In some embodiments, the binding moiety that specifically binds to claudin 18.2 comprises (a) a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 74, 96, and 119, respectively, and / or (b) a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 144, and 158, respectively.

[0022] In some embodiments, the binding moiety that specifically binds to claudin 18.2 comprises (a) a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 74, 96, and 130, respectively, and / or (b) a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 144, and 158, respectively.

[0023] In some embodiments, the binding moiety that specifically binds to claudin 18.2 comprises (a) a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 202, and 118, respectively, and / or (b) a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 455, respectively.

[0024] In some embodiments, the binding moiety that specifically binds to claudin 18.2 comprises (a) a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 72, 90, and 117, respectively, and / or (b) a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 137, 143, and 153, respectively.

[0025] In some embodiments, the binding moiety that specifically binds to claudin 18.2 comprises (a) a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 390, and 118, respectively, and / or (b) a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 249, respectively.

[0026] In some embodiments, the VH comprises (a) a VH and / or (b) a VL, wherein the VH is (1) SYX 27 X 28 H(X 27 is N or Y, X 28 is M or I, SEQ ID NO: 177), and (2) YIX 29 PX 30 NGGX 31 X 32 YX 33 X 34 KFX 35 X 36 (X 29 is Y, S, or D, X 30 is G or F, X 31 is T, S, or X 32 is N, Y, or R, X 33 is S, N, X 34 is Q or L, X 35 is K, R, or E, X 36 is G or D, SEQ ID NO: 178); and (3) X 37 RX 38 X 39 X 40 Y(X 37 is G or L, X 38 is G or F, X 39 is F or L, X 40 is A or T, SEQ ID NO: 179), and the VL comprises (1) KSSQSLX 41 NX 42 GNQX 43 NYLX 44 (X 41 is F or L, X 42 is T, S, or X 43is K, E, or X 44 is T or I, SEQ ID NO: 189), and (2) RASTRX 45 S(X 45 is E, D, or Q, SEQ ID NO: 190), and (3) QNDX 46 SYPLT(X 46 and a VL CDR3 comprising a VL CDR3 comprising a VL CDR3 wherein VL CDR3 is F or Y, SEQ ID NO: 191.

[0027] In some embodiments, a binding moiety that specifically binds to claudin-18.2 is provided, comprising: (a) a VH comprising: (1) a VH CDR1 comprising SYNIH (SEQ ID NO: 75); (2) a VH CDR2 comprising YIYPGNGGTNYNQKFKG (SEQ ID NO: 90); and (3) a VH CDR3 comprising GRGFAY (SEQ ID NO: 120), or a variant thereof with up to about five amino acid substitutions in the CDRs; and / or (b) a VL comprising: (1) a VL CDR1 comprising KSSQSLFNSGNQKNYLT (SEQ ID NO: 137); (2) a VL CDR2 comprising RASTRES (SEQ ID NO: 145); and (3) a VL CDR3 comprising QNDYSYPLT (SEQ ID NO: 160), or a variant thereof with up to about five amino acid substitutions in the CDRs.

[0028] In some embodiments, (a) a VH CDR1, a VH CDR2, and a VH CDR3 comprising: (1) the amino acid sequences of SEQ ID NOs: 70, 97, and 120, respectively; (2) the amino acid sequences of SEQ ID NOs: 70, 98, and 120, respectively; (3) the amino acid sequences of SEQ ID NOs: 75, 99, and 120, respectively; (4) the amino acid sequences of SEQ ID NOs: 75, 100, and 120, respectively; (5) the amino acid sequences of SEQ ID NOs: 70, 90, and 121, respectively; (6) the amino acid sequences of SEQ ID NOs: 76, 101, and 122, respectively; (7) the amino acid sequences of SEQ ID NOs: 76, 101, and 123, respectively; (8) the amino acid sequences of SEQ ID NOs: 70, 201, and 120, respectively; or (9) the amino acid sequences of SEQ ID NOs: 70, 202, and 120, respectively, or a variant thereof comprising up to about five amino acid substitutions in the CDRs. and / or (b) a VL comprising a VL CDR1, VL CDR2, and VL CDR3, each of which comprises (1) the amino acid sequences of SEQ ID NOs: 138, 145, and 159, respectively; (2) the amino acid sequences of SEQ ID NOs: 136, 145, and 160, respectively; (3) the amino acid sequences of SEQ ID NOs: 139, 146, and 160, respectively; (4) the amino acid sequences of SEQ ID NOs: 137, 145, and 160, respectively; (5) the amino acid sequences of SEQ ID NOs: 140, 147, and 160, respectively; or (6) the amino acid sequences of SEQ ID NOs: 136, 147, and 160, respectively, or a variant thereof with up to about five amino acid substitutions in the CDRs.

[0029] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 70, 97, and 120, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 138, 145, and 159, respectively.

[0030] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 70, 98, and 120, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 145, and 160, respectively.

[0031] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 75, 99, and 120, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 139, 146, and 160, respectively.

[0032] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 75, 100, and 120, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 139, 146, and 160, respectively.

[0033] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 70, 90, and 121, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 137, 145, and 160, respectively.

[0034] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 76, 101, and 122, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 140, 147, and 160, respectively.

[0035] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 76, 101, and 123, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 147, and 160, respectively.

[0036] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 70, 201, and 120, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 137, 145, and 160, respectively.

[0037] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 70, 202, and 120, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 145, and 160, respectively.

[0038] In some embodiments, the VH comprises (a) a VH and / or (b) a VL, wherein the VH comprises (1) X 47 YGVX 48 (X 47 is T, S, or R, X48 is H or S, SEQ ID NO: 180), and (2) VIWX 49 X 50 GX 51 TX 52 YX 53 X 54 X 55 X 56 X 57 S(X 49 is A, G, or S, X 50 is G or D, X 51 is S, N, X 52 is N or D, X 53 is N or H, X 54 is S, A, X 55 is A, T, or X 56 is L or F, X 57 is M or I, SEQ ID NO: 181); and (3) X 58 X 59 X 60 X 61 GNX 62 X 63 DY(X 58 is A or null, X 59 is A, G, or V, X 60 is Y or R, X 61 is Y, F, or null, X 62 is A, G, or S, X 63 is L, F, or M, SEQ ID NO: 182), and the VL comprises (1) KSSQX 64 LLNSGNQKX 65 YLT(X 64 is T, S, or X 65 is N or S, SEQ ID NO: 192), and (2) WASTX 66 X 67 S(X 66 is G or R, X 67 is E or D, SEQ ID NO: 193), and (3) QNX 68 YX 69 X 70 PX 71 T(X 68 is A, D, N, or V, X 69 is F, S, or I, X70 is Y or F, X 71 and a VL CDR3 comprising a VL CDR3 with a VL CDR3 where VL CDR3 is F or L, SEQ ID NO: 194.

[0039] In some embodiments, a binding moiety that specifically binds to claudin-18.2 is provided, comprising: (a) a VH comprising: (1) a VH CDR1 comprising: SYGVS (SEQ ID NO: 78); (2) a VH CDR2 comprising: VIWAGGSTNYHSALMS (SEQ ID NO: 197); and (3) a VH CDR3 comprising: AAYYGNALDY (SEQ ID NO: 198), or a variant thereof comprising up to about five amino acid substitutions in the CDRs; and / or (b) a VL comprising: (1) a VL CDR1 comprising: KSSQSLLNSGNQKNYLT (SEQ ID NO: 136); (2) a VL CDR2 comprising: WASTRES (SEQ ID NO: 143); and (3) a VL CDR3 comprising: QNAYFYPFT (SEQ ID NO: 161), or a variant thereof comprising up to about five amino acid substitutions in the CDRs.

[0040] In some embodiments, (a) a VH CDR1, a VH CDR2, and a VH CDR3 comprising: (1) the amino acid sequences of SEQ ID NOs: 77, 102, and 124, respectively; (2) the amino acid sequences of SEQ ID NOs: 78, 103, and 125, respectively; (3) the amino acid sequences of SEQ ID NOs: 79, 104, and 126, respectively; (4) the amino acid sequences of SEQ ID NOs: 78, 105, and 127, respectively; or (5) the amino acid sequences of SEQ ID NOs: 209, 103, and 125, respectively, or a variant thereof comprising up to about five amino acid substitutions in the CDRs. and / or (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3, each of which comprises (1) the amino acid sequences of SEQ ID NOs: 141, 148, and 161, respectively; (2) the amino acid sequences of SEQ ID NOs: 136, 143, and 162, respectively; (3) the amino acid sequences of SEQ ID NOs: 136, 149, and 163, respectively; or (4) the amino acid sequences of SEQ ID NOs: 142, 143, and 164, respectively, or a variant thereof with up to about five amino acid substitutions in the CDRs.

[0041] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 77, 102, and 124, respectively; and / or (b) a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 141, 148, and 161, respectively.

[0042] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 78, 103, and 125, respectively; and / or (b) a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 162, respectively.

[0043] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 79, 104, and 126, respectively; and / or (b) a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 149, and 163, respectively.

[0044] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 78, 105, and 127, respectively; and / or (b) a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 142, 143, and 164, respectively.

[0045] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 209, 103, and 125, respectively; and / or (b) a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 162, respectively.

[0046] In some embodiments, the VH comprises (a) a VH and / or (b) a VL, wherein the VH comprises (1) X 72 X 73 GMH(X 72 is S, G, or T, X 73 is F or S, SEQ ID NO: 183), and (2) YIX 74 X 75 GSX 76 X 77 IX 78 YAX 79 X 80 X 81 X 82 G(X 74 is S, N, X75 is S, G, or T, X 76 is S, R, T, or N, X 77 is T, P, X 78 is Y or F, X 79 is D or H, X 80 is T, S, or X 81 is V or L, X 82 is K or Q, SEQ ID NO: 184); and (3) X 83 YYGNSFX 84 X 85 (X 83 is F, I, X 84 is V, D, or A, X 85 is Y, N, or H, SEQ ID NO: 185), and the VL comprises (1) SSQX 86 LLNSGNQKNYLT(X 86 (1) a VL CDR1 comprising a VL CDR2 with a VL CDR3 (SEQ ID NO: 195) and a VL CDR4 with a VL CDR5 (SEQ ID NO: 143); and (2) a VL CDR6 with a VL CDR7 (SEQ ID NO: 144); 87 YX 88 X 89 PX 90 T(X 87 is A, D, or N, X 88 is I, S, T, or Y, X 89 is Y or F, X 90 and a VL CDR3 comprising a CDR1 wherein the CDR1 is L or V, SEQ ID NO: 196).

[0047] In some embodiments, a binding moiety that specifically binds to claudin-18.2 is provided, comprising: (a) a VH comprising: (1) a VH CDR1 comprising SGFTFSSFGMH (SEQ ID NO: 80); (2) a VH CDR2 comprising YISSGSSTIYYADTVKG (SEQ ID NO: 199); and (3) a VH CDR3 comprising FYYGNSFAY (SEQ ID NO: 130), or a variant thereof with up to about five amino acid substitutions in the CDRs; and / or (b) a VL comprising: (1) a VL CDR1 comprising KSSQSLLNSGNQKNYLT (SEQ ID NO: 136); (2) a VL CDR2 comprising WASTRES (SEQ ID NO: 143); and (3) a VL CDR3 comprising QNAYSYPLT (SEQ ID NO: 167), or a variant thereof with up to about five amino acid substitutions in the CDRs.

[0048] In some embodiments, (a) a VH CDR1, a VH CDR2, and a VH CDR3 comprising: (1) the amino acid sequences of SEQ ID NOs: 80, 106, and 128, respectively; (2) the amino acid sequences of SEQ ID NOs: 81, 107, and 129, respectively; (3) the amino acid sequences of SEQ ID NOs: 82, 108, and 130, respectively; (4) the amino acid sequences of SEQ ID NOs: 80, 109, and 130, respectively; (5) the amino acid sequences of SEQ ID NOs: 83, 110, and 130, respectively; (6) the amino acid sequences of SEQ ID NOs: 80, 109, and 131, respectively; (7) the amino acid sequences of SEQ ID NOs: 80, 111, and 132, respectively; (8) the amino acid sequences of SEQ ID NOs: 84, 112, and 132, respectively; (9) the amino acid sequences of SEQ ID NOs: 80, 110, and 130, respectively; or (10) the amino acid sequences of SEQ ID NOs: 81, 391, and 129, respectively, or a variant thereof comprising up to about five amino acid substitutions in the CDRs. a VH comprising a CDR3, and / or (b) (1) the amino acid sequences of SEQ ID NOs: 136, 143, and 165, respectively; (2) the amino acid sequences of SEQ ID NOs: 136, 143, and 166, respectively; (3) the amino acid sequences of SEQ ID NOs: 136, 143, and 167, respectively; (4) the amino acid sequences of SEQ ID NOs: 141, 143, and 168, respectively; (5) the amino acid sequences of SEQ ID NOs: 136, 143, and 169, respectively; (6) the amino acid sequences of SEQ ID NOs: 141, 143, and 17, respectively; (7) the amino acid sequences of SEQ ID NOs: 136, 143, and 160, respectively; (8) the amino acid sequences of SEQ ID NOs: 136, 143, and 171, respectively; (9) the amino acid sequences of SEQ ID NOs: 136, 143, and 162, respectively; (10) the amino acid sequences of SEQ ID NOs: 141, 143, and 167, respectively; or (11) the amino acid sequences of SEQ ID NOs: 141, 143, and 166, respectively, or variants thereof with up to about five amino acid substitutions in the CDRs.

[0049] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 106, and 128, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 165, respectively.

[0050] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 107, and 129, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 166, respectively.

[0051] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 82, 108, and 130, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 167, respectively.

[0052] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 109, and 130, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 141, 143, and 168, respectively.

[0053] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 83, 110, and 130, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 169, respectively.

[0054] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 109, and 131, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 141, 143, and 170, respectively.

[0055] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 111, and 132, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 160, respectively.

[0056] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 84, 112, and 132, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 171, respectively.

[0057] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 391, and 129, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 162, respectively.

[0058] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 109, and 131, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 141, 143, and 167, respectively.

[0059] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 107, and 129, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 141, 143, and 166, respectively.

[0060] In some embodiments, (a) (1) the amino acid sequences of SEQ ID NOs: 85, 113, and 133, respectively; (2) the amino acid sequences of SEQ ID NOs: 86, 114, and 134, respectively; (3) the amino acid sequences of SEQ ID NOs: 87, 115, and 131, respectively; (4) the amino acid sequences of SEQ ID NOs: 88, 116, and 135, respectively; (5) the amino acid sequences of SEQ ID NOs: 203, 211, and 225, respectively; (6) the amino acid sequences of SEQ ID NOs: 204, 212, and 226, respectively; (7) the amino acid sequences of SEQ ID NOs: 205, 213, and 227, respectively. (8) the amino acid sequences of SEQ ID NOs: 206, 214, and 131, respectively; (9) the amino acid sequences of SEQ ID NOs: 207, 215, and 228, respectively; (10) the amino acid sequences of SEQ ID NOs: 208, 216, and 229, respectively; (11) the amino acid sequences of SEQ ID NOs: 69, 90, and 230, respectively; (12) the amino acid sequences of SEQ ID NOs: 69, 217, and 117, respectively; (13) the amino acid sequences of SEQ ID NOs: 209, 218, and 231, respectively; (14) the amino acid sequences of SEQ ID NOs: 72, 219, and 117, respectively; (15) the amino acid sequences of SEQ ID NOs: (16) the amino acid sequences of SEQ ID NOs: 69, 221, and 117, respectively; (17) the amino acid sequences of SEQ ID NOs: 72, 222, and 118, respectively; (18) the amino acid sequences of SEQ ID NOs: 69, 223, and 118, respectively; (19) the amino acid sequences of SEQ ID NOs: 210, 224, and 232, respectively; (20) the amino acid sequences of SEQ ID NOs: 72, 217, and 118, respectively; (21) the amino acid sequences of SEQ ID NOs: 69, 90, and 117, respectively; (22) the amino acid sequences of SEQ ID NOs: 3, 4, 5, 6, 7, 8, 9, and 117, respectively; (23) the amino acid sequences of SEQ ID NOs: 392, 395, and 396, respectively; (24) the amino acid sequences of SEQ ID NOs: 397, 398, and 399, respectively; (25) the amino acid sequences of SEQ ID NOs: 75, 400, and 120, respectively; (26) the amino acid sequences of SEQ ID NOs: 70, 401, and 120, respectively; (27) the amino acid sequences of SEQ ID NOs: 402, 403, and 404, respectively; (28) the amino acid sequences of SEQ ID NOs: 69, 219, and 117, respectively; (29) the amino acid sequences of SEQ ID NOs: 71 and 405, respectively;and 117 amino acid sequences, (30) amino acid sequences of SEQ ID NOs: 406, 407, and 408, respectively, (31) amino acid sequences of SEQ ID NOs: 409, 410, and 411, respectively, (32) amino acid sequences of SEQ ID NOs: 69, 219, and 416, respectively, (33) amino acid sequences of SEQ ID NOs: 76, 412, and 411, respectively, (34) amino acid sequences of SEQ ID NOs: 413, 414, and 415, respectively, (35) amino acid sequences of SEQ ID NOs: 69, 219, and 416, respectively, (36) amino acid sequences of SEQ ID NOs: 417, 418, and 232, respectively. (37) the amino acid sequences of SEQ ID NOs: 69, 419, and 420, respectively; (38) the amino acid sequences of SEQ ID NOs: 205, 421, and 422, respectively; (39) the amino acid sequences of SEQ ID NOs: 205, 423, and 424, respectively; (40) the amino acid sequences of SEQ ID NOs: 81, 391, and 129, respectively; (41) the amino acid sequences of SEQ ID NOs: 88, 425, and 135, respectively; (42) the amino acid sequences of SEQ ID NOs: 81, 426, and 129, respectively; (43) the amino acid sequences of SEQ ID NOs: 80, 109, and 130, respectively; (44 ) the amino acid sequences of SEQ ID NOs: 81, 391, and 129, respectively; (45) the amino acid sequences of SEQ ID NOs: 430, 391, and 431, respectively; (46) the amino acid sequences of SEQ ID NOs: 80, 109, and 129, respectively; (47) the amino acid sequences of SEQ ID NOs: 81, 432, and 129, respectively; (48) the amino acid sequences of SEQ ID NOs: 433, 391, and 129, respectively; (49) the amino acid sequences of SEQ ID NOs: 434, 435, and 129, respectively; (50) the amino acid sequences of SEQ ID NOs: 436, 428, and 429, respectively; (51) the amino acid sequences of SEQ ID NOs: (52) the amino acid sequences of SEQ ID NOs: 81, 438, and 129, respectively; (53) the amino acid sequences of SEQ ID NOs: 80, 439, and 441, respectively; (54) the amino acid sequences of SEQ ID NOs: 433, 391, and 431, respectively; (55) the amino acid sequences of SEQ ID NOs: 80, 442, and 443, respectively; (56) the amino acid sequences of SEQ ID NOs: 80, 440, and 441, respectively; (57) the amino acid sequences of SEQ ID NOs: 444, 445, and 446, respectively; (58) the amino acid sequences of SEQ ID NOs: 447, 448,and 449, (59) the amino acid sequences of SEQ ID NOs: 450, 451, and 452, respectively, (60) the amino acid sequences of SEQ ID NOs: 81, 453, and 129, respectively, or (61) the amino acid sequences of SEQ ID NOs: 69, 89, and 454, respectively, or variants thereof comprising up to about five amino acid substitutions in the CDRs; and / or (b) a VH comprising: (1) the amino acid sequences of SEQ ID NOs: 136, 143, and 172, respectively; (2) the amino acid sequences of SEQ ID NOs: 136, 143, and 167, respectively; (3) the amino acid sequences of SEQ ID NOs: 136, 143, and 173, respectively; (4) the amino acid sequences of SEQ ID NOs: 223, 241, and 242, respectively; (5) the amino acid sequences of SEQ ID NOs: 136, 143, and 243, respectively; (6) the amino acid sequences of SEQ ID NOs: 136, 143, and 243, respectively; (7) the amino acid sequences of SEQ ID NOs: 235, 143, and 245, respectively; (8) the amino acid sequences of SEQ ID NOs: 136, 143, and 163, respectively; (9) the amino acid sequences of SEQ ID NOs: 236, 143, and 246, respectively; (10) the amino acid sequences of SEQ ID NOs: 237, 143, and 151, respectively; (11) the amino acid sequences of SEQ ID NOs: 137, 143, and 247, respectively; (12) the amino acid sequences of SEQ ID NOs: (13) the amino acid sequences of SEQ ID NOs: 238, 143, and 157, respectively; (14) the amino acid sequences of SEQ ID NOs: 137, 145, and 160, respectively; (15) the amino acid sequences of SEQ ID NOs: 136, 143, and 150, respectively; (16) the amino acid sequences of SEQ ID NOs: 136, 143, and 151, respectively; (17) the amino acid sequences of SEQ ID NOs: 239, 143, and 249, respectively; (18) the amino acid sequences of SEQ ID NOs: (19) the amino acid sequences of SEQ ID NOs: 136, 143, and 250, respectively; (20) the amino acid sequences of SEQ ID NOs: 137, 143, and 153, respectively; (21) the amino acid sequences of SEQ ID NOs: 136, 143, and 163, respectively; (22) the amino acid sequences of SEQ ID NOs: 456, 457, and 250, respectively; (23) the amino acid sequences of SEQ ID NOs: 458, 146, and 160, respectively;(24) the amino acid sequences of SEQ ID NOs: 136, 145, and 160, respectively; (25) the amino acid sequences of SEQ ID NOs: 240, 143, and 244, respectively; (26) the amino acid sequences of SEQ ID NOs: 137, 143, and 157, respectively; (27) the amino acid sequences of SEQ ID NOs: 136, 143, and 459, respectively; (28) the amino acid sequences of SEQ ID NOs: 460, 461, and 462, respectively; (29) the amino acid sequences of SEQ ID NOs: 137, 463, and 464, respectively; (30) the amino acid sequences of SEQ ID NOs: 465, 466, and 162, respectively; (31) the amino acid sequences of SEQ ID NOs: (32) the amino acid sequences of SEQ ID NOs: 136, 143, and 457, respectively; (33) the amino acid sequences of SEQ ID NOs: 136, 143, and 244, respectively; (34) the amino acid sequences of SEQ ID NOs: 136, 143, and 468, respectively; (35) the amino acid sequences of SEQ ID NOs: 136, 143, and 469, respectively; (36) the amino acid sequences of SEQ ID NOs: 136, 143, and 154, respectively; (37) the amino acid sequences of SEQ ID NOs: 240, 143, and 166, respectively; (38) the amino acid sequences of SEQ ID NOs: (39) the amino acid sequences of SEQ ID NOs: 136, 143, and 166, respectively; (40) the amino acid sequences of SEQ ID NOs: 136, 143, and 471, respectively; (41) the amino acid sequences of SEQ ID NOs: 472, 473, and 474, respectively; (42) the amino acid sequences of SEQ ID NOs: 475, 143, and 166, respectively; (43) the amino acid sequences of SEQ ID NOs: 476, 143, and 166, respectively; (44) the amino acid sequences of SEQ ID NOs: 136, 143, and 477, respectively; (45) the amino acid sequences of SEQ ID NOs: 47 (46) the amino acid sequences of SEQ ID NOs: 479, 143, and 163, respectively; (47) the amino acid sequences of SEQ ID NOs: 480, 143, and 481, respectively; (48) the amino acid sequences of SEQ ID NOs: 482, 143, and 483, respectively; (49) the amino acid sequences of SEQ ID NOs: 136, 143, and 160, respectively; (50) the amino acid sequences of SEQ ID NOs: 482, 143, and 484, respectively; (51) the amino acid sequences of SEQ ID NOs: 485, 486, and 487, respectively; (52) the amino acid sequences of SEQ ID NOs: 488 and 489, respectively;and 490, (53) the amino acid sequences of SEQ ID NOs: 491, 492, and 493, respectively, or (54) the amino acid sequences of SEQ ID NOs: 136, 143, and 494, respectively, or variants thereof with up to about five amino acid substitutions in the CDRs.

