Methods of antibody-drug conjugates targeting Claudin18.2 for treatment of solid tumors

Abstract

The present invention relates to a method for treating solid tumors by administering a Claudin18.2-targeting antibody-drug conjugate or a pharmaceutically acceptable salt thereof to an individual in need thereof, a single dose unit comprising the same, a kit and an application thereof.

Description

Technical Field

[0001] The present invention relates to the field of disease treatment. Specifically, the present invention relates to a method for treating solid tumors using an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof. Background Art

[0002] Gastric cancer is one of the most common malignant tumors in the world and one of the leading causes of death from cancer worldwide. According to GLOBOCAN data, the incidence and mortality of gastric cancer ranked fifth and fourth respectively in 2020, and the 5-year survival rate of patients with metastatic gastric cancer was less than 5%. At present, surgical resection remains the only radical treatment for gastric cancer, and chemotherapy combined with fluoropyrimidine and platinum is the standard treatment for patients with advanced metastatic gastric cancer. With the advent of immunotherapy and targeted therapy such as trastuzumab and ramucirumab, treatment options for gastric cancer have increased. However, systemic treatment has limited efficacy in advanced gastric cancer, and the median survival of patients is only about 1 year. In terms of immunotherapy, based on the results of the ATTRACTION-02 study, nivolumab was approved in Japan for advanced gastric and gastroesophageal junction cancer after failure of at least two systemic therapies. In April 2021, based on the results of the CheckMate-649 study, the FDA approved nivolumab in combination with fluoropyrimidine and platinum chemotherapy as a first-line treatment for advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. This is also the first FDA-approved first-line immunotherapy for gastric cancer. Although these studies have achieved encouraging results, new therapies are still needed to benefit more gastric cancer patients.

[0003] Pancreatic cancer is one of the most common malignant digestive system tumors. In 2020, there were 496,000 new cases of pancreatic cancer and 466,000 deaths worldwide, ranking seventh among all malignant tumors. Pancreatic cancer has a poor prognosis because it is often diagnosed in the late stage. According to the SEER (Surveillance, Epidemiology and End Results) database of the National Cancer Institute of the United States, the 5-year survival rate of pancreatic cancer is only 8%, and only 28.6% of patients survive for more than 1 year after the initial diagnosis. In addition, due to the high degree of malignancy, pancreatic cancer patients often relapse despite surgical intervention, and the 5-year survival rate of pancreatic cancer patients after radical resection is only 18-27%. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, accounting for more than 90% of pancreatic cancer cases. Although traditional therapies such as chemotherapy, surgery and radiotherapy have been applied, no significant improvement in survival has been found. Surgical resection and chemotherapy (gemcitabine combined with nab-paclitaxel and FOLFIRINOX) have been shown to improve survival in patients with early-stage pancreatic cancer, but these are not sufficient to treat patients with advanced pancreatic cancer.

[0004] Biliary tract cancer is divided into bile duct cancer and gallbladder cancer. Biliary duct cancer is further divided into extrahepatic bile duct cancer and intrahepatic bile duct cancer based on anatomy. In Western countries, the incidence of bile duct cancer is extremely low. However, in parts of Southeast Asia and China, liver fluke and other parasitic infections have led to a significant increase in the incidence of bile duct cancer. At the same time, the latest epidemiological studies have shown that the incidence and mortality of intrahepatic bile duct cancer are increasing. Biliary duct cancer is aggressive and is usually diagnosed at an advanced stage. Most patients with bile duct cancer have unresectable disease at the time of initial diagnosis, and in the few patients who can undergo radical surgery, the recurrence rate is high. The 5-year survival rates for American Joint Committee on Cancer stages I, II, III, and IV are 50%, 30%, 10%, and 0%, respectively. For most patients with bile duct cancer, palliative chemotherapy is the only treatment option. The first-line standard treatment for patients with unresectable and metastatic bile duct cancer is gemcitabine combined with cisplatin. Studies of this combination therapy have shown an objective response rate of 19.5% to 26.1%, a median PFS of 5.8 to 8.0 months, and a median OS of 11.2 to 11.7 months. There is currently no approved standard treatment for patients with biliary tract cancer whose disease progresses after first-line systemic treatment. Pembrolizumab has been approved for the treatment of MSI-H / dMMR solid tumors that have progressed after previous treatment, but because MSI-H / dMMR is rare in advanced cholangiocarcinoma, most patients are not suitable for this treatment.

[0005] Some drugs targeting CLDN18.2 have entered clinical research and have shown good efficacy and safety. Zolbetuximab (IMAB362, claudixmab, Astellas) is the first drug developed for the CLDN18.2 target. As a chimeric IgG1 monoclonal antibody, it can specifically bind to CLDN18.2 on the surface of tumor cells, causing antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), cell apoptosis and cell proliferation inhibition. Subsequently, several clinical trials have also evaluated its efficacy and safety in patients with gastroesophageal cancer.

[0006] A phase IIa trial (NCT01197885, MONO) evaluated the efficacy and safety of zolbetuximab monotherapy in 54 patients with relapsed or refractory advanced gastric or lower esophageal adenocarcinoma who had moderate or high CLDN18.2 expression in ≥50% of tumor cells. The study showed that 10 of the 43 evaluable subjects had clinical benefit, including 4 partial responses (PR) (objective response rate (ORR) 9%) and 6 (14%) with stable disease (SD). The median duration of response (DoR) in subjects who responded to zolbetuximab was 24.6 weeks (range: 13.1-156.1 weeks). Of the 10 subjects who achieved clinical benefit (complete response (CR) + PR + SD), 9 (90%) had moderate or high CLDN18.2 expression in ≥70% of tumor cells. Subgroup analysis of these 9 subjects found that 4 (14%) achieved PR and 5 (17%) achieved SD. Among all subjects, 52 (96%) experienced treatment-emergent adverse events (TEAEs), most of which were grade 1 or 2. TEAEs occurring in ≥30% of subjects included nausea (63%), vomiting (57%), fatigue (43%), and decreased appetite (30%). Grade 3 vomiting was reported in 12 subjects (22%), and grade 3 nausea was reported in 8 subjects (15%). Grade 4 TEAEs occurred in 2 subjects: dyspnea and diarrhea (1 subject each). Treatment-related adverse events (TRAEs) occurred in 44 subjects (82%), of which nausea, vomiting, fatigue, and decreased appetite occurred in ≥10% of subjects. Only 5 subjects experienced serious TRAEs. Grade 3 and grade 2 TEAEs (nausea and vomiting) occurred in 1 subject each, grade 2 hematemesis occurred in 1 subject, and grade 3 vomiting occurred in 2 subjects. Except for 1 subject who experienced grade 3 vomiting, all serious TRAEs occurred in patients receiving 600 mg / m 2 These TEAEs were alleviated by pausing or slowing the zolbetuximab infusion. Patients without prior gastrectomy were more likely to report nausea and vomiting. The incidence of these TEAEs decreased over time as subjects received repeated zolbetuximab infusions.

[0007] Another phase II trial (NCT01630083, FAST) evaluated the efficacy and safety of zolbetuximab combined with EOX versus EOX in the first-line treatment of CLDN18.2-positive advanced gastric / gastroesophageal junction adenocarcinoma (G / GEJ AC). The results showed that the median progression-free survival (PFS) improved from 5.3 months to 7.5 months [hazard ratio (HR), 0.44; 95% CI, 0.29-0.67; P < 0.0005]; the median overall survival (OS) increased from 8.3 months to 13.0 months (HR, 0.55; 95% CI, 0.39-0.77; P < 0.0005). The most frequently reported TEAEs in the zolbetuximab plus EOX group were nausea (81.8%) and vomiting (67.5%). The incidence of vomiting was low in patients with previous gastrectomy, and the incidence and severity of vomiting were dose-dependent with zolbetuximab. The most frequently reported serious adverse events (SAEs) in the zolbetuximab plus EOX group were malignancy (3.9%), pneumonia (2.6%), and febrile neutropenia (2.6%). The most frequently reported SAEs in the EOX group were malignancy (8.3%), gastric hemorrhage (3.6%), and nausea, renal failure, pulmonary embolism, and febrile neutropenia (2.4% each). Two Phase III clinical studies (NCT03504397 / NCT03653507) are underway to evaluate the efficacy of zolbetuximab combined with different chemotherapy regimens (mFOLFOX6 or CAPOX) versus placebo combined with chemotherapy as first-line treatment for CLDN18.2-positive and HER2-negative locally advanced unresectable or metastatic G / GEJ AC. These data provide safety and efficacy data for drugs targeting CLDN18.2.

[0008] Gastric cancer, pancreatic cancer, and biliary cancer are highly malignant and have poor prognosis. The efficacy and benefits of systemic chemotherapy and immune checkpoint inhibitors in advanced gastric cancer, pancreatic cancer, and biliary cancer are very limited, and there is an urgent need to explore and develop new therapeutic targets and combined treatments. CLDN18.2 is highly expressed in gastric cancer tissues and pancreatic cancer tissues, with an expression rate of 80% in gastric cancer patients; positive expression in pancreatic cancer accounts for about 60%, and medium-to-high expression accounts for 54.6%. It has been reported that the positive rate of CLDN18 in extrahepatic bile duct cancer tissues can reach 90%, and intrahepatic bile duct cancer can also reach 43%. Two Phase III clinical studies (NCT03504397 / NCT03653507) evaluating the efficacy of zolbetuximab combined with different chemotherapy regimens (mFOLFOX6 or CAPOX) versus placebo combined with chemotherapy in the first-line treatment of CLDN18.2-positive and HER2-negative locally advanced unresectable or metastatic G / GEJ AC are ongoing. Recent data revealed that both studies achieved the key endpoints of PFS and OS, confirming the efficacy and safety of treatment targeting CLDN18.2. However, zolbetuximab is only effective in first-line gastric / gastroesophageal junction adenocarcinoma patients with high CLDN18.2 expression. There is no effective treatment for gastric / gastroesophageal junction adenocarcinoma with medium / low CLDN18.2 expression and / or failure of standard treatment, as well as other tumors expressing CLDN18.2. SUMMARY OF THE INVENTION

[0010] The present invention meets the above needs by providing a method for treating solid tumors using an antibody-drug conjugate targeting Claudin18.2.

[0011] In order to achieve the above object, the present invention first provides a method for preventing or treating individual solid tumors, which comprises administering an effective amount of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof to an individual in need.

[0012] In order to achieve the above object, the present invention also provides a single-dose unit, comprising: an effective amount of the above-mentioned antibody-drug conjugate targeting Claudin18.2 of the present invention or a pharmaceutically acceptable salt thereof.

[0013] In order to achieve the above object, the present invention further provides a complete set of drug kits, which comprises the above effective amount of the antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof of the present invention.

[0014] The present invention also provides use of the single-dose unit or complete drug kit of the present invention in preparing a drug for preventing or treating solid tumors.

[0015] The present invention evaluates the safety and efficacy of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof in treating solid tumors expressing CLDN18.2, as well as the correlation between the expression level of CLDN18.2 in tumor tissue and the efficacy of the antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof of the present invention.

