Anti-CLDN18.2 antibody-drug conjugates, pharmaceutical compositions thereof and uses thereof

Abstract

The present invention relates to the field of biotechnology and provides an anti-CLDN18.2 antibody-drug conjugate comprising an antibody or antigen-binding fragment thereof linked to a linker and a cytotoxic drug, as well as pharmaceutical compositions and uses thereof. The provided antibody-drug conjugate exhibits excellent antitumor activity and / or good safety.

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims priority to and benefit of Chinese patent application No. CN202211521035.0, filed on November 30, 2022, which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to an antibody-drug conjugate in the field of biotechnology, comprising an antibody or antigen-binding fragment thereof, a linker, and a payload (e.g., a cytotoxic drug), which are linked together. The present disclosure also relates to the use of the antibody-drug conjugate in the manufacture of a medicament for treating tumors. [Background technology]

[0003] Tight junction protein 18 (CLDN18 or Claudin18) belongs to the cellular tight junction protein family and is involved in the formation of tight junctions between cells. It regulates the flow of molecules between cells and plays an important role in maintaining cell polarity, permeability, and intercellular signaling. CLDN18 is a four-transmembrane protein with both its N- and C-termini located intracellularly and two extracellular loop regions. Alternative RNA splicing results in two distinct isoforms in tissues: tight junction protein 18.1 (CLDN18.1, e.g., the Uniprot accession number for human CLDN18.1 is P56856-1) and tight junction protein 18.2 (CLDN18.2, e.g., the Uniprot accession number for human CLDN18.2 is P56856-2).

[0004] Although the protein sequences of CLDN18.1 (Claudin 18.1) and CLDN18.2 (Claudin 18.2) are highly similar, their expression distributions differ: CLDN18.1 is selectively expressed in normal lung tissue, whereas CLDN18.2 is expressed in very limited normal tissues and is specifically expressed only in differentiated epithelial cells of the gastric mucosa. However, studies have shown that CLDN18.2 is highly expressed in 70% of primary gastric cancers and their metastatic lesions, and that CLDN18.2 is frequently ectopically activated in various malignant tumors, including pancreatic cancer, esophageal cancer, lung cancer, breast cancer, ovarian cancer, and ENT tumors (Niimi et al., (2001) Mol Cell Biol 21(21):7380-7390, Sahin, U. et al., (2008) Clin Cancer Res.14,7624-34, 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(6Pt A):1170-1178, Sing h et al., (2017) J Hema tol Oncol 10(1):105, Tokumitsu et al., (2017) Cytopathology 28(2):116-121).

[0005] Antibody-drug conjugates (ADCs) combine the high specificity of therapeutic antibodies with the high killing activity of cytotoxic drugs, where the therapeutic antibody and cytotoxic drug moieties are linked by an intermediate linker. While there are reports of the development of CLDN18.2-targeting antibody-drug conjugates for anti-tumor research, current research is limited and more available candidates are still needed. Summary of the Invention

[0006] (Antibody-drug conjugates (ADCs)) The present disclosure provides an antibody-drug conjugate in which an antibody or antigen-binding fragment thereof is conjugated to a cytotoxic drug, and the antibody or antigen-binding fragment thereof specifically binds to CLDN18.2.

[0007] In one aspect, the present disclosure provides a compound having the general formula Ab-(LU) n wherein Ab is an antibody or antigen-binding fragment thereof, L is a linker, and U is a cytotoxic drug, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, n is an integer selected from 1 to 10.

[0008] In some embodiments, an antibody or antigen-binding fragment thereof, Ab, is linked to a linker, L, by a specific functional group, such that the antibody or antigen-binding fragment thereof is capable of specifically binding to an antigen. In some embodiments, Ab is linked to the linker, L, by a covalent bond.

[0009] In some embodiments, the antibody or antigen-binding fragment thereof binds to human CLDN18.2.

[0010] In some embodiments, the antibody or antigen-binding fragment thereof is a murine, chimeric, humanized, or human antibody. In some embodiments, the antibody or antigen-binding fragment thereof is a monoclonal antibody, a monospecific antibody, a multispecific antibody, a Fab fragment, a F(ab')2 fragment, an Fd fragment, an Fv fragment, a dAb, a single-chain Fv (scFv) molecule, or a nanobody.

[0011] In some embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises heavy chain CDR (HCDR) 1, HCDR2, and HCDR3, and light chain CDR (LCDR) 1, LCDR2, and LCDR3; (1) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 11, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 11, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 11, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 16, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 16, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 16; (2) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 12, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 12, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 12, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 17, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 17, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 17; (3) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 13, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 13, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 13, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 17, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 17, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 17; (4) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 14, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 14, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 14, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 17, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 17, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 17; (5) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 15, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 15, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 15, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 17, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 17, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 17; (6) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 12, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 12, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 12, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 18, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 18, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 18; (7) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 13, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 13, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 13, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 18, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 18, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 18; (8) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 14, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 14, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 14, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 18, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 18, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 18; (9) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 15, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 15, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 15, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 18, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 18, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 18; (10) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 29, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 29, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 29, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 34, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 34, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 34; (11) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 30, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 30, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 30, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 35, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 35, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 35; (12) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 31, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 31, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 31, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 35, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 35, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 35; (13) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 32, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 32, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 32, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 35, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 35, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 35; (14) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 33, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 33, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 33, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 35, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 35, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 35; (15) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 30, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 30, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 30, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 36, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 36, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 36; (16) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 31, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 31, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 31, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 36, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 36, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 36; (17) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 32, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 32, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 32, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 36, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 36, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 36; (18) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 33, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 33, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 33, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 36, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 36, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 36; (19) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 43, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 43, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 44, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 44, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 44; (20) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 51, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 51, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 52, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 52, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 52; or (21) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 59, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 59, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 59, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 60, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 60, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 60.

[0012] In some embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3; (1) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequences set forth in SEQ ID NOs: 3, 4, 7, 8, 9, and 10, respectively; (2) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequences set forth in SEQ ID NOs: 3, 5, 7, 8, 9, and 10, respectively; (3) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequences set forth in SEQ ID NOs: 3, 6, 7, 8, 9, and 10, respectively; (4) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 comprise an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequences set forth in SEQ ID NOs: 19, 20, 24, 25, 26 and 27, respectively; (5) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 each have an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences set forth in SEQ ID NOs: 19, 21, 24, 25, 26 and 27, respectively; (6) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 comprise an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequences set forth in SEQ ID NOs: 19, 22, 24, 25, 26 and 27, respectively; (7) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 comprise an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequences set forth in SEQ ID NOs: 19, 23, 24, 25, 26 and 27, respectively; (8) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 each have an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences set forth in SEQ ID NOs: 19, 20, 24, 25, 26 and 28, respectively; (9) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 comprise an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequences set forth in SEQ ID NOs: 19, 21, 24, 25, 26 and 28, respectively; (10) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 each comprise an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequences set forth in SEQ ID NOs: 19, 22, 24, 25, 26, and 28, respectively; (11) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 comprise an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequences set forth in SEQ ID NOs: 19, 23, 24, 25, 26 and 28, respectively; (12) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 comprise an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequences set forth in SEQ ID NOs: 37, 38, 39, 40, 41 and 42, respectively; (13) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 each comprise an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequences set forth in SEQ ID NOs: 45, 46, 47, 48, 49, and 50, respectively; or (14) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequences set forth in SEQ ID NOs: 53, 54, 55, 56, 57, and 58, respectively.

[0013] In some embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3; (1) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 3, 69, 7, 8, 9, and 10, respectively; (2) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 70, 24, 25, 26, and 71, respectively; (3) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 37, 38, 39, 40, 41, and 42, respectively; (4) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 45, 46, 47, 48, 49, and 50, respectively; or (5) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 53, 54, 55, 56, 57, and 58, respectively.

[0014] In some embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3; (1) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 3, 4, 7, 8, 9, and 10, respectively; (2) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 3, 5, 7, 8, 9, and 10, respectively; (3) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 3, 6, 7, 8, 9, and 10, respectively; (4) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 20, 24, 25, 26, and 27, respectively; (5) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 21, 24, 25, 26, and 27, respectively; (6) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 22, 24, 25, 26, and 27, respectively; (7) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 23, 24, 25, 26 and 27, respectively; (8) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 20, 24, 25, 26, and 28, respectively; (9) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 21, 24, 25, 26 and 28, respectively; (10) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 22, 24, 25, 26, and 28, respectively; (11) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 23, 24, 25, 26, and 28, respectively; (12) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 37, 38, 39, 40, 41, and 42, respectively; (13) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 45, 46, 47, 48, 49, and 50, respectively; or (14) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 53, 54, 55, 56, 57, and 58, respectively.

[0015] In some embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3; (1) The amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOs: 3, 4, 7, 8, 9, and 10, respectively; (2) The amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOs: 3, 5, 7, 8, 9, and 10, respectively; (3) The amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOs: 3, 6, 7, 8, 9, and 10, respectively; (4) The amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOs: 19, 20, 24, 25, 26, and 27, respectively; (5) The amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOs: 19, 21, 24, 25, 26, and 27, respectively; (6) The amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOs: 19, 22, 24, 25, 26, and 27, respectively; (7) The amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOs: 19, 23, 24, 25, 26, and 27, respectively; (8) The amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOs: 19, 20, 24, 25, 26, and 28, respectively; (9) The amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOs: 19, 21, 24, 25, 26, and 28, respectively; (10) The amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOs: 19, 22, 24, 25, 26, and 28, respectively; (11) The amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOs: 19, 23, 24, 25, 26, and 28, respectively; (12) The amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOs: 37, 38, 39, 40, 41, and 42, respectively; (13) The amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOs: 45, 46, 47, 48, 49, and 50, respectively; or (14) The amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as shown in SEQ ID NOs: 53, 54, 55, 56, 57, and 58, respectively.

[0016] In some embodiments, the anti-CLDN18.2 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region and a light chain variable region, (1) the heavy chain variable region and the light chain variable region comprise amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences set forth in SEQ ID NOs: 11 and 16, respectively; (2) the heavy chain variable region and the light chain variable region comprise amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences set forth in SEQ ID NOs: 12 and 17, respectively; (3) the heavy chain variable region and the light chain variable region comprise amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences set forth in SEQ ID NOs: 13 and 17, respectively; (4) the heavy chain variable region and the light chain variable region comprise amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences set forth in SEQ ID NOs: 14 and 17, respectively; (5) the heavy chain variable region and the light chain variable region comprise amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences set forth in SEQ ID NOs: 15 and 17, respectively; (6) the heavy chain variable region and the light chain variable region comprise amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences set forth in SEQ ID NOs: 12 and 18, respectively; (7) The heavy chain variable region and the light chain variable region comprise an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequences set forth in SEQ ID NOs: 13 and 18, respectively; (8) The heavy chain variable region and the light chain variable region comprise an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequences set forth in SEQ ID NOs: 14 and 18, respectively; (9) The heavy chain variable region and the light chain variable region comprise an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequences set forth in SEQ ID NOs: 15 and 18, respectively; (10) The heavy chain variable region and the light chain variable region comprise amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences set forth in SEQ ID NOs: 29 and 34, respectively; (11) The heavy chain variable region and the light chain variable region comprise an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequences set forth in SEQ ID NOs: 30 and 35, respectively; (12) The heavy chain variable region and the light chain variable region comprise amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences set forth in SEQ ID NOs: 31 and 35, respectively; (13) The heavy chain variable region and the light chain variable region comprise amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences set forth in SEQ ID NOs: 32 and 35, respectively; (14) The heavy chain variable region and the light chain variable region comprise amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences set forth in SEQ ID NOs: 33 and 35, respectively; (15) The heavy chain variable region and the light chain variable region comprise amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences set forth in SEQ ID NOs: 30 and 36, respectively; (16) The heavy chain variable region and the light chain variable region comprise amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences set forth in SEQ ID NOs: 31 and 36, respectively; (17) The heavy chain variable region and the light chain variable region comprise amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences set forth in SEQ ID NOs: 32 and 36, respectively; (18) The heavy chain variable region and the light chain variable region comprise amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences set forth in SEQ ID NOs: 33 and 36, respectively; (19) The heavy chain variable region and the light chain variable region comprise amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences set forth in SEQ ID NOs: 43 and 44, respectively; (20) The heavy chain variable region and the light chain variable region comprise an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequences set forth in SEQ ID NOs: 51 and 52, respectively; or (21) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequences set forth in SEQ ID NOs: 59 and 60, respectively.

[0017] In some embodiments, the different amino acids in an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any of the amino acid sequences set forth in SEQ ID NOs: 11 to 18, 29 to 36, 43, 44, 51, 52, 59, and 60 are present primarily (or entirely) in the FR regions (framework regions).

[0018] In some embodiments, the anti-CLDN18.2 antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region and a light chain variable region, (1) the heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 11 and 16, respectively; (2) the heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 12 and 17, respectively; (3) the heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 13 and 17, respectively; (4) the heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 14 and 17, respectively; (5) the heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 15 and 17, respectively; (6) The heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 12 and 18, respectively; (7) The heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 13 and 18, respectively; (8) The heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 14 and 18, respectively; (9) The heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 15 and 18, respectively; (10) The heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 29 and 34, respectively; (11) The heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 30 and 35, respectively; (12) The heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 31 and 35, respectively; (13) The heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 32 and 35, respectively; (14) The heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 33 and 35, respectively; (15) The heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 30 and 36, respectively; (16) The heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 31 and 36, respectively; (17) The heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 32 and 36, respectively; (18) The heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 33 and 36, respectively; (19) The heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 43 and 44, respectively; (20) The heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 51 and 52, respectively; or (21) The heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 59 and 60, respectively.

[0019] As used herein, various variants of the above anti-CLDN18.2 antibodies or antigen-binding fragments thereof retain the ability to specifically bind to the antigen CLDN18.2.

[0020] Table S1 provides the CDR sequences and variable region sequences of several exemplary anti-CLDN18.2 antibodies or antigen-binding fragments thereof, some of which have the same CDRs and some of which have the same VH or VL. [Table 1]

[0021] Given the amino acid sequence of an antibody variable region, one skilled in the art can routinely determine which residues constitute a particular CDR. As is well known to those skilled in the art, antibody CDRs can be defined in a variety of ways, including by numbering systems / methods such as Kabat, Chothia, IMGT, AbM, or Contact, or by a combination of two or more of the numbering systems / methods such as Kabat, Chothia, IMGT, AbM, and Contact, and by a combined numbering system including Kabat and Chothia, which combines the ranges defined by Kabat and Chothia to obtain a larger range (e.g., if HCDR1 defined by Kabat is H31 to H35 and HCDR1 defined by Chothia is H26 to H32, the combined HCDR1 is H26 to H35). The exact numbers and positions of CDRs vary depending on the numbering system. Unless otherwise specified, it will be understood by those skilled in the art that the terms "CDR" and "complementarity determining region" of a given antibody or a region thereof (e.g., a variable region) cover complementarity determining regions determined by any known scheme. The CDRs claimed for protection in this disclosure are based on the sequences shown in Table S1 (one definition scheme), but corresponding amino acid sequences based on other CDR definition rules are also intended to fall within the scope of protection of this disclosure.

[0022] In one embodiment, the antibody or antigen-binding fragment thereof of the disclosure is selected from a 28G3 antibody or antigen-binding fragment thereof, a 40F6 antibody or antigen-binding fragment thereof, a 34G6 antibody or antigen-binding fragment thereof, a 10D8 antibody or antigen-binding fragment thereof, or a 22F12 antibody or antigen-binding fragment thereof; The 28G3 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, each comprising the amino acid sequences set forth in SEQ ID NOs: 3, 69, 7, 8, 9, and 10, and preferably comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, and (1) comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3. (2) the amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOs: 3, 5, 7, 8, 9, and 10, respectively; or (3) the amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOs: 3, 6, 7, 8, 9, and 10, respectively; The 40F6 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, each comprising the amino acid sequences set forth in SEQ ID NOs: 19, 70, 24, 25, 26, and 71. Preferably, the 40F6 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, and (1) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3. (1) The amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as shown in SEQ ID NOs: 19, 20, 24, 25, 26, and 27, respectively; (2) The amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as shown in SEQ ID NOs: 19, 21, 24, 25, 26, and 27, respectively; and (3) The amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as shown in SEQ ID NOs: 19, 22, 24, 25, 26, and 27, respectively. (4) the amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as shown in SEQ ID NOs: 19, 23, 24, 25, 26, and 27, respectively; (5) the amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as shown in SEQ ID NOs: 19, 20, 24, 25, 26, and 28, respectively; and (6) the amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as shown in SEQ ID NOs: 19, 20, 24, 25, 26, and 28, respectively. (7) the amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as shown in SEQ ID NOs: 19, 22, 24, 25, 26, and 28, respectively; or (8) the amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are as shown in SEQ ID NOs: 19, 23, 24, 25, 26, and 28, respectively; the 34G6 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences set forth in 37, 38, 39, 40, 41, and 42, respectively; the 10D8 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences set forth in 45, 46, 47, 48, 49, and 50, respectively; or The 22F12 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences shown in 53, 54, 55, 56, 57, and 58, respectively.

[0023] In some preferred embodiments, the 28G3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 11 and 16, SEQ ID NOs: 12 and 17, SEQ ID NOs: 13 and 17, SEQ ID NOs: 14 and 17, SEQ ID NOs: 15 and 17, SEQ ID NOs: 12 and 18, SEQ ID NOs: 13 and 18, SEQ ID NOs: 14 and 18, or SEQ ID NOs: 15 and 18, respectively; The 40F6 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 29 and 34, SEQ ID NOs: 30 and 35, SEQ ID NOs: 31 and 35, SEQ ID NOs: 32 and 35, SEQ ID NOs: 33 and 35, SEQ ID NOs: 30 and 36, SEQ ID NOs: 31 and 36, SEQ ID NOs: 32 and 36, or SEQ ID NOs: 33 and 36, respectively; the 34G6 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 43 and 44, respectively; the 10D8 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in SEQ ID NOs: 51 and 52, respectively; or The 22F12 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, and the heavy chain variable region and light chain variable region comprise the amino acid sequences shown in SEQ ID NOs: 59 and 60, respectively.

[0024] The VH and / or VL sequences (or CDR sequences) of other antibodies that bind to CLDN18.2 can be "mixed and matched" with the VH and / or VL sequences (or CDR sequences) of an anti-CLDN18.2 antibody or antigen-binding fragment thereof of the present disclosure. Preferably, when VH and VL chains (or their CDRs) are mixed and matched, the VH sequence in a particular VH / VL pairing can be replaced with a structurally similar VH sequence. Similarly, preferably, the VL sequence in a particular VH / VL pairing is replaced with a structurally similar VL sequence.

[0025] Thus, in one embodiment, the antibody or antigen-binding fragment thereof of the present disclosure: (a) a heavy chain variable region comprising the amino acid sequence set forth in Table S1; (b) a light chain variable region comprising an amino acid sequence set forth in Table S1, or the VL of an anti-CLDN18.2 antibody of another species, wherein the antibody or antigen-binding fragment thereof specifically binds to CLDN18.2.

[0026] In another embodiment, the antibody or antigen-binding fragment thereof of the present disclosure: (a) HCDR1, HCDR2, and HCDR3 listed in Table S1; (b) The antibody or antigen-binding fragment thereof comprises LCDR1, LCDR2, and LCDR3 listed in Table S1, or the light chain variable region CDRs of an anti-CLDN18.2 antibody of another species, and specifically binds to CLDN18.2.