[0061] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 85, 113, and 133, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 172, respectively.

[0062] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 86, 114, and 134, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 172, respectively.

[0063] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 87, 115, and 131, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 167, respectively.

[0064] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 88, 116, and 135, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 173, respectively.

[0065] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 203, 211, and 225, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 223, 241, and 242, respectively.

[0066] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 204, 212, and 226, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 243, respectively.

[0067] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 205, 213, and 227, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 234, 143, and 244, respectively.

[0068] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 206, 214, and 131, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 235, 143, and 245, respectively.

[0069] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 207, 215, and 228, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 163, respectively.

[0070] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 208, 216, and 229, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 236, 143, and 246, respectively.

[0071] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 90, and 230, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 237, 143, and 151, respectively.

[0072] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 217, and 117, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 137, 143, and 247, respectively.

[0073] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 209, 218, and 231, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 248, respectively.

[0074] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 72, 219, and 117, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 238, 143, and 157, respectively.

[0075] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 75, 220, and 120, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 137, 145, and 160, respectively.

[0076] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 221, and 117, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 150, respectively.

[0077] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 72, 222, and 118, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 151, respectively.

[0078] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 223, and 118, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 239, 143, and 249, respectively.

[0079] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 210, 224, and 232, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 240, 143, and 245, respectively.

[0080] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 72, 217, and 118, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 250, respectively.

[0081] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 90, and 117, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 137, 143, and 153, respectively.

[0082] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 85, 113, and 133, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 172, respectively.

[0083] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 392, 393, and 394, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 163, respectively.

[0084] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 392, 395, and 396, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 163, respectively.

[0085] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 397, 398, and 399, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 456, 457, and 250, respectively.

[0086] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 75, 400, and 120, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 458, 146, and 160, respectively.

[0087] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 70, 401, and 120, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 145, and 160, respectively.

[0088] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 402, 403, and 404, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 240, 143, and 244, respectively.

[0089] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 219, and 117, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 137, 143, and 157, respectively.

[0090] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 71, 405, and 117, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 459, respectively.

[0091] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 406, 407, and 408, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 460, 461, and 462, respectively.

[0092] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 90, and 117, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 137, 463, and 464, respectively.

[0093] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 409, 410, and 411, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 465, 466, and 162, respectively.

[0094] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 219, and 416, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 137, 143, and 157, respectively.

[0095] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 76, 412, and 411, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 140, 147, and 160, respectively.

[0096] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 413, 414, and 415, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 467, respectively.

[0097] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 417, 418, and 232, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 244, respectively.

[0098] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 419, and 420, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 468, respectively.

[0099] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 205, 421, and 422, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 469, respectively.

[0100] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 205, 423, and 424, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 154, respectively.

[0101] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 391, and 129, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 240, 143, and 166, respectively.

[0102] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 88, 425, and 135, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 470, respectively.

[0103] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 426, and 129, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 166, respectively.

[0104] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 109, and 130, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 471, respectively.

[0105] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 427, 428, and 429, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 472, 473, and 474, respectively.

[0106] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 391, and 129, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 475, 143, and 166, respectively.

[0107] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 430, 391, and 431, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 476, 143, and 166, respectively.

[0108] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 109, and 129, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 477, respectively.

[0109] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 391, and 129, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 478, 143, and 166, respectively.

[0110] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 432, and 129, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 475, 143, and 166, respectively.

[0111] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 433, 391, and 129, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 475, 143, and 166, respectively.

[0112] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 109, and 129, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 479, 143, and 163, respectively.

[0113] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 434, 435, and 129, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 240, 143, and 166, respectively.

[0114] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 436, 428, and 429, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 472, 473, and 474, respectively.

[0115] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 437, and 129, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 479, 143, and 163, respectively.

[0116] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 391, and 129, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 478, 143, and 166, respectively.

[0117] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 438, and 129, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 166, respectively.

[0118] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 391, and 129, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 480, 143, and 481, respectively.

[0119] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 439, and 441, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 482, 143, and 483, respectively.

[0120] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 433, 391, and 431, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 475, 143, and 166, respectively.

[0121] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 442, and 443, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 160, respectively.

[0122] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 440, and 441, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 482, 143, and 484, respectively.

[0123] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 444, 445, and 446, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 485, 486, and 487, respectively.

[0124] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 447, 448, and 449, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 488, 489, and 490, respectively.

[0125] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 450, 451, and 452, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 491, 492, and 493, respectively.

[0126] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 453, and 129, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 166, respectively.

[0127] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (a) a VH comprising VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 89, and 454, respectively; and / or (b) a VL comprising VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 494, respectively.

[0128] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (i) a VH comprising an amino acid sequence having at least 80% sequence identity to an amino acid sequence selected from the group consisting of odd-numbered SEQ ID NOs: 1-68, 251-290, and 495-680, and both odd-numbered and even-numbered SEQ ID NOs: 337-345, 348-352, 355-362, 365-369, 372-374, 378-380, and 383-385; and / or (ii) a VL comprising an amino acid sequence having at least 80% sequence identity to an amino acid sequence selected from the group consisting of even-numbered SEQ ID NOs: 1-68, 251-290, and 495-680, and SEQ ID NOs: 346, 347, 353, 354, 363, 364, 370, 371, 375, 376, 377, 381, 382, 386, and 387.

[0129] In some embodiments, (i) a VH comprising an amino acid sequence having at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to an amino acid sequence selected from the group consisting of odd-numbered SEQ ID NOs: 1-68, 251-290, and 495-680, and both odd-numbered and even-numbered SEQ ID NOs: 337-345, 348-352, 355-362, 365-369, 372-374, 378-380, and 383-385; and (ii) an even-numbered VH comprising an amino acid sequence having at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to an amino acid sequence selected from the group consisting of odd-numbered SEQ ID NOs: 1-68, 251-290, and 495-680, and both odd-numbered and even-numbered SEQ ID NOs: 337-345, 348-352, 355-362, 365-369, 372-374, 378-380, and 383-385. and a VL comprising an amino acid sequence having at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-68, 251-290, and 495-680, and SEQ ID NOs: 346, 347, 353, 354, 363, 364, 370, 371, 375, 376, 377, 381, 382, 386, and 387.

[0130] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising: (i) a VH comprising an amino acid sequence selected from the group consisting of odd-numbered SEQ ID NOs: 1-68, 251-290, and 495-680, and both odd-numbered and even-numbered SEQ ID NOs: 337-345, 348-352, 355-362, 365-369, 372-374, 378-380, and 383-385; and (ii) a VL comprising an amino acid sequence selected from the group consisting of even-numbered SEQ ID NOs: 1-68, 251-290, and 495-680, and SEQ ID NOs: 346, 347, 353, 354, 363, 364, 370, 371, 375, 376, 377, 381, 382, 386, and 387.

[0131] In some embodiments, a binding portion that specifically binds to claudin 18.2 is provided, wherein the VH and VL are (1) the amino acid sequences of SEQ ID NOs: 1 and 2, respectively, (2) the amino acid sequences of SEQ ID NOs: 3 and 4, respectively, (3) the amino acid sequences of SEQ ID NOs: 5 and 6, respectively, (4) the amino acid sequences of SEQ ID NOs: 7 and 8, respectively, (5) the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, (6) the amino acid sequences of SEQ ID NOs: 11 and 12, respectively, (7) the amino acid sequences of SEQ ID NOs: 13 and 14, respectively, (8) the amino acid sequences of SEQ ID NOs: 15 and 16, respectively, and (9) the amino acid sequences of SEQ ID NOs: 17 and 18, respectively. (10) the amino acid sequences of SEQ ID NOs: 19 and 20, respectively; (11) the amino acid sequences of SEQ ID NOs: 21 and 22, respectively; (12) the amino acid sequences of SEQ ID NOs: 23 and 24, respectively; (13) the amino acid sequences of SEQ ID NOs: 25 and 26, respectively; (14) the amino acid sequences of SEQ ID NOs: 27 and 28, respectively; (15) the amino acid sequences of SEQ ID NOs: 29 and 30, respectively; (16) the amino acid sequences of SEQ ID NOs: 31 and 32, respectively; (17) the amino acid sequences of SEQ ID NOs: 33 and 34, respectively; (18) (19) the amino acid sequences of SEQ ID NOs: 37 and 38, respectively; (20) the amino acid sequences of SEQ ID NOs: 39 and 40, respectively; (21) the amino acid sequences of SEQ ID NOs: 41 and 42, respectively; (22) the amino acid sequences of SEQ ID NOs: 43 and 44, respectively; (23) the amino acid sequences of SEQ ID NOs: 45 and 46, respectively; (24) the amino acid sequences of SEQ ID NOs: 47 and 48, respectively; (25) the amino acid sequences of SEQ ID NOs: 49 and 50, respectively; (26) the amino acid sequences of SEQ ID NOs: 51 and 52, respectively; and 52, (27) the amino acid sequences of SEQ ID NOs: 53 and 54, respectively, (28) the amino acid sequences of SEQ ID NOs: 55 and 56, respectively, (29) the amino acid sequences of SEQ ID NOs: 57 and 58, respectively, (30) the amino acid sequences of SEQ ID NOs: 59 and 60, respectively, (31) the amino acid sequences of SEQ ID NOs: 61 and 62, respectively, (32) the amino acid sequences of SEQ ID NOs: 63 and 64, respectively, (33) the amino acid sequences of SEQ ID NOs: 65 and 66, respectively, (34) the amino acid sequences of SEQ ID NOs: 67 and 68, respectively,(35) The amino acid sequences of SEQ ID NOs: 251 and 252, respectively; (36) The amino acid sequences of SEQ ID NOs: 253 and 254, respectively; (37) The amino acid sequences of SEQ ID NOs: 255 and 256, respectively; (38) The amino acid sequences of SEQ ID NOs: 257 and 258, respectively; (39) The amino acid sequences of SEQ ID NOs: 259 and 260, respectively; (40) The amino acid sequences of SEQ ID NOs: 261 and 262, respectively; (41) The amino acid sequences of SEQ ID NOs: 263 and 264, respectively; (42) The amino acid sequences of SEQ ID NOs: 265 and 266, respectively. (43) the amino acid sequences of SEQ ID NOs: 267 and 268, respectively; (44) the amino acid sequences of SEQ ID NOs: 269 and 270, respectively; (45) the amino acid sequences of SEQ ID NOs: 271 and 272, respectively; (46) the amino acid sequences of SEQ ID NOs: 273 and 274, respectively; (47) the amino acid sequences of SEQ ID NOs: 275 and 276, respectively; (48) the amino acid sequences of SEQ ID NOs: 277 and 278, respectively; (49) the amino acid sequences of SEQ ID NOs: 279 and 280, respectively; (50) the amino acid sequences of SEQ ID NOs: 281 and 282, respectively. (51) the amino acid sequences of SEQ ID NOs: 283 and 284, respectively; (52) the amino acid sequences of SEQ ID NOs: 285 and 286, respectively; (53) the amino acid sequences of SEQ ID NOs: 287 and 288, respectively; (54) the amino acid sequences of SEQ ID NOs: 289 and 290, respectively; (55) the amino acid sequences of any of SEQ ID NOs: 337 to 345, respectively, and the amino acid sequence of SEQ ID NO: 346; (56) the amino acid sequences of any of SEQ ID NOs: 337 to 345, respectively, and the amino acid sequence of SEQ ID NO: 347; (57) the amino acid sequences of any of SEQ ID NOs: 34 (58) any of the amino acid sequences of SEQ ID NOs: 348 to 352 and the amino acid sequence of SEQ ID NO: 354; (59) any of the amino acid sequences of SEQ ID NOs: 355 to 362 and the amino acid sequence of SEQ ID NO: 363; (60) any of the amino acid sequences of SEQ ID NOs: 355 to 362 and the amino acid sequence of SEQ ID NO: 364; (61) any of the amino acid sequences of SEQ ID NOs: 365 to 369 and the amino acid sequence of SEQ ID NO: 370;(62) any of the amino acid sequences of SEQ ID NOs: 365 to 369 and 371, (63) any of the amino acid sequences of SEQ ID NOs: 372 to 374 and 375 to 377, (64) any of the amino acid sequences of SEQ ID NOs: 378 to 380 and 381, (65) any of the amino acid sequences of SEQ ID NOs: 378 to 380 and 382, (66) any of the amino acid sequences of SEQ ID NOs: 383 to 385 (67) the amino acid sequence of any one of SEQ ID NOs: 383 to 385 and the amino acid sequence of SEQ ID NO: 387, (68) the amino acid sequences of SEQ ID NOs: 495 and 496, respectively, (69) the amino acid sequences of SEQ ID NOs: 497 and 498, respectively, (70) the amino acid sequences of SEQ ID NOs: 499 and 500, respectively, (71) the amino acid sequences of SEQ ID NOs: 501 and 502, respectively, (72) the amino acid sequences of SEQ ID NOs: 503 and 504, respectively, (73) the amino acid sequences of SEQ ID NOs: 505 and 506, respectively (74) the amino acid sequences of SEQ ID NOs: 507 and 508, respectively; (75) the amino acid sequences of SEQ ID NOs: 509 and 510, respectively; (76) the amino acid sequences of SEQ ID NOs: 511 and 512, respectively; (77) the amino acid sequences of SEQ ID NOs: 513 and 514, respectively; (78) the amino acid sequences of SEQ ID NOs: 515 and 516, respectively; (79) the amino acid sequences of SEQ ID NOs: 517 and 518, respectively; (80) the amino acid sequences of SEQ ID NOs: 519 and 520, respectively; (81) the amino acid sequences of SEQ ID NOs: 521 and 522, respectively. (82) the amino acid sequences of SEQ ID NOs: 523 and 524, respectively; (83) the amino acid sequences of SEQ ID NOs: 525 and 526, respectively; (84) the amino acid sequences of SEQ ID NOs: 527 and 528, respectively; (85) the amino acid sequences of SEQ ID NOs: 529 and 530, respectively; (86) the amino acid sequences of SEQ ID NOs: 531 and 532, respectively; (87) the amino acid sequences of SEQ ID NOs: 533 and 534, respectively; (88) the amino acid sequences of SEQ ID NOs: 535 and 536, respectively; (89) the amino acid sequences of SEQ ID NOs: 537 and 538, respectively;(90) the amino acid sequences of SEQ ID NOs: 539 and 540, respectively; (91) the amino acid sequences of SEQ ID NOs: 541 and 542, respectively; (92) the amino acid sequences of SEQ ID NOs: 543 and 544, respectively; (93) the amino acid sequences of SEQ ID NOs: 545 and 546, respectively; (94) the amino acid sequences of SEQ ID NOs: 547 and 548, respectively; (95) the amino acid sequences of SEQ ID NOs: 549 and 550, respectively; (96) the amino acid sequences of SEQ ID NOs: 551 and 552, respectively; (97) the amino acid sequences of SEQ ID NOs: 553 and 554, respectively; (98) the amino acid sequences The amino acid sequences of the sequence numbers 555 and 556, respectively, (99) the amino acid sequences of the sequence numbers 557 and 558, respectively, (100) the amino acid sequences of the sequence numbers 559 and 560, respectively, (101) the amino acid sequences of the sequence numbers 561 and 562, respectively, (102) the amino acid sequences of the sequence numbers 563 and 564, respectively, (103) the amino acid sequences of the sequence numbers 565 and 566, respectively, (104) the amino acid sequences of the sequence numbers 567 and 568, respectively, (105) the amino acid sequences of the sequence numbers 569 and 570, respectively, (106) The amino acid sequences of SEQ ID NOs: 571 and 572, respectively, (107) the amino acid sequences of SEQ ID NOs: 573 and 574, respectively, (108) the amino acid sequences of SEQ ID NOs: 575 and 576, respectively, (109) the amino acid sequences of SEQ ID NOs: 577 and 578, respectively, (110) the amino acid sequences of SEQ ID NOs: 579 and 580, respectively, (111) the amino acid sequences of SEQ ID NOs: 581 and 582, respectively, (112) the amino acid sequences of SEQ ID NOs: 583 and 584, respectively, (113) the amino acid sequences of SEQ ID NOs: 585 and 586, respectively, (1 (14) the amino acid sequences of SEQ ID NOs: 587 and 588, respectively; (115) the amino acid sequences of SEQ ID NOs: 589 and 590, respectively; (116) the amino acid sequences of SEQ ID NOs: 591 and 592, respectively; (117) the amino acid sequences of SEQ ID NOs: 593 and 594, respectively; (118) the amino acid sequences of SEQ ID NOs: 595 and 596, respectively; (119) the amino acid sequences of SEQ ID NOs: 597 and 598, respectively; (120) the amino acid sequences of SEQ ID NOs: 599 and 600, respectively; (121) the amino acid sequences of SEQ ID NOs: 601 and 602, respectively;(122) the amino acid sequences of SEQ ID NOs: 603 and 604, respectively; (123) the amino acid sequences of SEQ ID NOs: 605 and 606, respectively; (124) the amino acid sequences of SEQ ID NOs: 607 and 608, respectively; (125) the amino acid sequences of SEQ ID NOs: 609 and 610, respectively; (126) the amino acid sequences of SEQ ID NOs: 611 and 612, respectively; (127) the amino acid sequences of SEQ ID NOs: 613 and 614, respectively; (128) the amino acid sequences of SEQ ID NOs: 615 and 616, respectively; (129) the amino acid sequences of SEQ ID NOs: 617 and 618, respectively; (130) the amino acid sequences of SEQ ID NOs: 619 and 620, respectively; (131) the amino acid sequences of SEQ ID NOs: 621 and 622, respectively; (132) the amino acid sequences of SEQ ID NOs: 623 and 624, respectively; (133) the amino acid sequences of SEQ ID NOs: 625 and 626, respectively; (134) the amino acid sequences of SEQ ID NOs: 627 and 628, respectively; (135) the amino acid sequences of SEQ ID NOs: 629 and 630, respectively; (136) the amino acid sequences of SEQ ID NOs: 631 and 632, respectively; (137) the amino acid sequences of SEQ ID NOs: 633 and 634, respectively; (138) the amino acid sequences of SEQ ID NOs: 635 and 636, respectively; (139) the amino acid sequences of SEQ ID NOs: 637 and 638, respectively; (140) the amino acid sequences of SEQ ID NOs: 639 and 640, respectively; (141) the amino acid sequences of SEQ ID NOs: 641 and 642, respectively; (142) the amino acid sequences of SEQ ID NOs: 643 and 644, respectively; (143) the amino acid sequences of SEQ ID NOs: 645 and 646, respectively; (144) the amino acid sequences of SEQ ID NOs: 647 and 648, respectively; (145) the amino acid sequences of SEQ ID NOs: 649 and 650, respectively; (155) the amino acid sequences of SEQ ID NOs: 651 and 652, respectively; (156) the amino acid sequences of SEQ ID NOs: 653 and 654, respectively; (157) the amino acid sequences of SEQ ID NOs: 655 and 656, respectively; (158) the amino acid sequences of SEQ ID NOs: 657 and 658, respectively; (159) the amino acid sequences of SEQ ID NOs: 659 and 660, respectively; (160) the amino acid sequences of SEQ ID NOs: 661 and 662, respectively; (167) the amino acid sequences of SEQ ID NOs: 663 and 664, respectively; (168) the amino acid sequences of SEQ ID NOs: 665 and 666, respectively;(169) the amino acid sequences of SEQ ID NOs: 667 and 668, respectively; (170) the amino acid sequences of SEQ ID NOs: 669 and 670, respectively; (171) the amino acid sequences of SEQ ID NOs: 671 and 672, respectively; (172) the amino acid sequences of SEQ ID NOs: 673 and 674, respectively; (173) the amino acid sequences of SEQ ID NOs: 675 and 676, respectively; (174) the amino acid sequences of SEQ ID NOs: 677 and 678, respectively; (175) the amino acid sequences of SEQ ID NOs: 679 and 680, respectively; or VH and / or and variants thereof with up to about 5 amino acid substitutions in the VL.