[0016] The antibody-drug conjugate targeting Claudin18.2 of the present invention or its pharmaceutically acceptable salt as an ADC with bystander effect has a significant tumor inhibitory effect in mouse tumor-bearing models with high and low expression of CLDN18.2. In the clinical study of the present invention, the subjects with various tumor types and different CLDN18.2 expression levels were subjected to a dosing regimen exploration test. It is preliminarily proved that the antibody-drug conjugate targeting Claudin18.2 of the present invention can achieve an ORR of even more than 25% in the treatment of gastric / gastroesophageal junction adenocarcinoma with high expression of CLDN18.2 that has failed previous second-line systemic treatment, improve PFS and OS, and have good tolerability.

[0017] Other embodiments of the present invention will become apparent by reference to the detailed description given hereinafter. DETAILED DESCRIPTION OF THE INVENTION

[0019] Before describing the present invention in detail, it should be understood that the present invention is not limited to the specific methods and experimental conditions in this specification, because the methods and conditions can be changed. In addition, the terminology used herein is only for the purpose of describing specific embodiments and is not intended to be limiting.

[0020] definition

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art. For the purposes of the present invention, the following terms are defined below. It should be understood that, whenever appropriate, terms used in the singular may also include the plural, and vice versa.

[0022] The term "about" when used in conjunction with a numerical value is meant to encompass the numerical value within a range having a lower limit that is 5% less than the specified numerical value and an upper limit that is 5% greater than the specified numerical value.

[0023] The term “and / or”, when used to connect two or more optional items, should be understood to mean any one of the optional items or any two or more of the optional items.

[0024] As used herein, the term "comprising" or "including" means including the stated elements, integers or steps, but does not exclude any other elements, integers or steps. In this article, when the term "comprising" or "including" is used, unless otherwise indicated, it also covers the situation consisting of the stated elements, integers or steps. For example, when referring to an antibody variable region "comprising" a specific sequence, it is also intended to cover the antibody variable region consisting of the specific sequence.

[0025] The term "CLAUDIN" or "CLDN" used in this article is the most important skeletal protein that determines the tight junction structure between cells. It participates in adhesion junctions and plays an important role in the metastasis and invasion of tumor cells. Claudin protein is widely present in mammalian epithelial and endothelial cells, and its distribution is mainly on the side of epithelial cells and on the plasma membrane of basal cells. Different Claudin proteins have their own specific expression in different tissues. Among them, the Claudin18 (CLDN18) gene is located at 3q22.3, with a molecular weight of 24kDa and 261 amino acid residues. It is a member of the Claudins superfamily, and its protein structure includes 2 extracellular loops and 4 transmembrane regions. The two subtypes of human CLDN18 or Claudin18 protein are Claudin18.1 or CLDN18.1 (UniProt ID: P56856-1) and Claudin18.2 or CLDN18.2 (UniProt ID: P56856-2). In the primary structure sequence of the two proteins, only the amino acid residues at certain positions from the N-terminal signal peptide to the extracellular loop 1 (Loop1) structure differ, especially in the extracellular loop 1, CLDN18.1 and CLDN18.2 only have 8 amino acids different. The sequence homology between species of the two subtypes of CLDN18 is also very high. Among them, the extracellular loop 1 of CLDN18.2 is completely consistent in sequence in different species such as humans, mice, and macaques, and the homology of CLDN18.2 proteins between humans and mice reaches 84%, indicating that the CLDN18.2 protein sequence is extremely conservative (O. Tureci et al., Gene 481: 83-92, 2011). CLDN18.2 or any variants and isoforms thereof can be isolated from cells or tissues that naturally express them, or recombinantly produced using techniques well known in the art and / or those described herein. In one embodiment, the CLDN18.2 described herein is human CLDN18.2.

[0026] The terms "antibody targeting CLDN18.2", "anti-CLDN18.2 antibody", "anti-CLDN18.2", "CLDN18.2 antibody", or "antibody that binds to CLDN18.2" or "antibody that specifically binds to CLDN18.2" as used herein refer to an antibody that is capable of binding to (human) CLDN18.2 with sufficient affinity so that the antibody can be used as a therapeutic agent targeting (human) CLDN18.2. In one embodiment, the (human) CLDN18.2 antibody binds to (human) CLDN18.2 with high affinity in vitro or in vivo. In one embodiment, the (human) CLDN18.2 antibody does not bind to CLDN18.1. In one embodiment, the (human) CLDN18.2 antibody binds to cells expressing CLDN18.2 without binding to cells expressing CLDN18.1. In some embodiments, the binding is measured, for example, by radioimmunoassay (RIA), biofilm thin layer interferometry (BLI), MSD electrochemiluminescence detection technology assay, or surface plasmon resonance (SPR), or flow cytometry.

[0027] The expression of CLDN18.2 in cells can be determined in a variety of ways, such as anti-CLDN18.2 antibodies. For example, the binding strength of cells "highly expressing CLDN18.2" to anti-CLDN18.2 antibodies (e.g., determined by FACS) can be 500, 600, 700, 800, 900 or preferably 1000 times or more, such as 1100 times, 1200, 1300, 1400 times or more than the binding strength of anti-CLDN18.2 antibodies to cells that do not express CLDN18.2. For example, cells that "moderately express CLDN18.2" may bind to an anti-CLDN18.2 antibody with an intensity (e.g., as determined by FACS) that is 5-500 times, such as 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100 times or more, but not more than 500 times, as strongly as the anti-CLDN18.2 antibody binds to cells that do not express CLDN18.2.

[0028] For conventional four-chain IgG antibodies, the full-length antibody heavy chain is usually composed of a heavy chain variable region (abbreviated as VH herein) and a heavy chain constant region, wherein the heavy chain constant region comprises at least three domains CH1, CH2 and CH3. The full-length antibody light chain is composed of a light chain variable region (abbreviated as VL herein) and a light chain constant region, wherein the light chain constant region consists of one domain CL. Each heavy chain variable region VH and each light chain variable region are composed of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0029] The term "antibody fragment" includes a portion of an intact antibody. In a preferred embodiment, the antibody fragment is an antigen-binding fragment.

[0030] "Antigen-binding fragment" refers to a molecule that is different from an intact antibody, comprises a portion of an intact antibody and binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2;

[0031] dAb (domain antibody); linear antibody; single chain antibody (eg scFv); single domain antibody such as VHH; bivalent antibody or fragment thereof; or camelid antibody.

[0032] The term "antigen" refers to a molecule that triggers an immune response. This immune response may involve antibody production or activation of specific immune cells, or both. The skilled person will understand that any macromolecule, including substantially all proteins or peptides, can be used as an antigen. In addition, antigens can be derived from recombinant or genomic DNA. As used herein, the term "epitope" refers to a portion of an antigen (e.g., CLDN18.2) that specifically interacts with an antibody molecule.

[0033] "Complementarity determining region" or "CDR region" or "CDR" is a region in an antibody variable domain that is highly variable in sequence and forms a structurally determined loop ("hypervariable loop") and / or contains antigen contact residues ("antigen contact points"). CDR is primarily responsible for binding to antigen epitopes. The CDRs of the heavy and light chains are usually referred to as CDR1, CDR2, and CDR3, and are numbered sequentially from the N-terminus. The CDRs located in the antibody heavy chain variable domain are referred to as HCDR1, HCDR2, and HCDR3, while the CDRs located in the antibody light chain variable domain are referred to as LCDR1, LCDR2, and LCDR3. In a given light chain variable region or heavy chain variable region amino acid sequence, the precise amino acid sequence boundaries of each CDR can be determined using any one or a combination of a number of well-known antibody CDR assignment systems, including, for example, Chothia based on the three-dimensional structure of the antibody and the topology of the CDR loops (Chothia et al. (1989) Nature 342:877-883, Al-Lazikani et al., "Standard conformations for the canonical structures of immunoglobulins", Journal of Molecular Biology, 273, 927-948 (1997)), Kabat based on antibody sequence variability (Kabat et al., Sequences of Proteins of Immunological Interest, 4th Edition, US Department of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath), Contact (University College London), International ImMunoGeneTics database (IMGT) (on the World Wide Web at imgt.cines.fr / ), and North's CDR definition based on affinity propagation clustering using a large number of crystal structures (North et al., "A New Clustering of Antibody CDR Loop Concepts", Journal of Molecular Biology, 406, 228-

[0034] 256(2011)).

[0035] The following are the regional ranges of CDRs defined using the Kabat, AbM, Chothia, Contact, and IMGT schemes.

[0036]

[0037] A CDR can also be identified based on having the same Kabat numbering position as a reference CDR sequence (eg, any of the exemplary CDRs of the invention).

[0038] Unless otherwise specified, in the present invention, the term "CDR" or "CDR sequence" encompasses a CDR sequence determined in any of the above-mentioned ways.

[0039] Unless otherwise indicated, in the present invention, when referring to the residue positions in the antibody variable region (including heavy chain variable region residues and light chain variable region residues), it refers to the numbering position according to the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)).

[0040] In one embodiment, the heavy chain variable region CDR of the antibody of the present invention is determined according to the following rules:

[0041] VH CDR1 was determined according to the AbM rule; and VH CDR2 and 3 were both determined according to the Kabat rule.

[0042] In one embodiment, the light chain variable region CDRs of the antibodies of the invention are determined according to the Kabat rules.

[0043] In one embodiment, the heavy chain variable region CDRs of the antibodies of the invention are determined according to the following rules: VH CDR1 is determined according to the AbM rule; and VH CDR2 and 3 are both determined according to the Kabat rule; and the light chain variable region CDRs are determined according to the Kabat rule.

[0044] It should be noted that the boundaries of the CDRs of the variable regions of the same antibody obtained based on different assignment systems may be different. That is, the CDR sequences of the variable regions of the same antibody defined under different assignment systems are different. Therefore, when it comes to defining antibodies using specific CDR sequences defined in the present invention, the scope of the antibodies also covers antibodies whose variable region sequences contain the specific CDR sequences, but whose claimed CDR boundaries are different from the specific CDR boundaries defined in the present invention due to the application of different schemes (e.g., different assignment system rules or combinations).

[0045] Antibodies with different specificities (i.e., different binding sites for different antigens) have different CDRs (under the same assignment system). However, although CDRs are different from antibody to antibody, only a limited number of amino acid positions in the CDR are directly involved in antigen binding. Using at least two of the Kabat, Chothia, AbM, Contact and North methods, the minimum overlapping region can be determined, thereby providing a "minimum binding unit" for antigen binding. The minimum binding unit can be a sub-portion of the CDR. As those skilled in the art will appreciate, the residues of the rest of the CDR sequence can be determined by the structure and protein folding of the antibody. Therefore, the present invention also contemplates variants of any CDR given herein. For example, in a variant of a CDR, the amino acid residues of the minimum binding unit can remain unchanged, while the remaining CDR residues defined according to Kabat or Chothia can be replaced by conservative amino acid residues.