[0027] In another embodiment, an antibody or antigen-binding fragment thereof of the present disclosure comprises an HCDR2 listed in Table S1 and a CDR of another anti-CLDN18.2 antibody, e.g., an HCDR1 and / or HCDR3 of another anti-CLDN18.2 antibody, and / or an LCDR1, LCDR2 and / or LCDR3 of another anti-CLDN18.2 antibody.

[0028] Furthermore, as is well known in the art, the CDR3 domain is independent of the CDR1 and / or CDR2 domain and can independently determine the binding specificity of an antibody to an antigen of the same species, and it is predicted that multiple types of antibodies with the same binding specificity can be produced based on the CDR3 sequence.

[0029] In another embodiment, an antibody or antigen-binding fragment thereof of the present disclosure comprises an HCDR2 listed in Table S1, an HCDR3 listed in Table S1 and / or an LCDR3 listed in Table S1, and the CDRs of another anti-CLDN18.2 antibody, and the antibody or antigen-binding fragment thereof specifically binds to CLDN18.2. In another embodiment, an antibody or antigen-binding fragment thereof of the present disclosure further comprises an LCDR2 listed in Table S1 and the CDRs of another anti-CLDN18.2 antibody, and the antibody or antigen-binding fragment thereof specifically binds to CLDN18.2. In another embodiment, an antibody or antigen-binding fragment thereof of the present disclosure further comprises an HCDR1 listed in Table S1 or an LCDR1 listed in Table S1, and the CDRs of another anti-CLDN18.2 antibody, and the antibody or antigen-binding fragment thereof specifically binds to CLDN18.2. Preferably, these antibodies (a) competitively bind to CLDN18.2, (b) retain the same functional characteristics, (c) bind to the same epitope, and / or (d) have similar binding affinity as the anti-CLDN18.2 antibodies of the present disclosure.

[0030] In some embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof further comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region comprises a human IgG1, human IgG2, or human IgG4 constant region or a variant thereof, preferably a human IgG1 constant region or a variant thereof, and the light chain constant region comprises a human κ constant region, a human λ constant region or a variant thereof, preferably a human κ constant region or a variant thereof. Exemplary variants include IgG1, IgG2, or IgG4 heavy chain constant region variants in which site-specific modifications and amino acid substitutions have been made to the heavy chain constant region, such as AAA mutation, DLE mutation (Shields et al., 2002; Lazar et al., 2006), YTE mutation, and LS mutation (Ghetie et al., 1997; Zalevsky et al., 2010), which are known in the art. The C-terminal lysine of the heavy chain constant region may be present or deleted.

[0031] In some embodiments, the heavy chain constant region comprises the amino acid sequence set forth in SEQ ID NO:1 or an amino acid sequence having one, two, three, four, or five amino acid substitutions, deletions, or additions compared to the amino acid sequence set forth in SEQ ID NO:1, and the light chain constant region comprises the amino acid sequence set forth in SEQ ID NO:2 or an amino acid sequence having one, two, three, four, or five amino acid substitutions, deletions, or additions compared to the amino acid sequence set forth in SEQ ID NO:2.

[0032] Herein, the amino acid substitution may be a conservative amino acid substitution, i.e., a substitution with another amino acid of the same type (having similar chemical properties or functions). For example, amino acids can be classified into (1) nonpolar amino acids: Ala (A), Val (V), Leu (L), Ile (I), Pro (P), Phe (F), Trp (W), Met (M), (2) uncharged polar amino acids: Gly (G), Ser (S), Thr (T), Cys (C), Tyr (Y), Asn (N), Gln (Q), (3) acidic amino acids: Asp (D), Glu (E), and (4) basic amino acids: Lys (K), Arg (R), and His (H) based on their side chain properties. Alternatively, based on common side chain properties, amino acids can be classified as follows: (1) hydrophobic amino acids: Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic amino acids: Cys, Ser, Thr, Asn, Gln; (3) acidic amino acids: Asp, Glu; (4) basic amino acids: His, Lys, Arg; (5) amino acids that affect chain orientation: Gly, Pro; and (6) aromatic amino acids: Trp, Tyr, Phe.

[0033] In some embodiments, the anti-CLDN18.2 antibody is a full-length antibody, e.g., a full-length antibody of the IgG1 isotype. In other embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof is a Fab fragment, a F(ab')2 fragment, a Fd fragment, a Fv fragment, a dAb, a single-chain Fv (scFv) molecule, or a nanobody.

[0034] In some embodiments, the anti-CLDN18.2 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 61, and the light chain comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO: 62.

[0035] In some embodiments, the anti-CLDN18.2 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 63, and the light chain comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO: 64.

[0036] In some embodiments, the anti-CLDN18.2 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 61 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 62.

[0037] In some embodiments, the anti-CLDN18.2 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 63 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 64.

[0038] It should be understood that some anti-CLDN18.2 antibodies are provided in which the C-terminal lysine of the heavy chain is deleted.

[0039] In some specific embodiments, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n, wherein L is a linker, U is a cytotoxic drug, and n is an integer selected from 1 to 10, and the Ab is an anti-CLDN18.2 antibody or an antigen-binding fragment thereof comprising an HCDR1 set forth in SEQ ID NO: 3, an HCDR2 set forth in SEQ ID NO: 5, an HCDR3 set forth in SEQ ID NO: 7, an LCDR1 set forth in SEQ ID NO: 8, an LCDR2 set forth in SEQ ID NO: 9, and an LCDR3 set forth in SEQ ID NO: 10.

[0040] In some specific embodiments, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n, wherein L is a linker, U is a cytotoxic drug, and n is an integer selected from 1 to 10; the Ab is an anti-CLDN18.2 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, and the heavy chain variable region has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 1109%, 1111, 112, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139%, 140%, 141%, 142%, 143%, 144%, 145%, 146%, 147%, 148%, 149%, 150%, 151, 152, 153%, 154%, 155%, 156%, 157%, 158%, 159%, 160%, 161%, 162%, 16 , 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17, and the light chain variable region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO: 17. Furthermore, in these specific embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises an HCDR1 set forth in SEQ ID NO: 3, an HCDR2 set forth in SEQ ID NO: 5, an HCDR3 set forth in SEQ ID NO: 7, an LCDR1 set forth in SEQ ID NO: 8, an LCDR2 set forth in SEQ ID NO: 9, and an LCDR3 set forth in SEQ ID NO: 10.

[0041] In some other specific embodiments, the general formula provided by the present disclosure is Ab-(LU) nor a pharmaceutically acceptable salt or solvate thereof, wherein L is a linker, U is a cytotoxic drug, and n is an integer selected from 1 to 10; the Ab is an anti-CLDN18.2 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, and the heavy chain variable region has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 1109%, 1110%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139%, 140%, 141%, 142%, 143%, 144%, 145%, 146%, 147%, 148%, 149%, 150%, 151, 152, 153, 154, 155%, 156%, 157%, 158%, 159%, 160%, 161%, 162%, 163%, 164%, 165%, 166%, 167%, 168%, and the light chain variable region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO: 17. Furthermore, in specific embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises an HCDR1 set forth in SEQ ID NO: 3, an HCDR2 set forth in SEQ ID NO: 5, an HCDR3 set forth in SEQ ID NO: 7, an LCDR1 set forth in SEQ ID NO: 8, an LCDR2 set forth in SEQ ID NO: 9, and an LCDR3 set forth in SEQ ID NO: 10.

[0042] In some specific embodiments, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n, wherein L is a linker, U is a cytotoxic drug, and n is an integer selected from 1 to 10; Ab is an anti-CLDN18.2 antibody or antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 12, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 17. In another specific embodiment, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n. nor a pharmaceutically acceptable salt or solvate thereof, wherein L is a linker, U is a cytotoxic drug, n is an integer selected from 1 to 10, and the Ab is an anti-CLDN18.2 antibody or antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 14 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 17.

[0043] In some specific embodiments, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n, wherein L is a linker, U is a cytotoxic drug, n is an integer selected from 1 to 10, and Ab is an anti-CLDN18.2 antibody or antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of the heavy chain variable region is as set forth in SEQ ID NO: 12 and the amino acid sequence of the light chain variable region is as set forth in SEQ ID NO: 17. In other specific embodiments, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n. n or a pharmaceutically acceptable salt or solvate thereof, wherein L is a linker, U is a cytotoxic drug, n is an integer selected from 1 to 10, the Ab is an anti-CLDN18.2 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, the amino acid sequence of the heavy chain variable region is as set forth in SEQ ID NO: 14, and the amino acid sequence of the light chain variable region is as set forth in SEQ ID NO: 17.

[0044] In some specific embodiments, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n, wherein L is a linker, U is a cytotoxic drug, and n is an integer selected from 1 to 10, and the Ab is an anti-CLDN18.2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 61 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 62. In another specific embodiment, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n. nor a pharmaceutically acceptable salt or solvate thereof, wherein L is a linker, U is a cytotoxic drug, n is an integer selected from 1 to 10, and the Ab is an anti-CLDN18.2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence shown in SEQ ID NO: 63 and the light chain comprises the amino acid sequence shown in SEQ ID NO: 64.

[0045] In some specific embodiments, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n, wherein L is a linker, U is a cytotoxic drug, and n is an integer selected from 1 to 10; the Ab is an anti-CLDN18.2 antibody comprising a heavy chain and a light chain, wherein the amino acid sequence of the heavy chain is as set forth in SEQ ID NO: 61, and the amino acid sequence of the light chain is as set forth in SEQ ID NO: 62. In other specific embodiments, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n. n or a pharmaceutically acceptable salt or solvate thereof, wherein L is a linker, U is a cytotoxic drug, and n is an integer selected from 1 to 10, and the Ab is an anti-CLDN18.2 antibody comprising a heavy chain and a light chain, wherein the amino acid sequence of the heavy chain is as set forth in SEQ ID NO: 63 and the amino acid sequence of the light chain is as set forth in SEQ ID NO: 64. In other specific embodiments, the C-terminal Lys of the heavy chain (e.g., SEQ ID NO: 63 or SEQ ID NO: 61) is absent.

[0046] In some embodiments, the anti-CLDN18.2 antibody comprises two heavy chains (H) and two light chains (L), or consists of two heavy chains and two light chains, the heavy chains and light chains being linked to each other by disulfide bonds, each heavy chain comprising the above-described heavy chain variable region (VH) and heavy chain constant region, the heavy chain variable region (VH) comprising framework regions (FR) and the above-described heavy chain complementarity-determining region (HCDR), each light chain comprising the above-described light chain variable region (VL) and light chain constant region, the light chain variable region (VL) comprising FR and the above-described light chain complementarity-determining region (LCDR), the C-terminus of the heavy chain variable region being linked to the N-terminus of the heavy chain constant region, and the C-terminus of the light chain variable region being linked to the N-terminus of the light chain constant region.

[0047] In some embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof can be modified, e.g., to include one or more amino acid alterations, additions, or deletions, provided that the antibody or antigen-binding fragment thereof retains its ability to specifically bind to its corresponding antigen.

[0048] The general formula provided by the present disclosure is Ab-(LU) n or a pharmaceutically acceptable salt or solvate thereof, wherein Ab is an antibody or an antigen-binding fragment thereof, and the antibody or antigen-binding fragment thereof binds to CLDN18.2, thereby inducing antibody-dependent cell-mediated cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC) against cells expressing CLDN18.2. In some embodiments, the general formula is Ab-(LU) n or a pharmaceutically acceptable salt or solvate thereof, wherein the antibody or antigen-binding fragment thereof binds to human CLDN18.2 and thereby induces ADCC and CDC against cells expressing human CLDN18.2. In some embodiments, the general formula is Ab-(LU) n or a pharmaceutically acceptable salt or solvate thereof, wherein the antibody or antigen-binding fragment thereof does not bind to CLDN18.1. In some embodiments, the general formula is Ab-(LU) nor a pharmaceutically acceptable salt or solvate thereof, wherein the antibody or antigen-binding fragment thereof does not bind to human CLDN18.1. In some embodiments, the general formula is Ab-(LU) n or a pharmaceutically acceptable salt or solvate thereof does not induce ADCC and / or CDC against cells expressing CLDN18.1. In some embodiments, the antibody-drug conjugate of the general formula Ab-(LU) n or a pharmaceutically acceptable salt or solvate thereof does not induce ADCC and / or CDC against cells expressing human CLDN18.1.

[0049] The general formula provided by the present disclosure is Ab-(LU) n In the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, wherein the cytotoxic drug U and the antibody or antigen-binding fragment thereof Ab are conjugated via a linker L. In some specific embodiments, in the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof provided by the present disclosure, each cytotoxic drug U and antibody or antigen-binding fragment thereof Ab are conjugated via one linker L. The linker L of the present disclosure can be linked to the antibody or antigen-binding fragment thereof by any method known in the art. In some preferred embodiments, the linker L is linked to the antibody or antigen-binding fragment thereof Ab via a sulfhydryl group and / or an amino group. In some more preferred embodiments, the linker L is linked to the antibody or antigen-binding fragment thereof Ab via a sulfhydryl group.

[0050] In some embodiments, the linker L is a cleavable linker or a non-cleavable linker. In some embodiments, the linker is a cleavable linker, and may be, for example, a low pH-dependent decomposition type (including a hydrazone bond, a carbonate ester bond, etc.), a proteolytic type (including a peptide bond), or a high glutathione concentration-dependent decomposition type (including a disulfide bond). A cleavable linker can be cleaved in target cells to release a cytotoxic drug. In other embodiments, the linker L is a non-cleavable linker, and may be, for example, a maleimidocaproyl group, etc.

[0051] In one aspect, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n, wherein the antibody or antigen-binding fragment thereof, Ab, is conjugated to one or more cytotoxic agents U, and the cytotoxic agents may be, for example, alkaloids, antimetabolites, antitumor antibiotics, alkylating agents, platinum-based drugs, etc. In some embodiments, the cytotoxic agent U is a tubulin inhibitor cytotoxic agent or a cytotoxic agent that acts on DNA. In some embodiments, the tubulin inhibitor cytotoxic agent includes, but is not limited to, maytansine (e.g., DM1, DM4), auristatin (e.g., MMAE or MMAF), and dolastatin. In some embodiments, the cytotoxic drugs that act on DNA include, but are not limited to, calicheamicin, doxorubicin, duocarmycin, pyrrolobenzodiazepines (PBDs), and topoisomerase I inhibitors.

[0052] In some specific embodiments, in the antibody-drug conjugates provided by the present disclosure having the general formula Ab-(LU)n or a pharmaceutically acceptable salt or solvate thereof, the cytotoxic drug U is a topoisomerase I inhibitor.

[0053] In some specific embodiments, in the antibody-drug conjugates provided by the present disclosure having the general formula Ab-(LU)n or a pharmaceutically acceptable salt or solvate thereof, the cytotoxic drug U is a camptothecin-based topoisomerase I inhibitor.

[0054] In some specific embodiments, in an antibody-drug conjugate or pharmaceutically acceptable salt or solvate thereof provided by the present disclosure having the general formula Ab-(LU)n, the cytotoxic agent U is SN-38, an SN-38 derivative, exatecan, or an exatecan derivative. In some specific embodiments, the cytotoxic agent U has a deuteration modification. In some specific embodiments, the cytotoxic agent U is an exatecan derivative and has a deuteration modification.

[0055] In some embodiments, the cytotoxic drug U is linked to the linker L by a functional group, and the cytotoxic drug molecule can be liberated in tumor cells to exert an anti-tumor effect.

[0056] In one aspect, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n, wherein Ab is an antibody or antigen-binding fragment thereof, L is a linker, U is a camptothecin-based topoisomerase I inhibitor, and n is an integer selected from 1 to 10. In some embodiments, L and / or U are deuterium-modified.

[0057] In some embodiments, the present disclosure provides an antibody-drug conjugate having the general formula Ab-(LU)n, or a pharmaceutically acceptable salt or solvate thereof, wherein Ab is an antibody or antigen-binding fragment thereof, L is a linker, U is a camptothecin-based topoisomerase I inhibitor, n is an integer selected from 1 to 10, L and / or U are deuterium-modified, and the cytotoxic drug U is SN-38, an SN-38 derivative, exatecan, or an exatecan derivative.

[0058] In some specific embodiments, the present disclosure provides an antibody-drug conjugate having the general formula Ab-(LU)n, or a pharmaceutically acceptable salt or solvate thereof, wherein Ab is an antibody or antigen-binding fragment thereof, L is a linker, U is a camptothecin-based topoisomerase I inhibitor, n is an integer selected from 1 to 10, U has a deuteration modification, and the cytotoxic drug U is an exatecan derivative.

[0059] In some embodiments, in the antibody-drug conjugates provided by the present disclosure having the general formula Ab-(LU)n or a pharmaceutically acceptable salt or solvate thereof, -U has the structure shown in formula Ia below: [ka]

[0060] In some embodiments, in the antibody-drug conjugates provided by the present disclosure having the general formula Ab-(LU)n or a pharmaceutically acceptable salt or solvate thereof, -L- is the structure shown in formula IIa below: [ka] wherein R1 and R2 are each independently selected from hydrogen (H) or deuterium (D); In the structure shown, the 3-position of -(succinimidyl-3-yl-N)- is linked to an antibody or antigen-binding fragment thereof, Ab, and the methylene group at the other end is linked to a cytotoxic drug, U.

[0061] In some embodiments, -L- has the structure shown in formula IIa-1, IIa-2, IIa-3, or IIa-4: [ka] [ka] [ka] or [ka] In the structure shown, the 3-position of -(succinimidyl-3-yl-N)- is linked to an antibody or antigen-binding fragment thereof, Ab, and the methylene group at the other end is linked to a cytotoxic drug, U.

[0062] In some embodiments, the present disclosure provides an antibody-drug conjugate having the general formula Ab-(LU)n, or a pharmaceutically acceptable salt or solvate thereof, wherein -LU has the structure shown in formula IIIa below: [ka] wherein R1 and R2 are each independently selected from hydrogen (H) or deuterium (D).

[0063] In some embodiments, -LU has the structure shown in formula IIIa-1, IIIa-2, IIIa-3, or IIIa-4: [ka] [ka] [ka] or [ka]

[0064] In some embodiments, the present disclosure provides an antibody-drug conjugate having the general formula Ab-(LU)n, or a pharmaceutically acceptable salt or solvate thereof, wherein the structure of the antibody-drug conjugate is as shown in Formula IV below: [ka] In the formula, Ab is an antibody or an antigen-binding fragment thereof, n is an integer selected from 1 to 10, and R1 and R2 are each independently selected from hydrogen (H) or deuterium (D).

[0065] In some specific embodiments, the structure of the antibody-drug conjugate is as shown in formula IV-1, IV-2, IV-3, or IV-4 below: [ka] [ka] [ka] or [ka] In the formula, Ab is an antibody or an antigen-binding fragment thereof, and n is an integer selected from 1 to 10.

[0066] In some embodiments, the present disclosure provides an antibody-drug conjugate having the general formula Ab-(LU)n or a pharmaceutically acceptable salt or solvate thereof, wherein the structure of the antibody-drug conjugate is as shown in Formula IV-1, and Ab is an anti-CLDN18.2 antibody or an antigen-binding fragment thereof.

[0067] In some embodiments, in the above-mentioned antibody-drug conjugate or pharmaceutically acceptable salt or solvate thereof, n is an integer selected from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 8, 5 to 7, 5 to 6, 6 to 8, 6 to 7, or 7 to 8. In some embodiments, n is an integer selected from 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, or 7 to 8.