[0132] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising a VH comprising VH CDR1, CDR2, and CDR3, and a VL comprising VL CDR1, CDR2, and CDR3, wherein the VH and VL are derived from an antibody comprising the VH and VL having the amino acid sequences set forth in the following SEQ ID NOs: (1) the amino acid sequences of SEQ ID NOs: 1 and 2, respectively; (2) the amino acid sequences of SEQ ID NOs: 3 and 4, respectively; (3) the amino acid sequences of SEQ ID NOs: 5 and 6, respectively; (4) the amino acid sequences of SEQ ID NOs: 7 and 8, respectively; (5) the amino acid sequences of SEQ ID NOs: 9 and 10, respectively; (6) the amino acid sequences of SEQ ID NOs: 11 and 12, respectively; (7) the amino acid sequences of SEQ ID NOs: 13 and 14, respectively; (8) the amino acid sequences of SEQ ID NOs: 15 and 16, respectively; (9) the amino acid sequences of SEQ ID NOs: 17 and 18, respectively; (10) the amino acid sequences of SEQ ID NOs: 19 and 20, respectively; (11) the amino acid sequences of SEQ ID NOs: 21 and 22, respectively; (12) the amino acid sequences of SEQ ID NOs: 23 and 24, respectively; (13) the amino acid sequences of SEQ ID NOs: 25 and 26, respectively; (14) the amino acid sequences of SEQ ID NOs: 27 and 28, respectively; (15) the amino acid sequences of SEQ ID NOs: 29 and 30, respectively; (16) the amino acid sequences of SEQ ID NOs: (17) the amino acid sequences of SEQ ID NOs: 33 and 34, respectively; (18) the amino acid sequences of SEQ ID NOs: 35 and 36, respectively; (19) the amino acid sequences of SEQ ID NOs: 37 and 38, respectively; (20) the amino acid sequences of SEQ ID NOs: 39 and 40, respectively; (21) the amino acid sequences of SEQ ID NOs: 41 and 42, respectively; (22) the amino acid sequences of SEQ ID NOs: 43 and 44, respectively; (23) the amino acid sequences of SEQ ID NOs: 45 and 46, respectively; (24) the amino acid sequences of SEQ ID NOs: 47 and 48, respectively; (25) the amino acid sequences of SEQ ID NOs: 49 and 50, respectively; (26) the amino acid sequences of SEQ ID NOs: 51 and 52, respectively; (27) the amino acid sequences of SEQ ID NOs: 53 and 54, respectively; (28) the amino acid sequences of SEQ ID NOs: 55 and 56, respectively; (29) the amino acid sequences of SEQ ID NOs: 57 and 58, respectively; (30) the amino acid sequences of SEQ ID NOs: 59 and 60, respectively;(31) The amino acid sequences of SEQ ID NOs: 61 and 62, respectively; (32) The amino acid sequences of SEQ ID NOs: 63 and 64, respectively; (33) The amino acid sequences of SEQ ID NOs: 65 and 66, respectively; (34) The amino acid sequences of SEQ ID NOs: 67 and 68, respectively; (35) The amino acid sequences of SEQ ID NOs: 251 and 252, respectively; (36) The amino acid sequences of SEQ ID NOs: 253 and 254, respectively; (37) The amino acid sequences of SEQ ID NOs: 255 and 256, respectively; (38) The amino acid sequences of SEQ ID NOs: 257 and 258, respectively; (39) The amino acid sequences of SEQ ID NOs: 259, respectively. and 260 amino acid sequences, (40) amino acid sequences of SEQ ID NOs: 261 and 262, respectively, (41) amino acid sequences of SEQ ID NOs: 263 and 264, respectively, (42) amino acid sequences of SEQ ID NOs: 265 and 266, respectively, (43) amino acid sequences of SEQ ID NOs: 267 and 268, respectively, (44) amino acid sequences of SEQ ID NOs: 269 and 270, respectively, (45) amino acid sequences of SEQ ID NOs: 271 and 272, respectively, (46) amino acid sequences of SEQ ID NOs: 273 and 274, respectively, (47) amino acid sequences of SEQ ID NOs: 275 and 276, respectively (48) the amino acid sequences of SEQ ID NOs: 277 and 278, respectively; (49) the amino acid sequences of SEQ ID NOs: 279 and 280, respectively; (50) the amino acid sequences of SEQ ID NOs: 281 and 282, respectively; (51) the amino acid sequences of SEQ ID NOs: 283 and 284, respectively; (52) the amino acid sequences of SEQ ID NOs: 285 and 286, respectively; (53) the amino acid sequences of SEQ ID NOs: 287 and 288, respectively; (54) the amino acid sequences of SEQ ID NOs: 289 and 290, respectively; (55) the amino acid sequences and sequences of any of SEQ ID NOs: 337 to 345. (56) an amino acid sequence having the number 346, (57) an amino acid sequence having the number 348 to 352 and an amino acid sequence having the number 353, (58) an amino acid sequence having the number 348 to 352 and an amino acid sequence having the number 354, (59) an amino acid sequence having the number 355 to 362 and an amino acid sequence having the number 363, (60) an amino acid sequence having the number 355 to 362 and an amino acid sequence having the number 364,(61) any of the amino acid sequences of SEQ ID NOs: 365 to 369 and the amino acid sequence of SEQ ID NO: 370, (62) any of the amino acid sequences of SEQ ID NOs: 365 to 369 and the amino acid sequence of SEQ ID NO: 371, (63) any of the amino acid sequences of SEQ ID NOs: 372 to 374 and the amino acid sequence of SEQ ID NOs: 375 to 377, (64) any of the amino acid sequences of SEQ ID NOs: 378 to 380 and the amino acid sequence of SEQ ID NO: 381, (65) any of the amino acid sequences of SEQ ID NOs: 378 to 380 and the amino acid sequence of SEQ ID NO: 382, (66 ) The amino acid sequence of any one of SEQ ID NOs: 383 to 385 and the amino acid sequence of SEQ ID NO: 386, (67) The amino acid sequence of any one of SEQ ID NOs: 383 to 385 and the amino acid sequence of SEQ ID NO: 387, (68) The amino acid sequences of SEQ ID NOs: 495 and 496, respectively, (69) The amino acid sequences of SEQ ID NOs: 497 and 498, respectively, (70) The amino acid sequences of SEQ ID NOs: 499 and 500, respectively, (71) The amino acid sequences of SEQ ID NOs: 501 and 502, respectively, (72) The amino acid sequences of SEQ ID NOs: 503 and 504, respectively, (73) The amino acid sequences of SEQ ID NOs: (74) the amino acid sequences of SEQ ID NOs: 507 and 508, respectively; (75) the amino acid sequences of SEQ ID NOs: 509 and 510, respectively; (76) the amino acid sequences of SEQ ID NOs: 511 and 512, respectively; (77) the amino acid sequences of SEQ ID NOs: 513 and 514, respectively; (78) the amino acid sequences of SEQ ID NOs: 515 and 516, respectively; (79) the amino acid sequences of SEQ ID NOs: 517 and 518, respectively; (80) the amino acid sequences of SEQ ID NOs: 519 and 520, respectively; (81) the amino acid sequences of SEQ ID NOs: 521 and 522, respectively; 522 amino acid sequence, (82) the amino acid sequence of SEQ ID NOs: 523 and 524, respectively, (83) the amino acid sequence of SEQ ID NOs: 525 and 526, respectively, (84) the amino acid sequence of SEQ ID NOs: 527 and 528, respectively, (85) the amino acid sequence of SEQ ID NOs: 529 and 530, respectively, (86) the amino acid sequence of SEQ ID NOs: 531 and 532, respectively, (87) the amino acid sequence of SEQ ID NOs: 533 and 534, respectively, (88) the amino acid sequence of SEQ ID NOs: 535 and 536, respectively, (89) the amino acid sequence of SEQ ID NOs: 537 and 538, respectively,(90) the amino acid sequences of SEQ ID NOs: 539 and 540, respectively; (91) the amino acid sequences of SEQ ID NOs: 541 and 542, respectively; (92) the amino acid sequences of SEQ ID NOs: 543 and 544, respectively; (93) the amino acid sequences of SEQ ID NOs: 545 and 546, respectively; (94) the amino acid sequences of SEQ ID NOs: 547 and 548, respectively; (95) the amino acid sequences of SEQ ID NOs: 549 and 550, respectively; (96) the amino acid sequences of SEQ ID NOs: 551 and 552, respectively; (97) the amino acid sequences of SEQ ID NOs: 553 and 554, respectively; (98) the amino acid sequences The amino acid sequences of the sequence numbers 555 and 556, respectively, (99) the amino acid sequences of the sequence numbers 557 and 558, respectively, (100) the amino acid sequences of the sequence numbers 559 and 560, respectively, (101) the amino acid sequences of the sequence numbers 561 and 562, respectively, (102) the amino acid sequences of the sequence numbers 563 and 564, respectively, (103) the amino acid sequences of the sequence numbers 565 and 566, respectively, (104) the amino acid sequences of the sequence numbers 567 and 568, respectively, (105) the amino acid sequences of the sequence numbers 569 and 570, respectively, (106) The amino acid sequences of SEQ ID NOs: 571 and 572, respectively, (107) the amino acid sequences of SEQ ID NOs: 573 and 574, respectively, (108) the amino acid sequences of SEQ ID NOs: 575 and 576, respectively, (109) the amino acid sequences of SEQ ID NOs: 577 and 578, respectively, (110) the amino acid sequences of SEQ ID NOs: 579 and 580, respectively, (111) the amino acid sequences of SEQ ID NOs: 581 and 582, respectively, (112) the amino acid sequences of SEQ ID NOs: 583 and 584, respectively, (113) the amino acid sequences of SEQ ID NOs: 585 and 586, respectively, (1 (14) the amino acid sequences of SEQ ID NOs: 587 and 588, respectively; (115) the amino acid sequences of SEQ ID NOs: 589 and 590, respectively; (116) the amino acid sequences of SEQ ID NOs: 591 and 592, respectively; (117) the amino acid sequences of SEQ ID NOs: 593 and 594, respectively; (118) the amino acid sequences of SEQ ID NOs: 595 and 596, respectively; (119) the amino acid sequences of SEQ ID NOs: 597 and 598, respectively; (120) the amino acid sequences of SEQ ID NOs: 599 and 600, respectively; (121) the amino acid sequences of SEQ ID NOs: 601 and 602, respectively;(122) the amino acid sequences of SEQ ID NOs: 603 and 604, respectively; (123) the amino acid sequences of SEQ ID NOs: 605 and 606, respectively; (124) the amino acid sequences of SEQ ID NOs: 607 and 608, respectively; (125) the amino acid sequences of SEQ ID NOs: 609 and 610, respectively; (126) the amino acid sequences of SEQ ID NOs: 611 and 612, respectively; (127) the amino acid sequences of SEQ ID NOs: 613 and 614, respectively; (128) the amino acid sequences of SEQ ID NOs: 615 and 616, respectively; (129) the amino acid sequences of SEQ ID NOs: 617 and 618, respectively; (130) the amino acid sequences of SEQ ID NOs: 619 and 620, respectively; (131) the amino acid sequences of SEQ ID NOs: 621 and 622, respectively; (132) the amino acid sequences of SEQ ID NOs: 623 and 624, respectively; (133) the amino acid sequences of SEQ ID NOs: 625 and 626, respectively; (134) the amino acid sequences of SEQ ID NOs: 627 and 628, respectively; (135) the amino acid sequences of SEQ ID NOs: 629 and 630, respectively; (136) the amino acid sequences of SEQ ID NOs: 631 and 632, respectively; (137) the amino acid sequences of SEQ ID NOs: 633 and 634, respectively; (138) the amino acid sequences of SEQ ID NOs: 635 and 636, respectively; (139) the amino acid sequences of SEQ ID NOs: 637 and 638, respectively; (140) the amino acid sequences of SEQ ID NOs: 639 and 640, respectively; (141) the amino acid sequences of SEQ ID NOs: 641 and 642, respectively; (142) the amino acid sequences of SEQ ID NOs: 643 and 644, respectively; (143) the amino acid sequences of SEQ ID NOs: 645 and 646, respectively; (144) the amino acid sequences of SEQ ID NOs: 647 and 648, respectively; (145) the amino acid sequences of SEQ ID NOs: 649 and 650, respectively; (155) the amino acid sequences of SEQ ID NOs: 651 and 652, respectively; (156) the amino acid sequences of SEQ ID NOs: 653 and 654, respectively; (157) the amino acid sequences of SEQ ID NOs: 655 and 656, respectively; (158) the amino acid sequences of SEQ ID NOs: 657 and 658, respectively; (159) the amino acid sequences of SEQ ID NOs: 659 and 660, respectively; (160) the amino acid sequences of SEQ ID NOs: 661 and 662, respectively; (167) the amino acid sequences of SEQ ID NOs: 663 and 664, respectively; (168) the amino acid sequences of SEQ ID NOs: 665 and 666, respectively;(169) The amino acid sequences of SEQ ID NOs: 667 and 668, respectively; (170) The amino acid sequences of SEQ ID NOs: 669 and 670, respectively; (171) The amino acid sequences of SEQ ID NOs: 671 and 672, respectively; (172) The amino acid sequences of SEQ ID NOs: 673 and 674, respectively; (173) The amino acid sequences of SEQ ID NOs: 675 and 676, respectively; (174) The amino acid sequences of SEQ ID NOs: 677 and 678, respectively; 678, (175) the amino acid sequences of SEQ ID NOs: 679 and 680, respectively.

[0133] The present invention further provides binding moieties that compete with the binding moiety for binding to claudin 18.2.

[0134] In some embodiments, the binding moieties disclosed herein do not bind to claudin 18.1 at detectable levels, and in some embodiments, the binding moieties disclosed herein bind to claudin 18.2 with an affinity that is at least 50-fold greater than its affinity for claudin 18.1.

[0135] In some embodiments, the binding moieties disclosed herein comprise or are antibodies. In some embodiments, the binding moieties disclosed herein comprise or are monoclonal antibodies. In some embodiments, the binding moieties disclosed herein comprise or are bispecific or multispecific antibodies. In some embodiments, the binding moieties provided herein are selected from the group consisting of a Fab, a Fab', a F(ab')2, a Fv, a scFv, and a(scFv)2. In some embodiments, the binding moieties provided herein are scFvs. In some embodiments, the binding moieties provided herein are IgG1, IgG2, IgG3, or IgG4 antibodies. In some embodiments, the binding moieties provided herein are chimeric, humanized, or human antibodies, or antigen-binding fragments thereof. In some embodiments, the binding moieties provided herein are humanized antibodies.

[0136] The antibodies described herein may comprise a heavy chain constant region linked to the C-terminus of the heavy chain variable region and / or a light chain constant region linked to the C-terminus of the light chain variable region. The heavy chain constant region may be, for example, a human IgG1 heavy chain constant region having the amino acid sequence set forth in SEQ ID NO: 388. The light chain constant region may be, for example, a human kappa light chain constant region having the amino acid sequence set forth in SEQ ID NO: 389.

[0137] In some embodiments, the invention provides polynucleotides encoding the binding moieties described herein. In some embodiments, the invention provides vectors comprising the polynucleotides described herein.

[0138] In some embodiments, the present invention provides an isolated cell comprising a polynucleotide described herein. In some embodiments, the present invention provides an isolated cell comprising a vector described herein.

[0139] In another aspect, the present invention provides a chimeric antigen receptor (CAR) comprising an anti-claudin 18.2 single-chain variable fragment (scFv), which comprises the heavy / light chain variable regions of a CDR or claudin 18.2 binding moiety as described herein.

[0140] In some embodiments, the anti-claudin 18.2 CAR comprises (a) an extracellular antigen-binding domain comprising an anti-claudin 18.2 single-chain variable fragment (scFv) comprising the CDRs or heavy / light chain variable regions of a claudin 18.2 binding moiety as described above, (b) a transmembrane domain, and (c) an intracellular signaling domain.

[0141] In some embodiments, the CAR comprises a heavy chain variable region having a VH CDR1, CDR2, and CDR3, and a light chain variable region having a VL CDR1, CDR2, and CDR3, wherein the VH CDR1, CDR2, CDR3 and the VL CDR1, CDR2, CDR3 comprise the amino acid sequences set forth in the following SEQ ID NOs: (1) SEQ ID NOs: 69, 89, 117, 136, 143, and 150, (2) SEQ ID NOs: 69, 90, 117, 137, 143, and 151, (3) SEQ ID NOs: 69, 90, 117, 137, 143, and 151, (4) SEQ ID NOs: 70, 90, 117, 136, 143, and 152, (5) SEQ ID NOs: 69, 91, 117, 137, 143, and 153, (6) SEQ ID NOs: 71, 92, 117, 136, 143, and 154, (7) SEQ ID NOs: 71, 92, 117, 13 6, 143 and 154, (8) SEQ ID NOs: 72, 93, 117, 136, 143 and 155, (9) SEQ ID NOs: 69, 94, 118, 136, 143 and 156, (10) SEQ ID NOs: 73, 95, 117, 137, 143 and 157, (11) SEQ ID NOs: 74, 96, 119, 136, 144 and 158, (12) SEQ ID NOs: 74, 96, 119, 136, 144 and 158, (13) SEQ ID NOs: 70, 97, 120, 138, 145 and 159, (14) SEQ ID NOs: 70, 98, 120, 136, 145 and 160, (15) SEQ ID NOs: 75, 99, 120, 139, 146 and 160, (16) SEQ ID NOs: 75, 100, 120, 139, 146 and 160, (17) SEQ ID NOs: 70, 90, 121, 137, 145 and 160, (18) SEQ ID NOs: 76, 101, 122, 140, 147 and 160, (19) SEQ ID NOs: 76, 101, 123, 136, 147 and 160, (20) SEQ ID NOs: 70, 201 , 120, 137, 145 and 160, (21) SEQ ID NOs: 70, 202, 120, 136, 145 and 160, (22) SEQ ID NOs: 77, 102, 124, 141, 148 and 161, (23) SEQ ID NOs: 78, 103, 125, 136, 143 and 162, (24) SEQ ID NOs: 79, 104, 126, 136, 149 and 163, (25) SEQ ID NOs: 78, 105, 127, 142, 143 and 164, (26) SEQ ID NOs: 80, 106, 128, 136,143 and 165, (27) SEQ ID NOs: 81, 107, 129, 136, 143 and 166, (28) SEQ ID NOs: 82, 108, 130, 136, 143 and 167, (29) SEQ ID NOs: 80, 109, 130, 141, 143 and 168, (30) SEQ ID NOs: 83, 110, 130, 136, 143 and 169, (31) SEQ ID NOs: 80, 109, 131, 141, 143 and 170, (32) SEQ ID NOs: 80, 111, 132, 136, 143 and 160, (33) SEQ ID NOs: 84, 112, 132, 136, 143 and 171, (3 4) SEQ ID NOs: 85, 113, 133, 136, 143, and 172, (35) SEQ ID NOs: 86, 114, 134, 136, 143, and 172, (36) SEQ ID NOs: 87, 115, 131, 136, 143, and 167, (37) SEQ ID NOs: 88, 116, 135, 136, 143, and 173, (38) SEQ ID NOs: 203, 211, 225, 233, 241, and 242, (39) SEQ ID NOs: 204, 212, 226, 136, 143, and 243, (40) SEQ ID NOs: 205, 213, 227, 234, 143, and 244, (41) SEQ ID NO: 20 6, 214, 131, 235, 143 and 245, (42) SEQ ID NOs: 207, 215, 228, 136, 143 and 163, (43) SEQ ID NOs: 208, 216, 229, 236, 143 and 246, (44) SEQ ID NOs: 69, 90, 230, 237, 143 and 151, (45) SEQ ID NOs: 69, 217, 117, 137, 143 and 247, (46) SEQ ID NOs: 209, 218, 231, 136, 143 and 248, (47) SEQ ID NOs: 72, 219, 117, 238, 143 and 157, (48) SEQ ID NOs: 75, 220, 120, 137, 145 and 160, (49) SEQ ID NOs: 69, 221, 117, 136, 143 and 150, (50) SEQ ID NOs: 72, 222, 118, 136, 143 and 151, (51) SEQ ID NOs: 69, 223, 118, 239, 143 and 249, (52) SEQ ID NOs: 210, 224, 232, 240, 143 and 245, (53) SEQ ID NOs: 72, 217, 118, 136, 143 and 250, (54) SEQ ID NOs: 69, 90, 117, 137, 143 and 153, (55) SEQ ID NOs: 74, 96, 130, 136, 144 and 158,(56) SEQ ID NOs: 69, 202, 118, 136, 143, and 455, (57) SEQ ID NOs: 72, 90, 117, 137, 143, and 153, (58) SEQ ID NOs: 69, 390, 118, 136, 143, and 249, (59) SEQ ID NOs: 209, 103, 125, 136, 143, and 162, (60) SEQ ID NOs: 81, 391, 129, 136, 143, and 162, (61) SEQ ID NOs: 80, 109, 131, 141, 143, and 167, (62) SEQ ID NOs: 81, 107, 129, 141, 143, and 166, (63) SEQ ID NOs: Sequence numbers: 85, 113, 133, 136, 143, and 172, (64) SEQ ID NOs: 392, 393, 394, 136, 143, and 163, (65) SEQ ID NOs: 392, 395, 396, 136, 143, and 163, (66) SEQ ID NOs: 397, 398, 399, 456, 457, and 250, (67) SEQ ID NOs: 75, 400, 120, 458, 146, and 160, (68) SEQ ID NOs: 70, 401, 120, 136, 145, and 160, (69) SEQ ID NOs: 402, 403, 404, 240, 143, and 244, (70) Sequence Sequence numbers: 69, 219, 117, 137, 143, and 157, (71) Sequence numbers: 71, 405, 117, 136, 143, and 459, (72) Sequence numbers: 406, 407, 408, 460, 461, and 462, (73) Sequence numbers: 69, 90, 117, 137, 463, and 464, (74) Sequence numbers: 409, 410, 411, 465, 466, and 162, (75) Sequence numbers: 69, 219, 416, 137, 143, and 157, (76) Sequence numbers: 76, 412, 411, 140, 147, and 160, (77) Sequence number: 4 13, 414, 415, 136, 143, and 467, (78) SEQ ID NOs: 417, 418, 232, 136, 143, and 244, (79) SEQ ID NOs: 69, 419, 420, 136, 143, and 468, (80) SEQ ID NOs: 205, 421, 422, 136, 143, and 469, (81) SEQ ID NOs: 205, 423, 424, 136, 143, and 154, (82) SEQ ID NOs: 81, 391, 129, 240, 143, and 166, (83) SEQ ID NOs: 88, 425, 135, 136, 143, and 470, (84) SEQ ID NO: 81,426, 129, 136, 143, and 166, (85) SEQ ID NOs: 80, 109, 130, 136, 143, and 471, (86) SEQ ID NOs: 427, 428, 429, 472, 473, and 474, (87) SEQ ID NOs: 81, 391, 129, 475, 143, and 166, (88) SEQ ID NOs: 430, 391, 431, 476, 143, and 166, (89) SEQ ID NOs: 80, 109, 129, 136, 143, and 477, (90) SEQ ID NOs: 80, 391, 129, 478, 143, and 166, (91) SEQ ID NOs: 81, 432, 129, 475, 143, and 166, (92) SEQ ID NOs: 433, 391, 129, 475, 143, and 166, (93) SEQ ID NOs: 80, 109, 129, 479, 143, and 163, (94) SEQ ID NOs: 434, 435, 129, 240, 143, and 166, (95) SEQ ID NOs: 436, 428, 429, 472, 473, and 474, (96) SEQ ID NOs: 80, 437, 129, 479, 143, and 163, (97) SEQ ID NOs: : 81, 391, 129, 478, 143, and 166, (98) SEQ ID NOs: 81, 438, 129, 136, 143, and 166, (99) SEQ ID NOs: 81, 391, 129, 480, 143, and 481, (100) SEQ ID NOs: 80, 439, 441, 482, 143, and 483, (101) SEQ ID NOs: 433, 391, 431, 475, 143, and 166, (102) SEQ ID NOs: 80, 442, 443, 136, 143, and 160, (103) SEQ ID NOs: 80, 440, 441, 4 82, 143, and 484, (104) SEQ ID NOs: 444, 445, 446, 485, 486, and 487, (105) SEQ ID NOs: 447, 448, 449, 488, 489, and 490, (106) SEQ ID NOs: 450, 451, 452, 491, 492, and 493, (107) SEQ ID NOs: 81, 453, 129, 136, 143, and 166, or (108) SEQ ID NOs: 69, 89, 454, 136, 143, and 494, or variants thereof having up to about five amino acid substitutions in the CDRs.