[0046] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain containing at least a portion of a constant region. The term includes native sequence Fc regions and variant Fc regions. A natural immunoglobulin "Fc domain" comprises two or three constant domains, i.e., a CH2 domain, a CH3 domain, and an optional CH4 domain. For example, in a natural antibody, an immunoglobulin Fc domain comprises the second and third constant domains (CH2 domain and CH3 domain) of two heavy chains derived from IgG, IgA, and IgD class antibodies; or comprises the second, third, and fourth constant domains (CH2 domain, CH3 domain, and CH4 domain) of two heavy chains derived from IgM and IgE class antibodies. Unless otherwise indicated herein, the numbering of amino acid residues in the Fc region or heavy chain constant region is numbered according to the EU numbering system (also referred to as the EU index) as described in Kabat et al., Sequences of Proteins of Immunological Interes, 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD, 1991. Herein, the term "Fc region" does not include the heavy chain variable region VH and the light chain variable region VL and the heavy chain constant region CH1 and the light chain constant region CL of an immunoglobulin, but may include the hinge region at the N-terminus of the heavy chain constant region in some cases.

[0047] An "IgG-type antibody" refers to an IgG-type antibody to which the heavy chain constant region belongs. The heavy chain constant region of all antibodies of the same type is the same, and the heavy chain constant region of antibodies of different types is different. For example, an IgG4-type antibody means that its heavy chain constant region is from IgG4, or an IgG1-type antibody means that its heavy chain constant region is from IgG1.

[0048] As used herein, the term "binding" or "specific binding" means that the binding is selective for the antigen and can be distinguished from unwanted or non-specific interactions. The ability of an antigen binding site to bind to a specific antigen can be determined by enzyme-linked immunosorbent assay (ELISA) or conventional binding assays known in the art such as by radioimmunoassay (RIA) or thin-layer interferometry or MSD assays or surface plasmon resonance (SPR).

[0049] As used herein, "antibody-drug conjugate (ADC)" refers to a compound obtained by linking an antibody and a drug via a linker.

[0050] The term "site-specific conjugation" as described herein refers to conjugation in which a drug / active substance is specifically linked to a specific site of an antibody via a linker.

[0051] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effects and properties of the antibody-drug conjugate (ADC) of the present invention, and the salt is not biologically or otherwise undesirable. The ADC of the present invention may exist in the form of their pharmaceutically acceptable salts, including acid addition salts or base addition salts. In the present invention, pharmaceutically acceptable non-toxic acid addition salts represent salts formed between the ADC conjugate of the present invention and an organic or inorganic acid, and the organic or inorganic acid includes but is not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. Pharmaceutically acceptable non-toxic base addition salts refer to salts formed by the ADC conjugates of the present invention and organic or inorganic bases, including but not limited to alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic base salts, such as ammonium salts formed by organic bases containing N groups.

[0052] The term "drug: antibody ratio" or "DAR" refers to the ratio of the small molecule drug moiety (D) coupled to the Ab moiety described herein to the Ab moiety. For example, the DAR can be 1 to 20, such as 2-18, 4-16, 5-12, 6-10, 2-8, 3-8, 2-6, 4-6, 6-10, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. The DAR can also be calculated as the average DAR of the population of molecules in the product, that is, the overall ratio of the small molecule drug moiety (D) coupled to the Ab moiety described herein to the Ab moiety in the product measured by a detection method (e.g., by conventional methods such as mass spectrometry, ELISA assay, electrophoresis and / or HPLC), and this DAR is referred to as the average DAR in the text. It should be understood that the overall ratio described above is a molar ratio. In some embodiments, the average DAR value of the conjugate of the invention is 1 to 20, such as 2-18, 4-16, 5-12, 6-10, 2-8, 3-8, 2-6, 4-6, 6-10, such as 1.0-8.0, 2.0-6.0, such as 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8.0, 7.9, 8, 8.1, 8.2, 8.3,

[0055] 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0, or a range having two of these values ​​as endpoints.

[0056] The term "effective amount" refers to an amount or dosage of an antibody-drug conjugate of the present invention or a pharmaceutically acceptable salt or antibody or fragment or composition or combination thereof, which, after single or multiple doses of administration to a patient or individual, produces the desired effect in a patient or individual in need of treatment or prevention.

[0057] A "therapeutically effective amount" refers to an amount effective to achieve the desired therapeutic outcome at the desired dosage and for the desired period of time. A therapeutically effective amount is also an amount in which any toxic or deleterious effects of the antibody-drug conjugate, or a pharmaceutically acceptable salt thereof, antibody or antibody fragment, or composition or combination of the invention are outweighed by the therapeutically beneficial effects. A "therapeutically effective amount" preferably inhibits a measurable parameter (e.g., tumor volume) by at least about 30%, even more preferably by at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or even 100%, relative to an untreated subject.

[0058] A "prophylactically effective amount" refers to an amount effective to achieve the desired prophylactic result at the required dosage and for the required period of time. Typically, since a prophylactic dose is used in a subject prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0059] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid is introduced, including progeny of such cells. Host cells include "transformants" and "transformed cells," which include primary transformed cells and progeny derived therefrom, without regard to the number of passages. Progeny may not be completely identical to the parent cell in nucleic acid content, but may contain mutations. Mutant progeny screened or selected for the same function or biological activity as in the initially transformed cell are included herein.

[0060] The term "label" as used herein refers to a compound or composition that is directly or indirectly conjugated or fused to a reagent (such as a polynucleotide probe or antibody) and facilitates the detection of the reagent to which it is conjugated or fused. The label itself can be detectable (e.g., a radioisotope label or a fluorescent label) or can catalyze a chemical change in a detectable substrate compound or composition in the case of an enzymatic label. The term is intended to encompass direct labeling of a probe or antibody by coupling (i.e., physically connecting) a detectable substance to the probe or antibody and indirect labeling of a probe or antibody by reacting with another reagent that is directly labeled.

[0061] "Individuals" or "subjects" include mammals. Mammals include, but are not limited to, domestic animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the individual or subject is a human.

[0062] An "isolated" antibody or other molecule (e.g., ADC molecule) is an antibody or molecule that has been separated from a component of its natural environment or the environment in which it is expressed. In some embodiments, the antibody or ADC molecule is purified to greater than 95% or 99% purity, as determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC).

[0063] The term "anti-tumor effect" refers to a biological effect that can be exhibited by a variety of means, including but not limited to, for example, a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in tumor cell proliferation, or a decrease in tumor cell survival.

[0064] The terms "tumor" and "cancer" are sometimes used interchangeably herein to encompass both solid tumors and hematological tumors.

[0065] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. In certain embodiments, cancers suitable for treatment by the antibody-drug conjugates of the invention include gastric cancer, pancreatic cancer, or gastroesophageal junction cancer, including metastatic forms of those cancers.

[0066] The term "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. The terms "cancer," "cancerous," and "tumor" are not mutually exclusive when referred to herein.

[0067] The term "solid tumor" includes advanced malignant solid tumors, tumors associated with Claudin18.2, such as Claudin18.2-positive tumors, such as one or more selected from the following: gastric cancer, breast cancer, liver cancer, colon cancer, lung cancer, gallbladder cancer, esophageal cancer, gastric / gastroesophageal junction adenocarcinoma, pancreatic ductal adenocarcinoma and biliary cancer (biliary cancer is divided into bile duct cancer and gallbladder cancer). In some embodiments, the solid tumor can be a first-line (1L) gastric / gastroesophageal junction adenocarcinoma, a back-line gastric / gastroesophageal junction adenocarcinoma; preferably, the back-line gastric / gastroesophageal junction adenocarcinoma is a 2L back gastric / gastroesophageal junction adenocarcinoma; more preferably, the back-line gastric / gastroesophageal junction adenocarcinoma is a 3L gastric / gastroesophageal junction adenocarcinoma. In some embodiments, the solid tumor is a first-line (1L) gastric cancer, a back-line gastric cancer; preferably, the back-line gastric cancer is a 2L back gastric cancer; more preferably, the gastric cancer is a 3L gastric / gastroesophageal junction adenocarcinoma. In some embodiments, the solid tumor is first-line (1L) pancreatic ductal adenocarcinoma, second-line pancreatic ductal adenocarcinoma; preferably, second-line pancreatic ductal adenocarcinoma is 2L pancreatic ductal adenocarcinoma. Herein, gastric / gastroesophageal junction adenocarcinoma may refer to gastric cancer or gastroesophageal junction adenocarcinoma.

[0068] The terms "first-line tumor", "1L tumor" or "first-line (1L) tumor" refer to a tumor that has not been treated with systemic anti-tumor therapy. For example, the term "first-line (1L) gastric / gastroesophageal junction adenocarcinoma" refers to gastric / gastroesophageal junction adenocarcinoma that has not been treated with systemic anti-tumor therapy. The terms "first-line (1L) gastric cancer" and "first-line (1L)" pancreatic ductal adenocarcinoma refer to gastric cancer and pancreatic ductal adenocarcinoma, respectively, that have not been treated with systemic anti-tumor therapy.

[0069] The term "second-line tumor" or "2L tumor" refers to a tumor that has failed first-line therapy (e.g., is ineffective or intolerant to first-line therapy). For example, second-line pancreatic ductal adenocarcinoma or 2L pancreatic ductal adenocarcinoma refers to a pancreatic ductal adenocarcinoma that has failed first-line therapy for pancreatic ductal adenocarcinoma, e.g., is ineffective or intolerant to first-line therapy.

[0070] The term "third-line tumor" or "3L tumor" refers to a tumor that has failed second-line therapy (e.g., is ineffective or intolerant to second-line therapy). For example, "third-line (3L) gastric / gastroesophageal junction adenocarcinoma" refers to a gastric / gastroesophageal junction adenocarcinoma that has failed second-line therapy for gastric / gastroesophageal junction adenocarcinoma, e.g., is ineffective or intolerant to second-line therapy.

[0071] The term "later-line tumor" refers to a tumor that has failed (eg, is ineffective or intolerant to) first-line therapy and subsequent treatments (eg, second-line therapy or third-line therapy).

[0072] It should be understood that for tumors, the meanings of first-line treatment, second-line treatment and third-line treatment and their treatment regimens are clear and well known to those skilled in the art. First-line treatment refers to the first round of treatment after tumor diagnosis; second-line treatment refers to the situation where the patient's tumor progresses again after first-line treatment and is resistant to the first-line treatment regimen, requiring a different treatment regimen; third-line treatment refers to the situation where another treatment regimen is used again after the failure of second-line treatment; for example, refer to

[0073] https: / / www.medsci.cn / article / show_article.do?id=1901e9517635. The treatment regimen is approved or recommended by an authority such as NMPA or FDA. For example, first-line treatment includes but is not limited to fluorouracil drugs (fluorouracil or capecitabine) combined with platinum drugs (oxaliplatin or cisplatin). Second-line treatment includes but is not limited to paclitaxel combined with ramucirumab. Third-line treatment includes but is not limited to nivolumab, irinotecan, or trifluridine / tipiracil.

[0074] As used herein, "treat," ...

[0075] As used herein, "prevention" includes inhibition of the occurrence or development of a disease or condition or symptoms of a particular disease or condition. In some embodiments, subjects with a family history of cancer are candidates for preventive regimens. Generally, in the context of cancer, the term "prevention" refers to the administration of a drug before the signs or symptoms of cancer occur, particularly in a subject at risk for cancer.