[0068] In some embodiments, n is an integer selected from 2 to 8. In some embodiments, n is an integer selected from 4 to 8. In some embodiments, n is an integer selected from 6 to 8. In some embodiments, n is 6, 7, or 8. In some embodiments, n is 2, 4, 6, or 8. In some embodiments, n is 2, 4, or 8. In some embodiments, n is 4, 6, or 8. In some embodiments, n is 4 or 8. In some embodiments, n is 6 or 8.

[0069] In some embodiments, in an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n provided by the present disclosure, the structure of the antibody-drug conjugate is as shown in formula IV-1, Ab is an anti-CLDN18.2 antibody or an antigen-binding fragment thereof, and the anti-CLDN18.2 antibody or an antigen-binding fragment thereof comprises an HCDR1 set forth in SEQ ID NO: 3, an HCDR2 set forth in SEQ ID NO: 5, an HCDR3 set forth in SEQ ID NO: 7, an LCDR1 set forth in SEQ ID NO: 8, an LCDR2 set forth in SEQ ID NO: 9, and an LCDR3 set forth in SEQ ID NO: 10. In some such embodiments, n is an integer selected from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 8, 5 to 7, 5 to 6, 6 to 8, 6 to 7, or 7 to 8; preferably, n is an integer selected from 4 to 8 or 6 to 8; more preferably, n is 4, 6, or 8.

[0070] In some embodiments, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n, wherein the structure of the antibody-drug conjugate is as shown in Formula IV-1, Ab is an anti-CLDN18.2 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, and the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequences set forth in SEQ ID NOs: 12 and 17, respectively. In some such embodiments, n is an integer selected from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 8, 5 to 7, 5 to 6, 6 to 8, 6 to 7, or 7 to 8, preferably n is an integer selected from 4 to 8 or 6 to 8, more preferably n is 4, 6, or 8. Furthermore, in some such embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises an HCDR1 set forth in SEQ ID NO: 3, an HCDR2 set forth in SEQ ID NO: 5, an HCDR3 set forth in SEQ ID NO: 7, an LCDR1 set forth in SEQ ID NO: 8, an LCDR2 set forth in SEQ ID NO: 9, and an LCDR3 set forth in SEQ ID NO: 10.

[0071] In some embodiments, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n, wherein the structure of the antibody-drug conjugate is as shown in Formula IV-1, Ab is an anti-CLDN18.2 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, and the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequences set forth in SEQ ID NOs: 14 and 17, respectively. In some such embodiments, n is an integer selected from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 8, 5 to 7, 5 to 6, 6 to 8, 6 to 7, or 7 to 8, preferably n is an integer selected from 4 to 8 or 6 to 8, more preferably n is 4, 6, or 8. Furthermore, in some such embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises an HCDR1 set forth in SEQ ID NO: 3, an HCDR2 set forth in SEQ ID NO: 5, an HCDR3 set forth in SEQ ID NO: 7, an LCDR1 set forth in SEQ ID NO: 8, an LCDR2 set forth in SEQ ID NO: 9, and an LCDR3 set forth in SEQ ID NO: 10.

[0072] In some embodiments, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n, wherein the structure of the antibody-drug conjugate is as shown in Formula IV-1, and Ab is an anti-CLDN18.2 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 12 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 17. In some such embodiments, n is an integer selected from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 8, 5 to 7, 5 to 6, 6 to 8, 6 to 7, or 7 to 8; preferably, n is an integer selected from 4 to 8 or 6 to 8; more preferably, n is 4, 6, or 8.

[0073] In some embodiments, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n, wherein the structure of the antibody-drug conjugate is as shown in Formula IV-1, and Ab is an anti-CLDN18.2 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 14 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 17. In some such embodiments, n is an integer selected from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 8, 5 to 7, 5 to 6, 6 to 8, 6 to 7, or 7 to 8; preferably, n is an integer selected from 4 to 8 or 6 to 8; more preferably, n is 4, 6, or 8.

[0074] In some embodiments, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n, wherein the structure of the antibody-drug conjugate is as shown in Formula IV-1, Ab is an anti-CLDN18.2 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, the amino acid sequence of the heavy chain variable region is as shown in SEQ ID NO: 12, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 17. In some such embodiments, n is an integer selected from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 8, 5 to 7, 5 to 6, 6 to 8, 6 to 7, or 7 to 8; preferably, n is an integer selected from 4 to 8 or 6 to 8; more preferably, n is 4, 6, or 8.

[0075] In some embodiments, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n, wherein the structure of the antibody-drug conjugate is as shown in Formula IV-1, Ab is an anti-CLDN18.2 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, the amino acid sequence of the heavy chain variable region is as shown in SEQ ID NO: 14, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 17. In some such embodiments, n is an integer selected from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 8, 5 to 7, 5 to 6, 6 to 8, 6 to 7, or 7 to 8; preferably, n is an integer selected from 4 to 8 or 6 to 8; more preferably, n is 4, 6, or 8.

[0076] In some embodiments, the present disclosure provides an antibody-drug conjugate having the general formula Ab-(LU)n, or a pharmaceutically acceptable salt or solvate thereof, wherein the structure of the antibody-drug conjugate is as shown in Formula IV-1, Ab is an anti-CLDN18.2 antibody comprising a heavy chain and a light chain, and the heavy chain has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 1109%, 1111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139%, 140%, 141%, 142%, 143%, 144%, 145%, 146%, 147%, 148%, 149%, 150%, 1510%, 1520%, 1530%, 1540%, 1550%, 1560%, 1570%, 1580%, 1590%, 1600%, 1611%, 1620%, 1630%, 1640%, and the light chain comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO:62. In some such embodiments, n is an integer selected from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 8, 5 to 7, 5 to 6, 6 to 8, 6 to 7, or 7 to 8, preferably n is an integer selected from 4 to 8 or 6 to 8, more preferably n is 4, 6, or 8. Furthermore, in some such embodiments, the anti-CLDN18.2 antibody comprises an HCDR1 shown in SEQ ID NO: 3, an HCDR2 shown in SEQ ID NO: 5, an HCDR3 shown in SEQ ID NO: 7, an LCDR1 shown in SEQ ID NO: 8, an LCDR2 shown in SEQ ID NO: 9, and an LCDR3 shown in SEQ ID NO: 10.

[0077] In some embodiments, the present disclosure provides an antibody-drug conjugate having the general formula Ab-(LU)n, or a pharmaceutically acceptable salt or solvate thereof, wherein the structure of the antibody-drug conjugate is as shown in Formula IV-1, Ab is an anti-CLDN18.2 antibody comprising a heavy chain and a light chain, and the heavy chain has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 1109%, 1111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139%, 140%, 141%, 142%, 143%, 144%, 145%, 146%, 147%, 148%, 149%, 150%, 1510%, 1520%, 1530%, 1540%, 1550%, 1560%, 1570%, 1580%, 1590%, 1610%, 1620%, 1630%, 1640%, 1650%, and the light chain comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO:64. In some such embodiments, n is an integer selected from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 8, 5 to 7, 5 to 6, 6 to 8, 6 to 7, or 7 to 8, preferably n is an integer selected from 4 to 8 or 6 to 8, more preferably n is 4, 6, or 8. Furthermore, in some such embodiments, the anti-CLDN18.2 antibody comprises an HCDR1 shown in SEQ ID NO: 3, an HCDR2 shown in SEQ ID NO: 5, an HCDR3 shown in SEQ ID NO: 7, an LCDR1 shown in SEQ ID NO: 8, an LCDR2 shown in SEQ ID NO: 9, and an LCDR3 shown in SEQ ID NO: 10.

[0078] In some embodiments, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n, wherein the structure of the antibody-drug conjugate is as shown in Formula IV-1, and Ab is an anti-CLDN18.2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 61, and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 62. In some such embodiments, n is an integer selected from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 8, 5 to 7, 5 to 6, 6 to 8, 6 to 7, or 7 to 8; preferably, n is an integer selected from 4 to 8 or 6 to 8; and more preferably, n is 4, 6, or 8.

[0079] In some embodiments, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n, wherein the structure of the antibody-drug conjugate is as shown in Formula IV-1, and Ab is an anti-CLDN18.2 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 63, and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 64. In some such embodiments, n is an integer selected from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 8, 5 to 7, 5 to 6, 6 to 8, 6 to 7, or 7 to 8; preferably, n is an integer selected from 4 to 8 or 6 to 8; and more preferably, n is 4, 6, or 8.

[0080] In some embodiments, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n, wherein the structure of the antibody-drug conjugate is as shown in Formula IV-1, Ab is an anti-CLDN18.2 antibody comprising a heavy chain and a light chain, the amino acid sequence of the heavy chain is as shown in SEQ ID NO: 61, and the amino acid sequence of the light chain is as shown in SEQ ID NO: 62. In some such embodiments, n is an integer selected from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 8, 5 to 7, 5 to 6, 6 to 8, 6 to 7, or 7 to 8; preferably, n is an integer selected from 4 to 8 or 6 to 8; and more preferably, n is 4, 6, or 8.

[0081] In some embodiments, in an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof having the general formula Ab-(LU)n provided by the present disclosure, the structure of the antibody-drug conjugate is as shown in Formula IV-1, Ab is an anti-CLDN18.2 antibody comprising a heavy chain and a light chain, the amino acid sequence of the heavy chain is as shown in SEQ ID NO: 63, and the amino acid sequence of the light chain is as shown in SEQ ID NO: 64. In some such embodiments, n is an integer selected from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 8, 5 to 7, 5 to 6, 6 to 8, 6 to 7, or 7 to 8; preferably, n is an integer selected from 4 to 8 or 6 to 8; more preferably, n is 4, 6, or 8.

[0082] In some embodiments, the present disclosure provides an antibody-drug conjugate, or a pharmaceutically acceptable salt or solvate thereof, comprising the structure shown in Formula IIIa below linked to an antibody or antigen-binding fragment thereof: [ka] wherein R1 and R2 are each independently selected from hydrogen (H) or deuterium (D), and position 3 of -(succinimidyl-3-yl-N)- in the structure shown in Formula IIIa is linked to an antibody or antigen-binding fragment thereof. In specific embodiments, the antibody-drug conjugate is one in which the structure shown in Formula IIIa is linked to an antibody or antigen-binding fragment thereof via a thioether bond. In specific embodiments, the antibody or antigen-binding fragment thereof is an anti-CLDN18.2 antibody or antigen-binding fragment thereof of the present disclosure.

[0083] In some embodiments, the present disclosure provides an antibody-drug conjugate, or a pharmaceutically acceptable salt or solvate thereof, comprising the structure shown in formula IIIa-1 below linked to an antibody or antigen-binding fragment thereof: [ka] wherein position 3 of -(succinimidyl-3-yl-N)- in the structure shown in Formula IIIa-1 is linked to an antibody or antigen-binding fragment thereof. In some specific embodiments, the antibody-drug conjugate has the structure shown in Formula IIIa-1 linked to an antibody or antigen-binding fragment thereof via a thioether bond. In some specific embodiments, the antibody or antigen-binding fragment thereof is an anti-CLDN18.2 antibody or antigen-binding fragment thereof of the present disclosure.

[0084] In some specific embodiments, the present disclosure provides an antibody-drug conjugate, or a pharmaceutically acceptable salt or solvate thereof, comprising the structure shown in formula IIIa-1 below linked to an antibody or antigen-binding fragment thereof: [ka] wherein position 3 of -(succinimidyl-3-yl-N)- in the structure shown in formula IIIa-1 is linked to an antibody or an antigen-binding fragment thereof, and the antibody or antigen-binding fragment thereof is an anti-CLDN18.2 antibody or an antigen-binding fragment thereof comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, and HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences shown in SEQ ID NOs: 3, 5, 7, 8, 9, and 10, respectively. Furthermore, in some specific embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein (1) the heavy chain variable region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO: 12, and the light chain variable region comprises at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO: 17. %, 99%, or 100% identity to the amino acid sequence set forth in SEQ ID NO: 14; or (2) the heavy chain variable region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO: 14, and the light chain variable region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence set forth in SEQ ID NO: 17. In some specific embodiments, the antibody-drug conjugate comprises the structure shown in formula IIIa-1 linked to the antibody or antigen-binding fragment thereof via a thioether bond.

[0085] In one aspect, the general formula provided by the present disclosure is Ab-(LU) nor a pharmaceutically acceptable salt or solvate thereof, (a) binding to CLDN18.2; (b) blocking the binding of CLDN18.2 to a ligand; (c) showing endocytosis in cells expressing CLDN18.2; (d) having killing activity against tumor cells expressing CLDN18.2; (e) There is a bystander effect. (f) having ADCC activity; (g) having CDC activity; (h) not binding to CLDN18.1; (i) not binding to cells that do not express CLDN18.2; (j) having no ADCC and / or CDC activity against cells expressing CLDN18.1; One or more combinations of the above characteristics are indicated.

[0086] In some embodiments, the antibody-drug conjugate, or a pharmaceutically acceptable salt or solvate thereof, has properties (a) through (j). In some embodiments, the antibody-drug conjugate, or a pharmaceutically acceptable salt or solvate thereof, has properties (a) and (c) through (j).

[0087] In some embodiments, the antibody-drug conjugate, or a pharmaceutically acceptable salt or solvate thereof, binds to human CLDN18.2. In some embodiments, the antibody-drug conjugate, or a pharmaceutically acceptable salt or solvate thereof, does not bind to human CLDN18.1.

[0088] In some embodiments, the antibody-drug conjugates or pharmaceutically acceptable salts or solvates thereof provided by the present disclosure exhibit strong endocytosis in cells with different CLDN18.2 expression levels, and can continuously accumulate the amount of internalized ADC as the endocytosis time increases.

[0089] (Pharmaceutical composition) In one aspect, the present disclosure provides a pharmaceutical composition comprising an antibody-drug conjugate of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the present disclosure provides a pharmaceutical composition comprising an antibody-drug conjugate according to the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include, for example, excipients, diluents, encapsulating materials, fillers, buffers, or other agents.

[0090] The number of cytotoxic drugs conjugated to the antibody or antigen-binding fragment thereof in the antibody-drug conjugate of the present disclosure can vary so that the antibody-drug conjugate or pharmaceutically acceptable salt or solvate thereof in the pharmaceutical composition provided by the present disclosure can be heterogeneous or homogeneous, where heterogeneity refers to the fact that the pharmaceutical composition includes an antibody-drug conjugate containing a different number of cytotoxic drugs, such as an antibody-drug conjugate in which one molecule of the antibody or antigen-binding fragment thereof is conjugated with 0 (i.e., no cytotoxic drug), 1, 2, 3, 4, 5, 6, 7, 8, or more other cytotoxic drug molecules. Antibody-drug conjugates in which one molecule of the antibody or antigen-binding fragment thereof is conjugated with 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9 molecules of cytotoxic drugs are referred to as D0, D1, D2, D3, D4, D5, D6, D7, D8, and D9, respectively.

[0091] By controlling the ratio of antibody-drug conjugates containing different numbers (n) of cytotoxic drugs in the above pharmaceutical composition, pharmaceutical compositions containing ADCs with different drug-antibody ratios (DARs) can be produced. It should be understood that the DAR refers to the average number of cytotoxic drugs conjugated per antibody or antigen-binding fragment thereof molecule in the pharmaceutical composition. For example, a "DAR of about 4" refers to an average number of cytotoxic drugs conjugated per antibody or antigen-binding fragment thereof molecule of about 4 in a pharmaceutical composition that is a heterogeneous mixture containing ADCs having the same or different numbers of cytotoxic drugs conjugated per antibody or antigen-binding fragment thereof molecule (e.g., 0, 1, 2, 3, 4, 5, 6, 7, or 8 cytotoxic drugs conjugated to each antibody or antigen-binding fragment thereof). Similarly, a "DAR of about 8" refers to an average number of cytotoxic drugs conjugated per antibody or antigen-binding fragment thereof molecule of about 8 in the pharmaceutical composition.

[0092] In some embodiments, the DAR of the pharmaceutical composition is 0 to 10, 0 to 9, 0 to 8, 1 to 10, 1 to 9, 1 to 8, 2 to 10, 2 to 9, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 7 to 8, 7.2 to 8, 7.4 to 8, 7.5 to 8, 7.6 to 8, 7.7 to 8, 7.8 to 8, 7.8 to 7.9, or 7.9 to 8. In some embodiments, the DAR of the pharmaceutical composition is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, or about 8.0.

[0093] In some embodiments, the DAR of the pharmaceutical composition is 7 to 8, 7.2 to 8, 7.4 to 8, 7.6 to 8, or 7.7 to 8. In some embodiments, the DAR of the pharmaceutical composition is about 7.1, about 7.2, about 7.4, about 7.6, about 7.7, or about 8.

[0094] In some embodiments, the antibody-drug conjugates or pharmaceutically acceptable salts or solvates thereof in the pharmaceutical composition are heterogeneous, with the distribution of each antibody-drug conjugate or pharmaceutically acceptable salts or solvates thereof linked to a different number of cytotoxic drugs being such that D0 to D7 account for 0% to 30%, D8 accounts for 60% to 100%, and D9 or greater accounts for 0% to 15%. In some alternative embodiments, D0 to D3 are 0% to 10%, D4 to D7 are 0% to 30%, D8 is 60% to 100%, and D9 or greater accounts for 0% to 15%. In some alternative embodiments, D0 to D6 are 0% to 30%, D7 to D8 are 60% to 100%, and D9 or greater accounts for 0% to 15%. In some alternative embodiments, D0 to D5 are 0% to 30%, D6 to D8 are 70% to 100%, and D9 or greater accounts for 0% to 15%. In some alternative embodiments, D0 is 0% to 10%, D1 is 0% to 10%, D2 is 0% to 10%, D3 is 0% to 10%, D4 is 0% to 20%, D5 is 0% to 10%, D6 is 0% to 20%, D7 is 0% to 10%, D8 is 60% to 100%, and D9 or greater is 0% to 10%. In some alternative embodiments, D0 is 0% to 6%, D1 is 0% to 6%, D2 is 0% to 6%, D3 is 0% to 6%, D4 is 0% to 15%, D5 is 0% to 6%, D6 is 0% to 20%, D7 is 0% to 6%, D8 is 60% to 100%, and D9 or greater is 0% to 10%. In some alternative embodiments, D0 is 0% to 6%, D1 to D3 are 0% to 6%, D4 is 0% to 15%, D5 to D7 are 0% to 20%, D8 is 60% to 100%, and D9 or greater is 0% to 10%. In some alternative embodiments, D0 is 0% to 5%, D1 to D3 are 0% to 5%, D4 is 0% to 15%, D5 to D7 are 0% to 20%, D8 is 85% to 100%, and D9 or greater is 0% to 5%. The distribution ratio of each antibody-drug conjugate or pharmaceutically acceptable salt or solvate thereof is based on the molar amount.

[0095] (use) The present disclosure provides uses of an antibody-drug conjugate of the present disclosure or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present disclosure.

[0096] In one aspect, the present disclosure provides use of an antibody-drug conjugate of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating a tumor. In one aspect, the present disclosure provides use of an antibody-drug conjugate of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, for treating a tumor. In one aspect, the present disclosure provides use of a pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating a tumor. In one aspect, the present disclosure provides use of a pharmaceutical composition of the present disclosure for treating a tumor.

[0097] In one aspect, the present disclosure provides use of an antibody-drug conjugate of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a second or another therapeutic agent in the manufacture of a medicament for treating a tumor. In one aspect, the present disclosure provides use of an antibody-drug conjugate of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a second or another therapeutic agent for treating a tumor. In one aspect, the present disclosure provides use of a pharmaceutical composition of the present disclosure and a second or another therapeutic agent in the manufacture of a medicament for treating a tumor. In one aspect, the present disclosure provides use of a pharmaceutical composition of the present disclosure and a second or another therapeutic agent for treating a tumor.