[0142] In some embodiments, the CAR comprises a heavy chain variable region having the amino acid sequence set forth in any of odd-numbered SEQ ID NOS: 1-68, 251-290, and 495-680, and odd- and even-numbered SEQ ID NOS: 337-345, 348-352, 355-362, 365-369, 372-374, 378-380, and 383-385, and a light chain variable region having the amino acid sequence set forth in any of even-numbered SEQ ID NOS: 1-68, 251-290, 495-680, and SEQ ID NOS: 346, 347, 353, 354, 363, 364, 370, 371, 375, 376, 377, 381, 382, 386, and 387. In some embodiments, the CAR comprises heavy chain variable regions and light chain variable regions having the amino acid sequences set forth in the following SEQ ID NOS: (1) SEQ ID NO: 1, 2, (2) SEQ ID NO: 3, 4, (3) SEQ ID NO: 5, 6, (4) SEQ ID NO: 7, 8, (5) SEQ ID NO: 9, 10, (6) SEQ ID NO: 11, 12, (7) SEQ ID NO: 13, 14, (8) SEQ ID NO: 15, 16, (9) SEQ ID NO: 17, 18, (10) SEQ ID NO: 19, 20, (11) SEQ ID NO: 21, 22, (12) SEQ ID NO: 23, 24, (13 ) SEQ ID NO: 25, 26, (14) SEQ ID NO: 27, 28, (15) SEQ ID NO: 29, 30, (16) SEQ ID NO: 31, 32, (17) SEQ ID NO: 33, 34, (18) SEQ ID NO: 35, 36, (19) SEQ ID NO: 37, 38, (20) SEQ ID NO: 39, 40, (21) SEQ ID NO: 41, 42, (22) SEQ ID NO: 43, 44, (23) SEQ ID NO: 45, 46, (24) SEQ ID NO: 47, 48, (25) SEQ ID NO: 49, 50, (26) SEQ ID NO: 51, 52, (27) SEQ ID NO: 53, 54, (28) SEQ ID NO: 55, 56, (29) SEQ ID NO: 57, 58, (30) SEQ ID NO: 59, 60, (31) SEQ ID NO: 61, 62, (32) SEQ ID NO: 63, 64, (33) SEQ ID NO: 65, 66, (34) SEQ ID NO: 67, 68, (35) SEQ ID NO: 251, 252, (36) SEQ ID NO: 253, 254, (37) SEQ ID NO: 255, 256, (38) SEQ ID NO: 257, 258, (39) SEQ ID NO: 259, 260, (40) SEQ ID NO: 261, 262, (41) SEQ ID NO: 263, 264, (42) SEQ ID NO: 265, 266, (43) SEQ ID NO: 267, 268, (44) SEQ ID NO: 269, 270,(45) SEQ ID NOs: 271, 272, (46) SEQ ID NOs: 273, 274, (47) SEQ ID NOs: 275, 276, (48) SEQ ID NOs: 277, 278, (49) SEQ ID NOs: 279, 280, (50) SEQ ID NOs: 281, 282, (51) SEQ ID NOs: 283, 284, (52) SEQ ID NOs: 285, 286, (53) SEQ ID NOs: 287, 288, (54) SEQ ID NOs: 289, 290, (55) any of SEQ ID NOs: 337 to 345 and SEQ ID NO: 346, (56) any of SEQ ID NOs: 337 to 345 and SEQ ID NO: 347, (57) any of SEQ ID NOs: 348 to 352 (58) any of SEQ ID NOs: 348 to 352 and SEQ ID NO: 354, (59) any of SEQ ID NOs: 355 to 362 and SEQ ID NO: 363, (60) any of SEQ ID NOs: 355 to 362 and SEQ ID NO: 364, (61) any of SEQ ID NOs: 365 to 369 and SEQ ID NO: 370, (62) any of SEQ ID NOs: 365 to 369 and SEQ ID NO: 371, (63) any of SEQ ID NOs: 372 to 374 and SEQ ID NOs: 375 to 377, (64) any of SEQ ID NOs: 378 to 380 and SEQ ID NO: 381, (65) SEQ ID NOs: 378 to 38 0 and SEQ ID NO: 382, (66) any of SEQ ID NOs: 383 to 385 and SEQ ID NO: 386, (67) any of SEQ ID NOs: 383 to 385 and SEQ ID NO: 387, (68) the amino acid sequences of SEQ ID NOs: 495 and 496, respectively, (69) the amino acid sequences of SEQ ID NOs: 497 and 498, respectively, (70) the amino acid sequences of SEQ ID NOs: 499 and 500, respectively, (71) the amino acid sequences of SEQ ID NOs: 501 and 502, respectively, (72) the amino acid sequences of SEQ ID NOs: 503 and 504, respectively, (73) the amino acid sequences of SEQ ID NOs: 505 and 506, respectively 06, (74) the amino acid sequences of SEQ ID NOs: 507 and 508, respectively, (75) the amino acid sequences of SEQ ID NOs: 509 and 510, respectively, (76) the amino acid sequences of SEQ ID NOs: 511 and 512, respectively, (77) the amino acid sequences of SEQ ID NOs: 513 and 514, respectively, (78) the amino acid sequences of SEQ ID NOs: 515 and 516, respectively, (79) the amino acid sequences of SEQ ID NOs: 517 and 518, respectively, (80) the amino acid sequences of SEQ ID NOs: 519 and 520, respectively, (81) the amino acid sequences of SEQ ID NOs: 521 and 522, respectively,(82) The amino acid sequences of SEQ ID NOs: 523 and 524, respectively; (83) The amino acid sequences of SEQ ID NOs: 525 and 526, respectively; (84) The amino acid sequences of SEQ ID NOs: 527 and 528, respectively; (85) The amino acid sequences of SEQ ID NOs: 529 and 530, respectively; (86) The amino acid sequences of SEQ ID NOs: 531 and 532, respectively; (87) The amino acid sequences of SEQ ID NOs: 533 and 534, respectively; (88) The amino acid sequences of SEQ ID NOs: 535 and 536, respectively; (89) The amino acid sequences of SEQ ID NOs: 537 and 538, respectively; (90 ) the amino acid sequences of SEQ ID NOs: 539 and 540, respectively; (91) the amino acid sequences of SEQ ID NOs: 541 and 542, respectively; (92) the amino acid sequences of SEQ ID NOs: 543 and 544, respectively; (93) the amino acid sequences of SEQ ID NOs: 545 and 546, respectively; (94) the amino acid sequences of SEQ ID NOs: 547 and 548, respectively; (95) the amino acid sequences of SEQ ID NOs: 549 and 550, respectively; (96) the amino acid sequences of SEQ ID NOs: 551 and 552, respectively; (97) the amino acid sequences of SEQ ID NOs: 553 and 554, respectively; (98) the amino acid sequences of SEQ ID NOs: (99) the amino acid sequences of SEQ ID NOs: 557 and 558, respectively; (100) the amino acid sequences of SEQ ID NOs: 559 and 560, respectively; (101) the amino acid sequences of SEQ ID NOs: 561 and 562, respectively; (102) the amino acid sequences of SEQ ID NOs: 563 and 564, respectively; (103) the amino acid sequences of SEQ ID NOs: 565 and 566, respectively; (104) the amino acid sequences of SEQ ID NOs: 567 and 568, respectively; (105) the amino acid sequences of SEQ ID NOs: 569 and 570, respectively; (106 ) the amino acid sequences of SEQ ID NOs: 571 and 572, respectively; (107) the amino acid sequences of SEQ ID NOs: 573 and 574, respectively; (108) the amino acid sequences of SEQ ID NOs: 575 and 576, respectively; (109) the amino acid sequences of SEQ ID NOs: 577 and 578, respectively; (110) the amino acid sequences of SEQ ID NOs: 579 and 580, respectively; (111) the amino acid sequences of SEQ ID NOs: 581 and 582, respectively; (112) the amino acid sequences of SEQ ID NOs: 583 and 584, respectively; (113) the amino acid sequences of SEQ ID NOs: 585 and 586, respectively;(114) The amino acid sequences of SEQ ID NOs: 587 and 588, respectively; (115) The amino acid sequences of SEQ ID NOs: 589 and 590, respectively; (116) The amino acid sequences of SEQ ID NOs: 591 and 592, respectively; (117) The amino acid sequences of SEQ ID NOs: 593 and 594, respectively; (118) The amino acid sequences of SEQ ID NOs: 595 and 596, respectively; (119) The amino acid sequences of SEQ ID NOs: 597 and 598, respectively; (120) The amino acid sequences of SEQ ID NOs: 599 and 600, respectively; (121) The amino acid sequences of SEQ ID NOs: 601 and 602, respectively; (122) the amino acid sequences of SEQ ID NOs: 603 and 604, respectively; (123) the amino acid sequences of SEQ ID NOs: 605 and 606, respectively; (124) the amino acid sequences of SEQ ID NOs: 607 and 608, respectively; (125) the amino acid sequences of SEQ ID NOs: 609 and 610, respectively; (126) the amino acid sequences of SEQ ID NOs: 611 and 612, respectively; (127) the amino acid sequences of SEQ ID NOs: 613 and 614, respectively; (128) the amino acid sequences of SEQ ID NOs: 615 and 616, respectively; (129) the amino acid sequences of SEQ ID NOs: 617 and 618, respectively; (130) the amino acid sequences of SEQ ID NOs: 619 and 620, respectively; (131) the amino acid sequences of SEQ ID NOs: 621 and 622, respectively; (132) the amino acid sequences of SEQ ID NOs: 623 and 624, respectively; (133) the amino acid sequences of SEQ ID NOs: 625 and 626, respectively; (134) the amino acid sequences of SEQ ID NOs: 627 and 628, respectively; (135) the amino acid sequences of SEQ ID NOs: 629 and 630, respectively; (136) the amino acid sequences of SEQ ID NOs: 631 and 632, respectively; (137) the amino acid sequences of SEQ ID NOs: 633 and 634, respectively; (138) the amino acid sequences of SEQ ID NOs: 635 and 636, respectively; (139) the amino acid sequences of SEQ ID NOs: 637 and 638, respectively; (140) the amino acid sequences of SEQ ID NOs: 639 and 640, respectively; (141) the amino acid sequences of SEQ ID NOs: 641 and 642, respectively; (142) the amino acid sequences of SEQ ID NOs: 643 and 644, respectively; (143) the amino acid sequences of SEQ ID NOs: 645 and 646, respectively; (144) the amino acid sequences of SEQ ID NOs: 647 and 648, respectively; (145) the amino acid sequences of SEQ ID NOs: 649 and 650, respectively;(155) the amino acid sequences of SEQ ID NOs: 651 and 652, respectively; (156) the amino acid sequences of SEQ ID NOs: 653 and 654, respectively; (157) the amino acid sequences of SEQ ID NOs: 655 and 656, respectively; (158) the amino acid sequences of SEQ ID NOs: 657 and 658, respectively; (159) the amino acid sequences of SEQ ID NOs: 659 and 660, respectively; (160) the amino acid sequences of SEQ ID NOs: 661 and 662, respectively; (167) the amino acid sequences of SEQ ID NOs: 663 and 664, respectively; (168) the amino acid sequences of SEQ ID NOs: 6 65 and 666, (169) the amino acid sequences of SEQ ID NOs: 667 and 668, respectively, (170) the amino acid sequences of SEQ ID NOs: 669 and 670, respectively, (171) the amino acid sequences of SEQ ID NOs: 671 and 672, respectively, (172) the amino acid sequences of SEQ ID NOs: 673 and 674, respectively, (173) the amino acid sequences of SEQ ID NOs: 675 and 676, respectively, (174) the amino acid sequences of SEQ ID NOs: 677 and 678, respectively, (175) the amino acid sequences of SEQ ID NOs: 679 and 680, respectively.

[0143] In some embodiments, the CAR comprises a heavy chain variable region and a light chain variable region having the amino acid sequences set forth in the following SEQ ID NOs: (1) SEQ ID NO: 251, 252, (2) SEQ ID NO: 253, 254, (3) SEQ ID NO: 67, 68, (4) SEQ ID NO: 255, 256, (5) SEQ ID NO: 257, 258, (6) SEQ ID NO: 43, 44, (7) SEQ ID NO: 27, 28, (8) SEQ ID NO: 13, 14, (9) SEQ ID NO: 9, 10, (10) SEQ ID NO: 3, 4, (11) SEQ ID NO: 35, 36, (12) SEQ ID NO: 15, 16, (13) SEQ ID NO: 1, 2, (14) SEQ ID NO: 17, 18, (15) SEQ ID NO: 21, 22, (16) SEQ ID NO: 37, 38, (17) SEQ ID NO: 41, 42, (18) SEQ ID NO: 259, 260, (19) SEQ ID NO: 25, 26, (20) SEQ ID NO: 31 , 32, (21) SEQ ID NO: 23, 24, (22) SEQ ID NO: 261, 262, (23) SEQ ID NO: 263, 264, (24) SEQ ID NO: 29, 30, (25) SEQ ID NO: 265, 266, (26) SEQ ID NO: 267, 268, (27) SEQ ID NO: 269, 270, (28) SEQ ID NO: 271, 272, (29) SEQ ID NO: 273, 274, (30) SEQ ID NO: 275, 276, (31) SEQ ID NO: 277, 278, (32) SEQ ID NO: 279, 280, (33) SEQ ID NO: 281, 282, (34) SEQ ID NO: 283, 284, (35) SEQ ID NO: 285, 286, (36) SEQ ID NO: 287, 288, or (37) SEQ ID NO: 289, 290.

[0144] In some embodiments, the anti-claudin 18.2 scFv comprises a heavy chain variable region and a light chain variable region connected by a linker. In some embodiments, the linker is a short linker peptide rich in glycine and serine or threonine and having approximately 10 to 25 amino acids (e.g., a linker having the amino acid sequence of SEQ ID NO: 297). In some embodiments, the linker is connected to the N-terminus of the heavy chain variable region and the C-terminus of the light chain variable region, or vice versa. In some embodiments, the CAR comprises one or more scFvs targeting the same or different antigens. Two scFvs within one CAR may be formed as a tandem di-scFv or diabody, and three scFvs may be formed as a tandem tri-scFv or tribody.

[0145] In some embodiments, the extracellular antigen-binding domain further comprises a signal peptide at its N-terminus. In some embodiments, the signal peptide may be derived from a molecule selected from the group consisting of CD8α, GM-CSF receptor α, and IgG1 heavy chain. In some embodiments, the signal peptide is derived from CD8α. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 291.

[0146] In some embodiments, the extracellular antigen-binding domain further comprises a hinge domain at its C-terminus. In some embodiments, the hinge domain is derived from CD8α. In some embodiments, the hinge domain comprises the amino acid sequence of SEQ ID NO: 292.

[0147] In some embodiments, the transmembrane domain is derived from a molecule selected from the group consisting of CD8α, CD4, CD28, CD137, CD80, CD86, CD152, and PD1. In some embodiments, the transmembrane domain is derived from CD8α or CD28. In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 293.

[0148] In some embodiments, the intracellular signaling domain comprises a primary intracellular signaling domain and a costimulatory signaling domain. In some embodiments, the primary intracellular signaling domain is an immunoreceptor tyrosine-based activation motif (ITAM)-containing domain. In some embodiments, the ITAM-containing domain is the cytoplasmic domain of CD3-zeta, which can have the amino acid sequence of SEQ ID NO: 296. In some embodiments, the costimulatory signaling domain is derived from a costimulatory molecule selected from the group consisting of CD27, CD28, CD137, OX40, CD30, CD40, CD3, LFA-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand of CD83, and combinations thereof. In some embodiments, the costimulatory signaling domain comprises the cytoplasmic domain of CD28 and / or the cytoplasmic domain of CD137. The cytoplasmic domain of CD28 and the cytoplasmic domain of CD137 can comprise the amino acid sequences of SEQ ID NOs: 294 and 295, respectively.

[0149] In some embodiments, the CAR comprises, from N-terminus to C-terminus, in order: a signal peptide of SEQ ID NO: 291; the aforementioned light chain variable region and heavy chain variable region of a claudin-18.2 binding moiety connected to a linker of SEQ ID NO: 297; a linker of SEQ ID NO: 298; a hinge of SEQ ID NO: 292; a CD137 cytoplasmic domain of SEQ ID NO: 294; and a CD3-zeta cytoplasmic domain of SEQ ID NO: 296.

[0150] In some embodiments, the CAR comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to any of the amino acid sequences of SEQ ID NOs: 299 to 335. In some embodiments, the CAR comprises an amino acid sequence of any of SEQ ID NOs: 299 to 335.

[0151] The present invention provides a nucleic acid encoding a CAR described herein. The present invention also provides a vector comprising any of the above-mentioned isolated nucleic acids. In some embodiments, the vector is an expression vector. In some embodiments, the vector is a viral vector, a lentiviral vector, or a non-viral vector.

[0152] The present invention provides a genetically engineered immune cell comprising any of the above-mentioned CARs, any of the above-mentioned isolated nucleic acids, or any of the above-mentioned vectors. In some embodiments, the immune cell is a T cell, a NK cell, a peripheral blood mononuclear cell (PBMC), a hematopoietic stem cell, a pluripotent stem cell, or an embryonic stem cell. In some embodiments, the immune cell is a T cell, such as a cytotoxic T cell, a helper T cell, a natural killer T cell, or a γδ T cell.

[0153] In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a binding moiety or an aforementioned CAR, and a pharmaceutically acceptable carrier.

[0154] The present invention also provides a method for treating a tumor or cancer that expresses claudin 18.2 in a subject in need thereof by administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

[0155] In some embodiments, the tumor or cancer expressing claudin 18.2 is a stomach, esophageal, gastroesophageal, pancreatic, ovarian, or lung tumor or cancer. In some embodiments, the tumor or cancer expressing claudin 18.2 is a gastric tumor or cancer. In some embodiments, the tumor or cancer expressing claudin 18.2 is a gastroesophageal tumor or cancer.

[0156] In some embodiments, the subject is a human.

[0157] In some embodiments, the genetically engineered immune cells for treating tumors or cancer are autologous. In some embodiments, the genetically engineered immune cells are allogeneic. [Brief explanation of the drawings]

[0158] [Figure 1-1] Figures 1A-1H: Non-humanized claudin 18.2 antibody ELISA assay showing the binding ability of indicator antibodies to claudin 18.2-His protein by indirect ELISA plotted against the logarithm of antibody concentration (ng / ml). [Figure 1-2] Figures 1I-1O: Non-humanized claudin 18.2 antibody ELISA assay showing the binding ability of indicator antibodies to claudin 18.2-His protein by indirect ELISA plotted against the logarithm of antibody concentration (ng / ml). [Figure 2-1] Figures 2A-2H: Non-humanized claudin 18.2 antibody-induced complement-dependent cytotoxicity (CDC) assay showing lysis of CHO-K1 target cells overexpressing human claudin 18.2 after incubation with the indicator antibody. IMAB362 (claudiximab) antibody was used as a positive control. Results are plotted as percent target cell lysis as a function of log antibody concentration (µg / ml). [Figure 2-2] Figures 2I-2P: Non-humanized claudin 18.2 antibody-induced complement-dependent cytotoxicity (CDC) assay showing lysis of CHO-K1 target cells overexpressing human claudin 18.2 after incubation with the indicator antibody. IMAB362 (claudiximab) antibody was used as a positive control. Results are plotted as percent target cell lysis as a function of log antibody concentration (µg / ml). [Figure 3-1]Figures 3A-3C: Non-humanized claudin 18.2 antibody cell-based ELISA assay showing binding of the indicator antibody to a HEK293T stable cell line expressing claudin 18.2 plotted against the logarithm of antibody concentration (nMol / L). IMAB362 (Claudiximab), mouse IgG, and human IgG1Fc served as controls. [Figure 3-2] Figures 3D-3F: Non-humanized claudin 18.2 antibody cell-based ELISA assay showing binding of the index antibody to a HEK293T stable cell line expressing claudin 18.2 plotted against the logarithm of antibody concentration (nMol / L). IMAB362 (Claudiximab), mouse IgG, and human IgG1Fc served as controls. [Figure 3-3] Figures 3G-3I: Non-humanized claudin 18.2 antibody cell-based ELISA assay showing binding of the index antibody to a HEK293T stable cell line expressing claudin 18.2 plotted against the logarithm of antibody concentration (nMol / L). IMAB362 (Claudiximab), mouse IgG, and human IgG1Fc served as controls. [Figure 3-4] Figures 3J-3L: Non-humanized claudin 18.2 antibody cell-based ELISA assay showing binding of the index antibody to a HEK293T stable cell line expressing claudin 18.2 plotted against the logarithm of antibody concentration (nMol / L). IMAB362 (Claudiximab), mouse IgG, and human IgG1Fc served as controls. [Figure 3-5] Figures 3M-3O: Non-humanized claudin 18.2 antibody cell-based ELISA assay showing binding of the index antibody to a HEK293T stable cell line expressing claudin 18.2 plotted against the logarithm of antibody concentration (nMol / L). IMAB362 (Claudiximab), mouse IgG, and human IgG1Fc served as controls. [Figure 3-6]Figures 3P-3Q: Non-humanized claudin 18.2 antibody cell-based ELISA assay showing binding of the index antibody to a HEK293T stable cell line expressing claudin 18.2 plotted against the logarithm of antibody concentration (nMol / L). IMAB362 (Claudiximab), mouse IgG, and human IgG1Fc served as controls. [Figure 4] Figures 4A-4C: Chimeric antibody FACS binding assay showing binding of the indicator chimeric antibodies to HEK293 cells expressing claudin 18.2 as a function of the logarithm of antibody concentration (nM). IMAB362 (Claudiximab) and human IgG served as controls. [Figure 5] Figures 5A-5C: Chimeric antibody CDC induction assay showing lysis of CHO-K1 target cells overexpressing human claudin 18.2 after incubation with the indicated chimeric antibody. Results are plotted as percent target cell lysis as a function of log antibody concentration (µg / ml). IMAB362 (Claudiximab) and human IgG served as controls. [Figure 6-1] Figures 6A-6F: Chimeric antibody-dependent cellular cytotoxicity (ADCC) induction assay showing the percent lysis of CHO-K1 target cells overexpressing human claudin 18.2 after incubation with indicator antibodies and freshly isolated human PBMCs. Results are plotted as the percent target cell lysis as a function of log antibody concentration (µg / ml). IMAB362 (Claudiximab) and human IgG served as controls. [Figure 6-2] Figures 6G-6J: Chimeric antibody-dependent cellular cytotoxicity (ADCC) induction assay showing the percent lysis of CHO-K1 target cells overexpressing human claudin 18.2 after incubation with the indicator antibody and freshly isolated human PBMCs. Results are plotted as the percent target cell lysis as a function of log antibody concentration (µg / ml). IMAB362 (Claudiximab) and human IgG served as controls. [Figure 7-1]Figures 7A-7C: Humanized antibody FACS binding assay showing binding of index humanized antibodies to HEK293 cells expressing claudin 18.2 as a function of log antibody concentration (nM). IMAB362 (Claudiximab) and human IgG served as controls. [Figure 7-2] Figures 7D-7G: Humanized antibody FACS binding assays showing binding of index humanized antibodies to HEK293 cells expressing claudin 18.2 as a function of log antibody concentration (nM). IMAB362 (Claudiximab) and human IgG served as controls. [Figure 8-1] Figures 8A-8C: Humanized antibody CDC induction assay showing lysis of CHO-K1 target cells overexpressing human claudin 18.2 after incubation with the indicated chimeric antibody. Results are plotted as percent target cell lysis as a function of log antibody concentration (µg / ml). IMAB362 (Claudiximab) and human IgG served as controls. [Figure 8-2] Figures 8D-8F: Humanized antibody CDC induction assay showing lysis of CHO-K1 target cells overexpressing human claudin 18.2 after incubation with the indicated chimeric antibody. Results are plotted as percent target cell lysis as a function of log antibody concentration (µg / ml). IMAB362 (Claudiximab) and human IgG served as controls. [Figure 8-3] Figures 8G-8H: Humanized antibody CDC induction assay showing lysis of CHO-K1 target cells overexpressing human claudin 18.2 after incubation with the indicated chimeric antibody. Results are plotted as percent target cell lysis as a function of log antibody concentration (µg / ml). IMAB362 (Claudiximab) and human IgG served as controls. [Figure 9-1]Figures 9A-9C: Humanized antibody-dependent cellular cytotoxicity (ADCC) induction assay showing the percent lysis of CHO-K1 target cells overexpressing human claudin 18.2 after incubation with indicator antibodies and freshly isolated human PBMCs. Results are plotted as the percent target cell lysis as a function of log antibody concentration (µg / ml). IMAB362 (Claudiximab) and human IgG served as controls. [Figure 9-2] Figures 9D-9F: Humanized antibody-dependent cellular cytotoxicity (ADCC) induction assay showing the percent lysis of CHO-K1 target cells overexpressing human claudin 18.2 after incubation with indicator antibodies and freshly isolated human PBMCs. Results are plotted as the percent target cell lysis as a function of log antibody concentration (µg / ml). IMAB362 (Claudiximab) and human IgG served as controls. [Figure 9-3] Figures 9G-9H: Humanized antibody-dependent cellular cytotoxicity (ADCC) induction assay showing the percent lysis of CHO-K1 target cells overexpressing human claudin 18.2 after incubation with the index antibody and freshly isolated human PBMCs. Results are plotted as the percent target cell lysis as a function of log antibody concentration (µg / ml). IMAB362 (Claudiximab) and human IgG served as controls. [Figure 10] 1 shows the results of an in vitro cytotoxicity assay of T cells expressing an exemplary CAR against CHO.18.2.Luc or CHO.18.1.Luc cells. [Figure 11] 1 shows the results of an in vitro cytotoxicity assay of T cells expressing an exemplary CAR against claudin 18.2-positive cell lines. [Figure 12] 1 shows the results of an in vitro cytotoxicity assay of T cells expressing an exemplary CAR against KATOIII.Luc, KATOIII.18.1.Luc, or KATOIII.18.2.Luc cells.