[0076] The term "vector" as used herein refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes vectors that are self-replicating nucleic acid structures as well as vectors that are incorporated into the genome of a host cell into which they have been introduced. Some vectors are capable of directing the expression of nucleic acids to which they are operably linked. Such vectors are referred to herein as "expression vectors."

[0077] "Subject / patient / individual sample" refers to a collection of cells or fluids obtained from a patient or subject. The source of the tissue or cell sample can be solid tissue, such as an organ or tissue sample or a biopsy sample or a puncture sample from fresh, frozen and / or preserved; blood or any blood component; body fluids, such as cerebrospinal fluid, amniotic fluid (amniotic fluid), peritoneal fluid (ascites), or interstitial fluid; cells from any time of pregnancy or development of the subject. Tissue samples may contain compounds that are not naturally mixed with tissues in nature, such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, etc.

[0078] The term "lyophilized preparation" refers to a composition obtained by freeze-drying a liquid preparation. Preferably, it is a solid composition having a water content of less than 5%, preferably less than 3%.

[0079] The term "buffer" refers to a pH buffer that can keep the pH value of a solution stable. Preferably, the buffer can keep the pH of the liquid preparation of the present invention or the liquid preparation obtained after reconstitution of the lyophilized preparation of the present invention at about 5.5-7.5, for example, about 6.0-6.5, about 5.5-7.2, about 6.0-7.0, or about 6.3-6.8. Preferably, the buffer is selected from one or more of histidine, citric acid, succinic acid, glutamic acid, phosphoric acid, acetic acid or a salt thereof. Wherein, the salt includes but is not limited to salts formed with acids such as hydrochloric acid or sulfuric acid, salts formed with alkali metals, such as lithium, sodium or potassium salts, such as histidine hydrochloride.

[0080] The term "stabilizer" refers to a chemical substance that can maintain the stability of the formulation at the chemical, physical and / or biological level. Preferably, the stabilizer is selected from one or more of sugars and polyols. The sugars may be selected from, but not limited to, sucrose, trehalose, glucose, lactose, maltose, cyclodextrin, maltodextrin and dextran. The polyols may be selected from, but not limited to, mannitol, sorbitol and xylitol. The sugars or polyols may be in the form of hydrates.

[0081] The term "surfactant" refers to a substance that can significantly reduce the surface tension of a solution system. The concentration of the surfactant in the liquid preparation is, for example, about 0.05-1 mg / ml, about 0.05-2, about 0.1-0.5, about 0.1-0.4, about 0.1-0.3, about 0.2-0.4 mg / ml. Preferably, the surfactant is a nonionic surfactant, including but not limited to, alkyl poly (ethylene oxide); polysorbate, such as polysorbate-20, polysorbate-80, polysorbate-60, or polysorbate-40; Pluronic; or a combination thereof.

[0082] The term "reconstituted" formulation refers to a liquid formulation obtained by dissolving and / or suspending a solid formulation (eg, a lyophilized formulation) in a physiologically acceptable solution. In this document, in some cases, "reconstitution" and "reconstitution" are used interchangeably for formulations.

[0083] As used herein, "w / v" means "weight / volume", for example, "1% w / v" means 1 g / 100 ml = 0.01 g / ml = 10 mg / ml.

[0084] Treatment

[0085] The present invention provides a method for preventing or treating solid tumors in an individual, comprising administering an effective amount of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof to the individual in need thereof.

[0086] In one embodiment of the present invention, the antibody-drug conjugate targeting Claudin18.2 is selected from:

[0087]

[0088] wherein Ab is an antibody or an antigen-binding fragment thereof targeting Claudin18.2;

[0089] q represents the average DAR, and is 2-11; for example, q is 2-5, for example, q is a value of 3-5, 3.5-4.5, 3.2-4.2 or 3-4, more specifically, q is 2, 2.5, 3, 3.5, 4, 4.8, or 5.

[0090] According to the context, it should be understood that when the variable after the square brackets of the ADC structural formula is specified as the average DAR, such as q in Formula IA, it represents the ratio of the drug portion (i.e., Exatecan) to the Ab determined by a conventional determination method, as described in the definition section herein. The average DAR can be a decimal. For the average DAR, for example, when it is mentioned that "q is 3-5" or "q is a value of 3-5", it means that q is any value selected from 3 to 5, including integers and decimals.

[0091] In a specific embodiment of the present invention, the antibody-drug conjugate targeting Claudin18.2 is selected from:

[0092]

[0093] wherein Ab is an antibody or an antigen-binding fragment thereof targeting Claudin18.2;

[0094] Wherein y is an integer of 1 or 2.

[0095] It should be understood that when the variable after the square brackets in the ADC structural formula is not specified as the average DAR, such as y in Formula IB, it does not represent the average DAR, but refers to the number of Linker-payloads (i.e., the structures in the square brackets of Formula IB) connected to each Ab in the ADC molecule, unless otherwise specified or contradictory according to the context. For example, when y is 2, it means that 1 Ab is connected to 2 Linker-payloads in the ADC molecule.

[0096] In a further specific embodiment of the present invention, the antibody or its antigen-binding fragment targeting Claudin18.2 comprises HCDR1, HCDR2, HCDR3 as shown in the following amino acid sequences, respectively: SEQ ID NO: 1 (GFTFSSYVMS), SEQ ID NO: 2 (TISHSGGSTYYADSVKG) and SEQ ID NO: 3 (DAPYYDILTGYRY), and LCDR1, LCDR2 and LCDR3 as shown in the following amino acid sequences, respectively: SEQ ID NO: 6 (RASQSISSWLA), SEQ ID NO: 7 (KASSLES) and SEQ ID NO: 8 (QQYNSYSYT).

[0097] In a further embodiment of the present invention, the antibody or antigen-binding fragment thereof targeting Claudin18.2 comprises a heavy chain variable region and / or a light chain variable region, wherein the heavy chain variable region

[0098] (i) comprises or consists of the amino acid sequence of SEQ ID NO: 4; or

[0099] (ii) comprises or consists of an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acids of SEQ ID NO:4; or

[0100] (iii) comprises or consists of an amino acid sequence having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 4, preferably, the amino acid changes do not occur in the CDR regions; and / or

[0101] Light chain variable region

[0102] (i) comprises or consists of the amino acid sequence of SEQ ID NO: 9; or

[0103] (ii) comprises or consists of an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acids of SEQ ID NO:9; or

[0104] (iii) comprises or consists of an amino acid sequence having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 9, preferably, the amino acid changes do not occur in the CDR regions.

[0105] In a further specific embodiment of the present invention, the antibody or antigen-binding fragment thereof targeting Claudin18.2 of the present invention comprises a heavy chain and a light chain.

[0106] wherein the heavy chain

[0107] (i) comprising or consisting of the amino acid sequence of SEQ ID NO: 11 as shown below:

[0108] EVQLLDSGGGLVQPGGSLRLSCAASGFTFSSYVMSWVRQAPGKGLNWVSTISHSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIDAPYYDILTGYRYWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK;

[0109] or

[0110] (ii) comprises or consists of an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acids of SEQ ID NO: 11; or

[0111] (iii) comprises or consists of an amino acid sequence having one or more (preferably no more than 20 or 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 11; and / or

[0112] The light chain

[0113] (i) comprising or consisting of the amino acid sequence of SEQ ID NO: 12 as shown below:

[0114] DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC;

[0115] or

[0116] (ii) comprises or consists of an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acids of SEQ ID NO: 12; or

[0117] (iii) comprises or consists of an amino acid sequence having one or more (preferably no more than 20 or 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 12.

[0118] In one embodiment of the present invention, the N-acetylglucosamine (GlcNAc) linked to Ab is present at the Asn297-glycosylation site of both heavy chains of the antibody.

[0119] In a specific embodiment of the present invention, the antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is formulated into a preparation for administration.

[0120] In a specific embodiment of the present invention, the preparation of the antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is a liquid preparation, which comprises:

[0121] About 15-60 mg / ml, such as about 20-40 mg / mL of the Claudin18.2-targeted antibody-drug conjugate or a pharmaceutically acceptable salt thereof;

[0122] About 5-50 mM, such as about 10-30 mM, of a buffer;

[0123] About 50-100 mg / ml, such as about 60-90 mg / ml, of a stabilizer; and

[0124] About 0.05-1 mg / ml, such as about 0.1-0.3 mg / ml, of a surfactant;

[0125] The pH of the formulation is about 5.5-7.5, preferably about 6.0-6.5, more preferably about 6.5.

[0126] In one embodiment of the present invention, the buffer is a combination of histidine and histidine hydrochloride or histidine;

[0127] The stabilizer is sucrose; and

[0128] The surfactant is polysorbate 80.

[0129] In a specific embodiment of the present invention, the preparation of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof has the following composition or its prescription: 20 mg / mL of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof, 20 mM histidine buffer, 8% sucrose (w / v), 0.02% polysorbate 80 (w / v), and pH 6.5.

[0130] It should be understood that, if not specifically stated, when the preparation is a liquid preparation, the preparation of the present invention further comprises a solvent, including but not limited to, for example, purified water such as ultrapure water, water for injection, sterile water, double distilled water, etc. The solvent that can be used to reconstitute the lyophilized preparation of the present invention includes but is not limited to, for example, purified water such as ultrapure water, water for injection, sterile water, double distilled water, physiological saline, Ringer's solution, glucose injection, etc.

[0131] In a further embodiment of the present invention, the antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is a lyophilized preparation. The lyophilized preparation is prepared by lyophilizing the above-mentioned pharmaceutical preparation of the present invention. For example, the lyophilized preparation is prepared by lyophilizing the liquid pharmaceutical preparation described in the above-mentioned specific embodiment.

[0132] In one embodiment of the invention, the lyophilized formulation is reconstituted prior to administration to a subject.

[0133] In one embodiment of the present invention, in the method of preventing or treating a solid tumor in an individual, the solid tumor is an advanced malignant solid tumor, and / or

[0134] The solid tumor can be a tumor associated with Claudin18.2, such as a Claudin18.2-positive tumor, such as one or more selected from the following: gastric cancer, breast cancer, liver cancer, colon cancer, lung cancer, gallbladder cancer, esophageal cancer, gastric / gastroesophageal junction adenocarcinoma, pancreatic ductal adenocarcinoma and biliary cancer (biliary cancer is divided into bile duct cancer and gallbladder cancer).

[0135] In a specific embodiment of the present invention, the advanced solid tumor is a tumor that has not undergone systemic anti-tumor treatment, a tumor that has failed at least one systemic anti-tumor treatment, a tumor that has failed first-line treatment (e.g., is ineffective or intolerant to first-line treatment), or a tumor that has failed second-line treatment (e.g., is ineffective or intolerant to second-line treatment).

[0136] In a specific embodiment of the present invention, the advanced malignant solid tumor is a locally advanced unresectable or metastatic solid tumor.

[0137] In a specific embodiment of the present invention, the advanced solid tumor is gastric cancer or gastroesophageal junction adenocarcinoma.