[0098] In one aspect, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as described above, for treating a tumor. In one aspect, the present disclosure provides an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as described above, in combination with a second or another therapeutic agent, for treating a tumor.

[0099] In one aspect, the present disclosure provides a method for treating a tumor comprising administering to a subject an antibody-drug conjugate of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof. In one aspect, the present disclosure provides a method for treating a tumor comprising administering to a subject in need thereof a therapeutically effective amount of an antibody-drug conjugate of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof. In one aspect, the present disclosure provides a method for treating a tumor comprising administering to a subject a pharmaceutical composition of the present disclosure. In one aspect, the present disclosure provides a method for treating a tumor comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of the present disclosure. In some embodiments, the method comprises contacting tumor cells with the antibody-drug conjugate, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, thereby killing or inhibiting tumor cell growth.

[0100] In one aspect, the present disclosure provides a method for treating a tumor comprising administering to a subject an antibody-drug conjugate of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a second or another therapeutic agent. In one aspect, the present disclosure provides a method for treating a tumor comprising administering to a subject in need thereof a therapeutically effective amount of an antibody-drug conjugate of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a second or another therapeutic agent. In one aspect, the present disclosure provides a method for treating a tumor comprising administering to a subject a pharmaceutical composition of the present disclosure and a second or another therapeutic agent. In one aspect, the present disclosure provides a method for treating a tumor comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of the present disclosure and a second or another therapeutic agent. In some embodiments, the method comprises contacting tumor cells with the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, and simultaneously or sequentially contacting the tumor cells with a second or another therapeutic agent, thereby killing the tumor cells or inhibiting tumor cell growth.

[0101] In some embodiments, administration of an antibody-drug conjugate of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, to a subject can kill tumor cells or inhibit tumor cell growth. In some embodiments, administration of a therapeutically effective amount of an antibody-drug conjugate of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, to a subject can kill tumor cells or inhibit tumor cell growth. In some embodiments, administration of a pharmaceutical composition of the present disclosure to a subject can kill tumor cells or inhibit tumor cell growth. In some embodiments, administration of a therapeutically effective amount of a pharmaceutical composition of the present disclosure to a subject can kill tumor cells or inhibit tumor cell growth.

[0102] In some embodiments, administration of an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof of the present disclosure and a second or another therapeutic agent to a subject can kill tumor cells or inhibit tumor cell growth. In some embodiments, administration of a therapeutically effective amount of an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof and a second or another therapeutic agent to a subject can kill tumor cells or inhibit tumor cell growth. In some embodiments, administration of a pharmaceutical composition of the present disclosure and a second or another therapeutic agent to a subject can kill tumor cells or inhibit tumor cell growth. In some embodiments, administration of a therapeutically effective amount of a pharmaceutical composition of the present disclosure and a second or another therapeutic agent to a subject can kill tumor cells or inhibit tumor cell growth.

[0103] In the above-mentioned methods or uses, the pharmaceutical composition comprises the antibody-drug conjugate of the present disclosure or a pharmaceutically acceptable salt or solvate thereof, and optionally further comprises a pharmaceutically acceptable carrier.

[0104] In some embodiments, in the above-described methods or uses, the tumor is a CLDN18.2-positive tumor. In some embodiments, administration of a therapeutically effective amount of an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof of the present disclosure, or a pharmaceutical composition of the present disclosure to a subject can kill tumor cells that express CLDN18.2 or inhibit the growth of tumor cells that express CLDN18.2. Examples of tumors include, but are not limited to, gastric cancer, esophageal cancer, gastrointestinal cancer (including colon cancer and rectal cancer), pancreatic cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), bronchial cancer, mesothelioma, kidney cancer, ovarian cancer (including Krukenberg's tumor), breast cancer, bladder cancer, uterine cancer, endometrial cancer, prostate cancer, testicular cancer, anal cancer, vaginal cancer, bile duct cancer, gallbladder cancer, head and neck cancer, spinal tumors, otorhinolaryngological tumors, thyroid cancer, mesothelioma, bone cancer, skin cancer, melanoma, adenocarcinoma, sarcoma, neuroblastoma, glioblastoma, brain cancer, central nervous system cancer, neuroendocrine tumors, leukemia, lymphoma, and myeloma.

[0105] (kit) The present disclosure provides a kit comprising an anti-CLDN18.2 antibody-drug conjugate of the present disclosure or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present disclosure.

[0106] The present disclosure describes a kit comprising the anti-CLDN18.2 antibody-drug conjugate, a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition. The kit can be used to practice or otherwise use the anti-CLDN18.2 antibody-drug conjugate, a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition provided by the present disclosure. In some embodiments, the kit can comprise the anti-CLDN18.2 antibody-drug conjugate, a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition. The kit can further comprise instructions for use. The kit can further comprise other materials necessary for the seller and user, such as other buffers, diluents, needles, syringes, etc.

[0107] (Cytotoxic drug and linker-payload) In some aspects, the present disclosure provides a linker-payload having the structure shown in Formula III below: [ka] wherein R1 and R2 are each independently selected from hydrogen (H) or deuterium (D). In some specific embodiments, the present disclosure provides a linker-payload having the structure shown in formula III-1, III-2, III-3, or III-4 below. [ka] [ka] [ka] or [ka]

[0108] The linker-payload is used to obtain an antibody-drug conjugate comprising an antibody or an antigen-binding fragment thereof linked to the linker-payload.

[0109] In some embodiments, the present disclosure provides compounds of the structure shown in Formula I below: [ka]

[0110] The antibody-drug conjugates or pharmaceutically acceptable salts or solvates thereof provided by the present disclosure achieve excellent anti-tumor efficacy and / or safety. In some embodiments, the provided anti-CLDN18.2 antibody-drug conjugates exhibit good killing activity against multiple types of tumor cells expressing CLDN18.2. In some embodiments, the provided anti-CLDN18.2 antibody-drug conjugates have no killing activity against cells expressing CLDN18.1. In some embodiments, the provided anti-CLDN18.2 antibody-drug conjugates effectively bind to cells expressing CLDN18.2 and effectively endocytose cells expressing CLDN18.2. In some embodiments, the provided anti-CLDN18.2 antibody-drug conjugates have good in vivo anti-tumor activity. In some embodiments, the provided anti-CLDN18.2 antibody-drug conjugates have excellent safety. In some embodiments, the provided anti-CLDN18.2 antibody-drug conjugates are less prone to aggregation.

[0111] The antibody-drug conjugates or pharmaceutically acceptable salts or solvates thereof provided by the present disclosure have excellent pharmacokinetic properties, which can result in low toxicity, high safety and / or tolerability, high efficacy, and a wide therapeutic window.

[0112] (Manufacturing method) The present disclosure provides a method for producing an antibody-drug conjugate of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, comprising treating an anti-CLDN18.2 antibody or antigen-binding fragment thereof under reducing conditions, and then reacting the anti-CLDN18.2 antibody or antigen-binding fragment thereof with a linker-payload selected from the structure shown in Formula III, wherein R1 and R2 are each independently selected from hydrogen or deuterium. In some embodiments, R1 and R2 are hydrogen.

[0113] In some embodiments, the method comprises treating an anti-CLDN18.2 antibody or antigen-binding fragment thereof under reducing conditions, and then reacting the anti-CLDN18.2 antibody or antigen-binding fragment thereof with a linker-payload having the structure shown in Formula III-1. In some embodiments, the method comprises reducing the anti-CLDN18.2 antibody or antigen-binding fragment thereof in the presence of TCEP, and then performing a conjugation reaction by mixing the anti-CLDN18.2 antibody or antigen-binding fragment thereof with a linker-payload having the structure shown in Formula III-1 to obtain the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof. [Brief explanation of the drawings]

[0114] [Figure 1A] Binding activity of hz28G3-1.1-DDDXd (DAR is 7.4), hz28G3-1.3-DDDXd (DAR is 7.6), hz28G3-1.1, and hz28G3-1.3 to NIH-3T3, BxPC-3, and NCI-N87 cells overexpressing CLDN18.2. [Figure 1B] Binding activity of hz28G3-1.1-DDDXd (DAR is 7.4), hz28G3-1.3-DDDXd (DAR is 7.6), hz28G3-1.1, and hz28G3-1.3 to NIH-3T3, BxPC-3, and NCI-N87 cells overexpressing CLDN18.2. [Figure 1C] Binding activity of hz28G3-1.1-DDDXd (DAR is 7.4), hz28G3-1.3-DDDXd (DAR is 7.6), hz28G3-1.1, and hz28G3-1.3 to NIH-3T3, BxPC-3, and NCI-N87 cells overexpressing CLDN18.2. [Figure 2A] Endocytosis of hz28G3-1.1-DDDXd (DAR is 7.4), hz28G3-1.3-DDDXd (DAR is 7.6), hz28G3-1.1, and hz28G3-1.3 in CLDN18.2-overexpressing NIH-3T3, BxPC-3, and NCI-N87 cells and the CLDN18.2-positive native cell line NUGC-4. [Figure 2B] Endocytosis of hz28G3-1.1-DDDXd (DAR is 7.4), hz28G3-1.3-DDDXd (DAR is 7.6), hz28G3-1.1, and hz28G3-1.3 in CLDN18.2-overexpressing NIH-3T3, BxPC-3, and NCI-N87 cells and the CLDN18.2-positive native cell line NUGC-4. [Figure 2C] Endocytosis of hz28G3-1.1-DDDXd (DAR is 7.4), hz28G3-1.3-DDDXd (DAR is 7.6), hz28G3-1.1, and hz28G3-1.3 in CLDN18.2-overexpressing NIH-3T3, BxPC-3, and NCI-N87 cells and the CLDN18.2-positive native cell line NUGC-4. [Figure 2D] Endocytosis of hz28G3-1.1-DDDXd (DAR is 7.4), hz28G3-1.3-DDDXd (DAR is 7.6), hz28G3-1.1, and hz28G3-1.3 in CLDN18.2-overexpressing NIH-3T3, BxPC-3, and NCI-N87 cells and the CLDN18.2-positive native cell line NUGC-4. [Figure 3A] Killing of hz28G3-1.1-DDDXd (DAR is 7.4) and hz28G3-1.3-DDDXd (DAR is 7.6) against NIH-3T3, BxPC-3, and NCI-N87 cells overexpressing CLDN18.2. [Figure 3B] Killing of hz28G3-1.1-DDDXd (DAR is 7.4) and hz28G3-1.3-DDDXd (DAR is 7.6) against NIH-3T3, BxPC-3, and NCI-N87 cells overexpressing CLDN18.2. [Figure 3C] Killing of hz28G3-1.1-DDDXd (DAR is 7.4) and hz28G3-1.3-DDDXd (DAR is 7.6) against NIH-3T3, BxPC-3, and NCI-N87 cells overexpressing CLDN18.2. [Figure 4]CDC activity of hz28G3-1.1-DDDXd (DAR is 7.4) and hz28G3-1.3-DDDXd (DAR is 7.6) against NIH-3T3 cells overexpressing CLDN18.2. [Figure 5] Non-specific killing of hz28G3-1.1-DDDXd (DAR is 7.4) and hz28G3-1.3-DDDXd (DAR is 7.6) against NIH-3T3-CLDN18.1 cells. [Figure 6] Bystander effect of hz28G3-1.1-DDDXd (DAR is 7.4) and hz28G3-1.3-DDDXd (DAR is 7.6), with CLDN18.2-overexpressing BxPC-3 cells as positive cells and U2OS-luciferase as negative cells.

[0115] (Explanation and Definition) Unless otherwise specified, the following terms used in this disclosure have the following meanings: Certain terms are to be understood in their ordinary sense in the art, and not as open-ended or indefinite, unless otherwise defined. When trade names are mentioned herein, they refer to the corresponding product or its active ingredient.

[0116] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, provided that the valence of the atom is normal and the resulting compound is stable. When the substituent is oxo (=O), two hydrogen atoms are replaced. Oxo does not occur in aryl groups.

[0117] When a particular variable (e.g., R) occurs more than one time in a compound composition or structure, each occurrence is independently defined. Thus, for example, if a group is substituted with two R, each R is an independent option.

[0118] As used herein, the structure of "-(succinimidyl-3-yl-N)-" is as shown below: [ka]

[0119] Unless otherwise stated, solid wedge bonds ( [ka] ) and wedge-shaped dashed bond ( [ka] ) represents the absolute configuration of the chiral center.

[0120] Unless otherwise specified, when a group has a linkable site, the chemical bond connecting that site to another group is represented by a wavy line ( [ka] ) can be expressed as: [ka] indicates that the nitrogen atom at position 1 and the carbon atom at position 3 of the -(succinimidyl-3-yl-N)- are linked to other groups.

[0121] A "derivative" is a compound formed by replacing an atom or atomic group of a parent compound molecule with another atom or atomic group, and is called a derivative of the parent compound.

[0122] The compounds and intermediates of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be interconverted via a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton transfer (e.g., ketone-enol and imine-enamine isomerizations). A specific example of a proton tautomer is an imidazole moiety, in which a proton can be transferred between two ring nitrogen atoms. Valence tautomers include interconversions via recombination of some bonding electrons.

[0123] The compounds of the present disclosure may be asymmetric, e.g., possess one or more stereoisomers. The compounds of the present disclosure may have specific geometric isomers. Unless otherwise specified, all geometric and stereoisomers are included, including cis and trans isomers, levo- and dextro-isomers, enantiomers, diastereomers, (D)- and (L)-isomers. Racemic mixtures and other mixtures of the isomers, e.g., enantiomer- or diastereomer-enriched mixtures, are also within the scope of the present disclosure. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0124] Unless otherwise specified, the terms "cis / trans isomers" or "geometric isomers" refer to those resulting from the lack of free rotation of double bonds or single bonds of ring carbon atoms. Unless otherwise specified, the term "enantiomers" refers to stereoisomers that are mirror images of each other. Unless otherwise specified, the term "diastereomers" refers to stereoisomers with two or more centers of chirality and whose molecules are not mirror images of one another.

[0125] Unless otherwise specified, in the structural formulae referred to in this disclosure, it is understood by those of skill in the art that D is equivalent to deuterium.

[0126] The term "bystander effect," as used herein, refers to the ability of a cytotoxic drug conjugated to an antibody or antigen-binding fragment thereof via a cleavable or non-cleavable linker to diffuse across the cell membrane upon release from the antibody or antigen-binding fragment thereof, resulting in killing of neighboring cells. The ability to diffuse across the cell membrane is related to the hydrophobicity of the cytotoxic drug or the combination of the cytotoxic drug and the linker. Examples of such cytotoxic drugs include exatecan derivatives and MMAE. The bystander effect may be particularly desirable for tumors with heterogeneous target expression and solid tumors in which antibody penetration is limited.

[0127] The term "treatment" means administering a compound or pharmaceutical composition described herein to prevent, ameliorate, or eliminate a disease or one or more symptoms associated with said disease, and includes, but is not limited to, (i) preventing the appearance of a disease or disease state in a mammal, particularly when a susceptible mammal has not been diagnosed with the disease state; (ii) inhibiting the disease or disease state, i.e., slowing its progression; (iii) alleviating the disease or disease state, i.e., causing the disease or disease state to resolve; and (iv) reducing any direct or indirect pathological effects of the disease or disease state.

[0128] The term "therapeutically effective amount" refers to a dose of a compound of the present disclosure that (i) treats or prevents a particular disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The dose that constitutes a "therapeutically effective amount" of a compound or pharmaceutical composition of the present disclosure can vary depending on several factors, including, for example, the compound or pharmaceutical composition and its ability to elicit a desired response in an individual, the state of the disease and its severity, the mode of administration, and the age, sex, and weight of the mammal being treated.

[0129] The term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are medically reliably determined to be suitable for use in contact with the tissues of humans and animals, are not toxic or irritating, and are not likely to cause allergic reactions or other problems or complications, and for which the benefit-risk ratio is reasonable.

[0130] The term "pharmaceutically acceptable salt" refers to a salt of a compound (e.g., an antibody-drug conjugate of the present disclosure) that is safe and effective when used in a mammalian body and has the desired biological activity, and may be, for example, a metal salt, an ammonium salt, a salt formed with an organic base, a salt formed with an inorganic acid, a salt formed with an organic acid, or a salt formed with a basic or acidic amino acid.

[0131] The term "solvate" refers to a substance formed when a compound is associated with solvent molecules.

[0132] The term "antibody" is used in the broadest sense to include, but is not limited to, various antibody structures, such as monoclonal antibodies, polyclonal antibodies, and multispecific antibodies (e.g., bispecific antibodies, trispecific antibodies), so long as they exhibit the desired antigen-binding activity.

[0133] An "antigen-binding fragment" of an antibody refers to one or more fragments of an antibody that retain the function of specifically binding to an antigen (e.g., a CLDN18.2 protein). It has been demonstrated that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples covered by the term "antigen-binding fragment of an antibody" include: (i) a Fab fragment, which is a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) an F(ab')2 fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of a single antibody arm; (v) a dAb fragment consisting of the VH domain (see Ward et al., Nature. 341:544-546 (1989)); and (vi) a nanobody, which is an antibody comprising one variable domain and two constant domains. Furthermore, although the two domains of an Fv fragment, VL and VH, are encoded by different genes, VH and VL can be linked into a single protein chain using a linker using recombinant techniques. Monovalent molecules formed by matching VL and VH are called single-chain Fvs (scFvs) (see Bird et al., Science. 242:423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. 85:5879-5883 (1988)). These single-chain antibodies are also encompassed by the term "antigen-binding fragment." These antibody fragments can be obtained using conventional techniques known to those skilled in the art, and the fragments can be screened for function in the same manner as full-length antibodies.

[0134] The anti-CLDN18.2 antibody or antigen-binding fragment thereof of the present disclosure may be of the IgG1, IgG2, IgG3, or IgG4 isotype. The term "isotype" refers to the class of antibody encoded by the heavy chain constant region gene. In some embodiments, the anti-CLDN18.2 antibody or antigen-binding fragment thereof of the present disclosure is of the IgG1 isotype. The anti-CLDN18.2 antibody or antigen-binding fragment thereof of the present disclosure may be derived from any species, including, but not limited to, mouse, rat, rabbit, non-human primate (e.g., chimpanzee, cynomolgus monkey, spider monkey, macaque), llama, or human. The anti-CLDN18.2 antibody or antigen-binding fragment thereof of the present disclosure may be a murine antibody, chimeric antibody, humanized antibody, or human antibody.

[0135] The term "murine antibody" or "rodent antibody" refers to an antibody in which both the framework and CDR regions in the variable region are derived from mouse germline immunoglobulin sequences. Also, if the antibody contains a constant region, the constant region is also derived from mouse germline immunoglobulin sequences. Murine antibodies of the present disclosure may include amino acid residues not encoded by mouse germline immunoglobulin sequences (e.g., mutations introduced by random or point mutation in vitro or by somatic mutation in vivo), however, "murine antibody" or "rodent antibody" does not include antibodies in which germline CDR sequences from other mammals have been inserted into mouse framework sequences.

[0136] A "chimeric antibody" is an antibody formed by fusing the variable region of a murine antibody with the constant region of a human antibody, which can reduce the immune response induced by murine antibodies. To produce a chimeric antibody, first, hybridomas secreting specific murine monoclonal antibodies must be produced. Then, variable region genes are cloned from the hybridoma cells. If necessary, human antibody constant region genes are cloned. The mouse variable region genes and human constant region genes are linked to obtain chimeric genes, which are then inserted into an expression vector and finally expressed in eukaryotic or prokaryotic systems.