[0159] definition Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0160] As used herein, the terms "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an antibody" means one antibody or two or more antibodies.

[0161] As used herein, the term "binding moiety" refers to a molecule or a portion of a molecule that binds to a target molecule (e.g., claudin 18.2). A binding moiety can comprise a protein, peptide, nucleic acid, carbohydrate, lipid, or low molecular weight compound. In some embodiments, a binding moiety comprises an antibody. In some embodiments, a binding moiety comprises an antigen-binding fragment of an antibody. In some embodiments, a binding moiety comprises a low molecular weight component. A binding moiety can also be an antibody or an antigen-binding fragment thereof. In some embodiments, a binding moiety comprises the ligand-binding domain of a receptor. In some embodiments, a binding moiety comprises the extracellular domain of a transmembrane receptor. A binding moiety can also be the ligand-binding domain of a receptor or the extracellular domain of a transmembrane receptor. A binding moiety can be monovalent, i.e., the binding moiety can comprise one binding site that specifically interacts with a target molecule. A binding moiety can be bivalent, i.e., the binding moiety can comprise two binding sites that specifically interact with a target molecule. Furthermore, a binding moiety can be multivalent, i.e., the binding moiety can comprise multiple binding sites that specifically interact with a target molecule. A bivalent or multivalent binding moiety can interact with one or more epitopes on a single target molecule. Additionally, bivalent or multivalent binding moieties can interact with two or more target molecules.

[0162] As used herein, the term "binding affinity" generally refers to the overall strength of non-covalent interactions between a binding moiety and a target molecule. Binding between a binding moiety and a target molecule is a reversible process, and binding affinity is usually measured by an equilibrium dissociation constant (K D ) is reported in K D is the dissociation rate (k off or k d ) and association rate (k on or k a ) is the ratio of the bond pair K D The lower the K, the higher the affinity. Various methods for measuring binding affinity are known in the art, any of which can be used for the purposes of the present invention. Specific exemplary embodiments include the following: In one embodiment, K D or K D The K value can be measured by assays well known in the art, such as, for example, binding assays. D can be measured by radiolabeled antigen binding assay (RIA) (Chen et al., (1999) J. Mol Biol 293:865-881). D or K D The K value can be measured by surface plasmon resonance assay using, for example, BIAcore™-2000 or BIAcore™-3000 (BIAcore, Inc., Piscataway, NJ). D or K DThe value can be measured by biolayer interferometry, for example, using the OctetQK384 system (ForteBio, Menlo Park, CA). When a target molecule containing multiple epitopes contacts a binding moiety containing multiple binding sites that bind to the target molecule, interaction between the binding molecule and the target molecule at one site increases the probability of reaction at a second site. The strength of such multiple interactions between a multivalent antibody and an antigen is called avidity. For example, as is sometimes seen with pentameric IgM antibodies, high avidity can compensate for low affinity; pentameric IgM antibodies may have lower affinity than IgG, but can effectively bind antigens due to the high avidity of IgM caused by its multivalency.

[0163] As used herein, the term "specifically binds" means that a polypeptide or molecule reacts with or binds to an epitope, protein, or target molecule more frequently, more rapidly, for a longer period of time, with higher affinity, or some combination of the above, than alternative substances, including related and unrelated proteins. Binding moieties (e.g., antibodies) that specifically bind to a target molecule (e.g., an antigen) can be recognized, for example, by immunoassays, ELISA, SPR (e.g., Biacore), or other techniques known to those skilled in the art. Typically, a specific response is at least two times the background signal or noise and may exceed 10 times the background. For example, see Paul (ed.), 1989, Fundamental Immunology, Second Edition, Raven Press, New York, pp. 332-336, for a discussion of antibody specificity. A binding moiety that specifically binds to a target molecule can bind to the target molecule with higher affinity than it does to a different molecule. In some embodiments, a binding moiety that specifically binds to a target molecule can bind to the target molecule with an affinity that is at least 20, 30, 40, 50, 60, 70, 80, 90, or 100 times greater than its affinity for a different molecule. In some embodiments, a binding moiety that specifically binds to a particular target molecule binds to a different molecule with such low affinity that binding cannot be detected using assays described herein or known in the art. In some embodiments, "specifically binds" refers to, for example, a binding moiety that binds to a target molecule with a K of about 0.1 mM or less. D In some embodiments, "specifically binds" refers to a polypeptide or molecule that binds to a target molecule with a K of about 10 μM or less, or about 1 μM or less. D In some embodiments, "specifically binds" refers to a polypeptide or molecule that binds to a target with a K of about 0.1 μM or less, about 0.01 μM or less, or about 1 nM or less. DSpecific binding refers to binding to a target at a specific site. Due to sequence identity between homologous proteins in different species, specific binding may include polypeptides or molecules that recognize proteins or targets in more than one species. Similarly, due to homology within certain regions of the polypeptide sequences of different proteins, specific binding may include polypeptides or molecules that recognize more than one protein or target. In some embodiments, it is understood that a binding moiety that specifically binds to a first target does not necessarily specifically bind to a second target. Thus, "specific binding" can include, but does not necessarily require, exclusive binding, i.e., binding to a single target. Thus, in some embodiments, a binding moiety can specifically bind to more than one target. For example, an antibody can contain two identical antigen-binding sites, each of which specifically binds to the same epitope on two or more proteins. In another embodiment, an antibody may be dual-specific, containing at least two antigen-binding sites with different specificities.

[0164] As used herein, the term "antibody" refers to an immunoglobulin molecule that recognizes and specifically binds to a target (e.g., a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or a combination thereof) typically via at least one antigen-binding site within the variable region of the immunoglobulin molecule. As used herein, the term encompasses intact polyclonal antibodies, intact monoclonal antibodies, single-chain Fv (scFv) antibodies, light chain antibodies (LCAbs), multispecific antibodies, bispecific antibodies, monospecific antibodies, monovalent antibodies, fusion proteins containing an antibody antigen-binding site, and any other modified immunoglobulin molecule containing an antigen-binding site (e.g., dual variable domain immunoglobulin molecules), so long as the antibody exhibits the desired biological activity. Antibodies also include, but are not limited to, murine antibodies, chimeric antibodies, humanized antibodies, and human antibodies. Antibodies may be any of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or their subclasses (isotypes) (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), based on the identity of their heavy chain constant domains, called alpha, delta, epsilon, gamma, and mu, respectively. Different classes of immunoglobulins have different known subunit structures and three-dimensional configurations. Antibodies may be naked or conjugated to other molecules (including, but not limited to, toxins and radioisotopes). Unless otherwise specified, the term "antibody" as used herein includes "antigen-binding fragments" of intact antibodies.

[0165] The term "antigen-binding fragment" when used in reference to an antibody refers to a portion of an intact antibody and to the antigen-determining variable region of the intact antibody. Antibody fragments include, but are not limited to, Fab, Fab', F(ab'), Fv, linear antibodies, single-chain variable fragment molecules (e.g., scFv), light-chain antibodies (LCAb), disulfide-linked scFv (dsscFv), diabodies, tribodies, tetrabodies, minibodies, dual variable domain antibodies (DVDs), and multispecific antibodies formed by antibody fragments.

[0166] As used herein, the term "variable region" of an antibody refers to the variable region of an antibody light chain or the variable region of an antibody heavy chain, either alone or in combination. Generally, each heavy and light chain variable region is composed of four framework regions (FRs), also known as "hypervariable regions," and three complementarity-determining regions (CDRs). The CDRs in each chain are held in close proximity by the framework regions and, together with the CDRs of the other chain, contribute to the formation of the antigen-binding site of the antibody. There are at least two methods for determining CDRs: (1) a method based on sequence variability between different species (Kabat et al., 1991, Sequences of Proteins of Immunological Interest (5th ed.). Bethesda, MD: National Institutes of Health), and (2) a method based on crystallographic studies of antigen-antibody complexes (Al-Lazikani et al., 1997, J. Mol. Biol., 273(4):927-48). Furthermore, a combination of these two methods is commonly used in the art to determine CDRs.

[0167] The term "single-chain variable fragment" or "scFv" refers to a fusion protein of the heavy and light chain variable regions of an immunoglobulin linked by a short linker peptide of 10 to 25 amino acids. The linker is usually glycine-rich to ensure flexibility and serine- or threonine-rich to ensure solubility. scFvs retain the specificity of the original immunoglobulin. scFvs can be linked by linkers of different lengths to form di-scFvs, diabodies, tri-scFvs, triabodies, or tetrabodies that exhibit specificity for one or more antigens.

[0168] The term "chimeric antigen receptor" or "CAR" refers to a genetically engineered receptor that transfers antigen specificity to immune effector cells, such as T cells, and enhances T cell function. Newer generation CARs contain an extracellular binding domain, including an scFv, hinge region, and transmembrane domain, and an intracellular signaling domain (primarily the cytoplasmic domain of CD3-zeta, the primary transmitter of T cell activation signals, and one or more costimulatory domains). CARs may also contain additional factors, such as cytokines and costimulatory ligands, that enhance T cell proliferation, persistence, and antitumor activity.

[0169] The term "autologous" refers to any material derived from the same individual that is later reintroduced into that individual.

[0170] The term "allogeneic" refers to a graft derived from a different individual of the same species.

[0171] As used herein, the term "humanized antibody" refers to a form of a non-human (e.g., murine) antibody that is a specific immunoglobulin chain, chimeric immunoglobulin, or fragment thereof, containing minimal non-human sequence. Typically, a humanized antibody is a human immunoglobulin. In some cases, Fv framework region residues of a human immunoglobulin are replaced with corresponding residues in an antibody from a non-human species having the desired specificity, affinity, and / or binding capacity. In some cases, CDR residues are replaced with residues from a CDR of a non-human species (e.g., mouse, rat, hamster) having the desired specificity, affinity, and / or binding capacity. Furthermore, humanized antibodies can be modified by substituting additional residues within the Fv framework region and / or within the substituted non-human residues to refine and optimize the antibody's specificity, affinity, and / or binding capacity. Humanized antibodies can be further modified by substituting additional residues in the Fv framework region and / or within the substituted non-human residues to refine and optimize the antibody's specificity, affinity, and / or binding capacity. Typically, a humanized antibody will comprise all or substantially all of the CDRs corresponding to a non-human immunoglobulin, while all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. In some embodiments, the variable domains comprise framework regions of human immunoglobulin sequences. In some embodiments, the variable domains comprise framework regions of human immunoglobulin consensus sequences. A humanized antibody may also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Humanized antibodies are generally considered to be distinct from chimeric antibodies.

[0172] As used herein, the term "chimeric antibody" refers to an antibody in which the amino acid sequences of the immunoglobulin molecule are derived from two or more species. Typically, the variable regions of both the light and heavy chains correspond to the variable regions of antibodies derived from one species of mammal (e.g., mouse, rat, rabbit, etc.) having the desired specificity, affinity, and / or binding capacity, while the constant regions correspond to sequences in antibodies derived from another species (usually human) to avoid eliciting an immune response in that species.

[0173] As used herein, the term "human antibody" refers to an antibody produced by a human, an antibody having an amino acid sequence corresponding to an antibody produced by a human. Human antibodies may be made using any technique known in the art.

[0174] The terms "epitope" and "antigenic determinant" are used interchangeably herein and refer to a site on the surface of a target molecule to which a binding moiety binds, such as a localized region on the surface of an antigen. Target molecules can include proteins, peptides, nucleic acids, carbohydrates, or lipids. An epitope with immunogenic activity is a portion of a target molecule that elicits an immune response in an animal. An epitope of a target molecule with antigenic activity is a portion of the target molecule to which an antibody binds, as determined by any method known in the art, such as immunoassays. An antigenic epitope need not be immunogenic. Epitopes are often composed of surface groupings of chemically active molecules, such as amino acids or sugar side chains, and have specific three-dimensional structural characteristics and specific charge characteristics. The term "epitope" includes linear epitopes and conformational epitopes. The region of a target molecule (e.g., a polypeptide) that contributes to an epitope can be consecutive amino acids of the polypeptide, or the epitope can be derived from two or more non-contiguous regions of the target molecule. Epitopes are not necessarily three-dimensional surface features of a target molecule. Epitopes formed by contiguous amino acids (also called linear epitopes) are typically retained when a protein is denatured, whereas epitopes formed by tertiary folding (also called conformational epitopes) are typically lost when a protein is denatured. Epitopes typically contain at least three amino acids, more commonly at least five, six, seven, or eight to ten amino acids, in a unique spatial conformation.

[0175] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. Polymers may be linear or branched, may contain non-natural or modified amino acids, or may be interrupted by non-amino acids. Polypeptides, peptides, or proteins may also be modified, for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification.

[0176] The terms "polynucleotide" and "nucleic acid" are used interchangeably herein to refer to a polymer of nucleotides of any length, including DNA and RNA. The nucleotides may be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase.

[0177] An "isolated" polypeptide, peptide, protein, antibody, polypeptide, vector, cell, or composition is a polypeptide, peptide, protein, antibody, polynucleotide, vector, cell, or composition in a form not found in nature. Isolated polypeptides, peptides, proteins, antibodies, polynucleotides, vectors, cells, or compositions include those that have been purified to the extent that they are no longer in a form in which they are found in nature. In some embodiments, an isolated polypeptide, peptide, protein, antibody, polynucleotide, vector, cell, or composition is essentially pure.

[0178] As used herein, the term "identical" or percent "identity" in the context of two or more nucleic acids or polypeptides refers to two or more sequences or subsequences that are the same or have a specified percentage of identical nucleotides or amino acid residues when compared and aligned for maximum correspondence (introducing gaps, if necessary), without considering any conservative amino acid substitutions as part of the sequence identity. Percent identity may be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software that can be used to align amino acid or nucleotide sequences are well known in the art. These include, but are not limited to, BLAST, ALIGN, Megalign, BestFit, GCG Wisconsin Package, and variations thereof. In some embodiments, two nucleic acids or polypeptides of the invention are substantially identical, meaning that when compared and aligned for maximum correspondence, they have at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% nucleotide or amino acid residue identity, and in some embodiments, at least 95%, 96%, 97%, 98%, or 99% nucleotide or amino acid residue identity, as measured using a sequence comparison algorithm or by visual inspection. In some embodiments, identity exists over a region of the sequence that is at least about 10, at least about 20, at least about 40-60 residues, at least about 60-80 residues in length, or any integer value therebetween. In some embodiments, identity exists over a region longer than 60-80 residues (e.g., at least about 80-100 residues), and in some embodiments, the sequences are substantially identical over the entire length of the sequences being compared (e.g., the coding regions of target proteins or antibodies). In some embodiments, identity exists over a region of the sequence that is at least about 10, at least about 20, at least about 40-60 bases, at least about 60-80 bases in length, or any integer value therebetween.In some embodiments, the identity exists over a region longer than 60-80 bases (e.g., at least about 80-100 bases), and in some embodiments, the sequences are substantially identical over the entire length of the sequences being compared (e.g., nucleotide sequences encoding the proteins being analyzed).

[0179] The term "amino acid substitution" used herein refers to the substitution of one amino acid residue with another amino acid residue in a polypeptide sequence. "Conservative amino acid substitution" refers to the substitution of one amino acid residue with another amino acid residue that has a side chain with similar chemical properties. Generally, a family of amino acid residues with similar side chains is defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). For example, the substitution of tyrosine with phenylalanine is a conservative substitution. In general, conservative substitutions in sequences in the polypeptides, soluble proteins, and / or antibodies of the present invention do not abolish binding of the polypeptide, soluble protein, or antibody containing that amino acid sequence to the target binding site. Methods for identifying conservative amino acid substitutions that do not abolish binding are well known in the art.

[0180] As used herein, the term "variant" in reference to a binding moiety (e.g., an "antibody") having a polypeptide (reference binding moiety) with specific sequence characteristics refers to a different binding moiety having a polypeptide that contains one or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) amino acid sequence substitutions, deletions, and / or additions compared to the reference binding moiety. A variant of an anti-claudin 18.2 binding moiety or an anti-claudin 18.2 antibody retains at least specific binding to claudin 18.2. In some embodiments, a variant of a binding moiety can result from one or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) changes to the amino acid sequence of the reference binding moiety. Further, by way of example, variants of anti-claudin 18.2 antibodies can result from one or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) changes to the amino acid sequence of a reference anti-claudin 18.2 antibody. The changes to the amino acid sequence may be amino acid substitutions. In some embodiments, the changes to the amino acid sequence may be conservative amino acid substitutions. In some embodiments, variants of anti-claudin 18.2 binding moieties or variants of anti-claudin 18.2 antibodies can result from one or more (e.g., about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) amino acid substitutions in the VH or VL region or subregion, such as one or more CDRs. In some embodiments, variants of anti-claudin 18.2 binding moieties or variants of anti-claudin 18.2 antibodies can result from one, up to two, up to three, up to four, or up to five amino acid substitutions in the VH or VL regions, respectively. In some embodiments, variants of anti-claudin 18.2 binding moieties or variants of anti-claudin 18.2 antibodies can result from one, up to two, up to three, up to four, or up to five amino acid substitutions in each CDR region.

[0181] The term "vector" refers to a substance used to transport or contain a nucleic acid sequence, for example, to introduce the nucleic acid sequence into a host cell. Usable vectors include, for example, expression vectors, plasmids, phage vectors, viral vectors, episomes, and artificial chromosomes, which may contain selection sequences or markers that can be used for stable integration into a host cell chromosome. Furthermore, a vector may contain one or more selectable marker genes and appropriate expression control sequences. Selectable marker genes that may be included confer, for example, resistance to antibiotics or toxins, complement auxotrophic deficiencies, or supply critical nutrients not present in the culture medium. Expression control sequences may include constitutive and inducible promoters, transcription enhancers, transcription terminators, and the like, as are well known in the art. When two or more nucleic acid molecules are co-expressed (e.g., both antibody heavy and light chains, or antibody VH and VL), both nucleic acid molecules can be inserted, for example, into a single expression vector or into separate expression vectors. For single vector expression, the encoding nucleic acid can be operably linked to one common expression control sequence, or can be linked to different expression control sequences, such as one inducible promoter and one constitutive promoter. Introduction of nucleic acid molecules into host cells can be confirmed using methods well known in the art. It is understood by those skilled in the art that the nucleic acid molecule is expressed in an amount sufficient to produce the desired product (e.g., the anti-claudin 18.2 antibody described herein), and it is further understood that the expression level can be optimized to obtain sufficient expression using methods well known in the art.

[0182] The term "subject" refers to any animal (e.g., mammal) that is the subject of a particular treatment, including, but not limited to, humans, non-human primates, dogs, cats, rodents, etc. In some embodiments, the subject is a human. A "subject" may also be a patient with a particular disease. In some embodiments, the subject is a patient with a cancer or tumor that expresses claudin 18.2.

[0183] As used herein, the term "treating" as used in reference to a disease or condition, or a subject having a disease or condition, refers to an action that suppresses, eliminates, reduces, and / or ameliorates the symptoms, the severity of symptoms, and / or the frequency of symptoms associated with the disease or disorder being treated. When used in reference to a cancer or tumor, the term "treating" refers to an action that reduces the severity of the cancer or tumor or slows or slows the progression of the cancer or tumor, including (a) preventing the growth or spread of the cancer or tumor, (b) causing the cancer or tumor to regress, or (c) delaying, reducing, or minimizing one or more symptoms associated with the presence of the cancer or tumor.

[0184] As used herein, the terms "administer," "administering," or "administration" refer to the act of delivering or causing to be delivered a therapeutic or pharmaceutical composition to the body of a subject, by methods described herein or known in the art. The therapeutic agent may be a compound, a polypeptide, a cell, or a cell population. Administering a therapeutic or pharmaceutical composition involves defining the therapeutic or pharmaceutical composition to be delivered into the patient's body. Exemplary dosage forms include oral dosage forms such as tablets, capsules, syrups, and suspensions; injectable dosage forms such as intravenous (IV), intramuscular (IM), or intraperitoneal (IP); transdermal dosage forms such as creams, jellies, powders, or patches; buccal dosage forms; inhalation powders; sprays; suspensions; and rectal suppositories.

[0185] As used herein, the term "therapeutically effective amount" refers to an amount of a compound, polypeptide, cell, preparation, material, or composition described herein that is effective to treat a disease or disorder, or to delay or minimize one or more symptoms associated with a disease or disorder. The disease or disorder may be a cancer or tumor that expresses claudin 18.2.

[0186] As used herein, the term "carrier" includes a "pharmaceutically acceptable carrier," excipient, or stabilizer that is nontoxic to cells or mammals exposed thereto at the dosage and concentration employed. The term "carrier" can also refer to a diluent, adjuvant (e.g., Freund's adjuvant (complete or incomplete)), excipient, or vehicle with which a therapeutic agent is administered. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences (1990) Mack Publishing Co., Easton, PA. A composition such as a pharmaceutical compound contains a prophylactically or therapeutically effective amount of the antibody, e.g., in isolated or purified form, together with a suitable amount of carrier to provide the form for proper administration to a subject (e.g., a patient). The formulation should suit the mode of administration.

[0187] Claudin 18.2 binding site Claudin 18.2 is isoform 2 of claudin 18, a member of the claudin family of cell surface proteins. Claudins are important structural components of tight cell junctions, forming intercellular barriers that regulate the flow of molecules between cells. Different types of claudins are expressed in different tissues, and alterations in their function can lead to the development of cancer in these tissues. In normal tissues, claudin 18.2 expression is restricted to epithelial cells of the gastric mucosa. Claudin 18.2 expression is maintained during malignant transformation in gastric cancer and its metastases. Ectopic activation of claudin 18.2 has also been observed in pancreatic, esophageal, ovarian, and lung tumors.

[0188] Human claudin 18.2 protein has 261 amino acids (NCBI, NP_001002026.1, SEQ ID NO: 200). Claudin 18.2 exists in the cytoplasm as a tetraspan transmembrane protein with N- and C-termini. Claudin 18.2 has two extracellular loops that are involved in functions such as cell-cell tightness and paracellular ion pore formation.

[0189] MAVTACQGLG FVVSLIGIAG IIAATCMDQW STQDLYNNPV TAVFNYQGLW RSCVRESSGF TECRGYFTLL GLPAMLQAVR ALMIVGIVLG AIGLLVSIFA LKCIRIGSME DSAKANMTLT SGIMFIVSGL CAIAGVSVFA NMLVTNFWMS TANMYTGMGG MVQTVQTRYT FGAALFVGWV AGGLTLIGGV MMCIACRGLA PEETNYKAVS YHASGHSVAY KPGGFKASTG FGSNTKNKKI YDGGARTEDE VQSYPSKHDY V (SEQ ID NO: 200)

[0190] The claudin 18.2 binding moiety specifically binds to claudin 18.2, a fragment thereof, or a variant thereof. In some embodiments, the claudin 18.2 binding moiety specifically binds to human claudin 18.2. In some embodiments, the claudin 18.2 binding moiety specifically binds to the extracellular domain of claudin 18.2. In some embodiments, the claudin 18.2 binding moiety specifically binds to the first extracellular loop of claudin 18.2. In some embodiments, the claudin 18.2 binding moiety specifically binds to the second extracellular loop of claudin 18.2. In some embodiments, the claudin 18.2 binding moiety specifically binds to both the first and second extracellular loops of claudin 18.2. In some embodiments, the claudin 18.2 binding moiety binds to claudin 18.2 with an affinity that is at least 20-fold greater than the affinity of an antibody for claudin 18.1. In some embodiments, the claudin 18.2 binding moiety binds to claudin 18.2 with an affinity that is at least 50-fold greater than the affinity of an antibody for claudin 18.1. In some embodiments, the claudin 18.2 binding moiety binds to claudin 18.2 with an affinity that is at least 100-fold greater than the affinity of the antibody for claudin 18.1. In some embodiments, the claudin 18.2 binding moiety does not detectably bind to claudin 18.1.