[0138] The solid tumor is first-line (1L) gastric / gastroesophageal junction adenocarcinoma, back-line gastric / gastroesophageal junction adenocarcinoma; preferably, the back-line gastric / gastroesophageal junction adenocarcinoma is 2L back-line gastric / gastroesophageal junction adenocarcinoma; more preferably, the back-line gastric / gastroesophageal junction adenocarcinoma is 3L gastric / gastroesophageal junction adenocarcinoma. The solid tumor is first-line (1L) gastric cancer, back-line gastric cancer; preferably, the back-line gastric cancer is 2L back-line gastric cancer; more preferably, the gastric cancer is 3L gastric cancer. The solid tumor is first-line (1L) pancreatic ductal adenocarcinoma, back-line pancreatic ductal adenocarcinoma; preferably, the back-line pancreatic ductal adenocarcinoma is 2L pancreatic ductal adenocarcinoma.

[0139] In a specific embodiment of the present invention, the advanced malignant solid tumor is locally advanced unresectable or metastatic gastric / gastroesophageal junction adenocarcinoma.

[0140] In a specific embodiment of the present invention, the advanced malignant solid tumor is Her-2 negative.

[0141] In a specific embodiment of the present invention, the individual has previously received treatment for the solid tumor.

[0142] In a specific embodiment of the present invention, the method of preventing or treating an advanced malignant solid tumor in an individual of the present invention comprises administering to the individual 0.1 mg / kg-100 mg / kg of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof; further, the method comprises administering to the individual 0.2 mg / kg-50 mg / kg of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof; further, the method comprises administering to the individual 0.3 mg / kg-30 mg / kg of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof. For example: the method comprises administering to the individual 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 4.5 mg / kg, 6 mg / kg, 7.5 mg / kg, 8 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13.5 mg / kg, or 15 mg / kg of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof. Further, the method comprises administering to the individual 0.3 mg / kg-10 mg / kg, such as 2 mg / kg-9 mg / kg, 4 mg / kg-8 mg / kg, or 5 mg / kg-7 mg / kg of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof. For example: the method comprises administering to the individual 6 mg / kg of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof.

[0143] In a specific embodiment of the present invention, the method of preventing or treating an advanced malignant solid tumor in an individual comprises administering to the individual 10 mg-1500 mg, e.g., 50 mg-1000 mg, 100 mg-800 mg, 200 mg-600 mg or 300 mg-500 mg of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof.

[0144] In a specific embodiment of the present invention, the antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is administered according to an administration cycle.

[0145] In a specific embodiment of the present invention, the dosing cycle of the method is 2 weeks / 14 days (Q2W)-5 weeks / 35 days (Q5W), for example, 18-24 days, 16-28 days or 15-30 days; for example, 19, 20, 21, 22 or 23 days, and the drug is administered once in each dosing cycle; further, the dosing cycle of the method is 2 weeks / 14 days (Q2W), 3 weeks / 21 days (Q3W), 4 weeks / 28 days (Q4W) or 5 weeks / 35 days (Q5W), and the drug is administered once in each cycle, that is, once every two weeks, once every three weeks, once every four weeks or once every five weeks; preferably, it is administered once on the first day of each cycle.

[0146] In a more specific embodiment of the present invention, the method comprises administering 6 mg / kg of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof to the individual at a frequency of once every 3 weeks / 21 days (administered once on day 1 of each cycle).

[0147] In a specific embodiment of the present invention, the administration method of the method of the present invention includes intravenous infusion such as intravenous drip or intravenous push; wherein, intravenous drip can be performed through a peripheral vein, a central venous catheter or an infusion port.

[0148] Antibody-drug conjugate or pharmaceutically acceptable salt thereof for use in treatment

[0149] The present invention provides an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof, which is used for preventing or treating individual solid tumors;

[0150] Wherein, the antibody-drug conjugate targeting Claudin18.2 is selected from the antibody-drug conjugate of Formula IA or Formula IB as defined in the "Therapeutic Methods" section herein.

[0151] In a specific embodiment of the present invention, the antibody or antigen-binding fragment thereof targeting Claudin18.2 is as defined in the "Therapeutic Methods" section herein.

[0152] In a specific embodiment of the present invention, the solid tumor is as defined herein, for example, in the "Methods of Treatment" section.

[0153] In a specific embodiment of the present invention, the antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is administered to an individual at a dose as described in the "treatment methods" section herein.

[0154] In a specific embodiment of the present invention, the antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is administered according to the dosage regimen described in the "treatment methods" section herein.

[0155] Medical Uses

[0156] The present invention provides a use of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating individual solid tumors.

[0157] Wherein, the antibody-drug conjugate targeting Claudin18.2 is selected from the antibody-drug conjugate of Formula IA or Formula IB as defined in the "Therapeutic Methods" section herein.

[0158] In a specific embodiment of the present invention, the antibody or antigen-binding fragment thereof targeting Claudin18.2 is as defined in the "Therapeutic Methods" section herein.

[0159] In a specific embodiment of the present invention, the solid tumor is as defined herein, for example, in the "Methods of Treatment" section.

[0160] In a specific embodiment of the present invention, the antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is administered to an individual at a dose as described in the "treatment methods" section herein.

[0161] In a specific embodiment of the present invention, the antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is administered according to the dosage regimen described in the "treatment methods" section herein.

[0162] Single dose unit

[0163] A single-dose unit, comprising: an effective amount of an antibody-drug conjugate targeting Claudin18.2 of the present invention or a pharmaceutically acceptable salt thereof. Preferably, it comprises 1-500 mg, for example, 100-500 mg of a fixed dose of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof. For example, it comprises 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200 or 500 mg of a fixed dose of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof.

[0164] In one embodiment of the invention, the single dosage unit is a unit dosage form.

[0165] Complete set of medicine boxes

[0166] A complete drug kit, comprising an effective amount of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof according to the present invention;

[0167] Preferably, a fixed dose of 1-500 mg, for example 100-500 mg, of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is included. For example, a fixed dose of 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200 or 500 mg of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is included.

[0168] Preferably, the kit further comprises a package insert printed with instructions for using the antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof to prevent or treat an advanced malignant solid tumor in an individual.

[0169] application

[0170] The single-dose unit or complete kit of the present invention is used in the preparation of a drug for preventing or treating advanced malignant solid tumors. The advanced malignant solid tumors include but are not limited to gastric cancer, breast cancer, liver cancer, colon cancer, lung cancer, gallbladder cancer, esophageal cancer, gastric / gastroesophageal junction adenocarcinoma, pancreatic ductal adenocarcinoma, and biliary cancer (biliary cancer is divided into cholangiocarcinoma and gallbladder cancer). Example

[0171] Example 1 Preparation of Antibody-Drug Conjugate Targeting Claudin18.2

[0172] The anti-CLDN18.2 monoclonal antibody HB37A6 (see CN202010570517.X (corresponding to PCT application PCT / CN2021 / 100870)) and the control antibody zolbetuximab (abbreviated as Zmab, sequence derived from INN117) were expressed in the form of full-length monoclonal antibodies in HEK293 cells (Invitrogen, A14527).

[0173] Based on HB37A6, a synthetic ADC (IEX019-02) was further designed as described below. The specific synthesis steps can also refer to the preparation steps of IEX019-02 in PCT / CN2022 / 139637 (which is incorporated herein by reference in its entirety).

[0174] 1). Preparation of Compound 6

[0175]

[0176] Under N2 atmosphere, chlorosulfonyl isocyanate (CSI) (0.87 mL, 1.4 g, 10 mmol), Et3N (2.8 mL, 2.0 g, 20 mmol) and 2-(2-aminoethoxy)ethanol (1.2 mL, 1.26 g, 12 mmol) were added to a solution of BCN-OH (5, 1.5 g, 10 mmol) in DCM (150 mL). The mixture was stirred for 10 minutes and quenched by adding NH4Cl aqueous solution (saturated, 150 mL). After separation, the aqueous layer was extracted with DCM (150 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by column chromatography. The product 6 (2.06 g, 5.72 mmol, 57%) was obtained as a light yellow thick oil. 1 H NMR (400MHz, CDCl3) δ (ppm) 6.0 (bs, 1H), 4.28 (d, J = 8.2Hz, 2H), 3.78–3.73 (m, 2H), 3.66–3.61 (m, 2H), 3.61–3.55 (m ,2H),3.34(t,J=4.9Hz,2H),2.37–2.15(m,6H),1.64–1.48(m,2H),1.40(quintet,J=8.7Hz,1H),1.05–0.92(m,2H).

[0177] 2) Preparation of Compound 7

[0178]

[0179] To a stirred solution of 6 (47 mg, 0.13 mmol) in DCM (10 mL) was added CSI (11 μL, 18 mg, 0.13 mmol). After 30 minutes, a solution of Et3N (91 μL, 66 mg, 0.65 mmol) and diethanolamine (16 mg, 0.16 mmol) in DMF (0.5 mL) was added. After 30 minutes, p-nitrophenyl chloroformate (52 mg, 0.26 mmol) and Et3N (54 μL, 39 mg, 0.39 mmol) were added. After another 4.5 hours, the reaction mixture was concentrated and the residue was purified by gradient column chromatography (33→66% EtOAc / heptane (1% AcOH)) to give 7 (88 mg, 0.098 mmol, 75%) as a colorless oil.1H NMR (400MHz, CDCl3) δ (ppm) 8.28–8.23 (m, 4H), 7.42–7.35 (m, 4H), 4.52 (t, J = 5.4Hz, 4H), 4.30 (d, J = 8.3Hz, 2H), 4.27–4.22 (m, 2H), 3.86 (t, J = 5.3Hz, 4H),3.69–3.65(m,2H),3.64–3.59(m,2H),3.30–3.22(m,2H),2.34–2.14( m,6H),1.62–1.46(m,2H),1.38(quintet,J=8.7Hz,1H),1.04–0.92(m,2H).

[0180] 3). Preparation of Compound 9

[0181]

[0182] Compound 8 (163 mg, 240 μmol) was added to a mixture of exatecan mesylate (125 mg, 235 μmol) and DIPEA (61 mg, 82 μL, 0.47 mmol) in dry DMF (0.9 mL). After 20 hours, the reaction mixture was diluted to 9 mL DCM and purified by gradient column chromatography (0→40% MeOH / DCM) to give 9 (155 mg, 159 μmol, 68%). LCMS (ESI+) C 55 H 54 F6O 10 + (M+H) + Calculated value: 977.39; measured value: 977.80.

[0183] 4) Preparation of Compound 1

[0184] To a solution of compound 9 (155 mg, 159 μmol) in DMF (1.6 mL) was added Et3N (73 mg, 101 μL, 0.72 mmol) and a solution of compound 7 (65 mg, 72 μmol) in DMF (1.4 mL). The reaction mixture was stirred for 24 hours, diluted with DCM (20 mL) and purified by gradient column chromatography (0→40% MeOH / DCM) to give compound 1 (94 mg, 44 μmol, 28%) as a light yellow solid. LCMS (ESI+) C 102 H 118 F2N 16 O 29 S2 2+ (M / 2+H) + Calculated value: 1066.88; measured value: 1067.12.