[0137] A "humanized antibody" is an antibody containing complementarity-determining regions (CDRs) derived from a non-human antibody and framework and constant regions derived from a human antibody. For example, a humanized antibody that binds to CLDN18.2 in an antibody-drug conjugate provided herein can contain CDRs derived from one or more murine antibodies and human framework and constant regions. Thus, in some embodiments, a humanized antibody in an antibody-drug conjugate provided herein binds to the same epitope on CLDN18.2 as the murine antibody from which its CDRs are derived. The present specification provides exemplary humanized antibodies. Other humanized antibodies or variants thereof that bind to CLDN18.2, including the heavy and light chain CDRs provided herein, can be produced using any human framework sequences and are also included in the present disclosure. In some embodiments, framework sequences suitable for use in accordance with the present disclosure include those framework sequences that are structurally similar to the framework sequences provided herein. Other modifications can be made in the framework regions to alter the properties of the antibodies provided herein. Such additional framework modifications can include chemical modifications, point mutations to reduce immunogenicity or eliminate T-cell epitopes, or backmutations to residues in the original germline sequence. In some embodiments, such additional modifications include those modifications corresponding to the exemplary mutations herein, such as backmutations to the germline sequence. For example, in some embodiments, one or more amino acids in the human framework regions of the VH and / or VL of a humanized antibody provided herein are backmutated to the corresponding amino acid in the parent murine antibody. In the present disclosure, humanized antibodies are sometimes referred to as "hz."

[0138] The term "CDR (complementarity determining region)" is also called "hypervariable region." Naturally occurring four-chain antibodies generally contain six CDRs: three in the heavy chain variable region and three in the light chain variable region.

[0139] The term "variable region" refers to the domain of the N-terminal domain of an antibody light chain or heavy chain, consisting of approximately 100 to 110 or more amino acids, which is primarily involved in antigen recognition. The terms "light chain variable region (VL)" and "heavy chain variable region (VH)" refer to these light chain and heavy chain domains, respectively.

[0140] As used herein, the term "EC 50 " refers to the effective concentration that induces 50% of the maximal response of an antibody or antigen-binding fragment thereof, or ADC, and the term "IC 50 " refers to the inhibitory concentration that induces 50% of the maximal response of an antibody or antigen-binding fragment thereof, or ADC. EC 50 and IC 50 can be measured by ELISA or FACS analysis, or any other method known in the art.

[0141] "K D " is K d and K. a The ratio of (i.e., K d / K a ) and is expressed as a molar concentration (M). D The K value can be measured by methods well established in the art. D A preferred method for measuring is surface plasmon resonance technology, preferably analyzed using a biosensor system, such as a BIACORE® surface plasmon resonance system.

[0142] The term "identity" is also referred to as "matching." The "percent identity" of an amino acid sequence refers to the percentage of amino acid residues in a compared sequence that are identical to those in a specific amino acid sequence set forth herein, after comparing the compared sequence with the specific amino acid sequence set forth herein and, if necessary, introducing gaps to achieve the maximum percent sequence identity, and not counting any conservative substitutions as part of the sequence identity. Comparing identical amino acid sequences can be performed using a variety of methods within the skill of the art, for example, using the software BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR). Those skilled in the art can determine appropriate parameters for sequence comparison, including any algorithm that will maximize the coverage across the entire length of the sequences being compared.

[0143] As used herein, the terms "X" and "Xaa" are synonymous and refer to an unspecified amino acid, with the scope of coverage determined by the definition in the relevant text. To distinguish between multiple "X"s in the same amino acid sequence, consecutive occurrences of X are numbered (i.e., X n ) define the range they cover.

[0144] The term "subject" includes any human or non-human animal. The term "non-human animal" includes all vertebrates, including mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, and reptiles. Preferably, the subject of the present disclosure is a human. Unless otherwise specified, the terms "patient" and "subject" can be used interchangeably. A "subject in need" includes a subject already suffering from a disease or condition, a subject at risk of developing a disease or condition, and a subject at risk of developing a disease or condition and who desires prevention, delay, or amelioration of the disease or condition.

[0145] As used herein, "about" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which is determined in part by how the value is measured or determined, i.e., the limitations of the measurement system. For example, according to common knowledge in the art, "about" can represent a standard deviation of 1 or more. Alternatively, "about" can represent a range of up to ±5%, e.g., a variation within a given numerical range of ±2%, ±1%, or ±0.5%. When a specific value is given in the scope of this disclosure, unless otherwise specified, the meaning of "about" is understood to be within an acceptable error range for the specific value. In this specification, unless otherwise specified, any value given as a parameter or condition of a step is considered to be modified by "about."

[0146] The terms "comprise," "comprises," or "comprising" or equivalent terms (e.g., contain, contains, containing, include, includes, and including) are understood to mean "including, but not limited to," that is, to include listed elements, components, and steps, as well as additional elements, components, and steps that are not specifically listed.

[0147] As used herein, singular terms cover plural referents and vice versa unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise. DETAILED DESCRIPTION OF THE INVENTION

[0148] The present disclosure also provides the following several specific embodiments, but the protection scope of the present disclosure is not limited thereto. (Embodiment 1) The general formula is Ab-(LU) nor a pharmaceutically acceptable salt or solvate thereof, wherein Ab is an antibody or an antigen-binding fragment thereof, L is a linker, U is a cytotoxic drug, and n is an integer selected from 1 to 10, and said Ab is an anti-CLDN18.2 antibody or an antigen-binding fragment thereof comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3; (1) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 11, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 11, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 11, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 16, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 16, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 16; (2) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 12, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 12, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 12, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 17, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 17, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 17; (3) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 13, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 13, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 13, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 17, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 17, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 17; (4) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 14, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 14, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 14, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 17, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 17, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 17; (5) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 15, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 15, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 15, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 17, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 17, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 17; (6) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 12, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 12, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 12, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 18, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 18, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 18; (7) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 13, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 13, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 13, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 18, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 18, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 18; (8) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 14, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 14, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 14, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 18, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 18, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 18; (9) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 15, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 15, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 15, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 18, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 18, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 18; (10) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 29, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 29, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 29, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 34, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 34, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 34; (11) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 30, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 30, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 30, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 35, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 35, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 35; (12) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 31, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 31, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 31, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 35, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 35, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 35; (13) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 32, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 32, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 32, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 35, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 35, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 35; (14) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 33, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 33, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 33, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 35, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 35, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 35; (15) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 30, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 30, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 30, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 36, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 36, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 36; (16) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 31, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 31, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 31, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 36, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 36, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 36; (17) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 32, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 32, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 32, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 36, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 36, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 36; (18) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 33, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 33, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 33, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 36, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 36, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 36; (19) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 43, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 43, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 44, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 44, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 44; (20) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 51, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 51, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 52, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 52, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 52; or (21) An antibody-drug conjugate, or a pharmaceutically acceptable salt or solvate thereof, wherein HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 59, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 59, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 59, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 60, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 60, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 60.

[0149] (Embodiment 2) (1) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 3, 4, 7, 8, 9, and 10, respectively; (2) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 3, 5, 7, 8, 9, and 10, respectively; (3) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 3, 6, 7, 8, 9, and 10, respectively; (4) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 20, 24, 25, 26, and 27, respectively; (5) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 21, 24, 25, 26, and 27, respectively; (6) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 22, 24, 25, 26, and 27, respectively; (7) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 23, 24, 25, 26 and 27, respectively; (8) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 20, 24, 25, 26, and 28, respectively; (9) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 21, 24, 25, 26 and 28, respectively; (10) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 22, 24, 25, 26, and 28, respectively; (11) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 23, 24, 25, 26, and 28, respectively; (12) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 37, 38, 39, 40, 41, and 42, respectively; (13) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 45, 46, 47, 48, 49, and 50, respectively; or (14) The antibody-drug conjugate of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 53, 54, 55, 56, 57, and 58, respectively.

[0150] (Embodiment 3) the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region; (1) the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 11 and 16, respectively; (2) the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 12 and 17, respectively; (3) the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 13 and 17, respectively; (4) the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 14 and 17, respectively; (5) the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 15 and 17, respectively; (6) the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 12 and 18, respectively; (7) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 13 and 18, respectively; (8) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 14 and 18, respectively; (9) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 15 and 18, respectively; (10) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 29 and 34, respectively; (11) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 30 and 35, respectively; (12) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 31 and 35, respectively; (13) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 32 and 35, respectively; (14) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 33 and 35, respectively; (15) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 30 and 36, respectively; (16) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 31 and 36, respectively; (17) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 32 and 36, respectively; (18) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 33 and 36, respectively; (19) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 43 and 44, respectively; (20) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 51 and 52, respectively; or (21) The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to embodiment 1 or 2, wherein the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 59 and 60, respectively.

[0151] (Embodiment 4) The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 3, wherein the anti-CLDN18.2 antibody or antigen-binding fragment thereof is of the IgG1, IgG2, or IgG4 isotype.

[0152] (Embodiment 5) The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 4, wherein the anti-CLDN18.2 antibody further comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 1 or an amino acid sequence having one, two, three, four, or five amino acid substitutions, deletions, or additions compared to the amino acid sequence set forth in SEQ ID NO: 1, and the light chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 2 or an amino acid sequence having one, two, three, four, or five amino acid substitutions, deletions, or additions compared to the amino acid sequence set forth in SEQ ID NO: 2.

[0153] (Embodiment 6) The anti-CLDN18.2 antibody comprises a heavy chain and a light chain, (1) the heavy chain comprises an amino acid sequence having at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 61, and the light chain comprises an amino acid sequence having at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 62; or (2) The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 5, wherein the heavy chain comprises an amino acid sequence having at least 80% identity with the amino acid sequence set forth in SEQ ID NO: 63, and the light chain comprises an amino acid sequence having at least 80% identity with the amino acid sequence set forth in SEQ ID NO: 64.

[0154] (Embodiment 7) 7. The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 6, wherein U is a camptothecin-based topoisomerase I inhibitor, and L and / or U have a deuteration modification.

[0155] (Embodiment 8) The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof of embodiment 7, wherein U is SN-38, an SN-38 derivative, exatecan, or an exatecan derivative, preferably an exatecan derivative.

[0156] (Embodiment 9) -U is the structure shown in formula Ia below: [ka] 9. The antibody-drug conjugate of embodiment 8, or a pharmaceutically acceptable salt or solvate thereof.

[0157] (Embodiment 10) -L- is the structure shown in formula IIa below: [ka] wherein R1 and R2 are each independently selected from hydrogen or deuterium; and in the structure shown, position 3 of -(succinimidyl-3-yl-N)- is linked to the Ab, and the methylene group at the other end is linked to the U. The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 7 to 9.

[0158] (Embodiment 11) -LU is the structure shown in formula IIIa below: [ka] wherein R1 and R2 are each independently selected from hydrogen or deuterium, or a pharmaceutically acceptable salt or solvate thereof, according to embodiment 7.

[0159] (Embodiment 12) -LU is a structure shown in formula IIIa-1, IIIa-2, IIIa-3 or IIIa-4 below: [ka] [ka] [ka] or [ka] 12. The antibody-drug conjugate of embodiment 11, or a pharmaceutically acceptable salt or solvate thereof.

[0160] (Embodiment 13) The structure of the antibody-drug conjugate is as shown in Formula IV below: [ka] wherein R1 and R2 are each independently selected from hydrogen or deuterium, or a pharmaceutically acceptable salt or solvate thereof, according to embodiment 7.

[0161] (Embodiment 14) The structure of the antibody-drug conjugate is as shown in the following formula IV-1, IV-2, IV-3 or IV-4: [ka] [ka] [ka] or [ka] 14. The antibody-drug conjugate of embodiment 13, or a pharmaceutically acceptable salt or solvate thereof.

[0162] (Embodiment 15) The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 14, wherein n is an integer selected from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 8, 5 to 7, 5 to 6, 6 to 8, 6 to 7, or 7 to 8, preferably an integer selected from 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, or 7 to 8, and more preferably an integer selected from 6 to 8.

[0163] (Embodiment 16) The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof is (a) binding to CLDN18.2; (b) blocking the binding of CLDN18.2 to a ligand; (c) showing endocytosis in cells expressing CLDN18.2; (d) having killing activity against tumor cells expressing CLDN18.2; (e) There is a bystander effect. (f) having ADCC activity; (g) having CDC activity; (h) not binding to CLDN18.1; (i) not binding to cells that do not express CLDN18.2; and (j) having no ADCC and / or CDC activity against cells expressing CLDN18.1; 16. The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 15, which exhibits one or a combination of more than one of the above properties.

[0164] (Embodiment 17) A pharmaceutical composition comprising the antibody-drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 16, wherein preferably the antibody-drug conjugate or the pharmaceutically acceptable salt or solvate thereof in the pharmaceutical composition is heterogeneous or homogeneous, and optionally further comprises a pharmaceutically acceptable carrier.

[0165] (Embodiment 18) The pharmaceutical composition according to embodiment 17, wherein the antibody-drug conjugate or the pharmaceutically acceptable salt or solvate thereof in the pharmaceutical composition is heterogeneous, and the DAR of the pharmaceutical composition is 0 to 10, 0 to 9, 0 to 8, 1 to 10, 1 to 9, 1 to 8, 2 to 10, 2 to 9, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 7 to 8, 7.2 to 8, 7.4 to 8, 7.5 to 8, 7.6 to 8, 7.7 to 8, 7.8 to 8, 7.8 to 7.9, or 7.9 to 8, preferably 7 to 8, 7.2 to 8, 7.4 to 8, 7.6 to 8, or 7.7 to 8, and more preferably about 7.1, about 7.2, about 7.4, about 7.6, about 7.7, or about 8.

[0166] (Embodiment 19) Use of the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 16, or the pharmaceutical composition according to embodiment 17 or 18, in the manufacture of a medicament for tumor treatment.

[0167] (Embodiment 20) Use of the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 1 to 16, or the pharmaceutical composition according to Embodiment 17 or 18, together with a second therapeutic agent, in the manufacture of a medicament for tumor treatment.

[0168] (Embodiment 21) The use according to embodiment 19 or 20, wherein the tumor is a CLDN18.2-positive tumor, preferably the tumor is gastric cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, liver cancer, lung cancer, bronchial cancer, mesothelioma, kidney cancer, ovarian cancer, breast cancer, bladder cancer, uterine cancer, endometrial cancer, prostate cancer, testicular cancer, anal cancer, vaginal cancer, bile duct cancer, gallbladder cancer, head and neck cancer, spinal tumors, otorhinolaryngological tumors, thyroid cancer, mesothelioma, bone cancer, skin cancer, melanoma, adenocarcinoma, sarcoma, neuroblastoma, glioblastoma, brain cancer, central nervous system cancer, neuroendocrine tumors, leukemia, lymphoma and / or myeloma.

[0169] (Embodiment 22) A method for treating a tumor, comprising administering to a patient in need thereof a therapeutically effective amount of the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 1 to 16, or the pharmaceutical composition according to embodiment 17 or 18.

[0170] (Embodiment 23) The method of embodiment 22, wherein the method comprises contacting tumor cells with the antibody-drug conjugate of any one of embodiments 1 to 16 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of embodiment 17 or 18, thereby killing or inhibiting the growth of tumor cells.

[0171] (Embodiment 24) 24. The method of embodiment 22 or 23, wherein the method further comprises administering a second therapeutic agent.

[0172] (Embodiment 25) The method according to any one of embodiments 22 to 24, wherein the tumor is a CLDN18.2-positive tumor, preferably, the tumor is gastric cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, liver cancer, lung cancer, bronchial cancer, mesothelioma, kidney cancer, ovarian cancer, breast cancer, bladder cancer, uterine cancer, endometrial cancer, prostate cancer, testicular cancer, anal cancer, vaginal cancer, bile duct cancer, gallbladder cancer, head and neck cancer, spinal tumor, otorhinolaryngological tumor, thyroid cancer, mesothelioma, bone cancer, skin cancer, melanoma, adenocarcinoma, sarcoma, neuroblastoma, glioblastoma, brain cancer, central nervous system cancer, neuroendocrine tumor, leukemia, lymphoma and / or myeloma.

[0173] (Embodiment 26) treating an anti-CLDN18.2 antibody or antigen-binding fragment thereof under reducing conditions, and then reacting the anti-CLDN18.2 antibody or antigen-binding fragment thereof with a linker-payload selected from the structure shown in Formula III, wherein the structure shown in Formula III is: [ka] A method for producing an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 11 to 16, wherein R1 and R2 are each independently selected from hydrogen or deuterium.

[0174] (Embodiment 27) 27. The method of embodiment 26, wherein R1 and R2 are hydrogen.

[0175] (Embodiment 28) An antibody-drug conjugate, or a pharmaceutically acceptable salt or solvate thereof, comprising a structure shown in the following formula IIIa linked to an antibody or an antigen-binding fragment thereof: [ka] wherein R1 and R2 are each independently selected from hydrogen or deuterium, and position 3 of -(succinimidyl-3-yl-N)- in the structure shown in formula IIIa is linked to an antibody or antigen-binding fragment thereof; the antibody or antigen-binding fragment thereof is an anti-CLDN18.2 antibody or antigen-binding fragment thereof comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3; (1) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 11, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 11, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 11, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 16, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 16, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 16; (2) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 12, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 12, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 12, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 17, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 17, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 17; (3) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 13, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 13, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 13, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 17, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 17, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 17; (4) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 14, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 14, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 14, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 17, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 17, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 17; (5) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 15, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 15, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 15, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 17, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 17, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 17; (6) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 12, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 12, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 12, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 18, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 18, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 18; (7) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 13, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 13, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 13, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 18, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 18, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 18; (8) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 14, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 14, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 14, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 18, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 18, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 18; (9) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 15, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 15, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 15, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 18, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 18, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 18; (10) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 29, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 29, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 29, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 34, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 34, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 34; (11) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 30, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 30, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 30, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 35, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 35, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 35; (12) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 31, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 31, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 31, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 35, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 35, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 35; (13) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 32, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 32, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 32, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 35, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 35, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 35; (14) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 33, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 33, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 33, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 35, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 35, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 35; (15) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 30, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 30, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 30, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 36, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 36, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 36; (16) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 31, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 31, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 31, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 36, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 36, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 36; (17) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 32, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 32, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 32, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 36, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 36, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 36; (18) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 33, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 33, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 33, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 36, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 36, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 36; (19) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 43, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 43, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 44, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 44, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 44; (20) HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 51, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 51, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 52, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 52, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 52; or (21) An antibody-drug conjugate, or a pharmaceutically acceptable salt or solvate thereof, wherein HCDR1 comprises the amino acid sequence of HCDR1 in SEQ ID NO: 59, HCDR2 comprises the amino acid sequence of HCDR2 in SEQ ID NO: 59, HCDR3 comprises the amino acid sequence of HCDR3 in SEQ ID NO: 59, LCDR1 comprises the amino acid sequence of LCDR1 in SEQ ID NO: 60, LCDR2 comprises the amino acid sequence of LCDR2 in SEQ ID NO: 60, and LCDR3 comprises the amino acid sequence of LCDR3 in SEQ ID NO: 60.