[0191] The antibody may be a Fab', a F(ab')2, a Fv, a scFv, a(scFv)2, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody.

[0192] In some embodiments, the claudin 18.2-binding moiety comprises an antibody. In some embodiments, the claudin 18.2-binding moiety comprises an antigen-binding fragment of an antibody. In some embodiments, the antibody is an IgA, IgD, IgE, IgG, or IgM antibody. In some embodiments, the antibody is an IgA antibody. In some embodiments, the antibody is an IgD antibody. In some embodiments, the antibody is an IgE antibody. In some embodiments, the antibody is an IgG antibody. In some embodiments, the antibody is an IgM antibody. In some embodiments, the antibody is an IgG1 antibody. In some embodiments, the antibody is an IgG2 antibody. In some embodiments, the antibody is an IgG3 antibody. In some embodiments, the antibody is an IgG4 antibody.

[0193] In some embodiments, the claudin 18.2 binding moiety comprises a Fab. In some embodiments, the antibody is a Fab'. In some embodiments, the claudin 18.2 binding moiety comprises a F(ab')2. In some embodiments, the claudin 18.2 binding moiety comprises an Fv. In some embodiments, the claudin 18.2 binding moiety comprises an scFv. In some embodiments, the claudin 18.2 binding moiety comprises a disulfide-linked scFv [(scFv)2]. In some embodiments, the claudin 18.2 binding moiety comprises a diabody (dAb).

[0194] In some embodiments, the claudin18.2-binding moiety comprises a recombinant antibody. In some embodiments, the claudin18.2-binding moiety comprises a monoclonal antibody. In some embodiments, the claudin18.2-binding moiety comprises a polyclonal antibody. In some embodiments, the claudin18.2-binding moiety comprises a chimeric antibody. In some embodiments, the claudin18.2-binding moiety comprises a humanized antibody. In some embodiments, the claudin18.2-binding moiety comprises a human antibody.

[0195] In some embodiments, the antibody is isolated. In some embodiments, the antibody is essentially pure.

[0196] In some embodiments, the claudin 18.2 binding moiety comprises a bispecific binding moiety. In some embodiments, the claudin 18.2 binding moiety comprises a multispecific binding moiety.

[0197] In some embodiments, the claudin 18.2 binding moiety (e.g., an antibody) comprises a monovalent binding moiety. In some embodiments, the claudin 18.2 binding moiety (e.g., an antibody) comprises a monospecific binding moiety. In some embodiments, the claudin 18.2 binding moiety (e.g., an antibody) comprises a bivalent binding moiety. In some embodiments, the bivalent binding moiety comprises two antibodies. In some embodiments, the bivalent binding moiety comprises a first antibody and a second antibody. In some embodiments, the first antibody and the second antibody are connected by a linker. In some embodiments, the claudin 18.2 binding moiety (e.g., an antibody) comprises, from N-terminus to C-terminus, a first antibody, a linker, and a second antibody. In some embodiments, the second antibody is a tandem repeat of the first antibody. In some embodiments, the first antibody and the second antibody recognize different epitopes of claudin 18.2. In some embodiments, the first antibody and the second antibody recognize the same epitope of claudin 18.2.

[0198] In some embodiments, the claudin 18.2-binding moiety is a monoclonal antibody. Monoclonal antibodies can be prepared by any method known to those skilled in the art. One exemplary method is screening a protein expression library, such as a phage or ribosome display library. Phage display is described, for example, in Ladner et al., U.S. Pat. No. 5,223,409, Smith (1985) Science 228:1315-1317, and WO 92 / 18619. In some embodiments, recombinant monoclonal antibodies are isolated from a phage display library expressing the variable domain or CDR of a desired species. Screening of the phage library can be performed by any technique known in the art.

[0199] Methods for achieving high-affinity binding with humanized antibodies are well known in the art. Such methods include, but are not limited to, hypermutation of the variable region and selection of cells expressing such high-affinity antibodies (affinity maturation). In addition to using a display library, a specific antigen (e.g., recombinant claudin 18.2 or an epitope thereof) can be used to immunize non-human animals such as rodents. In certain embodiments, rodent antigen-binding fragments (e.g., mouse antigen-binding fragments) can be generated and isolated using methods well known in the art and / or disclosed herein. In some embodiments, mice can be immunized with an antigen (e.g., recombinant claudin 18.2 or an epitope thereof).

[0200] In some embodiments, monoclonal antibodies are prepared by hybridoma methods known to those skilled in the art. For example, mice, rats, rabbits, hamsters, or other suitable host animals are immunized as described above by hybridoma methods. In some embodiments, lymphocytes are immunized in vitro. In some embodiments, the immunizing antigen is a human protein or a fragment thereof. In some embodiments, the immunizing antigen is a human protein or a fragment thereof.

[0201] After immunization, lymphocytes are isolated and fused with an appropriate myeloma cell line, for example, using polyethylene glycol. Hybridoma cells are selected using specialized media known in the art, but unfused lymphocytes and myeloma cells do not survive this selection process. Hybridomas producing monoclonal antibodies specifically directed against a selected antigen can be identified by various methods. These methods include, but are not limited to, immunoprecipitation, immunoblotting, and in vitro binding assays (e.g., flow cytometry, FACS, ELISA, SPR (e.g., Biacore), and radioimmunoassay). Once hybridoma cells producing antibodies with the desired specificity, affinity, and / or activity are identified, the clones may be subcloned by limiting dilution or other techniques. Hybridomas can be grown either in vitro in culture using standard methods or in vivo as ascites tumors in animals. Monoclonal antibodies can be purified from the culture medium or ascites fluid according to standard methods in the art. Such standard methods include, but are not limited to, affinity chromatography, ion exchange chromatography, gel electrophoresis, and dialysis.

[0202] In some embodiments, monoclonal antibodies are produced using recombinant DNA techniques known to those skilled in the art. For example, polynucleotides encoding the antibodies are isolated from mature B cells or hybridoma cells, e.g., by RT-PCR using oligonucleotide primers that specifically amplify genes encoding the antibody heavy and light chains, and their sequences are determined using standard techniques. The isolated polynucleotides encoding the heavy and light chains are then cloned into appropriate expression vectors that produce the monoclonal antibodies when transfected into host cells, such as E. coli, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells, which do not otherwise produce immunoglobulin proteins.

[0203] In some embodiments, recombinant monoclonal antibodies are isolated from phage display libraries expressing variable domains or CDRs of the desired species. Screening of phage libraries can be accomplished by various techniques well known in the art.

[0204] In some embodiments, monoclonal antibodies are modified using recombinant DNA technology to generate surrogate antibodies. In some embodiments, the light and heavy chain constant domains of a murine monoclonal antibody are replaced with constant regions of a human antibody to generate a chimeric antibody. In some embodiments, the constant regions are truncated or removed to generate desired antibody fragments of the monoclonal antibody. In some embodiments, site-directed or high-density mutagenesis of the variable regions is used to optimize the specificity and / or affinity of the monoclonal antibody.

[0205] In some embodiments, the claudin 18.2-binding moiety is a humanized antibody. Various methods for generating humanized antibodies are well known in the art. In some embodiments, a humanized antibody contains one or more amino acid residues introduced into its sequence from a non-human source. In some embodiments, humanization is performed by replacing one or more non-human CDR sequences with the corresponding CDR sequences of a human antibody. In some embodiments, a humanized antibody is constructed by replacing all (three) CDRs of a non-human antibody (e.g., a heavy or light chain antibody) with the corresponding CDRs of a human antibody. In some embodiments, a humanized antibody is constructed by replacing all (six) CDRs of a non-human antibody (e.g., a murine antibody) with the corresponding CDRs of a human antibody.

[0206] The human heavy and / or light chain variable regions used to generate the humanized antibody can be selected based on various factors and using various methods well known in the art. In some embodiments, a particular variable region fragment derived from the consensus sequence of all human antibodies of a particular light or heavy chain subgroup is selected as the variable region fragment. In some embodiments, the variable region fragment sequence is derived from the consensus sequence of the most abundant human subclass. In some embodiments, human germline genes are used as the source of the variable region fragment sequence.

[0207] In some embodiments, the claudin 18.2-binding moiety is a human antibody. Human antibodies can be prepared using a variety of techniques well known in the art. In some embodiments, human antibodies are generated from immortalized human B lymphocytes immunized in vitro. In some embodiments, human antibodies are generated from lymphocytes isolated from immunized individuals. In either case, cells producing antibodies against the target antigen can be generated and isolated. In some embodiments, human antibodies are selected from phage libraries expressing human antibodies. Alternatively, phage display technology can be used to generate human antibodies and antibody fragments in vitro from immunoglobulin variable region gene repertoires from unimmunized donors. Techniques for generating and using antibody phage libraries are well known in the art. Once an antibody is identified, affinity maturation strategies well known in the art (including, but not limited to, chain shuffling and site-directed mutagenesis) can be used to generate high-affinity human antibodies. In some embodiments, human antibodies are generated in transgenic mice containing human immunoglobulin loci. Upon immunization, these mice are capable of producing the full repertoire of human antibodies in the absence of endogenous immunoglobulin production.

[0208] In some embodiments, the claudin 18.2-binding moiety is an antibody that binds to claudin 18.2. In some embodiments, the anti-claudin 18.2 antibody binds to human claudin 18.2. In some embodiments, the anti-claudin 18.2 antibody binds to a claudin 18.2 epitope. In some embodiments, the anti-claudin 18.2 antibody binds to the extracellular domain of claudin 18.2. In some embodiments, the anti-claudin 18.2 antibody binds to the first extracellular loop of claudin 18.2. In some embodiments, the anti-claudin 18.2 antibody binds to the second extracellular loop of claudin 18.2. In some embodiments, the anti-claudin 18.2 antibody binds to claudin 18.2 with an affinity that is at least 20-fold greater than the antibody's affinity for claudin 18.1. In some embodiments, the anti-claudin 18.2 antibody binds to claudin 18.2 with an affinity that is at least 50-fold greater than the antibody's affinity for claudin 18.1. In some embodiments, the anti-claudin 18.2 antibody binds to claudin 18.2 with an affinity that is at least 100-fold greater than the affinity of the antibody for claudin 18.1. In some embodiments, the anti-claudin 18.2 antibody does not detectably bind to claudin 18.1.

[0209] Those skilled in the art can define antibody CDRs using a variety of methods / systems. These systems and / or definitions have been developed and refined over the years and include Kabat, Chothia, IMGT, AbM, and Contact. The Kabat definition is based on sequence variability and is the most commonly used. The Chothia definition is based on the location of structural loop regions. The IMGT system is based on sequence variability and location within the variable domain structure. The AbM definition is a compromise between Kabat and Chothia, while the Contact definition is based on analysis of available antibody crystal structures. An exemplary system is a combination of Kabat and Chothia. As known to those skilled in the art, software programs (e.g., abYsis) are available for analyzing antibody sequences and determining CDRs.

[0210] Specific CDR sequences herein are generally defined based on a combination of the Kabat and Chothia definitions (an exemplary system), however, it will be understood that the heavy chain CDR or CDRs and / or light chain CDR or CDRs of a specific antibody encompass all CDR definitions known to those skilled in the art.

[0211] Claudin 18.2 binding moieties provided herein include the anti-claudin 18.2 antibodies provided herein, and humanized versions thereof. In some embodiments, the anti-claudin-18.2 antibody is selected from the group consisting of 260G9E8, 252F1B10, 257B1G9, 265E6G2, 250F4G4, 262C7C10, 240F8G2, 232C5E3, 252E7C9, 257G7B9, 241H10A1, 273C10E5, 185F2G12, 194D3B2, 207F8G5, 222B6G5, 182D10F1, 234B9D4, 253E4F7, 198F10B8, 213B10A4, 370E2B12C3, 237D2A4, 203A6C9, 201F4H6, 429H 6C5, 407D8G1, 419B5G9, 393C2C5, 412B6E4, 414A5F7, 418D2F9, 410H6H3, and others including 59B6C4, 246B5F2 (IgM), 418G6A5, 417A6F11, 28C5B1, 35E8D2, 61H12G10, 69D5C1, 181C7B2, 196A12B10, 232D7C8, 233D5E5, 232F1E4, 231H4G11, 226A4B5, 235A10C9, 239H12G9, 248E6A7, 254A8D5, 259C6F4, and 280F3B6.

[0212] As shown in Tables 1 and 2, the anti-claudin-18.2 antibodies provided herein can be classified into five groups based on CDR sequence similarity.

[0213] In some embodiments, the claudin 18.2-binding portion is an anti-claudin 18.2 antibody that comprises one, two, three, four, five, and / or six CDRs of any of the antibodies described herein. In some embodiments, the anti-claudin 18.2 antibody comprises one, two, and / or three VH CDRs or variable regions shown in Table 1. In some embodiments, the anti-claudin 18.2 antibody comprises one, two, and / or three VL CDRs or variable regions shown in Table 2. In some embodiments, the anti-claudin 18.2 antibody comprises one, two, and / or three VH CDRs or variable regions shown in Table 1 and one, two, and / or three VL CDRs or variable regions shown in Table 2.

[0214] The heavy and light chain variable region CDRs in Tables 1 and 2 are defined by the Kabat numbering system, but as is well known in the art, CDR regions can also be determined based on the heavy / light chain variable region sequences by other systems such as Chothia, IMGT, AbM, or the Contact numbering system / method.

[0215] [Table 1] TIFF0007724332000002.tif192134TIFF0007724332000003.tif196132TIFF0007724332 000004.tif190133TIFF0007724332000005.tif191132TIFF0007724332000006.tif19413 2TIFF0007724332000007.tif193132TIFF0007724332000008.tif191132TIFF0007724332 000009.tif190132TIFF0007724332000010.tif190132TIFF0007724332000011.tif15131

[0216] [Table 2] TIFF0007724332000013.tif191142TIFF0007724332000014.tif193142TIFF0007724332000015.tif190142TIFF0007724332000016.tif190142TIFF0007724332000017.tif190142TIFF0007724332000018.tif190142TIFF0007724332000019.tif55142

[0217] In some embodiments, the claudin 18.2-binding moiety comprises an antibody. In some embodiments, the claudin 18.2-binding moiety comprises a humanized antibody. In some embodiments, the claudin 18.2-binding moiety comprises an antibody having a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 from an antibody described herein. In some embodiments, the claudin 18.2-binding moiety comprises a humanized version of an antibody described herein. In some embodiments, the claudin 18.2-binding moiety comprises a variant of an anti-claudin 18.2 antibody described herein. In some embodiments, the variant of an anti-claudin 18.2 antibody comprises 1 to 30 conservative amino acid substitutions. In some embodiments, the variant of an anti-claudin 18.2 antibody comprises 1 to 25 conservative amino acid substitutions. In some embodiments, the variant of an anti-claudin 18.2 antibody comprises 1 to 20 conservative amino acid substitutions. In some embodiments, the variant of an anti-claudin 18.2 antibody comprises 1 to 15 conservative amino acid substitutions. In some embodiments, the variant anti-claudin 18.2 antibody comprises 1 to 10 conservative amino acid substitutions. In some embodiments, the variant anti-claudin 18.2 antibody comprises 1 to 5 conservative amino acid substitutions. In some embodiments, the variant anti-claudin 18.2 antibody comprises 1 to 3 conservative amino acid substitutions. In some embodiments, the conservative amino acid substitutions are present in the CDRs of the antibody. In some embodiments, the conservative amino acid substitutions are not present in the CDRs of the antibody. In some embodiments, the conservative amino acid substitutions are present in the framework regions of the antibody.

[0218] In some embodiments, the claudin 18.2-binding portion comprises (a) a heavy chain variable region (VH) and / or (b) a light chain variable region (VL). The heavy chain variable region (VH) comprises (1) an amino acid sequence selected from the group consisting of SEQ ID NOs: 69-88, 203-210, 392, 397, 402, 406, 409, 413, 417, 427, 430, 433, 434, 436, 444, 447, and 450, or a variant thereof comprising one, two, three, or four amino acid substitutions. (2) a VH having an amino acid sequence selected from the group consisting of SEQ ID NOs: 89 to 116, 201, 202, 211 to 224, 390, 391, 393, 395, 398, 400, 401, 403, 405, 407, 410, 412, 414, 418, 419, 421, 423, 425, 426, 428, 432, 435, 437, 438, 439, 440, 442, 445, 448, 451, and 453, or a variant thereof having one, two, three, or four amino acid substitutions. and (3) a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 117-135, 225-232, 394, 396, 399, 404, 408, 411, 415, 416, 420, 422, 424, 429, 431, 441, 443, 446, 449, 452, and 454, or a variant thereof comprising one, two, three, or four amino acid substitutions.The light chain variable region (VL) comprises: (1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 136 to 142, 233 to 240, 456, 458, 460, 465, 472, 475, 476, 478, 479, 480, 482, 485, 488, and 491, or a variant thereof having one, two, three, or four amino acid substitutions; and (2) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 143 to 149, 241, 457, 461, 463, 466, 473, 486, 489, and 492, or a variant thereof having one, two, three, or four amino acid substitutions. and (3) a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 150-173, 242-250, 455, 459, 462, 464, 467, 468, 469, 470, 471, 474, 477, 470, 474, 481, 483, 484, 487, 490, 493, and 494, or a variant thereof comprising one, two, three, or four amino acid substitutions. In some embodiments, the CDRs (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3) comprise one amino acid substitution. In some embodiments, the CDRs (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3) comprise two amino acid substitutions. In some embodiments, the CDRs (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and / or VL CDR3) comprise three amino acid substitutions. In some embodiments, the CDRs (VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and / or VL CDR3) comprise four amino acid substitutions. In some embodiments, one or more amino acid substitutions are conservative substitutions. In some embodiments, one or more substitutions are part of a humanization process. In some embodiments, one or more substitutions are part of a germline humanization process. In some embodiments, one or more substitutions are part of an affinity maturation process.In some embodiments, one or more substitutions are part of the optimization process.

[0219] In some embodiments, the claudin 18.2-binding portion comprises an antibody having a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 from an antibody described herein as a Group 1 antibody. Group 1 antibodies include 260G9E8, 252F1B10, 257B1G9, 265E6G2, 250F4G4, 262C7C10, 240F8G2, 232C5E3, 252E7C9, 257G7B9, 241H10A1, and 273C10E5. In some embodiments, the claudin 18.2-binding portion comprises a VH CDR1, CDR2, CDR3, and / or VL CDR1, CDR2, CDR3 from a Group 1 antibody described herein, or a humanized version thereof. In some embodiments, the claudin 18.2-binding moiety comprises a VH CDR1, CDR2, and CDR3 from a Group 1 antibody described herein. In some embodiments, the claudin 18.2-binding moiety comprises a VL CDR1, CDR2, and CDR3 from a Group 1 antibody described herein. In some embodiments, the claudin 18.2-binding moiety comprises a VH CDR1, CDR2, and CDR3 and a VL CDR1, CDR2, and CDR3 from a Group 1 antibody described herein. In some embodiments, the claudin 18.2-binding moiety is a humanized Group 1 antibody described herein. In some embodiments, the claudin 18.2-binding moiety is a variant of a Group 1 antibody described herein.

[0220] In some embodiments, the claudin 18.2-binding moiety comprises a humanized Group 1 antibody described herein. In some embodiments, the claudin 18.2-binding moiety comprises a variant of a Group 1 anti-claudin 18.2 antibody described herein. In some embodiments, the variant anti-claudin 18.2 antibody comprises 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, or 1 to 3 conservative amino acid substitutions. In some embodiments, the conservative amino acid substitutions are present in the CDRs of the antibody. In some embodiments, the conservative amino acid substitutions are not present in the CDRs of the antibody. In some embodiments, the conservative amino acid substitutions are present in the framework regions of the antibody.

[0221] In some embodiments, the heavy chain variable region (VH) comprises (a) a heavy chain variable region (VH) and / or (b) a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises: (1) a heavy chain CDR1 (VH CDR1) comprising X1X2X3X4X5 (X1 is S or N, X2 is H, Y, or F, X3 is N or G, X4 is M, I, or L, and X5 is H or N; SEQ ID NO: 174); and (2) X6IX7PGX8GX9X 10 X 11 YNX 12 X 13 FX 14 X 15 (X6 is Y or W, X7 is Y or F, X8 is N or D, X9 is G, R, or N, X 10 is T, N, or S, X 11 is K, N, or Y, X 12 is Q, E, or X 13 is K, N, or X 14 is T, K, or X 15 (3) a heavy chain CDR2 (VH CDR2) comprising X 16 YYGNSFX 17 X 18 (X 16 is D or F, X 17 is A or V, X 18is Y or N, SEQ ID NO: 176), and the light chain variable region (VL) comprises: (1) KSSQSLX 19 NSGNQKNYLT(X 19 (2) a light chain CDR1 (VL CDR1) comprising a WAX 20 TRES(X 20 is S or A, SEQ ID NO: 187); and (3) QNX 21 X 22 X 23 X 24 PX 25 X 26 (X 21 is D, G, or N, X 22 is Y or F, X 23 is M, R, S, W, Y, or F, X 24 is F or Y, X 25 is F or L, X 26 and a light chain CDR3 (VL CDR3) comprising:

[0222] In some embodiments, the claudin 18.2-binding portion comprises (a) a VH and / or (b) a VL. The VH comprises (1) a VH CDR1 comprising SHNMH (SEQ ID NO: 69), (2) a VH CDR2 comprising YIYPGNGGTNYNQKFKG (SEQ ID NO: 90), and (3) DYYGNSFAY (SEQ ID NO: 117). The VL comprises (1) a VL CDR1 comprising KSSQSLLNSGNQKNYLT (SEQ ID NO: 136), (2) a VL CDR2 comprising WASTRES (SEQ ID NO: 143), and (3) a VL CDR3 comprising QNDYRYPFT (SEQ ID NO: 151).

[0223] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 69, 89, and 117, respectively, or a variant thereof with up to about 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 150, respectively, or a variant thereof with up to about 5 amino acid substitutions in the CDRs.

[0224] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 69, 90, and 117, respectively, or a variant thereof with up to about 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 137, 143, and 151, respectively, or a variant thereof with up to about 5 amino acid substitutions in the CDRs.

[0225] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 70, 90, and 117, respectively, or a variant thereof with up to about 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 152, respectively, or a variant thereof with up to about 5 amino acid substitutions in the CDRs.

[0226] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 69, 91, and 117, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 137, 143, and 153, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0227] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 71, 92, and 117, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 143, and 154, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0228] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 72, 93, and 117, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 143, and 155, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0229] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 69, 94, and 118, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 143, and 156, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0230] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 73, 95, and 117, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 137, 143, and 157, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0231] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 74, 96, and 119, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 144, and 158, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0232] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 74, 96, and 130, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 144, and 158, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0233] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 202, and 118, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 455, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0234] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 72, 90, and 117, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 137, 143, and 153, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0235] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 390, and 118, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 249, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0236] In some embodiments, the claudin 18.2 binding portion comprises an antibody having a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 from an antibody described herein as a Group 2 antibody, i.e., 185F2G12, 194D3B2, 207F8G5, 222B6G5, 182D10F1, 234B9D4, 253E4F7, 241H10A1, or 273C10E5.