[0185] 5) Enzymatic remodeling of HB37A6 to HB37A6-(GlcNAc(Fuc)1-6-N3-GalNAc)2

[0186] According to the expression and purification of HB37A6 in HEK293 cells. The obtained HB37A6 (16.4 mg / mL) was incubated with EndoSH (1% w / w) as described in PCT / EP2017 / 052792 to obtain trimmed HB37A6 with -GlcNAc or GlcNAc (Fuc) at the Asn297 position. The trimmed HB37A6 was incubated with the enzyme His-TnGalNAcT (4.5% w / w) disclosed in PCT / EP2016 / 059194 and 6-azido-GalNAc-UDP (25 eq (equivalent) compared to the antibody) disclosed in PCT / EP2016 / 059194 (in a solution of histidine (20 mM) + NaCl (150 mM) containing 6 mM MnCl2) at 30°C for 16 hours.

[0187] Next, the incubation mixture obtained above was purified using a 50mL protA column (Hitrap Mabselect Sure, GE, 11-0034-95). The incubation mixture obtained above was loaded onto the column and washed with TBS+0.2% Triton and TBS. The column was then eluted with 0.1M acetate buffer pH 2.9 and neutralized with 2.5MTris-HCl pH 7.2. After dialysis 3 times with PBS, the (modified) glycosylated antibody obtained was concentrated to 32.6mg / mL using a Vivaspin Turbo 15 ultrafiltration device (Sartorius).

[0188] The obtained glycosylated antibodies were analyzed by mass spectrometry, and the main steps were as follows: Before mass spectrometry analysis, the glycosylated antibodies were treated with IdeS so that the Fc / 2 fragment could be analyzed. 20 μg (modified) glycosylated antibody solution was incubated with IdeS (FabricatorTM) (1.25U / μL) in PBS pH 6.6 in a total volume of 10 μL at 37°C for 1 hour. The sample was diluted to 80 μL and then analyzed on a JEOL AccuTOF (ESI-TOF), and the deconvoluted spectrum was obtained using Magtran software. Mass spectrometry analysis of the IdeS digested sample showed that the main product corresponded to the obtained HB37A6-(GlcNAc(Fuc)1-6-N3-GalNAc)2, with an observed mass of 24330.4.

[0189] Therefore, the above results demonstrated that HB37A6-(GlcNAc(Fuc)1-6-N3-GalNAc)2 in which GlcNAc at Asn297 of both heavy chains was substituted with 6-azido-GalNAc (4-position substitution) was obtained.

[0190] 6). Preparation of HB37A6-SYNtecan E conjugate (IEX019-02)

[0191] The bioconjugate IEX019-02 according to the present invention is prepared by coupling compound 1 (linker-payload) as a linker-conjugate to azide-modified HB37A6-(GlcNAc(Fuc)1-6-N3-GalNAc)2 as a biomolecule. Therefore, PBS pH 7.4 (808 μL) was added to a solution of HB37A6-(GlcNAc(Fuc)1-6-N3-GalNAc)2 (10.8 mL, 350 mg, 32.6 mg / ml, PBS pH 7.4), as well as 1,2-propylene glycol (11.3 mL) and compound 1 (350 μL, 40 mM DMF solution). The reaction was incubated at room temperature overnight, then filtered and dialyzed to PBS pH 7.4. Residual free payload was removed by adding charcoal (350 mg) and then rotating overnight at room temperature. The charcoal was removed by centrifugation and filtration, and the ADC was purified on an AKTA Purifier-10 (GE Healthcare) with a Superdex200 26 / 600 SEC (GE Healthcare) column.

[0192] Mass spectrometry analysis of the IdeS digested sample showed two major products, both corresponding to the obtained ADC, namely HB37A6-SYNtecan E conjugate. The first peak: observed mass 26469Da (calculated mass 26465Da), corresponds to the coupled Fc / 2 fragment (2x closed lactone form of the payload). The second peak: observed mass 26499Da (calculated mass 26501Da), corresponds to the bound Fc / 2 fragment (2x open carboxylate form of the payload). The obtained structure is as follows. The concentration, DAR value and SEC purity of the ADC product were determined by UV, SEC, RP-HPLC, and LC-MS. The monomer purity detected by SE-HPLC was >99% and the concentration was 6.12mg / ml.

[0193]

[0194] Wherein q represents the average DAR, for example, 3-5, 3.2-4.8, or 3.5-4.5, such as 3.52.

[0195] Among them, Ab is HB37A6.

[0196] It should be understood that the average DAR is the DAR measured for the prepared ADC product, and the average DAR of different batches of products may be different.

[0197] Example 2. Preparation of formulation

[0198] 20 mg / mL IEX019-02 ADC, 20 mM histidine solution, 8% (w / v) sucrose, 0.02% (w / v) polysorbate 80, pH 6.5 were freeze-dried (the freeze-drying process can be prepared according to the conventional process in the art), and the freeze-drying process parameters are shown in Table 1.

[0199] Table 1

[0200]

[0201] Example 3 Phase Ia and Ib clinical trials

[0202] 1. Test antibodies and other drugs

[0203] Study drug: Antibody-drug conjugate targeting Claudin18.2 of the present invention (IEX019-02)

[0204] Specification: 100mg / vial

[0205] 2. Inclusion / Exclusion Criteria

[0206] Inclusion criteria:

[0207] Subjects must meet all of the following conditions to participate in the study:

[0208] The inclusion criteria that need to be met for both phases Ia and Ib are:

[0209] 1. Sign the written informed consent form (ICF), and be willing and able to comply with the visits and related procedures specified in the protocol.

[0210] 2. Phase Ia dose escalation phase: according to the solid tumor efficacy evaluation criteria RECIST v1.1, there is at least one evaluable lesion; Phase Ia dose expansion phase, Phase Ib: according to the solid tumor efficacy evaluation criteria RECIST v1.1, there is at least one measurable lesion.

[0211] 3. Age ≥ 18 years old, no gender restrictions.

[0212] 4. The Eastern Cooperative Oncology Group Performance Status (ECOGPS) score is 0 or 1.

[0213] 5. Expected survival period ≥ 12 weeks.

[0214] 6. Have adequate bone marrow and organ function:

[0215] Blood routine test: ANC ≥ 1.5 × 10 9 / L; platelet count ≥100×10 9 / L; hemoglobin content ≥9.0g / dL, the subjects must not have received blood product transfusion (including red blood suspension, single platelet, cryoprecipitate, etc.), erythropoietin (EPO), G-colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) treatment within 7 days before blood sample collection;

[0216] Liver function: TBIL ≤ 1.5 × ULN (TBIL ≤ 3 × ULN is allowed for patients with Gilbert syndrome); ALT and AST ≤ 2.5 × ULN for patients without liver metastasis, ALT and AST ≤ 5 × ULN for patients with liver metastasis; albumin ≥ 28 g / L;

[0217] Renal function: serum creatinine ≤1.5×ULN or creatinine clearance ≥60mL / min (using Cockcroft-Gault formula); urine protein <2+ or total urine protein in 24 hours <1g;

[0218] Coagulation function: international normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN (subjects who are allowed to receive anticoagulation therapy and whose coagulation function is within the above range).

[0219] 7. Female subjects of childbearing age or male subjects whose partners are female subjects of childbearing age must take effective contraceptive measures throughout the treatment period and for 6 months after the treatment.

[0220] Inclusion criteria for Phase Ia dose expansion phase:

[0221] 1. Subjects with unresectable locally advanced or metastatic G / GEJ AC, PDAC, BTC or other solid tumors confirmed by histopathology who have failed or are intolerant to standard treatment or have no standard treatment.

[0222] 2. Pathological tissue testing confirmed that the patient was *CLDN18.2 positive (G / GEJ AC patients were given priority in the group **CLDN18.2 high expression, PDAC patients were given priority in the group ***CLDN18.2 medium to high expression).

[0223] Inclusion criteria for Phase Ib Cohort A:

[0224] 1. Histopathologically confirmed unresectable locally advanced or metastatic G / GEJ AC.

[0225] 2. Subjects who have received at least 2 systemic therapies [anti-PD-(L)1+platinum, fluorouracil, paclitaxel / docetaxel or irinotecan; subjects with HER2 overexpression (defined as immunohistochemistry results of 3+ or 2+ and ISH+) must have received anti-HER2 treatment, and subjects who have not previously used anti-PD-(L)1 or anti-HER2 treatment must have contraindications or reasonable reasons for not benefiting] and have experienced disease progression.

[0226] 3. Pathological tissue testing confirmed that **CLDN18.2 was highly expressed.

[0227] Inclusion criteria for Phase Ib Cohort B:

[0228] 1. Histopathologically confirmed unresectable locally advanced or metastatic G / GEJ AC.

[0229] 2. Disease progression after first-line standard treatment (HER2-overexpressing subjects must have received anti-HER2 treatment unless there are contraindications or reasonable reasons for lack of benefit).

[0230] 3. Pathological tissue testing confirmed that *CLDN18.2 was positive.

[0231] Inclusion criteria for Phase Ib Cohort C:

[0232] 1. Histopathologically confirmed unresectable locally advanced or metastatic PDAC.

[0233] 2. Disease progression after at least one systemic therapy.

[0234] Inclusion criteria for Phase Ib Cohort D:

[0235] 1. Unresectable locally advanced or metastatic BTC confirmed by histopathology.

[0236] 2. Disease progression after at least one systemic therapy.

[0237] 3. Pathological tissue testing confirmed that *CLDN18.2 was positive.

[0238] Remark:

[0239] *CLDN18.2 positivity: defined as the proportion of tumor cells with membrane staining of any intensity in tumor tissue detected by immunohistochemistry ≥ 1%, accepting previous test results, research center test results, and central laboratory test results.

[0240] **CLDN18.2 high expression: Claudin18.2 immunohistochemical membrane staining intensity ≥2+ in ≥75% of tumor cells.

[0241] ***CLDN18.2 medium to high expression: Claudin18.2 immunohistochemical membrane staining intensity ≥2+ in ≥50% of tumor cells.

[0242] Exclusion criteria:

[0243] Subjects will not be included in this study if they meet any of the following criteria:

[0244] Common exclusion criteria for both phase Ia and Ib:

[0245] 1. Currently participating in another interventional clinical study, excluding observational (non-interventional) clinical studies or in the survival follow-up phase of an interventional study.

[0246] 2. Received the last anti-tumor treatment within 4 weeks before the first dose of study drug or within 5 half-lives of the anti-tumor drug (whichever is shorter).

[0247] 3. Plan to receive other anti-tumor treatments during the treatment with this study drug [palliative radiotherapy for the purpose of relieving symptoms (such as pain) and not affecting the efficacy evaluation is allowed].

[0248] 4. Patients who have been treated with strong cytochrome P4503A4 (CYP3A4) inhibitors within 2 weeks or 5 half-lives (whichever is longer) before the first dose of study drug.

[0249] 5. Any live vaccine received within 4 weeks before the first dose of study drug or planned during the study.

[0250] 6. The patient had toxicity caused by previous treatment that had not recovered to Grade 0 or 1 in NCI CTCAE v5.0 before the first dose of the study drug (excluding alopecia, fatigue, pigmentation, and other conditions judged by the investigator to have no safety risks).

[0251] 7. Patients who have undergone major surgery (craniotomy, thoracotomy, or laparotomy or other surgery defined by the investigator, excluding puncture biopsy) within 4 weeks before the first dose of study drug or have unhealed wounds, ulcers, or fractures; or are planned to undergo major surgery during the study; Note: For the purpose of palliative treatment, local surgical treatment of isolated lesions is acceptable.