[0176] (Embodiment 29) (1) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 3, 4, 7, 8, 9, and 10, respectively; (2) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 3, 5, 7, 8, 9, and 10, respectively; (3) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 3, 6, 7, 8, 9, and 10, respectively; (4) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 20, 24, 25, 26, and 27, respectively; (5) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 21, 24, 25, 26, and 27, respectively; (6) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 22, 24, 25, 26, and 27, respectively; (7) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 23, 24, 25, 26 and 27, respectively; (8) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 20, 24, 25, 26, and 28, respectively; (9) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 21, 24, 25, 26 and 28, respectively; (10) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 22, 24, 25, 26, and 28, respectively; (11) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 23, 24, 25, 26, and 28, respectively; (12) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 37, 38, 39, 40, 41, and 42, respectively; (13) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 45, 46, 47, 48, 49, and 50, respectively; or (14) The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to embodiment 28, wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 53, 54, 55, 56, 57, and 58, respectively.

[0177] (Embodiment 30) the anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region; (1) the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 11 and 16, respectively; (2) the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 12 and 17, respectively; (3) the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 13 and 17, respectively; (4) the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 14 and 17, respectively; (5) the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 15 and 17, respectively; (6) the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 12 and 18, respectively; (7) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 13 and 18, respectively; (8) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 14 and 18, respectively; (9) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 15 and 18, respectively; (10) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 29 and 34, respectively; (11) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 30 and 35, respectively; (12) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 31 and 35, respectively; (13) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 32 and 35, respectively; (14) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 33 and 35, respectively; (15) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 30 and 36, respectively; (16) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 31 and 36, respectively; (17) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 32 and 36, respectively; (18) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 33 and 36, respectively; (19) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 43 and 44, respectively; (20) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 51 and 52, respectively; or (21) The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to embodiment 28 or 29, wherein the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 59 and 60, respectively.

[0178] (Embodiment 31) The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 28 to 30, wherein the anti-CLDN18.2 antibody or antigen-binding fragment thereof is of the IgG1, IgG2, or IgG4 isotype.

[0179] (Embodiment 32) The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 28 to 31, wherein the anti-CLDN18.2 antibody further comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 1 or an amino acid sequence having one, two, three, four, or five amino acid substitutions, deletions, or additions compared to the amino acid sequence set forth in SEQ ID NO: 1, and the light chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 2 or an amino acid sequence having one, two, three, four, or five amino acid substitutions, deletions, or additions compared to the amino acid sequence set forth in SEQ ID NO: 2.

[0180] (Embodiment 33) The anti-CLDN18.2 antibody comprises a heavy chain and a light chain, (1) the heavy chain comprises an amino acid sequence having at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 61, and the light chain comprises an amino acid sequence having at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 62; or (2) The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 28 to 32, wherein the heavy chain comprises an amino acid sequence having at least 80% identity with the amino acid sequence set forth in SEQ ID NO: 63, and the light chain comprises an amino acid sequence having at least 80% identity with the amino acid sequence set forth in SEQ ID NO: 64.

[0181] (Embodiment 34) The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 28 to 33, wherein R1 and R2 are both hydrogen.

[0182] (Embodiment 35) The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 28 to 34, wherein the antibody-drug conjugate is one in which the structure shown in Formula IIIa is linked to the antibody or antigen-binding fragment thereof via a thioether bond.

[0183] (Embodiment 36) The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof is (a) binding to CLDN18.2; (b) blocking the binding of CLDN18.2 to a ligand; (c) showing endocytosis in cells expressing CLDN18.2; (d) having killing activity against tumor cells expressing CLDN18.2; (e) There is a bystander effect. (f) having ADCC activity; (g) having CDC activity; (h) not binding to CLDN18.1; (i) not binding to cells that do not express CLDN18.2; and (j) having no ADCC and / or CDC activity against cells expressing CLDN18.1; The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 28 to 35, which exhibits one or a combination of more than one of the above properties.

[0184] (Embodiment 37) A pharmaceutical composition comprising the antibody-drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 28 to 36, wherein preferably the antibody-drug conjugate or the pharmaceutically acceptable salt or solvate thereof in the pharmaceutical composition is heterogeneous or homogeneous, and optionally further comprises a pharmaceutically acceptable carrier.

[0185] (Embodiment 38) The pharmaceutical composition according to embodiment 37, wherein the antibody-drug conjugate or the pharmaceutically acceptable salt or solvate thereof in the pharmaceutical composition is heterogeneous, and the DAR of the pharmaceutical composition is 0 to 10, 0 to 9, 0 to 8, 1 to 10, 1 to 9, 1 to 8, 2 to 10, 2 to 9, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 7 to 8, 7.2 to 8, 7.4 to 8, 7.5 to 8, 7.6 to 8, 7.7 to 8, 7.8 to 8, 7.8 to 7.9, or 7.9 to 8, preferably 7 to 8, 7.2 to 8, 7.4 to 8, 7.6 to 8, or 7.7 to 8, and more preferably about 7.1, about 7.2, about 7.4, about 7.6, about 7.7, or about 8.

[0186] (Embodiment 39) Use of the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 28 to 36, or the pharmaceutical composition according to embodiment 37 or 38, in the manufacture of a medicament for tumor treatment.

[0187] (Embodiment 40) Use of the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of Embodiments 28 to 36, or the pharmaceutical composition according to Embodiment 37 or 38, together with a second therapeutic agent, in the manufacture of a medicament for tumor treatment.

[0188] (Embodiment 41) The use according to embodiment 39 or 40, wherein the tumor is a CLDN18.2-positive tumor, preferably the tumor is gastric cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, liver cancer, lung cancer, bronchial cancer, mesothelioma, kidney cancer, ovarian cancer, breast cancer, bladder cancer, uterine cancer, endometrial cancer, prostate cancer, testicular cancer, anal cancer, vaginal cancer, bile duct cancer, gallbladder cancer, head and neck cancer, spinal tumors, otorhinolaryngological tumors, thyroid cancer, mesothelioma, bone cancer, skin cancer, melanoma, adenocarcinoma, sarcoma, neuroblastoma, glioblastoma, brain cancer, central nervous system cancer, neuroendocrine tumors, leukemia, lymphoma and / or myeloma.

[0189] (Embodiment 42) A method for treating a tumor, comprising administering to a patient in need thereof a therapeutically effective amount of the antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof described in any one of embodiments 28 to 36, or the pharmaceutical composition described in embodiment 37 or 38.

[0190] (Embodiment 43) The method of embodiment 42, wherein the method comprises contacting tumor cells with the antibody-drug conjugate of any one of embodiments 28 to 36 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of embodiment 37 or 38, thereby killing or inhibiting the growth of tumor cells.

[0191] (Embodiment 44) 44. The method of embodiment 42 or 43, wherein the method further comprises administering a second therapeutic agent.

[0192] (Embodiment 45) The method according to any one of embodiments 42 to 44, wherein the tumor is a CLDN18.2-positive tumor, preferably, the tumor is gastric cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, liver cancer, lung cancer, bronchial cancer, mesothelioma, kidney cancer, ovarian cancer, breast cancer, bladder cancer, uterine cancer, endometrial cancer, prostate cancer, testicular cancer, anal cancer, vaginal cancer, bile duct cancer, gallbladder cancer, head and neck cancer, spinal tumor, otorhinolaryngological tumor, thyroid cancer, mesothelioma, bone cancer, skin cancer, melanoma, adenocarcinoma, sarcoma, neuroblastoma, glioblastoma, brain cancer, central nervous system cancer, neuroendocrine tumor, leukemia, lymphoma and / or myeloma.

[0193] (Example) The present disclosure will be further described below using examples to make the disclosure clearer, but the scope of the disclosure is not limited to the examples. The reagents used in the present disclosure are generally commercially available products and can be used without purification.

[0194] The cells and their sources referred to in the examples of this disclosure are as shown in the following table. [Table 2]

[0195] Example 1: Production of anti-CLDN18.2 monoclonal antibodies (Construction of stable cell lines) A cDNA encoding human CLDN18.2 (SEQ ID NO: 65) was obtained by gene synthesis and then subcloned into the expression vector pcDNA3.1. The expression vector was transfected into U2OS cells and NIH-3T3 cells, respectively, according to the instructions for Lipofectamine 2000 transfection reagent (Thermo, catalog no. 11668019), to obtain stable cell lines U2OS-CLDN18.2 and NIH-3T3-CLDN18.2.

[0196] (Mouse Immunization) Balb / c mice were immunized with the immunogen NIH-3T3-CLDN18.2 cells, and each mouse received 5 × 10 6 ~10×10 6Three days before fusion, each mouse was intraperitoneally injected with 1 × 10 NIH-3T3-CLDN18.2 cells, once every two weeks for a total of five immunizations. 7 Mice were immunized by intraperitoneal injection of NIH-3T3-CLDN18.2 cells. After immunization, serum was collected from each mouse and the anti-CLDN18.2-specific antibody titer was measured. Mice with high antibody titers were selected for subsequent spleen cell fusion.

[0197] (cell fusion) Spleen cells (1 × 10) from immunized mice were fused using an electrofusion apparatus (BTX, ECM2001). 8 cells) and SP2 / 0 myeloma cells (5 × 10 7 Hybridoma cells were obtained by fusing the cells. After fusion, the cells were resuspended in HAT complete medium and dispensed at 0.2 mL per well into a 96-well plate. They were cultured at 37°C in a 5% CO2 incubator. After 7 to 10 days, the hybridoma cell culture supernatant was collected and analyzed.

[0198] (Hybridoma screening) The binding activity of the antibody against CLDN18.2 was measured by ELISA. U2OS-CLDN18.2 cells were plated at 10,000 cells / well into a 96-well plate and cultured overnight in a 37°C, 5% CO2 incubator. The cell culture supernatant was discarded, and the 96-well plate was washed three times with PBS buffer. Cells were fixed with 2% paraformaldehyde for 30 minutes at room temperature. The 96-well plate was washed three times with PBS buffer, and 100 μL of hybridoma cell culture supernatant was added to each well and incubated for 1 hour at room temperature. The 96-well plate was washed three times with PBS buffer, and 100 μL of HRP-Goat Anti-Mouse IgG Fcγ (Jackson immunoresearch, catalog number 115-035-071) was added to each well and incubated for 1 hour at room temperature. The 96-well plate was washed three times with PBS buffer, and 100 μL of TMB (Thermo, Cat. No. 00-4201-56) was added to each well and incubated for 10 minutes. The reaction was then stopped by adding 50 μL of stop solution (1 M H2SO4) to each well. The OD value was read at 450 nm using a microplate reader (Thermo, Varioskan Flash).

[0199] Hybridoma cells detected as positive by ELISA were selected, and the binding activity of the antibodies in the culture supernatant of the hybridoma cells to the cell lines KATOIII and NUGC-4, which naturally express CLDN18.2, was measured by the FACS method.

[0200] (cDNA acquisition) Hybridoma cells that were positive by ELISA and FACS were selected, and total RNA was isolated from the cells using a total RNA extraction kit (Takara, catalog no. 9767) as a template. First-strand cDNA was synthesized using Superscript III reverse transcriptase according to the kit's instructions (Thermo, catalog no. 18080051). Using the first-strand cDNA as a template, the antibody heavy and light chain variable region sequences were then amplified by PCR using mouse IgG and kappa primers. The PCR mixture was separated by electrophoresis on a 1% agarose / Tris(trimethylsilyl)borate gel containing 0.5 μg / mL ethidium bromide. DNA fragments of the desired size were excised from the gel and purified. The purified PCR product was cloned into the pMD-19T vector (Takara, catalog no. 6013) and transformed into DH5α E. coli competent cells (Takara, catalog no. 9057) for growth. Single colonies were picked from the LB solid culture plates and subjected to DNA sequencing to obtain the heavy and light chain variable region sequences of the antibodies (murine antibodies 28G3, 40F6, 22F12, 34G6, and 10D8).

[0201] Construction and Expression of Humanized Antibodies Murine antibodies 28G3 (heavy chain variable region sequence SEQ ID NO: 11, light chain variable region sequence SEQ ID NO: 16) and 40F6 (heavy chain variable region sequence SEQ ID NO: 29, light chain variable region sequence SEQ ID NO: 34) were selected for humanization design.

[0202] Humanization of the murine antibodies 28G3 and 40F6 was performed using a combination of CDR-grafting and computer-aided design. The heavy and light chain variable region sequences of the murine antibodies were compared and analyzed with protein databases to screen for human germline antibody sequences with the highest sequence homology. The CDRs of the murine antibodies 28G3 and 40F6 were grafted onto the frameworks of the screened human germline antibody sequences, and amino acid residues in the CDRs and / or frameworks were mutated to obtain more candidate variable region sequences.

[0203] The humanized VL region gene fragment was ligated to a human κ chain constant region (amino acid sequence shown in SEQ ID NO: 2) to construct a humanized light chain, and the humanized VH region gene fragment was ligated to a human IgG1 constant region (amino acid sequence shown in SEQ ID NO: 1) to construct a humanized heavy chain. The humanized heavy chain expression plasmid and the humanized light chain expression plasmid were co-transfected into CHO cells to express the proteins. After transfection, the cells were cultured at 37°C and 8% CO2. After 7 to 10 days of culture, the cells were centrifuged to obtain the cell culture supernatant, and the humanized antibody in the cell culture supernatant was purified using a Protein A column (GE Healthcare).

[0204] The amino acid sequence of the heavy chain of humanized antibody hz28G3-1.1 is as shown in SEQ ID NO: 61, and the amino acid sequence of the light chain is as shown in SEQ ID NO: 62. The amino acid sequence of the heavy chain of humanized antibody hz28G3-1.3 is as shown in SEQ ID NO: 63, and the amino acid sequence of the light chain is as shown in SEQ ID NO: 64. See Table S1 for the amino acid sequences of the variable regions of other humanized antibodies.

[0205] Example 2: Preparation of MC-GGFG-deuterated DXd (MC-GGFG-DDDXd) [ka]

[0206] Step 1: Synthesis of intermediate A Under nitrogen protection, 80 g of ethyl diazoacetate was added to a 3 L single-neck flask, followed by 800 mL of dichloromethane and 800 mL of 1% deuterated acetic acid solution (8 g of deuterated acetic acid dissolved in 800 mL of deuterium oxide). The flask was then placed in a darkened environment and stirred at room temperature for 75 hours. The organic phase was separated and collected. The aqueous phase was extracted twice with dichloromethane (200 mL x 2), and the combined organic phases were washed with 200 mL of deuterium oxide. The resulting organic phase was dried over anhydrous sodium sulfate and filtered to remove the sodium sulfate. The filtrate was concentrated to dryness under reduced pressure at 20 °C to give 49.25 g of intermediate A in a 66% yield. The CAS number of intermediate A was 1356471-71-0.

[0207] Step 2: Synthesis of intermediate B 50 g of N-fluorenemethoxycarbonyl-glycylglycine was weighed and added to a 2 L round-bottom flask, followed by the addition of 750 mL of tetrahydrofuran and 150 mL of glacial acetic acid. The mixture was stirred at 40°C for 20 minutes, 100 g of lead tetraacetate was added, and the temperature was raised to 80°C, followed by a reaction time of 3 hours. The mixture was cooled to room temperature, suction filtered, and the cake was washed with 250 mL of ethyl acetate. The filtrate was concentrated to dryness, and dissolved in 330 mL of dichloromethane and 670 mL of ethyl acetate to obtain an organic phase. The organic phase was washed three times with 30% aqueous potassium bicarbonate solution (500 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and 100 mL of dichloromethane was added to dissolve the solid. 100 mL of n-hexane was added and stirred at room temperature until a solid precipitated. Next, 300 mL of a mixed solution of n-hexane and dichloromethane (n-hexane:dichloromethane = 1:1) was added and stirred overnight. After filtration, the cake was dried in a vacuum oven at 40 °C for 4 hours to obtain 37.3 g of intermediate B. The yield was 72%. LC-MS (ESI) m / z: 391.09 [M+Na] + The CAS number of the intermediate B was 1599440-06-8.

[0208] Step 3: Synthesis of intermediate C 78 g of intermediate B was weighed and added to a 3000 mL single-neck flask. 800 mL of dichloromethane and 45 g of intermediate A were then added to the flask. The flask was then placed in an ice-water bath and cooled to 0 °C. 16 g of lithium tert-butoxide was dissolved in 400 mL of dichloromethane to prepare a lithium tert-butoxide solution. The lithium tert-butoxide solution was added to the 3000 mL single-neck flask and allowed to react at 0 °C for 3 hours. The mixture was then returned to room temperature, and 800 mL of water was added and stirred. The organic phase was separated and collected. The aqueous phase was extracted with 400 mL of dichloromethane, and the combined organic phases were washed once with 800 mL of saturated brine, dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure and chromatographed on a silica gel column (petroleum ether:ethyl acetate = 3:1) to obtain 61 g of intermediate C. The yield was 70%. LC-MS(ESI)m / z:437.34[M+Na] + The CAS number of the intermediate C was 2760715-83-9.

[0209] Step 4: Synthesis of Compound D 31.2 g of intermediate C was added to 270 mL of deuterated methanol and 70 mL of heavy water and stirred in an ice bath. Subsequently, 5.5 g of NaOH was added, and the mixture was allowed to return to room temperature and stirred overnight. The reaction mixture was extracted with 300 mL of ethyl acetate and 300 mL of water. 20 mL of glacial acetic acid was added to the aqueous layer to adjust the pH to 2-3. A solid precipitated and was filtered with suction to obtain 20.3 g of compound D. The yield was 69.8%. 1 H NMR(500MHz,DMSO-d6)δ 8.70(1H,t,J=6.6),7.89(2H,d,J=7.5),7.72(2H,d,J=7.5),7.57(1H,t,J=6.0),7.42(2H,t,J=7. 5),7.34(2H,t,J=7.5),4.61(2H,d,J=6.6),4.30(2H,d,J=7.1),4.23(1H,m),3.64(2H,d,J=6.0). LC-MS(ESI)m / z:409.08[M+Na] + .

[0210] Step 5: Synthesis of Compound E 2.0 g of exatecan mesylate dihydrate and 1.63 g of compound D were weighed and placed in a 100 mL round-bottom flask. 40 mL of N,N-dimethylformamide was added and stirred. The temperature was cooled to 0 °C. 2.0 g of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and 1.82 g of N,N-diisopropylethylamine were added in that order and reacted at 0 °C for 3 hours. The reaction solution was poured into 120 mL of ice water and stirred for 1 hour. The mixture was filtered, and the cake was dissolved in dichloromethane. Chromatography was performed on a silica gel column (100-200 mesh silica gel, 100 g, dichloromethane:methanol = 30:1, 2 L) to obtain 2.6 g of compound E. The yield was 92%. 1 H NMR(500MHz,DMSO-d6)δ 8.78(1H,t,J=6.6),8.47(1H,d,J=9.0),7.86(2H,d,J=7.5),7.73(1H,d,J=11.0),7.68(2H ,d,J=7.5),7.53(1H,t,J=6.0),7.39(2H,t,J=7.5),7.30(2H,m),7.29(1H,s),6.50(1H,br s),5.56(1H,m),5.39(2H,m),5.14(2H,m),4.64(2H,m),4.25(2H,d,J=6.8),4.19(1H,m),3 .62(2H,d,J=6.0),3.15(2H,m),2.35(3H,s),2.17(2H,m),1.83(2H,m),0.85(3H,t,J=7.3). LC-MS(ESI)m / z:804.84[M+H] + .