[0237] In some embodiments, the claudin 18.2-binding portion comprises the VH CDR1, CDR2, and CDR3, and / or the VL CDR1, CDR2, and CDR3, from a Group 2 antibody described herein, or a humanized version thereof. In some embodiments, the claudin 18.2-binding portion comprises the VH CDR1, CDR2, and CDR3, from a Group 2 antibody described herein. In some embodiments, the claudin 18.2-binding portion comprises the VL CDR1, CDR2, and CDR3, from a Group 2 antibody described herein. In some embodiments, the claudin 18.2-binding portion comprises the VH CDR1, CDR2, and CDR3, and the VL CDR1, CDR2, and CDR3, from a Group 2 antibody described herein. In some embodiments, the claudin 18.2-binding portion is a humanized version of a Group 2 antibody described herein. In some embodiments, the claudin 18.2-binding portion is a variant of a Group 2 antibody described herein.

[0238] In some embodiments, the claudin 18.2-binding moiety comprises a humanized version of a Group 2 antibody described herein. In some embodiments, the claudin 18.2-binding moiety comprises a variant of a Group 2 anti-claudin 18.2 antibody described herein. In some embodiments, the variant anti-claudin 18.2 antibody comprises 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, or 1 to 3 conservative amino acid substitutions. In some embodiments, the conservative amino acid substitutions are present in the CDRs of the antibody. In some embodiments, the conservative amino acid substitutions are not present in the CDRs of the antibody. In some embodiments, the conservative amino acid substitutions are present in the framework regions of the antibody.

[0239] In some embodiments, the VH comprises (a) a VH and / or (b) a VL, wherein the VH is (1) SYX 27 X 28 H(X 27 is N or Y, X 28 is M or I, SEQ ID NO: 177), and (2) YIX 29 PX 30 NGGX 31 X 32 YX 33 X 34 KFX 35 X 36 (X 29 is Y, S, or D, X 30 is G or F, X 31 is T, S, or X 32 is N, Y, or R, X 33 is S, N, X 34 is Q or L, X 35 is K, R, or E, X 36 is G or D, SEQ ID NO: 178); and (3) X 37 RX 38 X 39 X 40 Y(X 37 is G or L, X 38 is G or F, X 39 is F or L, X 40is A or T, SEQ ID NO: 179), and the VL comprises (1) KSSQSLX 41 NX 42 GNQX 43 NYLX 44 (X 41 is F or L, X 42 is T, S, or X 43 is K, E, or X 44 is T or I, SEQ ID NO: 189), and (2) RASTRX 45 S(X 45 is E, D, or Q, SEQ ID NO: 190), and (3) QNDX 46 SYPLT(X 46 and a VL CDR3 comprising a VL CDR3 comprising a VL CDR3 wherein VL CDR3 is F or Y, SEQ ID NO: 191.

[0240] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising (a) a VH and / or (b) a VL, wherein the VH comprises (1) a VH CDR1 comprising SYNIH (SEQ ID NO: 75), (2) a VH CDR2 comprising YIYPGNGGTNYNQKFKG (SEQ ID NO: 90), and (3) GRGFAY (SEQ ID NO: 120), and the VL comprises (1) a VL CDR1 comprising KSSQSLFNSGNQKNYLT (SEQ ID NO: 137), (2) a VL CDR2 comprising RASTRES (SEQ ID NO: 145), and (3) a VL CDR3 comprising QNDYSYPLT (SEQ ID NO: 160).

[0241] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 70, 97, and 120, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 138, 145, and 159, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0242] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 70, 98, and 120, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 145, and 160, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0243] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 75, 99, and 120, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 139, 146, and 160, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0244] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 75, 100, and 120, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 139, 146, and 160, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0245] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 70, 90, and 121, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 137, 145, and 160, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0246] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 76, 101, and 122, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 140, 147, and 160, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0247] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 76, 101, and 123, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 147, and 160, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0248] In some embodiments, the claudin 18.2 binding portion comprises an antibody having a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 from an antibody as Group 3 antibodies, including 370E2B12C3, 237D2A4, 203A6C9, and 201F4H6.

[0249] In some embodiments, the claudin 18.2-binding portion comprises the VH CDR1, CDR2, and CDR3, and / or the VL CDR1, CDR2, and CDR3, from a Group 3 antibody described herein, or a humanized version thereof. In some embodiments, the claudin 18.2-binding portion comprises the VH CDR1, CDR2, and CDR3, from a Group 3 antibody described herein. In some embodiments, the claudin 18.2-binding portion comprises the VL CDR1, CDR2, and CDR3, from a Group 3 antibody described herein. In some embodiments, the claudin 18.2-binding portion comprises the VH CDR1, CDR2, and CDR3, and the VL CDR1, CDR2, and CDR3, from a Group 3 antibody described herein. In some embodiments, the claudin 18.2-binding portion is a humanized version of a Group 3 antibody described herein. In some embodiments, the claudin 18.2-binding portion is a variant of a Group 3 antibody described herein.

[0250] In some embodiments, the claudin 18.2-binding moiety comprises a humanized version of a Group 3 antibody described herein. In some embodiments, the claudin 18.2-binding moiety comprises a variant of a Group 3 anti-claudin 18.2 antibody described herein. In some embodiments, the variant anti-claudin 18.2 antibody comprises 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, or 1 to 3 conservative amino acid substitutions. In some embodiments, the conservative amino acid substitutions are present in the CDRs of the antibody. In some embodiments, the conservative amino acid substitutions are not present in the CDRs of the antibody. In some embodiments, the conservative amino acid substitutions are present in the framework regions of the antibody.

[0251] In some embodiments, the VH comprises (a) a VH and / or (b) a VL, wherein the VH comprises (1) X 47 YGVX 48 (X 47 is T, S, or R, X 48 is H or S, SEQ ID NO: 180), and (2) VIWX 49 X 50 GX 51 TX 52 YX 53 X 54 X 55 X 56 X 57 S(X 49 is A, G, or S, X 50 is G or D, X 51 is S, N, X 52 is N or D, X 53 is N or H, X 54 is S, A, X 55 is A, T, or X 56 is L or F, X 57 is M or I, SEQ ID NO: 181); and (3) X 58 X 59 X 60 X 61 GNX 62 X 63 DY(X 58 is A or null, X 59is A, G, or V, X 60 is Y or R, X 61 is Y, F, or null, X 62 is A, G, or S, X 63 is L, F, or M, SEQ ID NO: 182), and the VL comprises (1) KSSQX 64 LLNSGNQKX 65 YLT(X 64 is T, S, or X 65 is N or S, SEQ ID NO: 192), and (2) WASTX 66 X 67 S(X 66 is G or R, X 67 is E or D, SEQ ID NO: 193), and (3) QNX 68 YX 69 X 70 PX 71 T(X 68 is A, D, N, or V, X 69 is F, S, or I, X 70 is Y or F, X 71 and a VL CDR3 comprising a VL CDR3 with a VL CDR3 where VL CDR3 is F or L, SEQ ID NO: 194.

[0252] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising (a) a VH and / or (b) a VL, wherein the VH comprises (1) a VH CDR1 comprising SYGVS (SEQ ID NO: 78), (2) a VH CDR2 comprising VIWAGGSTNYHSALMS (SEQ ID NO: 197), and (3) AAYYGNALDY (SEQ ID NO: 198), and the VL comprises (1) a VL CDR1 comprising KSSQSLLNSGNQKNYLT (SEQ ID NO: 136), (2) a VL CDR2 comprising WASTRES (SEQ ID NO: 143), and (3) a VL CDR3 comprising QNAYFYPFT (SEQ ID NO: 161).

[0253] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 77, 102, and 124, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 141, 148, and 161, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0254] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 78, 103, and 125, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 143, and 162, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0255] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 79, 104, and 126, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 149, and 163, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0256] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 78, 105, and 127, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 142, 143, and 164, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0257] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 209, 103, and 125, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 162, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0258] In some embodiments, the claudin 18.2 binding portion comprises an antibody having a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 from the antibodies described herein as Group 4 antibodies, including 429H6C5, 407D8G1, 419B5G9, 393C2C5, 412B6E4, 414A5F7, 418D2F9, and 410H6H3.

[0259] In some embodiments, the claudin 18.2-binding portion comprises the VH CDR1, CDR2, and CDR3, and / or the VL CDR1, CDR2, and CDR3, from a Group 4 antibody described herein, or a humanized version thereof. In some embodiments, the claudin 18.2-binding portion comprises the VH CDR1, CDR2, and CDR3, from a Group 4 antibody described herein. In some embodiments, the claudin 18.2-binding portion comprises the VL CDR1, CDR2, and CDR3, from a Group 4 antibody described herein. In some embodiments, the claudin 18.2-binding portion comprises the VH CDR1, CDR2, and CDR3, and the VL CDR1, CDR2, and CDR3, from a Group 4 antibody described herein. In some embodiments, the claudin 18.2-binding portion is a humanized version of a Group 4 antibody described herein. In some embodiments, the claudin 18.2-binding portion is a variant of a Group 4 antibody described herein.

[0260] In some embodiments, the claudin 18.2-binding moiety comprises a humanized version of a Group 4 antibody described herein. In some embodiments, the claudin 18.2-binding moiety comprises a variant of a Group 4 anti-claudin 18.2 antibody described herein. In some embodiments, the variant anti-claudin 18.2 antibody comprises 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, or 1 to 3 conservative amino acid substitutions. In some embodiments, the conservative amino acid substitutions are present in the CDRs of the antibody. In some embodiments, the conservative amino acid substitutions are not present in the CDRs of the antibody. In some embodiments, the conservative amino acid substitutions are present in the framework regions of the antibody.

[0261] In some embodiments, the VH comprises (a) a VH and / or (b) a VL, wherein the VH comprises (1) X 72 X 73 GMH(X 72 is S, G, or T, X 73is F or S, SEQ ID NO: 183), and (2) YIX 74 X 75 GSX 76 X 77 IX 78 YAX 79 X 80 X 81 X 82 G(X 74 is S, N, X 75 is S, G, or T, X 76 is S, R, T, or N, X 77 is T, P, X 78 is Y or F, X 79 is D or H, X 80 is T, S, or X 81 is V or L, X 82 is K or Q, SEQ ID NO: 184); and (3) X 83 YYGNSFX 84 X 85 (X 83 is F, I, X 84 is V, D, or A, X 85 is Y, N, or H, SEQ ID NO: 185), and the VL comprises (1) SSQX 86 LLNSGNQKNYLT(X 86 (1) a VL CDR1 comprising a VL CDR2 with a VL CDR3 (SEQ ID NO: 195) and a VL CDR4 with a VL CDR5 (SEQ ID NO: 143); and (2) a VL CDR6 with a VL CDR7 (SEQ ID NO: 144); 87 YX 88 X 89 PX 90 T(X 87 is A, D, or N, X 88 is I, S, T, or Y, X 89 is Y or F, X 90 and a VL CDR3 comprising a CDR1 wherein the CDR1 is L or V, SEQ ID NO: 196).

[0262] In some embodiments, a binding moiety that specifically binds to claudin 18.2 is provided, comprising (a) a VH and / or (b) a VL, wherein the VH comprises (1) a VH CDR1 comprising SGFTFSSFGMH (SEQ ID NO: 80), (2) a VH CDR2 comprising YISSGSSTIYYADTVKG (SEQ ID NO: 199), and (3) FYYGNSFAY (SEQ ID NO: 130), and the VL comprises (1) a VL CDR1 comprising KSSQSLLNSGNQKNYLT (SEQ ID NO: 136), (2) a VL CDR2 comprising WASTRES (SEQ ID NO: 143), and (3) a VL CDR3 comprising QNAYSYPLT (SEQ ID NO: 167).

[0263] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 80, 106, and 128, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 143, and 165, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0264] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 81, 107, and 129, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 143, and 166, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0265] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 82, 108, and 130, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 143, and 167, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0266] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 80, 109, and 130, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 141, 143, and 168, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0267] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 83, 110, and 130, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 143, and 169, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0268] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 80, 109, and 131, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 141, 143, and 170, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0269] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 80, 111, and 132, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 143, and 160, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0270] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 84, 112, and 132, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 171, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0271] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 391, and 129, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 162, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0272] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 109, and 131, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 141, 143, and 167, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0273] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 107, and 129, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 141, 143, and 166, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0274] In some embodiments, the claudin-18.2 binding portion comprises an antibody having a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and / or VL CDR3 from an antibody designated as the group "other" antibodies, including 59B6C4, 246B5F2, 418G6A5, 417A6F11, 28C5B1, 35E8D2, 61H12G10, 69D5C1, 181C7B2, 196A12B10, 232D7C8, 233D5E5, 232F1E4, 231H4G11, 226A4B5, 235A10C9, 239H12G9, 248E6A7, 254A8D5, 259C6F4, or 280F3B6.

[0275] In some embodiments, the claudin 18.2-binding moiety comprises a VH CDR1, CDR2, and CDR3, and / or a VL CDR1, CDR2, and CDR3, from a Group "Other" antibody described herein, or a humanized version thereof. In some embodiments, the claudin 18.2-binding moiety comprises a VH CDR1, CDR2, and CDR3, from a Group "Other" antibody described herein. In some embodiments, the claudin 18.2-binding moiety comprises a VL CDR1, CDR2, and CDR3, from a Group "Other" antibody described herein. In some embodiments, the claudin 18.2-binding moiety comprises a VH CDR1, CDR2, and CDR3, and a VL CDR1, CDR2, and CDR3, from a Group "Other" antibody described herein. In some embodiments, the claudin 18.2-binding moiety is a humanized version of a Group "Other" antibody described herein. In some embodiments, the claudin 18.2-binding moiety is a variant of a Group "Other" antibody described herein.

[0276] In some embodiments, the claudin 18.2-binding portion comprises a variant of an antibody from the group "other" described herein. In some embodiments, the variant anti-claudin 18.2 antibody comprises 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, or 1 to 3 conservative amino acid substitutions. In some embodiments, the conservative amino acid substitutions are present in the CDRs of the antibody. In some embodiments, the conservative amino acid substitutions are not present in the CDRs of the antibody. In some embodiments, the conservative amino acid substitutions are present in the framework regions of the antibody.

[0277] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 85, 113, and 133, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 143, and 172, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0278] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 86, 114, and 134, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 172, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0279] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 87, 115, and 131, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 143, and 167, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0280] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 88, 116, and 135, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 173, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0281] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequences of SEQ ID NOs: 203, 211, and 225, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequences of SEQ ID NOs: 233, 241, and 242, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0282] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 204, 212, and 226, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 143, and 243, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0283] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 205, 213, and 227, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 234, 143, and 244, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0284] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 206, 214, and 131, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 235, 143, and 245, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0285] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 207, 215, and 228, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 143, and 163, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0286] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 208, 216, and 229, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 236, 143, and 246, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0287] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 69, 90, and 230, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 237, 143, and 151, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0288] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 69, 217, and 117, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 137, 143, and 247, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0289] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 209, 218, and 231, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 143, and 248, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0290] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 72, 219, and 117, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 238, 143, and 157, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0291] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 75, 220, and 120, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 137, 145, and 160, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0292] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 69, 221, and 117, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 143, and 150, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0293] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 72, 222, and 118, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 143, and 151, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0294] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 69, 223, and 118, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 239, 143, and 249, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0295] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 210, 224, and 232, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 240, 143, and 245, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0296] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 72, 217, and 118, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 136, 143, and 250, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0297] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 with the amino acid sequences of SEQ ID NOs: 69, 90, and 117, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs, and / or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 with the amino acid sequences of SEQ ID NOs: 137, 143, and 153, respectively, or variants thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0298] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 85, 113, and 133, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 172, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0299] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 392, 393, and 394, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 163, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0300] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 392, 395, and 396, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 163, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0301] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 397, 398, and 399, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 456, 457, and 250, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0302] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 75, 400, and 120, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 458, 146, and 160, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0303] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 70, 401, and 120, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 145, and 160, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0304] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 402, 403, and 404, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 240, 143, and 244, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0305] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 219, and 117, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 137, 143, and 157, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0306] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 71, 405, and 117, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 459, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0307] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 406, 407, and 408, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 460, 461, and 462, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0308] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 90, and 117, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 137, 463, and 464, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0309] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 409, 410, and 411, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 465, 466, and 162, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0310] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 219, and 416, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 137, 143, and 157, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0311] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 76, 412, and 411, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 140, 147, and 160, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0312] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 413, 414, and 415, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 467, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0313] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 417, 418, and 232, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 244, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0314] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 419, and 420, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 468, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0315] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 205, 421, and 422, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 469, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0316] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 205, 423, and 424, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 154, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0317] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 391, and 129, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 240, 143, and 166, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0318] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 88, 425, and 135, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 470, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0319] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 426, and 129, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 166, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0320] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 109, and 130, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 471, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0321] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 427, 428, and 429, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 472, 473, and 474, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0322] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 391, and 129, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 475, 143, and 166, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0323] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 430, 391, and 431, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 476, 143, and 166, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0324] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 109, and 129, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 477, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0325] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 391, and 129, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 478, 143, and 166, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0326] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 432, and 129, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 475, 143, and 166, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0327] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 433, 391, and 129, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 475, 143, and 166, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0328] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 109, and 129, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 479, 143, and 163, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0329] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 434, 435, and 129, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 240, 143, and 166, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0330] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 436, 428, and 429, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 472, 473, and 474, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0331] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 437, and 129, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 479, 143, and 163, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0332] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 391, and 129, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 478, 143, and 166, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0333] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 438, and 129, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 166, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0334] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 391, and 129, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 480, 143, and 481, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0335] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 439, and 441, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 482, 143, and 483, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0336] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 433, 391, and 431, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 475, 143, and 166, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0337] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 442, and 443, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 160, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0338] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 80, 440, and 441, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 482, 143, and 484, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0339] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 444, 445, and 446, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 485, 486, and 487, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0340] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 447, 448, and 449, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 488, 489, and 490, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0341] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 450, 451, and 452, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 491, 492, and 493, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0342] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 81, 453, and 129, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 166, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0343] In some embodiments, the claudin 18.2 binding portion comprises a VH comprising a VH CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 69, 89, and 454, respectively, and / or a VL comprising a VL CDR1, CDR2, and CDR3 having the amino acid sequences of SEQ ID NOs: 136, 143, and 494, respectively, or a variant thereof with 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs.

[0344] In some embodiments, the claudin 18.2-binding portion comprises an amino acid sequence having at least about 80% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-68, 251-290, 337-387, and 495-680. In some embodiments, the claudin 18.2-binding portion comprises an amino acid sequence having at least about 85%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-68, 251-290, 337-387, and 495-680. In some embodiments, the claudin 18.2-binding portion comprises an amino acid sequence having at least about 85% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-68, 251-290, 337-387, and 495-680. In some embodiments, the claudin 18.2-binding portion comprises an amino acid sequence having at least about 90% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-68, 251-290, 337-387, and 495-680. In some embodiments, the claudin 18.2-binding portion comprises an amino acid sequence having at least about 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-68, 251-290, 337-387, and 495-680. In some embodiments, the claudin 18.2-binding portion comprises an amino acid sequence having at least about 97% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-68, 251-290, 337-387, and 495-680. In some embodiments, the claudin 18.2-binding portion comprises an amino acid sequence having at least about 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-68, 251-290, 337-387, and 495-680. In some embodiments, the claudin 18.2-binding portion comprises an amino acid sequence that is an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-68, 251-290, 337-387, and 495-680.

[0345] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80% sequence identity to an amino acid sequence selected from the group consisting of odd-numbered SEQ ID NOs: 1-68, 251-290, and 495-680, and both odd-numbered and even-numbered SEQ ID NOs: 337-345, 348-352, 355-362, 365-369, 372-374, 378-380, and 383-385, and / or (ii) a VL comprising an amino acid sequence having at least 80% sequence identity to an amino acid sequence selected from the group consisting of even-numbered SEQ ID NOs: 1-68, 251-290, and 495-680, and SEQ ID NOs: 346, 347, 353, 354, 363, 364, 370, 371, 375, 376, 377, 381, 382, 386, and 387. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 85% sequence identity to an amino acid sequence selected from the group consisting of odd-numbered SEQ ID NOs: 1-68, 251-290, and 495-680, and both odd-numbered and even-numbered SEQ ID NOs: 337-345, 348-352, 355-362, 365-369, 372-374, 378-380, and 383-385, and / or (ii) a VL comprising an amino acid sequence having at least 85% sequence identity to an amino acid sequence selected from the group consisting of even-numbered SEQ ID NOs: 1-68, 251-290, and 495-680, and SEQ ID NOs: 346, 347, 353, 354, 363, 364, 370, 371, 375, 376, 377, 381, 382, 386, and 387.In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 90% sequence identity to an amino acid sequence selected from the group consisting of odd-numbered SEQ ID NOs: 1-68, 251-290, and 495-680, and both odd-numbered and even-numbered SEQ ID NOs: 337-345, 348-352, 355-362, 365-369, 372-374, 378-380, and 383-385, and / or (ii) a VL comprising an amino acid sequence having at least 90% sequence identity to an amino acid sequence selected from the group consisting of even-numbered SEQ ID NOs: 1-68, 251-290, and 495-680, and SEQ ID NOs: 346, 347, 353, 354, 363, 364, 370, 371, 375, 376, 377, 381, 382, 386, and 387. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 95% sequence identity to an amino acid sequence selected from the group consisting of odd-numbered SEQ ID NOs: 1-68, 251-290, and 495-680, and both odd-numbered and even-numbered SEQ ID NOs: 337-345, 348-352, 355-362, 365-369, 372-374, 378-380, and 383-385, and / or (ii) a VL comprising an amino acid sequence having at least 95% sequence identity to an amino acid sequence selected from the group consisting of even-numbered SEQ ID NOs: 1-68, 251-290, and 495-680, and SEQ ID NOs: 346, 347, 353, 354, 363, 364, 370, 371, 375, 376, 377, 381, 382, 386, and 387.In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 98% sequence identity to an amino acid sequence selected from the group consisting of odd-numbered SEQ ID NOs: 1-68, 251-290, and 495-680, and both odd-numbered and even-numbered SEQ ID NOs: 337-345, 348-352, 355-362, 365-369, 372-374, 378-380, and 383-385, and / or (ii) a VL comprising an amino acid sequence having at least 98% sequence identity to an amino acid sequence selected from the group consisting of even-numbered SEQ ID NOs: 1-68, 251-290, and 495-680, and SEQ ID NOs: 346, 347, 353, 354, 363, 364, 370, 371, 375, 376, 377, 381, 382, 386, and 387. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence selected from the group consisting of odd-numbered SEQ ID NOs: 1-68, 251-290, and 495-680, and both odd-numbered and even-numbered SEQ ID NOs: 337-345, 348-352, 355-362, 365-369, 372-374, 378-380, and 383-385; and / or (ii) a VL comprising an amino acid sequence selected from the group consisting of even-numbered SEQ ID NOs: 1-68, 251-290, and 495-680, and SEQ ID NOs: 346, 347, 353, 354, 363, 364, 370, 371, 375, 376, 377, 381, 382, 386, and 387.

[0346] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 1, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 2. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 1, and / or (ii) a VL comprising SEQ ID NO: 2.

[0347] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 3, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 4. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 3, and / or (ii) a VL comprising SEQ ID NO: 4.