[0252] 8. Previous whole pelvic radiotherapy.

[0253] 9. Presence of pyloric obstruction and / or persistent recurrent vomiting (vomiting ≥ 3 times within 24 hours).

[0254] 10. Patients with a history of gastrointestinal perforation and / or fistula within 6 months before the first administration of study drug, which has not been cured by surgical treatment.

[0255] 11. Symptomatic central nervous system metastases. Patients with asymptomatic brain metastases (i.e., no neurological symptoms, no need for glucocorticoid treatment, and brain metastases ≤1.5 cm) or patients with stable symptoms after treatment of brain metastases must meet all of the following criteria to participate in this study: no metastases to the midbrain, pons, cerebellum, meninges, medulla oblongata, or spinal cord; clinical status remains stable for at least 4 weeks, clinical evidence confirms that there are no new or enlarged brain metastases, and corticosteroid and anticonvulsant treatment is stopped for at least 2 weeks before the first dose of study drug. Note: The central nervous system is not a target lesion.

[0256] 12. Have a history of pneumonia and require hormone treatment, or have a history of interstitial lung disease, non-infectious pneumonia, severely impaired lung function or uncontrolled lung disease such as pulmonary fibrosis, severe radiation pneumonitis, acute lung injury, etc., or are suspected of having the above diseases during the screening period.

[0257] 13. The presence of uncontrolled diseases, such as:

[0258] Infection that was poorly controlled and required systemic anti-infective drugs (antibiotics, antivirals, or antifungals) within 4 weeks prior to the first dose of study drug.

[0259] ·People infected with human immunodeficiency virus (HIV) (HIV 1 / 2 antibody positive).

[0260] ·Acute or chronic active hepatitis B (defined as positive hepatitis B surface antigen (HBsAg) and / or hepatitis B core antibody (HBcAb) and hepatitis B virus DNA copy number ≥104 copies / mL or ≥2000 IU / mL or above the detection limit) or acute or chronic active hepatitis C [positive hepatitis C virus antibody (HCVAb), HCV RNA>103 copies / mL]. Subjects whose test results are lower than the above standards after nucleotide antiviral treatment and those with positive HCV antibodies but negative RNA tests are allowed to be enrolled.

[0261] Active COVID-19 infection.

[0262] Active pulmonary tuberculosis, currently receiving anti-tuberculosis treatment or having received anti-tuberculosis treatment within 1 year before the first dose of study drug.

[0263] Active or latent syphilis requires treatment.

[0264] Symptomatic congestive heart failure (NYHA class II-IV), symptomatic or poorly controlled arrhythmias, QTc interval >480ms, or personal or family history of congenital long / short QT syndrome.

[0265] · Treat poorly controlled hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg) with standard treatment.

[0266] 14. Any arterial thromboembolic event within 6 months before the first administration of study drug, including myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, etc.

[0267] 15. The tumor invades surrounding important structures (such as large blood vessels, trachea, etc.) or there is a risk of gastrointestinal / respiratory fistula.

[0268] 16. After endotracheal or gastrointestinal stent implantation.

[0269] 17. Pleural effusion, ascites, or pericardial effusion that is symptomatic and requires intervention (e.g., drainage).

[0270] 18. Subjects with esophageal or gastric varices that require immediate intervention (e.g., banding or sclerotherapy) or who are considered at high risk of bleeding based on the investigator's opinion or consultation with a gastroenterologist or hepatologist, evidence of portal hypertension (including splenomegaly on imaging examinations), or a history of varicose bleeding must undergo endoscopic evaluation within 3 months before the first dose of study drug.

[0271] 19. Any life-threatening bleeding event or grade 3 or 4 gastrointestinal / variceal bleeding event requiring transfusion, endoscopic or surgical treatment within 3 months before the first dose of study drug.

[0272] 20. History of deep vein thrombosis, pulmonary embolism, or any other serious venous thromboembolism within 3 months before the first dose of study drug (implanted venous port or catheter-derived thrombosis, or superficial vein thrombosis is not considered "serious" venous thromboembolism).

[0273] 21. Hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh class B or more severe cirrhosis.

[0274] 22. Patients with risk of intestinal obstruction or intestinal perforation (including but not limited to history of acute diverticulitis and intra-abdominal abscess) or history of the following diseases: inflammatory bowel disease or extensive intestinal resection (partial colectomy or extensive small bowel resection, complicated by chronic diarrhea), Crohn's disease, ulcerative colitis or chronic diarrhea.

[0275] 23. Significant malnutrition, requiring intravenous nutrition supplementation, except for those whose malnutrition has been corrected for more than 4 weeks before the first administration of the study drug.

[0276] 24. Other acute or chronic diseases or laboratory abnormalities that may result in: increasing the risks associated with study participation or study drug administration, or interfering with the interpretation of study results, and, based on the investigator's judgment, classifying the subject as ineligible to participate in this study.

[0277] 25. Neurological, psychiatric, or social conditions that affect compliance with study requirements, significantly increase the risk of AEs, or affect the subject's ability to provide a written ICF.

[0278] 26. History of other primary malignant tumors, except for the following:

[0279] · Malignant tumors that have been cured, with no known active disease for ≥ 2 years before study entry and a very low risk of recurrence;

[0280] Adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease recurrence;

[0281] Adequately treated carcinoma in situ with no evidence of disease recurrence.

[0282] 27. Known history of immunodeficiency.

[0283] 28. History of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation.

[0284] 29. Patients with a history of severe allergic reactions to other monoclonal antibodies and / or allergies to any of the ingredients of the antibody-drug conjugate targeting Claudin18.2 of the present invention.

[0285] 30. Pregnant or lactating female subjects.

[0286] 31. Others deemed by the researchers as not meeting the conditions for participating in this study.

[0287] 3. Dosage method and process

[0288] The dosage is 0.3mg / kg, 1mg / kg, 3mg / kg, 4.5mg / kg, 6mg / kg, 8mg / kg, 10mg / kg. The actual dosage (mg) will be calculated based on the subject's body weight (kg). The first dosage is calculated based on the subject's baseline body weight. If the subject's body weight changes by less than ±10% from the baseline (first dose of study treatment), the baseline body weight will be used to calculate the dosage. Otherwise, the actual dosage will be calculated based on the body weight on the scheduled dosing day or the day before dosing.

[0289] Administration route: Intravenous infusion (peripheral vein, central venous catheter or infusion port). If indicated, an infusion pump can be used.

[0290] Dosing frequency: The dosing cycle is 3 weeks / 21 days (Q3W), with one dose on the first day of each cycle.

[0291] 4. Experimental Results

[0292] Safety Assessment

[0293] The incidence, relevance to study drug, and severity of all TEAEs, AESIs, and SAEs.

[0294] · Changes in vital signs, physical examinations, and laboratory test results before, during, and after study drug treatment.

[0295] Immunogenicity: All subjects will be tested for ADA, and ADA-positive serum samples will be tested for neutralizing antibodies (NAb) if necessary.

[0296] PK evaluation

[0297] ·PK characteristics of drugs in humans after single and multiple administrations, and determination of key PK parameters, including but not limited to: AUC, Tmax, Ctrough, Cmax, CL, V and t 1 / 2 .

[0298] Efficacy evaluation

[0299] The efficacy of solid tumors was evaluated according to RECIST v1.1. Evaluation indicators included ORR, DoR, DCR, TTR, and PFS.

[0300] ·OS.

[0301] Biomarker Assessment

[0302] To evaluate the relationship between CLDN18.2 expression level in tumor tissues before treatment and efficacy.

[0303] Sample size

[0304] Phase Ia dose escalation phase: It is planned to enroll approximately 14-30 DLT-evaluable subjects to accurately assess the MTD.

[0305] Phase Ia dose expansion phase: For each tumor type: 2-4 doses are planned to be selected for expansion, and each expansion dose is planned to enroll approximately 6-60 subjects, for a total of approximately 40-140 subjects.

[0306] Phase Ib: Approximately 261 subjects are planned to be enrolled.

[0307] Cohort A: According to the main estimation target of this cohort, assuming that the ORR can reach 25% after monotherapy with the antibody-drug conjugate targeting Claudin18.2, at the unilateral 0.025 level, 100 samples can have about 90% confidence to observe that the lower limit of the 95% confidence interval of the ORR after treatment with the antibody-drug conjugate targeting Claudin18.2 of the present invention is 12%. Assuming a dropout rate of 10%, 111 subjects need to be enrolled.

[0308] Cohort B: It is planned to enroll approximately 50 subjects to evaluate the efficacy of the monotherapy of the antibody-drug conjugate targeting Claudin18.2 of the present invention.

[0309] Cohorts C and D: Each cohort is planned to enroll approximately 50 subjects (including subjects who received RP2D in the Phase Ia dose expansion phase) to evaluate the efficacy of the antibody-drug conjugate targeting Claudin18.2 of the present invention as a monotherapy.

[0310] Statistical methods

[0311] Descriptive statistics were used to summarize all safety, PK, immunogenicity, and efficacy data. For continuous variables, descriptive statistics (including number of cases, mean, standard deviation, median, minimum, and maximum values; for PK indicators, geometric mean and geometric coefficient of variation) were used for summary; for discrete variables, frequencies and percentages were used for summary.

[0312] Anti-tumor efficacy indicators include:

[0313] - Best overall response [complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD)]

[0314] -ORR (CR+PR) and DCR (CR+PR+SD)

[0315] -DoR or TTR

[0316] -PFS

[0317] -OS

[0318] If data permit, ORR and DCR and their 95% CIs will be provided. The proportion of subjects with a best response of CR, PR, SD or PD will also be calculated. The median time to DoR, TTR, PFS and OS and their 95% CIs will be calculated using the Kaplan-Meier method, as will the rates and their 95% CIs at specified time points (if applicable, e.g., 6th and 12th months and every 6 months thereafter).

[0319] The antibody-drug conjugate targeting Claudin18.2 of the present invention is an ADC with a bystander effect, and has a significant tumor inhibitory effect in mouse tumor-bearing models with high and low expression of CLDN18.2. In order to verify the above conclusion, in the clinical study of the present invention, a dosing regimen exploration test was conducted on subjects with various tumor types and different CLDN18.2 expression levels. It is estimated that the antibody-drug conjugate targeting Claudin18.2 of the present invention can achieve an ORR of 25% for monotherapy of gastric / gastroesophageal junction adenocarcinoma with high expression of CLDN18.2 that has failed previous second-line systemic treatment, improve PFS and OS, and have good tolerability.

[0320] Patients (pts) with advanced solid tumors who had failed or were intolerant to standard therapy were enrolled. Six dose levels of an antibody-drug conjugate targeting CLAUDIN18.2 (0.3 / 1 / 3 / 6 / 8 / 10 mg / kg IV Q3W) were evaluated during dose escalation. Selected dose levels were expanded in patients with gastric / gastroesophageal junction adenocarcinoma (G / GEJ AC, gastric or gastroesophageal junction adenocarcinoma) with positive CLDN18.2 expression, defined as ≥1% of tumor cells with membranous staining of any intensity (1+ / 2+ / 3+) by immunohistochemistry. The primary endpoint was safety. Secondary endpoints included objective response rate (ORR), duration of response (DoR), disease control rate (DCR), and progression-free survival (PFS), assessed by the investigator according to RECIST v1.1.