[0211] Step 6: Preparation of Compound F 0.38 g of 1,8-diazabicyclo[5.4.0]-7-undecene was weighed and added to a 100 mL round-bottom flask. 20 mL of tetrahydrofuran was added to the round-bottom flask and stirred. The temperature was cooled to 0°C. 2.0 g of compound E was weighed and dissolved in 20 mL of tetrahydrofuran. The solution of compound E was slowly added to the 100 mL round-bottom flask. After allowing the mixture to warm to room temperature, the reaction was allowed to proceed for 3 hours. Filtration under nitrogen protection yielded 1.45 g of compound F. The yield was 98%.1 H NMR(500MHz,DMSO-d6)δ 8.76(1H,m),7.72(1H,m),7.28(1H,s),5.48(3H,m),5.16(2H,m),4.61(2H,m),3.4 0(2H,m),3.20(2H,m),2.35(3H,s),2.17(2H,m),1.83(2H,m),0.86(3H,t,J=7.1). LC-MS(ESI)m / z:582.39[M+H] + .

[0212] Step 7: Preparation of Compound H 1.00 g of compound F and 0.97 g of compound G were weighed and placed in a 100 mL round-bottom flask, followed by the addition of 10 mL of N,N-dimethylformamide. The temperature was lowered to -20 °C, and 0.34 g of 1-hydroxybenzotriazole and 0.49 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added, followed by a reaction at -20 °C for 3 hours. 20 mL of dichloromethane and 20 mL of water were added to the reaction mixture, which was then stirred for 30 minutes. The mixture was then allowed to stand, separated, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. Silica gel column chromatography (dichloromethane:methanol = 15:1) afforded 400 mg of compound H. The yield was approximately 22%. MS m / z: 1037.08 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ 8.62(1H,t,J=6.5),8.49(1H,d,J=8.5),8.29(1H,t,J=5.5),8.12(1H,d,J=8.0),8.06(1H,t,J=5.5),8.00(1H,t,J=5.5),7.74(1H,d,J =10.5),7.30(1H,s),7.27~7.12(5H,m),6.98(2H,s),6.51(1H,brs),5.61~5.58(1H,m),5.45~5.37(2H,m),5.22~5.13(2H,m),4.64(2H, d,J=6.5),4.49~4.45(1H,m),3.76~3.57(6H,m),3.37~3.32(2H,m),3.24~3.09(2H,m),3.02(1H,dd,J=4.5,14.0),2.77(1H,dd,J=9.5,1 3.5),2.36(3H,s),2.23~2.14(2H,m),2.09(2H,t,J=7.5),1.91~1.79(2H,m),1.49~1.42(4H,m),1.20~1.14(2H,m),0.87(3H,t,J=7.5). HR-MS m / z:1036.4194[M+H] + .

[0213] Example 3: Preparation of anti-CLDN18.2 antibody-drug conjugate (reagent) The antibodies used were the anti-CLDN18.2 antibodies hz28G3-1.1 and hz28G3-1.3 produced in Example 1, and 15F9 (prepared in-house; the amino acid sequences of the heavy and light chains are shown in SEQ ID NOs: 67 and 68 of the present disclosure). Compound H (MC-GGFG-DDDXd) prepared in Example 2 was used as the linker-payload.

[0214] (Experimental Procedure) 1. Antibody reduction. The antibody was replaced with histidine buffer (pH 6.0, L-histidine 1.43 mg / mL, L-histidine hydrochloride monohydrate 2.27 mg / mL), and the antibody concentration was adjusted to 10 mg / mL with histidine buffer (pH 6.0). This solution was placed in a light-shielding glass bottle, and 10 mM TCEP (tris(2-carboxyethyl)phosphine hydrochloride) solution was added to it, resulting in an antibody to TCEP molar ratio of 1:8. The mixture was incubated at 35°C for 1 hour in the dark with gentle stirring to reduce the interchain disulfide bonds of the antibody, yielding reaction solution 1.

[0215] 2. Conjugation of antibody and linker-payload. After incubating reaction solution 1 at 22°C for 10 minutes, DMSO solution (DMSO solution: reaction solution 1 (v / v) = 1:20) was added and mixed to homogenize. A 10 mg / mL linker-payload solution dissolved in DMSO was added to achieve a molar ratio of antibody to linker-payload of 1:10. The mixture was incubated at 22°C in the dark for 2 hours and gently stirred to conjugate the antibody and linker-payload, yielding reaction solution 2.

[0216] 3. Conjugation termination and purification: Reaction solution 2 was ultrafiltrated with histidine buffer (pH 6.0) to obtain anti-CLDN18.2 antibody-drug conjugates hz28G3-1.1-DDDXd, hz28G3-1.3-DDDXd, and 15F9-DDDXd.

[0217] Example 4: Determination of DAR of antibody drug conjugates The DAR was measured using LC-MS. An appropriate amount of the anti-CLDN18.2 antibody-drug conjugate from Example 3 was taken, and an appropriate amount of glycosidase PNGase F (SUZHOU RHINO BIOTECHNOLOGY CO., LTD., China) was added and allowed to react overnight at 37°C. Mass spectrometry was performed using a high-resolution mass spectrometer, Xevo G2-XS (Waters, USA), and data were collected in native positive ion mode. Data were processed using the software UNIFI 1.8.2.169 (Waters, USA).

[0218] The anti-CLDN18.2 antibody-drug conjugate prepared by the method of Example 3 includes the following: [ka] hz28G3-1.1-DDDXd, DAR measured at 7.2 [ka] hz28G3-1.3-DDDXd, DAR measured value is 7.4 [ka] 15F9-DDDXd, DAR measurement value is 7.7

[0219] Example 5: Preparation of anti-CLDN18.2 antibody-drug conjugate and measurement of DAR The anti-CLDN18.2 antibody-drug conjugate shown below was prepared by referring to the method in Example 3 and the DAR was measured by referring to the method in Example 4. [ka] hz28G3-1.1-DDDXd, DAR measured at 7.4 [ka] hz28G3-1.3-DDDXd, DAR measured at 7.6

[0220] Example 6: Verification of Aggregation of Antibody-Drug Conjugates The components of the anti-CLDN18.2 antibody-drug conjugate prepared in Example 3 were separated using a gel chromatography column. Elution was performed using a pH-neutral buffer containing 10% isopropanol as the mobile phase, and the components were eluted sequentially in descending order of molecular weight. The chromatography column was a gel chromatography column with specifications of an ACQUITY UPLC Protein BEH SEC Column 200 Å, 1.7 μm, 4.6 × 300 mm, and the column temperature was 25°C. The mobile phase was 50 mM phosphate buffer-200 mM sodium chloride-10% isopropanol, pH 7.0. (12.53 g of disodium hydrogen phosphate dodecahydrate, 2.33 g of sodium dihydrogen phosphate dihydrate, and 11.69 g of sodium chloride were weighed, added to approximately 800 mL of ultrapure water, stirred until fully dissolved, added 100 mL of isopropanol, and then added ultrapure water until the total volume was 1000 mL. After mixing to achieve uniformity, the mixture was filtered through a 0.22 μm filter.) 20 μg of the anti-CLDN18.2 antibody conjugate was accurately injected into the liquid chromatograph and measured at a wavelength of 280 nm. The flow rate was 0.3 mL / min, and the mixture was eluted isocratically for 15 minutes.

[0221] The data was processed and the results were quantitatively analyzed using the area percentage method. The peak area percentages of the aggregates, monomers, and low molecular weight impurities of the anti-CLDN18.2 antibody-drug conjugate were calculated, with the area before the main peak representing the aggregates, the area after the main peak representing the monomers, and the area after the main peak representing the low molecular weight impurities. The contents of the monomers, aggregates, and low molecular weight impurities of the anti-CLDN18.2 antibody-drug conjugate are shown in Table 1. [Table 3]

[0222] Example 7: Cell-binding activity of anti-CLDN18.2 antibody-drug conjugates Flow cytometry was used to measure the cell binding activity of the anti-CLDN18.2 antibody-drug conjugates prepared in Example 5, using hz28G3-1.1 and hz28G3-1.3 as controls. CLDN18.2-overexpressing NIH-3T3, BxPC-3, and NCI-N87 cell lines were cultured at 1 × 10 6 The anti-CLDN 18.2 antibody-drug conjugate was diluted to 100 cells / mL and added to a 96-well plate at 100 μL per well. The anti-CLDN 18.2 antibody-drug conjugate was gradient diluted with FACS buffer (Miltenyi Biotec, catalog number 130-091-221) and added (for BxPC-3 cells, the starting concentration of the gradient dilution was the amount when the final concentration in the well was 300 nM, and a total of 10 concentrations were obtained by 4-fold gradient dilution. For NIH-3T3 and BxPC-3 cells, the starting concentration of the gradient dilution was the amount when the final concentration in the well was 333.33 nM, and a total of 10 concentrations were obtained by 4-fold gradient dilution). The conjugate was incubated at 4°C for 60 minutes, then centrifuged at 1000 rpm for 5 minutes. The supernatant was discarded, and the cells were washed three times with pre-cooled PBS (pH 7.4). A goat-anti-human IgG Fcγ-PE secondary antibody (Jackson Immunoresearch, Catalog No. 109-116-170) was added at 100 μL / well and incubated at 4°C for 30 minutes. The cells were washed three times with pre-chilled PBS (pH 7.4) and resuspended in 100 μL of PBS (pH 7.4). The fluorescent signal was then measured using a flow cytometer (Sartorius, iQUE). The mean fluorescence intensity (MFI) of the staining represents the binding activity of the anti-CLDN18.2 antibody-drug conjugate to cell surface CLDN18.2. The data were analyzed using GraphPad Prism 5, and the results are shown in Figures 1A-1C. The calculated EC 50 The results are shown in Table 2 below. The results revealed that both hz28G3-1.1-DDDXd and hz28G3-1.3-DDDXd could effectively bind to cells overexpressing CLDN18.2. [Table 4]

[0223] Example 8: Endocytosis experiment of anti-CLDN18.2 antibody-drug conjugate Using flow cytometry, the endocytosis of the anti-CLDN18.2 antibody-drug conjugates prepared in Example 5 in cells overexpressing CLDN18.2 was measured using hz28G3-1.1 and hz28G3-1.3 as controls. CLDN18.2-overexpressing NIH-3T3, BxPC-3, and NCI-N87 cell lines, and the CLDN18.2-positive natural cell line NUGC-4, were measured at a cell concentration of 2 × 10 6 The concentration was adjusted to 1 / mL and added at 20 μL per well to a 96-well plate. Labeled antibody (Sartorius, 90564) and anti-CLDN18.2 antibody-drug conjugate (labeled antibody to ADC volumetric ratio 1:1) gradient diluted with FACS buffer (Miltenyi Biotec, catalog no. 130-091-221) were co-incubated at 37°C for 15 minutes, after which the co-incubation system was added at 20 μL per well to a 96-well plate. The starting concentration of the anti-CLDN18.2 antibody-drug conjugate in the gradient was the amount that resulted in a final concentration of 20 nM in the well, and a total of 8 concentrations were obtained by a 3-fold gradient dilution. After 2 hours of incubation, the system was loaded onto a flow cytometer (Sartorius, iQUE) and fluorescence values ​​in the RL1 channel were measured. Data were analyzed using GraphPad Prism 5, and the results are shown in Figures 2A–2D. The calculated EC 50 The results are shown in Table 3 below. The results revealed that hz28G3-1.1-DDDXd and hz28G3-1.3-DDDXd could effectively exert endocytosis in cells overexpressing CLDN18.2. [Table 5]

[0224] Example 9: Killing of anti-CLDN18.2 antibody drug conjugates against tumor cells To measure the killing activity of the anti-CLDN18.2 antibody-drug conjugates prepared in Example 5 against CLDN18.2-positive tumor cells, the killing activity was measured using NIH-3T3, BxPC-3, and NCI-N87 cells, each of which overexpresses CLDN18.2.

[0225] Logarithmic growth phase cells were used, and the cell density of NIH-3T3, BxPC-3, and NCI-N87 cells was 1 × 10 4 pieces / mL, 2×10 4 cells / mL and 2 x 10 4 The solution was adjusted to a concentration of 100 μL / well and added to a 96-well plate. The cells were incubated overnight at 37°C in 5% CO2 with the anti-CLDN18.2 antibody-drug conjugate in DMEM medium containing 10% FBS. For NIH-3T3 cells, a starting concentration of 3 μg / mL was diluted three-fold to a total of nine concentrations. For BxPC-3 and NCI-N87 cells, a starting concentration of 5 μg / mL was diluted five-fold to a total of nine concentrations. After overnight incubation, the cells were removed from the plate and 50 μL / well of the diluted anti-CLDN18.2 antibody-drug conjugate was added to the experimental group, while 50 μL / well of DMEM medium containing 10% FBS was added to the control group. After incubation for 96 or 120 hours, the cells were measured using a CellTiter-Glo Luminescent Cell Kit (Promega, catalog number G7572). Specifically, a 96-well plate was taken out, 75 μL of CTG assay solution (Promega, catalog number G7572) was added to each well, and the plate was shaken to mix uniformly. After incubation at room temperature and in the dark for 10 minutes, 180 μL was aspirated from each well and transferred to an opaque white plate to remove air bubbles. The chemiluminescence value was read and the cell viability was calculated. [Number 1] Survival rate (%) = (luminescence value of experimental group / luminescence value of control group) × 100%

[0226] Data were analyzed using Graphpad Prism 5, and the results are shown in Figures 3A-3C, with calculated IC 50The results are shown in Table 4 below. The results revealed that both hz28G3-1.1-DDDXd and hz28G3-1.3-DDDXd could effectively exert killing activity on tumor cells overexpressing CLDN18.2. [Table 6]

[0227] Example 10: CDC activity of anti-CLDN18.2 antibody-drug conjugates NIH-3T3 was selected as the target cell, and human complement (quidel corporation, catalog number A112) was used to measure the CDC activity of the anti-CLDN18.2 antibody-drug conjugate prepared in Example 5.

[0228] Using a basal cell culture medium containing 0.1% BSA, the target cell line NIH-3T3 was grown to a cell density of 8 × 10 5 The concentration of the anti-CLDN18.2 antibody-drug conjugate was adjusted to 100 nM / mL and 50 μL / well was inoculated into a 96-well plate. The gradient-diluted anti-CLDN18.2 antibody-drug conjugate was inoculated into a 96-well plate at 50 μL / well. The starting concentration of the gradient dilution was the amount of anti-CLDN18.2 antibody-drug conjugate when the final concentration in the well was 100 nM. A total of eight concentrations were obtained through a 4-fold gradient dilution. Human complement was diluted in basal cell culture medium containing 0.1% BSA and added to the 96-well plate at 50 μL / well to achieve a final human complement concentration of 10%. After centrifugation at 200 g for 1 minute, the 96-well plate was shaken on a shaker at 37°C for 30 minutes to thoroughly mix and uniformly contact the complement and target cells. Finally, the plate was incubated in a 37°C, 5% CO2 incubator for 2 hours. After incubation, 110 μL of CellTiter-Glo Luminescent Cell Viability Assay (Promega, G7570) was added to each well and incubated for 10 ± 5 minutes at room temperature in the dark. Fluorescence values ​​were measured using a microplate reader (Thermo) and the killing rate was calculated. Data were analyzed using GraphPad Prism 5, and the results are shown in Figure 4. The calculated IC 50The results are shown in Table 5 below. The results revealed that both hz28G3-1.1-DDDXd and hz28G3-1.3-DDDXd could induce strong CDC effects on CLDN18.2-positive tumor cells. [Number 2] Killing rate (%) = 1 - ((fluorescence value of experimental group - fluorescence value of blank control group) / (fluorescence value of target cell control group - fluorescence value of blank control group)) x 100% [Table 7]

[0229] Example 11: Nonspecific killing of anti-CLDN18.2 antibody drug conjugates To measure the non-specific killing effect of the anti-CLDN18.2 antibody-drug conjugate prepared in Example 5 on CLDN18.2-negative cells, the killing activity was measured using NIH-3T3 cells overexpressing CLDN18.1.

[0230] cDNA encoding human CLDN18.1 (SEQ ID NO: 66) was obtained by gene synthesis and then subcloned into the expression vector pcDNA3.1. The expression vector was transfected into NIH-3T3 cells according to the instructions for Lipofectamine 2000 transfection reagent (Thermo, catalog number 11668019) to obtain NIH-3T3-CLDN18.1 overexpressing CLDN18.1.

[0231] NIH-3T3-CLDN18.1 cells in the logarithmic growth phase were used, and the cell density was 1 × 10 4The solution was adjusted to cells / mL and added at 100 μL per well to a 96-well plate. The cells were cultured overnight in a 37°C, 5% CO2 incubator, allowing them to adhere to the plate. Anti-CLDN18.2 antibody-drug conjugates were prepared in DMEM medium containing 10% FBS. After overnight cell culture, the cells were removed and 50 μL of diluted anti-CLDN18.2 antibody-drug conjugate was added per well to the experimental group. The starting concentration of the dilution was the amount of the conjugate in the well that resulted in a final concentration of 20 nM. A three-fold gradient dilution was performed, resulting in a total of nine concentrations. The control group received 50 μL of DMEM medium containing 10% FBS per well. After 96 hours of culture, the cells were measured using the CellTiter-Glo Luminescent Cell Kit (Promega, catalog number G7572). Specifically, a 96-well plate was taken out, 75 μL of CTG assay solution (Promega, catalog number G7572) was added to each well, and the plate was shaken to mix uniformly. After incubation at room temperature and in the dark for 10 minutes, 180 μL was aspirated from each well and transferred to an opaque white plate to remove air bubbles. The chemiluminescence value was read and the cell viability was calculated. [Number 3] Survival rate (%) = (luminescence value of experimental group / luminescence value of control group) × 100%

[0232] The data were analyzed using Graphpad Prism 5, and the results are shown in Figure 5. The results revealed that hz28G3-1.1-DDDXd and hz28G3-1.3-DDDXd had no killing activity against NIH-3T3-CLDN18.1 cells.

[0233] Example 12: Bystander effect of anti-CLDN18.2 antibody-drug conjugates BxPC-3 cells overexpressing CLDN18.2 were selected as positive cells, and U2OS cells stably expressing luciferase (U2OS-luciferase) were selected as negative cells. The cells were mixed and cultured to measure the bystander effect of the anti-CLDN18.2 antibody-drug conjugate prepared in Example 5.

[0234] Positive and negative cells in the logarithmic growth phase were used, and both were grown at a cell density of 4 × 104 The anti-CLDN18.2 antibody-drug conjugate was diluted in McCoy's 5A complete medium (GIBCO, catalog no. 16600-082) containing 10% FBS at a starting concentration of 33.3 nM, and 50 μL of the dilution was added to each well of a 96-well plate. The starting concentration of the anti-CLDN18.2 antibody-drug conjugate was 33.3 nM, and the dilution was performed five-fold, resulting in a total of eight concentrations. The 96-well plate was then placed in a 37°C, 5% CO2 incubator and cultured for 120 hours. After incubation, 20 μL of interleukin-31 (IL-31) (R&D Systems, catalog no. 2824-IL-010 / CF) was added to each well to stimulate the cells (final concentration: 10 ng / mL) and then incubated for 4–6 hours in a 37°C, 5% CO2 cell incubator. After the incubation was completed, 120 μL of Luciferase Assay Substrate (Vazyme, catalog number DD1201-02) was added to each well, and the chemiluminescence value was measured using a microplate reader to calculate the viability of U2OS-luciferase cells. [Number 4] Survival rate (%) = (luminescence value of experimental group / luminescence value of control group) × 100%

[0235] The data were analyzed using GraphPad Prism 5, and the results are shown in Figure 6. The results revealed that both hz28G3-1.1-DDDXd and hz28G3-1.3-DDDXd had a clear bystander effect and had equivalent killing activity against negative cells in the presence of positive cells.