[0348] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 5, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 6. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 5, and / or (ii) a VL comprising SEQ ID NO: 6.

[0349] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 7, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 8. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 7, and / or (ii) a VL comprising SEQ ID NO: 8.

[0350] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 9, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 10. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 9, and / or (ii) a VL comprising SEQ ID NO: 10.

[0351] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 11, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 12. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 11, and / or (ii) a VL comprising SEQ ID NO: 12.

[0352] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 13, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 14. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 13, and / or (ii) a VL comprising SEQ ID NO: 14.

[0353] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 15, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 16. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 15, and / or (ii) a VL comprising SEQ ID NO: 16.

[0354] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 17, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 18. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 17, and / or (ii) a VL comprising SEQ ID NO: 18.

[0355] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 19, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 20. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 19, and / or (ii) a VL comprising SEQ ID NO: 20.

[0356] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 21, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 22. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 21, and / or (ii) a VL comprising SEQ ID NO: 22.

[0357] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 23, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 24. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 23, and / or (ii) a VL comprising SEQ ID NO: 24.

[0358] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 25, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 26. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 25, and / or (ii) a VL comprising SEQ ID NO: 26.

[0359] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 27, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 28. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 27, and / or (ii) a VL comprising SEQ ID NO: 28.

[0360] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 29, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 30. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 29, and / or (ii) a VL comprising SEQ ID NO: 30.

[0361] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 31, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 32. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 31, and / or (ii) a VL comprising SEQ ID NO: 32.

[0362] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 33, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 34. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 33, and / or (ii) a VL comprising SEQ ID NO: 34.

[0363] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 35, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 36. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 35, and / or (ii) a VL comprising SEQ ID NO: 36.

[0364] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 37, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 38. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 37, and / or (ii) a VL comprising SEQ ID NO: 38.

[0365] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 39, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 40. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 39, and / or (ii) a VL comprising SEQ ID NO: 40.

[0366] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 41, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 42. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 41, and / or (ii) a VL comprising SEQ ID NO: 42.

[0367] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 43, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 44. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 43, and / or (ii) a VL comprising SEQ ID NO: 44.

[0368] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 45, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 46. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 45, and / or (ii) a VL comprising SEQ ID NO: 46.

[0369] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 47, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 48. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 47, and / or (ii) a VL comprising SEQ ID NO: 48.

[0370] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 49, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 50. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 49, and / or (ii) a VL comprising SEQ ID NO: 50.

[0371] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 51, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 52. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 51, and / or (ii) a VL comprising SEQ ID NO: 52.

[0372] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 53, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 54. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 53, and / or (ii) a VL comprising SEQ ID NO: 54.

[0373] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 55, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 56. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 55, and / or (ii) a VL comprising SEQ ID NO: 56.

[0374] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 57, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 58. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 57, and / or (ii) a VL comprising SEQ ID NO: 58.

[0375] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 59, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 60. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 59, and / or (ii) a VL comprising SEQ ID NO: 60.

[0376] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 61, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 62. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 61, and / or (ii) a VL comprising SEQ ID NO: 62.

[0377] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 63, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 64. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 63, and / or (ii) a VL comprising SEQ ID NO: 64.

[0378] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 65, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 66. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 65, and / or (ii) a VL comprising SEQ ID NO: 66.

[0379] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 67, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 68. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 67, and / or (ii) a VL comprising SEQ ID NO: 68.

[0380] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 251, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 252. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 251, and / or (ii) a VL comprising SEQ ID NO: 252.

[0381] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 253, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 254. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 253, and / or (ii) a VL comprising SEQ ID NO: 254.

[0382] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 255, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 256. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 255, and / or (ii) a VL comprising SEQ ID NO: 256.

[0383] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 257, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 258. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 257, and / or (ii) a VL comprising SEQ ID NO: 258.

[0384] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 259, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 260. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 259, and / or (ii) a VL comprising SEQ ID NO: 260.

[0385] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 261, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 262. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 261, and / or (ii) a VL comprising SEQ ID NO: 262.

[0386] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 263, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 264. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 263, and / or (ii) a VL comprising SEQ ID NO: 264.

[0387] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 265, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 266. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 265, and / or (ii) a VL comprising SEQ ID NO: 266.

[0388] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 267, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 268. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 267, and / or (ii) a VL comprising SEQ ID NO: 268.

[0389] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 269, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 270. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 269, and / or (ii) a VL comprising SEQ ID NO: 270.

[0390] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 271, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 272. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 271, and / or (ii) a VL comprising SEQ ID NO: 272.

[0391] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 273, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 274. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 273, and / or (ii) a VL comprising SEQ ID NO: 274.

[0392] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 275, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 276. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 275, and / or (ii) a VL comprising SEQ ID NO: 276.

[0393] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 277, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 278. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 277, and / or (ii) a VL comprising SEQ ID NO: 278.

[0394] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 279, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 280. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 279, and / or (ii) a VL comprising SEQ ID NO: 280.

[0395] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 281, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 282. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 281, and / or (ii) a VL comprising SEQ ID NO: 282.

[0396] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 283, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 284. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 283, and / or (ii) a VL comprising SEQ ID NO: 284.

[0397] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 285, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 286. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 285, and / or (ii) a VL comprising SEQ ID NO: 286.

[0398] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 287, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 288. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 287, and / or (ii) a VL comprising SEQ ID NO: 288.

[0399] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 289, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to SEQ ID NO: 290. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising SEQ ID NO: 289, and / or (ii) a VL comprising SEQ ID NO: 290.

[0400] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to any of SEQ ID NOs: 337-345, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to any of SEQ ID NOs: 346 and 347. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising any of SEQ ID NOs: 337-345, and / or (ii) a VL comprising any of SEQ ID NOs: 346 and 347.

[0401] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to any of SEQ ID NOs: 348-352, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to any of SEQ ID NOs: 353 and 354. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising any of SEQ ID NOs: 348-352, and / or (ii) a VL comprising any of SEQ ID NOs: 353 and 354.

[0402] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to any of SEQ ID NOs: 355-362, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to any of SEQ ID NOs: 363 and 364. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising any of SEQ ID NOs: 355-362, and / or (ii) a VL comprising any of SEQ ID NOs: 363 and 364.

[0403] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to any of SEQ ID NOs: 365-369, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to any of SEQ ID NOs: 370 and 371. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising any of SEQ ID NOs: 365-369, and / or (ii) a VL comprising any of SEQ ID NOs: 370 and 371.

[0404] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to any of SEQ ID NOs: 372-374, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to any of SEQ ID NOs: 375-377. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising any of SEQ ID NOs: 372-374, and / or (ii) a VL comprising any of SEQ ID NOs: 375-377.

[0405] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to any of SEQ ID NOs: 378-380, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to any of SEQ ID NOs: 381 and 382. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising any of SEQ ID NOs: 378-380, and / or (ii) a VL comprising any of SEQ ID NOs: 381 and 382.

[0406] In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to any of SEQ ID NOs: 383-385, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to any of SEQ ID NOs: 386 and 387. In some embodiments, the claudin 18.2-binding portion comprises (i) a VH comprising any of SEQ ID NOs: 383-385, and / or (ii) a VL comprising any of SEQ ID NOs: 386 and 387.

[0407] In some embodiments, as shown in Tables 1 and 2, the claudin 18.2-binding portion comprises (i) a VH comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to any of odd-numbered SEQ ID NOs: 495-680, and / or (ii) a VL comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% sequence identity to any of even-numbered SEQ ID NOs: 495-680 that matches an odd-numbered SEQ ID NO: 495-680. In some embodiments, as shown in Tables 1 and 2, the claudin 18.2-binding portion comprises (i) a VH comprising one of odd-numbered SEQ ID NOs: 495-680, and / or (ii) a VL comprising one of even-numbered SEQ ID NOs: 495-680 that matches an odd-numbered SEQ ID NO: 495-680.

[0408] In some embodiments, the binding moiety competes with an anti-claudin-18.2 antibody disclosed herein for binding to claudin-18.2. In some embodiments, the binding moiety competes with an antibody listed in Tables 1 and 2 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 260G9E8 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 252F1B10 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 257B1G9 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 265E6G2 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 250F4G4 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 262C7C10 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 240F8G2 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 232C5E3 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 252E7C9 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 257G7B9 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 241H10A1 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 273C10E5 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 185F2G12 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 194D3B2 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 207F8G5 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 222B6G5 for binding to claudin 18.2.In some embodiments, the binding moiety competes with 182D10F1 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 234B9D4 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 253E4F7 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 198F10B8 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 213B10A4 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 370E2B12C3 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 237D2A4 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 203A6C9 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 201F4H6 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 429H6C5 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 407D8G1 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 419B5G9 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 393C2C5 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 412B6E4 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 414A5F7 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 418D2F9 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 410H6H3 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 59B6C4 for binding to claudin 18.2. In some embodiments, the binding moiety competes with 246B5F2 for binding to claudin 18.2.In some embodiments, the binding moiety competes with 418G6A5 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 417A6F11 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 28C5B1 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 35E8D2 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 61H12G10 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 69D5C1 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 181C7B2 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 196A12B10 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 232D7C8 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 233D5E5 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 232F1E4 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 231H4G11 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 226A4B5 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 235A10C9 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 239H12G9 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 248E6A7 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 254A8D5 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 259C6F4 for binding to claudin-18.2. In some embodiments, the binding moiety competes with 280F3B6 for binding to claudin 18.2.In some embodiments, the binding moiety competes for binding to claudin 18.2 with any of the other anti-claudin 18.2 antibodies described herein, including murine, chimeric, and humanized antibodies.

[0409] The present invention further encompasses additional variants and equivalents that are substantially homologous to the recombinant antibodies, monoclonal antibodies, chimeric antibodies, humanized antibodies, and human antibodies described herein, or antibody fragments thereof. In some embodiments, it is desirable to improve the binding affinity of the antibody. In some embodiments, it is desirable to modulate the biological properties of the antibody, including, but not limited to, specificity, thermal stability, expression level, effector function, glycosylation, immunogenicity, and / or solubility. Those skilled in the art will understand that amino acid changes can alter post-translational processes of the antibody, such as the number or position of glycosylation sites or membrane anchoring properties.

[0410] Mutations may be substitutions, deletions, or insertions of one or more nucleotides encoding the antibody or polypeptide, resulting in a change in the amino acid sequence compared to the native antibody or polypeptide sequence. In some embodiments, amino acid substitutions result in the substitution of one amino acid with another having similar structural and / or chemical properties, e.g., a serine for a leucine, i.e., a conservative amino acid substitution. Insertions or deletions may range from about 1 to 5 amino acids. In some embodiments, substitutions, deletions, or insertions include Fc receptors (epsilon receptors), IgA (alpha receptors), and IgM (mu receptors). Binding of antibodies to Fc receptors on the cell surface triggers many important and diverse biological responses, such as phagocytosis and destruction of antibody-coated particles, clearance of immune complexes, lysis of antibody-coated target cells by killer cells (termed antibody-dependent cellular cytotoxicity, ADCC), release of inflammatory mediators, placental transfer, and regulation of immunoglobulin production.

[0411] In some embodiments, the claudin 18.2-binding moieties described herein include antibodies in which at least one or more of the constant regions have been modified or deleted. In some embodiments, the antibodies include modifications to one or more of the three heavy chain constant regions (CH1, CH2, or CH3) and / or the light chain constant region (CL). In some embodiments, the heavy chain constant region of the modified antibody includes at least one human constant region. In some embodiments, the heavy chain constant region of the modified antibody includes two or more human constant regions. In some embodiments, modifications to the constant region include the addition, deletion, or substitution of one or more amino acids in one or more regions. In some embodiments, one or more regions are partially or completely deleted from the constant region of the modified antibody. In some embodiments, the entire CH2 domain is removed from the antibody (ΔCH2 construct). In some embodiments, the deleted constant region is replaced by a short amino acid spacer that confers some of the molecular flexibility typically imparted by the absent constant region. In some embodiments, the modified antibody includes a CH3 domain fused directly to the hinge region of the antibody. In some embodiments, the modified antibody comprises a peptide spacer inserted between the hinge region and the modified CH2 and / or CH3 domain.

[0412] It is well known in the art that the constant region of an antibody mediates several effector functions, and these effector functions can vary depending on the antibody isotype. For example, binding of the C1 component of complement to the Fc region of an IgG or IgM antibody (which binds to an antigen) activates the complement system. Complement activation is important in the opsonization and lysis of cellular pathogens. Complement activation also stimulates inflammatory responses and may be involved in autoimmune hypersensitivity. Furthermore, the Fc region of an antibody can bind to cells expressing Fc receptors (FcRs). There are many Fc receptors specific for different classes of antibodies, including IgG (gamma receptors), IgE (epsilon receptors), IgA (alpha receptors), and IgM (mu receptors). The binding of antibodies to Fc receptors on cell surfaces triggers many important and diverse biological responses, including the phagocytosis and destruction of antibody-coated particles, clearance of immune complexes, lysis of antibody-coated target cells by killer cells (called antibody-dependent cellular cytotoxicity, ADCC), release of inflammatory mediators, placental transfer, and regulation of immunoglobulin production.

[0413] In some embodiments, the claudin 18.2-binding moiety comprises an Fc region. The amino acid sequences of the Fc regions of human IgG1, IgG2, IgG3, and IgG4 are known to those skilled in the art. In some cases, Fc regions with amino acid mutations are recognized by natural antibodies. In some embodiments, modified antibodies (e.g., modified Fc regions) result in altered effector functions, which in turn affect the biological profile of the antibody. For example, in some embodiments, deletion or inactivation of the constant region (by point mutation or other means) reduces Fc receptor binding of the modified antibody in circulation. In some embodiments, modification of the constant region extends the serum half-life of the antibody. In some embodiments, modification of the constant region shortens the serum half-life of the antibody. In some embodiments, modification of the constant region reduces or eliminates ADCC and / or complement-dependent cytotoxicity (CDC) of the antibody. In some embodiments, substitution of specific amino acids in the human IgG1 Fc region with corresponding IgG2 or IgG4 residues reduces effector function (e.g., ADCC and CDC) in the modified antibody. In some embodiments, the antibody does not have one or more effector functions (e.g., an effectorless antibody). In some embodiments, the antibody does not have ADCC activity and / or CDC activity. In some embodiments, the antibody does not bind to Fc receptors and / or complement factors. In some embodiments, the antibody does not have effector functions. In some embodiments, modification of the constant region increases or improves the ADCC and / or CDC of the antibody. In some embodiments, the constant region is altered to eliminate disulfide bonds or oligosaccharide moieties. In some embodiments, the constant region is altered to add / substitute one or more amino acids to provide one or more cytotoxin, oligosaccharide, or carbohydrate attachment sites. In some embodiments, the claudin-18.2-binding moiety comprises a mutant Fc region altered by substitutions at specific amino acid positions compared to a native Fc region. In some embodiments, the Fc region is fused via a hinge.The hinge can be an IgG1 hinge, an IgG2 hinge, or an IgG3 hinge.

[0414] In some embodiments, variants may include additional amino acid residues at the amino and / or carboxyl termini of the antibody or polypeptide. The length of the additional amino acid residues may range from 1 to 100 or more residues. In some embodiments, variants include an N-terminal methionyl residue. In some embodiments, variants include an additional polypeptide / protein (e.g., an Fc region) to create a fusion protein. In some embodiments, variants may be modified to be detectable and include a detectable label and / or protein (e.g., a fluorescent tag or an enzyme).

[0415] Mutant antibodies or polypeptides described herein can be produced by methods well known in the art, including but not limited to site-directed mutagenesis, alanine scanning mutagenesis, and PCR mutagenesis.

[0416] In some embodiments, variants of claudin 18.2-binding moieties disclosed herein can retain the ability to recognize a target (e.g., claudin 18.2) to a similar, identical, or greater extent than the parent binding moiety. In some embodiments, the amino acid sequence of the variant has at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identity to the amino acid sequence of the parent binding moiety. In some embodiments, the amino acid sequence of the variant can have at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identity to the amino acid sequence of an antibody disclosed herein.

[0417] In certain embodiments, the variant of the claudin 18.2-binding moiety comprises the amino acid sequence of the parent claudin 18.2-binding moiety with one or more conservative amino acid substitutions. Conservative amino acid substitutions are known in the art and include amino acid substitutions in which an amino acid with certain physical and / or chemical properties is replaced with another amino acid with the same or similar chemical or physical properties.

[0418] In some embodiments, a variant of a claudin 18.2-binding moiety comprises the amino acid sequence of a parent binding moiety with one or more non-conservative amino acid substitutions. In some embodiments, a variant of a claudin 18.2-binding moiety comprises the amino acid sequence of a parent binding moiety with one or more non-conservative amino acid substitutions that do not interfere with or inhibit one or more biological activities (e.g., claudin 18.2 binding) of the variant. In certain embodiments, the one or more conservative amino acid substitutions and / or one or more non-conservative amino acid substitutions can improve the biological activity of the variant. As a result, the biological activity of the functional variant is greater than that of the parent binding moiety.

[0419] In some embodiments, functional variants may have 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs of the binding moiety (e.g., VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3).

[0420] In some embodiments, the claudin 18.2-binding moieties described herein are chemically modified, either naturally or by intervention. In some embodiments, the claudin 18.2-binding moiety is an anti-claudin 18.2 antibody that has been chemically modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, and / or binding to a cellular ligand or other protein. Any of a number of chemical modifications can be performed using conventional techniques. The antigen-binding fragments of embodiments of the present invention can include one or more analogs of amino acids (e.g., including unnatural amino acids), as well as other modifications known in the art.

[0421] In some embodiments, the claudin 18.2 binding moiety (e.g., an antibody) has a dissociation constant (K) of about 1 μM or less, about 100 nM or less, about 40 nM or less, about 20 nM or less, about 10 nM or less, about 1 nM or less, about 0.1 nM or less, 50 pM or less, 10 pM or less, or 1 pM or less. D In some embodiments, the claudin 18.2-binding moiety binds to claudin 18.2 (e.g., human claudin 18.2) with a K of about 20 nM or less. D In some embodiments, the claudin 18.2-binding moiety binds to claudin 18.2 (e.g., human claudin 18.2) with a K of about 10 nM or less. D In some embodiments, the claudin 18.2-binding moiety binds to claudin 18.2 (e.g., human claudin 18.2) with a K of about 1 nM or less. D In some embodiments, the claudin 18.2-binding moiety binds to claudin 18.2 (e.g., human claudin 18.2) with a K of about 0.5 nM or less. D In some embodiments, the claudin 18.2-binding moiety binds to claudin 18.2 (e.g., human claudin 18.2) with a K of about 0.1 nM or less. DIn some embodiments, the claudin 18.2-binding moiety binds to claudin 18.2 (e.g., human claudin 18.2) with a K of about 50 pM or less. D In some embodiments, the claudin 18.2-binding moiety binds to claudin 18.2 (e.g., human claudin 18.2) with a K of about 25 pM or less. D In some embodiments, the claudin 18.2-binding moiety binds to claudin 18.2 (e.g., human claudin 18.2) with a K of about 10 pM or less. D In some embodiments, the claudin 18.2-binding moiety binds to claudin 18.2 (e.g., human claudin 18.2) with a K of about 1 pM or less. D In some embodiments, the dissociation constant of a binding agent (e.g., an antibody) for claudin 18.2 is determined by immobilizing claudin 18.2 protein on a Biacore chip and flowing the binding agent over the chip. In some embodiments, the dissociation constant of a binding agent (e.g., an antibody) for claudin 18.2 is determined by capturing the binding agent with an anti-human IgG antibody on a Biacore chip and flowing soluble claudin 18.2 over the chip.

[0422] In some embodiments, the claudin 18.2 binding moiety (e.g., an antibody) has a median effective concentration (EC ) of about 1 μM or less, about 100 nM or less, about 40 nM or less, about 20 nM or less, about 10 nM or less, about 1 nM or less, or about 0.1 nM or less. 50 In some embodiments, the claudin 18.2-binding moiety binds to claudin 18.2 (e.g., human claudin 18.2) with an EC of about 1 μM or less, about 100 nM or less, about 40 nM or less, about 20 nM or less, about 10 nM or less, about 1 nM or less, or about 0.1 nM or less. 50 In some embodiments, the claudin 18.2-binding moiety binds to human claudin 18.2 with an EC 50In some embodiments, the claudin 18.2-binding moiety binds to human claudin 18.2 with an EC 50 In some embodiments, the claudin 18.2-binding moiety binds to human claudin 18.2 with an EC 50 In some embodiments, the claudin 18.2-binding moiety binds to human claudin 18.2 with an EC 50 In some embodiments, the claudin 18.2 binding moiety binds to human claudin 18.2 with an EC 50 Binds to human claudin 18.2 at 1000 kJ / s.

[0423] In some embodiments, polynucleotides are provided, including polynucleotides encoding the polypeptides (i.e., claudin 18.2-binding moieties) described herein. The term "polynucleotide encoding a polypeptide" encompasses polynucleotides that contain only the coding sequence of the polypeptide, as well as polynucleotides that contain additional coding and / or non-coding sequences. Polynucleotides of the present invention may be in the form of RNA or DNA. DNA includes cDNA, genomic DNA, and synthetic DNA, and may be double-stranded or single-stranded, and the single strand may be the coding strand or non-coding (antisense) strand.

[0424] In some embodiments, the polynucleotide comprises a polynucleotide (eg, a nucleotide sequence) that encodes a polypeptide comprising an amino acid sequence selected from SEQ ID NOs: 1-68, 251-290, 337-387, and 495-680.

[0425] The present invention also provides variants of polynucleotides, which encode, for example, fragments, analogs, and / or derivatives of the claudin 18.2-binding moieties described herein. In some embodiments, the present invention provides polynucleotides comprising a polynucleotide, including polynucleotides having a nucleotide sequence that is at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to a polynucleotide sequence encoding a polypeptide described herein.

[0426] As used herein, the phrase "a polynucleotide having a nucleotide sequence with at least about 95% identity to a polynucleotide sequence" means that the nucleotide sequence of the polynucleotide is identical to the reference sequence, except that the polynucleotide sequence may contain up to 5 point mutations for every 100 nucleotides of the reference nucleotide sequence.In other words, to obtain a polynucleotide having a nucleotide sequence wit...

Claims

1. A binding moiety that specifically binds to claudin 18.2, comprising a VH and a VL, wherein the VH and VL are: (1) the amino acid sequences of SEQ ID NOs: 37 and 38, respectively; (2) an amino acid sequence of any one of SEQ ID NOs: 372 to 374 and an amino acid sequence of any one of SEQ ID NOs: 375 to 377; (3) the amino acid sequences of SEQ ID NOs: 39 and 40, respectively; (4) the amino acid sequences of SEQ ID NOs: 41 and 42, respectively; or (5) The amino acid sequence of any one of SEQ ID NOs: 355 to 362 and the amino acid sequence of SEQ ID NO: 363 or 364 A coupling portion comprising:

2. Fab, Fab', F(ab') ２ , Fv, scFv, (scFv) ２ 10. The binding moiety of claim 1, which is a full-length antibody.

3. 10. A pharmaceutical composition comprising a therapeutically effective amount of the binding moiety of claim 1 or 2 and a pharmaceutically acceptable carrier.

4. A compound according to claim 3 for use in treating tumors or cancers that express claudin 18.

2. A pharmaceutical composition comprising:

5. The pharmaceutical composition described in claim 4, wherein the tumor or cancer expressing claudin 18.2 is a tumor or cancer of the stomach, esophagus, gastroesophageal, pancreas, ovary, or lung.

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