[0236] Example 13: In vivo pharmacokinetic evaluation of anti-CLDN18.2 antibody-drug conjugates in rats SD rats (160-180g) (provided by the Shanghai Institute of Family Planning, Department of Experimental Animal Management) were randomly divided into three groups of four rats each, and 15F9-DDDXd, hz28G3-1.1-DDDXd, and hz28G3-1.1-DDDXd prepared in Example 3 were intravenously injected at a dose of 10mg / kg each. The SD rats were not fasted before or after administration, and were allowed free access to water.

[0237] Approximately 0.2 mL of blood was collected from the jugular vein at 30 minutes, 2 hours (±1 minute), 8 hours (±1 minute), 24 hours (±5 minutes), 48 hours (±5 minutes), 4 days (±10 minutes), 7 days (±10 minutes), 10 days (±10 minutes), 14 days (±20 minutes), 21 days (±20 minutes), or 28 days (±20 minutes) after administration, anticoagulated with EDTA-K2, and centrifuged at 4°C and 4000 rpm for 10 minutes to separate the plasma.

[0238] An appropriate amount of the separated plasma was aspirated and diluted to the minimum dilution factor (20x) with sample diluent (PBST containing 1% BSA). For samples requiring a higher dilution, the sample was further diluted with sample diluent containing 5% blank rat plasma and vortexed to obtain the test sample. The quantitative range of the measurement method was 19.53125 ng / mL to 2500 ng / mL. AffiniPure Goat Anti-Human IgG, F(ab')2 fragment specific (Jackson ImmunoResearch, 109-005-097) was diluted in PBS buffer (pH 7.4) to a concentration of 1 μg / mL, and 100 μL was coated per well of a 96-well plate and incubated overnight at 4°C. A 96-well plate was washed with PBST (PBS containing 0.5% Tween-20), followed by addition of 200 μL / well of blocking solution (PBST containing 1% BSA) for 2–3 hours at room temperature. The blocking solution was discarded, and 100 μL / well of the diluted standard curve samples, control samples, and test samples were added and incubated at room temperature for 2 hours. After washing the 96-well plate with PBST, a 1:10,000 dilution of goat anti-human kappa light chain cross-adsorbed secondary antibody (Goat Anti-Human Kappa Light Chain Cross-Adsorbed Secondary Antibody) and HRP (Thermofisher, A18859) was added and incubated at room temperature for 1 hour. After washing the 96-well plate with PBST, 100 μL / well of TMB solution (Tiangen, catalog no. PA107-01) was added and incubated at room temperature for 14 minutes in the dark. The reaction was stopped with 1M H2SO4. Absorbance was read at wavelengths of 450 nm / 630 nm using a Tecan Spark microplate reader, and curve fitting employed a 4 parameter logistic fit.

[0239] The exposure of the anti-CLDN18.2 antibody-drug conjugate to intravenous injection was evaluated by in vivo pharmacokinetics in rats, and the maximum blood concentration (C ) of the total antibody (including both cytotoxic drug-conjugated and unconjugated antibodies) in each group of SD rats was measured. max ), time to reach maximum blood concentration (T max ), area under the blood concentration time curve (AUC (0~t) ), half-life (t 1 / 2 ), mean residence time (MRT (0~t) The mean pharmacokinetic parameters including saturation (S) and clearance (CL) were calculated and are shown in Table 6 below.

[0240] In rats, the internal exposure, mean residence time, and clearance of hz28G3-1.1-DDDXd and hz28G3-1.3-DDDXd were comparable to those of the reference product 15F9-DDDXd, and the half-life of hz28G3-1.3-DDDXd was superior to that of hz28G3-1.1-DDDXd. [Table 8]

[0241] Example 14: Pharmacodynamic evaluation of anti-CLDN18.2 antibody-drug conjugates in the NUGC-4 human gastric cancer CB-17 SCID mouse xenograft tumor model SPF female CB-17 SCID mice (provided by Shanghai Lingchang Biotechnology Co., Ltd.) were inoculated with NUGC-4 human gastric cancer cells at 5 × 10 in the right axilla. 6 The average tumor volume was 150 mm 3 When the dose reached this level, the animals were divided into three groups of six animals each. Details of the group division and the administered dose are shown in Table 7. hz28G3-1.3-DDDXd and 15F9-DDDXd were both produced in Example 3, and the DAR was measured in Example 4. The DAR of hz28G3-1.3-DDDXd was 7.4, and the DAR of 15F9-DDDXd was 7.7. [Table 9]

[0242] The day of group allocation was day 0, and on day 2 after group allocation, the mice were administered a single dose via the tail vein. Tumor volume was measured two to three times a week, and the mice were weighed and recorded. The general behavior of the mice was observed and recorded daily. After the experiment was completed, the tumors were excised, weighed, and photographed.

[0243] The measurement indicators and calculation formulas were as follows: Tumor volume [Number 5] TV(mm 3 )=1 / 2×(a×b 2 ) Here, a is the long diameter of the tumor and b is the short diameter of the tumor.

[0244] Relative tumor volume [Number 6] RTV=TV t / TV0 where TV0 is the tumor volume on day 0 and TV t is the tumor volume at each measurement.

[0245] Relative tumor growth rate [Number 7] T / C(%)=T RTV / C RTV ×100% where T RTV is the RTV of the treatment group, and C RTV is the RTV of the vehicle control group.

[0246] Tumor growth inhibition rate [Number 8] TGI(%)=(1-TW / TW0)×100% where TW is the tumor weight in the treatment group and TW0 is the tumor weight in the vehicle control group.

[0247] Weight change rate [Number 9] WCR(%)=(Wt t -Wt0) / Wt0×100% where Wt0 is the weight of the mouse on day 0, and Wt tis the body weight of the mouse at each measurement.

[0248] The results of each measurement index on day 33 are shown in Table 8 below. hz28G3-1.3-DDDXd has no obvious toxicity and has the same inhibitory activity as the reference product 15F9-DDDXd against mouse NUGC-4 human gastric cancer xenograft tumors. [Table 10]

[0249] Example 15: Pharmacodynamic evaluation of anti-CLDN18.2 antibody drug conjugates in the BxPC-3 human pancreatic cancer CD-17 SCID mouse xenograft tumor model SPF female CB-17 SCID mice (provided by Shanghai Slake Experimental Animal Co., Ltd.) were subcutaneously inoculated with BxPC-3 human pancreatic cancer tumors highly expressing CLDN18.2 in the right axilla. The tumors had an average volume of 200 mm. 3 When the dose reached this level, the animals were divided into three groups of four animals each. Details of the group division and administration dose are shown in Table 9. hz28G3-1.3-DDDXd and 15F9-DDDXd were both produced in Example 3 and measured at the DAR in Example 4. The DAR of hz28G3-1.3-DDDXd was 7.4, and the DAR of 15F9-DDDXd was 7.7. [Table 11]

[0250] The day of group allocation was day 0, and mice were administered a single dose via the tail vein. Tumor volume was measured two to three times a week, and the mice were weighed and recorded. The general behavior of the mice was observed and recorded daily. After the experiment was completed, tumors were excised, weighed, and photographed.

[0251] The measurement indicators and calculation formulas were as follows: Tumor volume [Number 10] TV(mm3 )=1 / 2×(a×b 2 ) Here, a is the long diameter of the tumor and b is the short diameter of the tumor.

[0252] Relative tumor volume [Number 11] RTV=TV t / TV0 where TV0 is the tumor volume on day 0 and TV t is the tumor volume at each measurement.

[0253] Relative tumor growth rate [Number 12] T / C(%)=T RTV / C RTV ×100% where TRTV is the RTV of the treatment group and C RTV is the RTV of the vehicle control group.

[0254] Tumor growth inhibition rate [Number 13] TGI(%)=(1-TW / TW0)×100% where TW is the tumor weight in the treatment group and TW0 is the tumor weight in the vehicle control group.

[0255] Weight change rate [Number 14] WCR(%)=(Wt t -Wt0) / Wt0×100% where Wt0 is the animal weight on day 0 and Wt t is the animal weight at each measurement.

[0256] The measurement results of each index on the 21st day are shown in Table 10 below. hz28G3-1.3-DDDXd had no obvious toxicity and had a clear inhibitory effect on BxPC-3 human pancreatic cancer CB-17 SCID mouse xenograft tumors, which highly express CLDN18.2, superior to the reference product 15F9-DDDXd. [Table 12]

[0257] Example 16: Preparation of anti-CLDN18.2 antibody-drug conjugate (reagent) The anti-CLDN18.2 antibody hz28G3-1.3 produced in Example 1 was used as the antibody. Compound H (MC-GGFG-DDDXd) prepared in Example 2 was used as the linker-payload.

[0258] (Experimental Procedure) 1. Antibody reduction. The antibody was replaced with histidine buffer (pH 6.0, L-histidine 1.43 mg / mL, L-histidine hydrochloride monohydrate 2.27 mg / mL). The antibody concentration was adjusted to 10 mg / mL with histidine buffer (pH 6.0). The pH was adjusted to 6.3, and ethylenediaminetetraacetic acid disodium (EDTA·Na2) solution was added to a final concentration of 5 mM. This solution was placed in a light-shielding glass bottle, and when the solution temperature rose to 30°C, 10 mM TCEP solution was added to achieve a molar ratio of antibody to TCEP of 1:8. The mixture was incubated at 30°C for 100 minutes, protected from light, and stirred to reduce the interchain disulfide bonds of the antibody, yielding reaction solution 1.

[0259] 2. Conjugation of antibody and linker-payload. After reaction solution 1 was cooled to 22°C, a DMSO solution (DMSO solution: reaction solution 1 (v / v) = 1:20) was added and mixed until homogenous. A 10 mg / mL linker-payload solution dissolved in DMSO was added to achieve an antibody to linker-payload molar ratio of 1:9.5. The mixture was incubated at 22°C for 2 hours in the dark and gently stirred to conjugate the antibody and linker-payload, yielding reaction solution 2.

[0260] 3. Conjugation termination and purification: Reaction solution 2 was ultrafiltrated with histidine buffer (pH 6.0) to obtain the anti-CLDN18.2 antibody-drug conjugate hz28G3-1.3-DDDXd.

[0261] The structure of the produced hz28G3-1.3-DDDXd was as follows: [ka] The measured DAR was 7.93, of which D8 accounted for 97.04% and D0 to D7 accounted for 2.96%. The above ratios are based on molar amounts.

[0262] The sequence information of this disclosure is summarized in Table S2 below. [Table 13] TIFF2025540696000065.tif255169TIFF2025540696000066.tif255169TIFF2025540696000067.tif25516 9TIFF2025540696000068.tif255169TIFF2025540696000069.tif251170TIFF2025540696000070.tif96170

[0263] All patents, patent applications, and other established publications are expressly incorporated herein by reference for purposes of description and disclosure. These publications may be provided because they were published prior to the filing date of the present disclosure. Any statement as to the disclosure date of such a document or any statement as to the contents of such a document is based on the information known to applicant and does not constitute an admission that such a document's disclosure date or the contents of such a document are correct. Furthermore, reference to such publications herein does not constitute an admission that such publications are part of the common general knowledge in the art in any country.

[0264] Although the present disclosure has been described in detail above using general descriptions and specific embodiments, some modifications or improvements can be made in light of the present disclosure, which will be obvious to those skilled in the art. Therefore, if any such modifications or improvements are made without departing from the spirit of the present disclosure, they all fall within the scope of protection claimed in the present disclosure.

Claims

1. The general formula is Ab-(LU) ｎ or a pharmaceutically acceptable salt or solvate thereof, wherein Ab is an antibody or an antigen-binding fragment thereof, L is a linker, U is a cytotoxic drug, and n is an integer selected from 1 to 10, wherein Ab is an anti-CLDN18.2 antibody or an antigen-binding fragment thereof comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3; (1) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 3, 5, 7, 8, 9, and 10, respectively; (2) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 3, 4, 7, 8, 9, and 10, respectively; (3) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 3, 6, 7, 8, 9, and 10, respectively; (4) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 20, 24, 25, 26, and 27, respectively; (5) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 21, 24, 25, 26, and 27, respectively; (6) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 22, 24, 25, 26, and 27, respectively; (7) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 23, 24, 25, 26, and 27, respectively; (8) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 20, 24, 25, 26, and 28, respectively; (9) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 21, 24, 25, 26 and 28, respectively; (10) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 22, 24, 25, 26, and 28, respectively; (11) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 19, 23, 24, 25, 26, and 28, respectively; (12) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 37, 38, 39, 40, 41, and 42, respectively; (13) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 45, 46, 47, 48, 49, and 50, respectively; or (14) An antibody-drug conjugate, or a pharmaceutically acceptable salt or solvate thereof, wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences set forth in SEQ ID NOs: 53, 54, 55, 56, 57, and 58, respectively.

2. The anti-CLDN18.2 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region; (1) the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 14 and 17, respectively; (2) the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 12 and 17, respectively; (3) the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 13 and 17, respectively; (4) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 11 and 16, respectively; (5) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 15 and 17, respectively; (6) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 12 and 18, respectively; (7) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 13 and 18, respectively; (8) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 14 and 18, respectively; (9) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 15 and 18, respectively; (10) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 29 and 34, respectively; (11) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 30 and 35, respectively; (12) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 31 and 35, respectively; (13) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 32 and 35, respectively; (14) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 33 and 35, respectively; (15) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 30 and 36, respectively; (16) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 31 and 36, respectively; (17) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 32 and 36, respectively; (18) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 33 and 36, respectively; (19) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 43 and 44, respectively; (20) The heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 51 and 52, respectively; or (21) The antibody-drug conjugate of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 80% identity to the amino acid sequences set forth in SEQ ID NOs: 59 and 60, respectively.

3. The antibody-drug conjugate or pharmaceutically acceptable salt or solvate thereof of claim 1 or 2, wherein the anti-CLDN18.2 antibody or antigen-binding fragment thereof is an IgG1, IgG2, or IgG4 isotype.

4. The anti-CLDN18.2 antibody further comprises a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 1 or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, and additions compared to the amino acid sequence set forth in SEQ ID NO: 1, and the light chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 2 or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, and additions compared to the amino acid sequence set forth in SEQ ID NO:

2. The antibody-drug conjugate according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof.

5. The anti-CLDN18.2 antibody comprises a heavy chain and a light chain, (1) the heavy chain comprises an amino acid sequence having at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 63, and the light chain comprises an amino acid sequence having at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 64; or (2) The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 3, wherein the heavy chain comprises an amino acid sequence having at least 80% identity with the amino acid sequence set forth in SEQ ID NO: 61, and the light chain comprises an amino acid sequence having at least 80% identity with the amino acid sequence set forth in SEQ ID NO:

62.

6. The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 5, wherein U is a camptothecin-based topoisomerase I inhibitor, and L and / or U have a deuteration modification, preferably U is SN-38, an SN-38 derivative, exatecan, or an exatecan derivative, more preferably U is an exatecan derivative.

7. -U is the structure shown in formula Ia below: 【Chemistry 1】 The antibody-drug conjugate according to claim 6, or a pharmaceutically acceptable salt or solvate thereof.

8. -L- is the structure shown in formula IIa below: 【Chemistry 2】 In the formula, R １ and R ２ are each independently selected from hydrogen or deuterium; and in the structure shown, position 3 of -(succinimidyl-3-yl-N)- is linked to Ab, and the methylene group at the other end is linked to U, or a pharmaceutically acceptable salt or solvate thereof according to claim 6 or 7.

9. -LU is a structure shown in formula IIIa below, 【Transformation 3】 In the formula, R １ and R ２ and n are independently selected from hydrogen and deuterium, respectively.

10. -LU is a structure shown in the following formula IIIa-1, IIIa-2, IIIa-3 or IIIa-4: 【Chemistry 4】 【Transformation 5】 【Transformation 6】 or 【Transformation 7】 The antibody-drug conjugate of claim 9, or a pharmaceutically acceptable salt or solvate thereof.

11. The structure of the antibody-drug conjugate is as shown in Formula IV below: 【Transformation 8】 In the formula, R １ and R ２ and n are independently selected from hydrogen and deuterium, respectively.

12. The structure of the antibody-drug conjugate is as shown in the following formula IV-1, IV-2, IV-3 or IV-4: 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 or 【Chemistry 12】 12. The antibody-drug conjugate of claim 11, or a pharmaceutically acceptable salt or solvate thereof.

13. The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 12, wherein n is an integer selected from 1 to 10, 1 to 9, 1 to 8, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 8, 5 to 7, 5 to 6, 6 to 8, 6 to 7, or 7 to 8, preferably an integer selected from 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, and 7 to 8, more preferably an integer selected from 6 to 8.

14. The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof has the following characteristics: (a) binding to CLDN18.2; (b) blocking the binding of CLDN18.2 to a ligand; (c) exhibiting endocytosis in cells expressing CLDN18.2; (d) having killing activity against tumor cells expressing CLDN18.2; (e) There is a bystander effect; (f) having ADCC activity; (g) having CDC activity; (h) does not bind to CLDN18.1; (i) does not bind to cells that do not express CLDN18.2; and (j) having no ADCC and / or CDC activity against cells expressing CLDN18.1; The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 13, wherein the antibody-drug conjugate exhibits one or more combinations of:

15. A pharmaceutical composition comprising the antibody-drug conjugate or the pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 14, wherein preferably the antibody-drug conjugate or the pharmaceutically acceptable salt or solvate thereof in the pharmaceutical composition is heterogeneous or homogeneous, and optionally the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15, wherein the antibody-drug conjugate or the pharmaceutically acceptable salt or solvate thereof in the pharmaceutical composition is heterogeneous, and the DAR of the pharmaceutical composition is 0 to 10, 0 to 9, 0 to 8, 1 to 10, 1 to 9, 1 to 8, 2 to 10, 2 to 9, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 7 to 8, 7.2 to 8, 7.4 to 8, 7.5 to 8, 7.6 to 8, 7.7 to 8, 7.8 to 8, 7.8 to 7.9, or 7.9 to 8, preferably 7 to 8, 7.2 to 8, 7.4 to 8, 7.6 to 8, 7.7 to 8, and more preferably about 7.1, about 7.2, about 7.4, about 7.6, about 7.7, or about 8.

17. The antibody-drug conjugate of any one of claims 1 to 14 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 15 or 16, for use in treating a tumor, comprising: The antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition, optionally used in combination with a second or another therapeutic agent.

18. The tumor is a CLDN18.2-positive tumor, preferably the tumor is gastric cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, liver cancer, lung cancer, bronchial cancer, mesothelioma, kidney cancer, ovarian cancer, breast cancer, bladder cancer, uterine cancer, endometrial cancer, prostate cancer, testicular cancer, anal cancer, vaginal cancer, bile duct cancer, gallbladder cancer, head and neck cancer, spinal tumors, otorhinolaryngological tumors, thyroid cancer, mesothelioma, bone cancer, skin cancer, melanoma, adenocarcinoma, sarcoma, neuroblastoma, glioblastoma, brain cancer, central nervous system cancer, neuroendocrine tumors, leukemia, lymphoma and myeloma. An antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition for use according to claim 17.

19. The method comprises treating an anti-CLDN18.2 antibody or antigen-binding fragment thereof under reducing conditions, and then reacting the anti-CLDN18.2 antibody or antigen-binding fragment thereof with a linker-payload selected from the structure shown in formula III, wherein the structure shown in formula III is as follows: 【Chemistry 13】 In the formula, R １ , R ２ and are each independently selected from hydrogen and deuterium.

20. R １ and R ２ 20. The method of claim 19, wherein is hydrogen.

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