[0321] As of January 15, 2024, a total of 159 patients (61.0% male; median age: 58.0 years; ECOGPS 1: 82.4%; Phase IV: 96.8%; median number of previous treatments: 2; G / EJ AC: 66.7%) were enrolled in China and Australia, of which 79 took 6 mg / kg and 51 took 8 mg / kg. The median treatment duration was 13.7 weeks (range: 3.0-40.6 weeks). At 10 mg / kg, dose-limiting toxicity (DLT) was observed in 2 of 6 patients (1 G4 bone marrow suppression, 1 G4 neutropenia, G3 febrile neutropenia). Among all patients, 149 patients (93.7%) experienced treatment adverse events (TEAEs), and 79 patients (49.7%) experienced TAEs ≥ G3. The most common TEAs were anemia (54.7%), decreased white blood cell count (47.8%), and decreased neutrophil count (46.4%). The incidence of gastrointestinal toxicity ≥G3 was low, including vomiting (1.9%), nausea (1.3%), and decreased appetite (1.3%). Hypoalbuminemia occurred in 24.5% of patients, and no patients had ≥G3 events. The incidence of treatment-related adverse events (TRAEs) leading to discontinuation was 2 cases (1.3%). No TRAEs resulted in death. As of February 2, 2024, the efficacy of cldn18.2-positive (1+ / 2+ / 3+≥1%) G / GEJ AC patients (n=95) was evaluable. The overall ORR and DCR were 29.5% (95% CI: 20.6-39.7) and 73.7% (63.6-82.2), respectively. In patients with high CLDN18.2 expression (2+ / 3+≥75%), the ORR was 43.5% (95% CI: 23.2-65.5) in the 6mg / kg group (n=23) and 47.1% (95% CI: 23.0-72.2) in the 8mg / kg group (n=17). In patients with high CLDN18.2 expression at 6mg / kg, the median PFS was 6.8 months (95% CI: 4.2-NC), and 13 patients had events. PFS and DoR for other pts are immature.

[0322] Eligible patients who have failed or are intolerant to standard treatment are included. The antibody-drug conjugate targeting CLAUDIN18.2 of the present invention is intravenously administered at 6 mg / kg or 8 mg / kg Q3W. In dose escalation, patients are enrolled regardless of whether CLDN18.2 is expressed or not. In dose expansion, patients are required to have CLDN18.2 expression ≥40% (immunohistochemical staining intensity of 1+ / 2+ / 3+). The primary endpoint is safety. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and progression-free survival (PFS), which are evaluated by the investigator according to RECIST v1.1.

[0323] As of December 19, 2023, 35 patients (1 dose-escalation patient and 34 dose-expansion patients) from China and Australia were enrolled (male: 57.1%, median age: 58.0 years, ECOGPS1: 71.4%, stage IV: 91.4%, midline of previous treatment: 2) including 28 PDAC patients and 7 BTC patients. Patients received 6 mg / kg (n=17) or 8 mg / kg (n=18) doses of antibody-drug conjugate targeting CLAUDIN18.2. The median treatment duration was 7.0 weeks (range:

[0324] 3.0-23.6), of which 23 (65.7%) patients are still receiving treatment. Among all patients, 28 patients (80.0%) experienced treatment-related adverse events (TRAEs), of which 9 patients (25.7%) experienced ≥ grade 3 TRAEs. Common TRAEs (≥20%) were anemia (42.9%), decreased neutrophil count (28.6%), nausea (25.7%), vomiting (25.7%), and decreased white blood cell count (22.9%). Severe TRAEs occurred in 4 patients (11.4%). TRAEs leading to dose interruptions and treatment discontinuation occurred in 7 (20.0%) patients and 1 (2.9%) patients, respectively. No TRAEs resulted in death. The safety of the antibody-drug conjugate targeting CLAUDIN18.2 in PDAC and BTC was comparable to that of the entire study cohort, and no new safety signals were observed. As of January 15, 2024, 25 patients at 6 mg / kg and 8 mg / kg were evaluable for efficacy. Partial remission (PR) was observed in 7 patients (5 PDAC and 2BTC). The ORR was 28.0% (95% CI: 12.1-49.4) and the DCR was 80.0% (95% CI: 59.3-93.2). Among the evaluable patients with CLDN18.2 expression ≥60% (1+ / 2+ / 3+, n=13) at 6 mg / kg, 5 patients achieved PR, with an ORR of 38.5% (95% CI: 13.9-68.4) and a DCR of 84.6% (95% CI: 54.6-98.1). In the 10 PDAC patients in this subgroup, the ORR was 40% (95% CI: 12.2-73.8). DoR and PFS data are immature.

[0325] 5. Study of dosing regimen

[0326] Based on the comprehensive analysis of the clinical safety, efficacy and PK data of the antibody-drug conjugate targeting CLAUDIN18.2 of the present invention, a dose of 6 mg / kg Q3W is selected as the recommended dosing regimen for the key clinical study of the antibody-drug conjugate targeting CLAUDIN18.2 of the present invention:

[0327] Pharmacokinetics

[0328] The half-life of the antibody-drug conjugate targeting CLAUDIN18.2 of the present invention in tumor patients is about 2 weeks (NCA method), which supports a 3-week dosing interval.

[0329] Clinical safety

[0330] The results of the exposure-safety analysis showed that within the dose range of 1 to 10 mg / kg, the clinical safety risk of the antibody-drug conjugate targeting CLAUDIN18.2 of the present invention increased with increasing dose. Within the dose range of 1 to 6 mg / kg, the exposure-safety relationship was relatively flat, and the overall safety of 6 mg / kg was good. When the dose was greater than 6 mg / kg, the safety risk increased significantly.

[0331] Clinical effectiveness

[0332] The results of exposure-effectiveness analysis showed that within the dose range of 3-6 mg / kg, the PR rate had no obvious exposure-dependent trend and reached a plateau. DC (Disease control, SD+PR) had a significant exposure-dependent trend and at a dose of 6 mg / kg, DCR reached a plateau. 6 mg / kg was the best efficacy dose.

[0333] In summary, the 6 mg / kg Q3W dosing regimen is the optimal dosing regimen that balances clinical benefits and safety.

[0334] Example 4 Phase III clinical trial

[0335] 1Study drug

[0336] Antibody-drug conjugate targeting CLAUDIN18.2 of the present invention for injection (IEX019-02)

[0337] Irinotecan

[0338] Paclitaxel

[0339] 2. Research objectives

[0340] 2.1 Main research objectives

[0341] The present invention is to compare the progression-free survival (PFS) and overall survival (OS) and other efficacy indicators of the antibody-drug conjugate targeting CLAUDIN18.2 alone (experimental group) and the treatment selected by the investigator (control group) in the later-line treatment of subjects with gastric cancer or gastroesophageal junction adenocarcinoma.

[0342] 2.2. Other research purposes

[0343] Compare the antibody-drug conjugate targeting CLAUDIN18.2 of the present invention alone (experimental group) and the treatment selected by the investigator (control group) for the second-line treatment of other efficacy indicators (including ORR, DCR, DoR, TTR) in subjects with gastric cancer or gastroesophageal junction adenocarcinoma.

[0344] The quality of life of the two groups of subjects was evaluated.

[0345] The safety and tolerability of the antibody-drug conjugate targeting CLAUDIN18.2 of the present invention as a single drug (experimental group) in subjects were further evaluated.

[0346] The pharmacokinetic (PK) characteristics of total CLDN18.2 antibody-drug conjugates and exatecan were evaluated.

[0347] The immunogenicity of the antibody-drug conjugates targeting CLAUDIN18.2 of the present invention was evaluated.

[0348] 3. Inclusion / Exclusion Criteria

[0349] Inclusion criteria

[0350] Subjects must meet all of the following conditions to participate in the study:

[0351] Common inclusion criteria for the safety introduction phase and the key research phase:

[0352] 1. Sign the written informed consent form (ICF), and be willing and able to comply with the visits and related procedures specified in the protocol.

[0353] 2. The age at the time of signing the informed consent form meets the definition of an adult as stipulated by local laws and regulations (e.g., ≥18 years old in the United States), regardless of gender.

[0354] 3. The Eastern Cooperative Oncology Group Performance Status (ECOGPS) score is 0 or 1.

[0355] 4. Expected survival period ≥12 weeks.

[0356] 5. Have adequate bone marrow and organ function:

[0357] Blood routine test: ANC ≥ 1.5 × 10 9 / L; platelet count ≥100×10 9 / L; hemoglobin content ≥9.0g / dL. The subjects must not have received blood product transfusion (including red blood suspension, single platelet, cryoprecipitate, etc.), erythropoietin (EPO), G-colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) treatment within 7 days before blood sample collection;

[0358] Liver function: TBIL ≤ 1.5 × ULN (TBIL ≤ 3 × ULN is allowed for Gilbert syndrome subjects); ALT and AST ≤ 2.5 × ULN for subjects without liver metastasis, ALT and AST ≤ 5 × ULN for subjects with liver metastasis; Albumin ≥ 28 g / L (subjects must not have received human albumin transfusion therapy within 7 days before blood sample collection);

[0359] Renal function: creatinine clearance ≥ 60 mL / min (using Cockcroft-Gault formula); urine protein < 2+ or total urine protein in 24 hours < 1 g;

[0360] Coagulation function: international normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN (subjects who are allowed to receive anticoagulation therapy and whose coagulation function is within the above range).

[0361] 6. Female subjects must agree not to breastfeed from screening to 6 months after the last dose.

[0362] 7. Female subjects of childbearing age or male subjects whose partners are female subjects of childbearing age must take effective contraceptive measures from screening to the entire treatment period and within 6 months after the last dose of treatment.

[0363] Male subjects must agree not to donate sperm from screening to the entire treatment study and within 6 months after the last dose;

[0364] Female subjects must agree not to donate oocytes from screening to the entire treatment study and within 6 months after the last dose;

[0365] Female subjects must agree not to breastfeed from screening to the entire treatment period of this study and within 6 months after the last dose.

[0366] Additional inclusion criteria for key study phases:

[0367] 8. Histopathologically confirmed unresectable locally advanced or metastatic gastric / gastro-esophageal junction adenocarcinoma (G / GEJA).

[0368] 9. Locally advanced or metastatic gastric / gastroesophageal junction adenocarcinoma confirmed by imaging.

[0369] 10. Patients with radiologically evaluable disease lesions (measurable and / or unmeasurable disease) according to RECIST 1.1. For subjects with only one radiologically evaluable lesion, if the lesion has received local radiotherapy in the past, the progression after radiotherapy must be confirmed.

[0370] 11. Patients who have received at least 2 systemic treatments [previous treatments must include fluorouracil, platinum, and paclitaxel / docetaxel, irinotecan or taxanes] and have disease progression. The number of previous systemic treatment lines is ≤ 4.

[0371] a) The time from the end of previous (neo)adjuvant systemic treatment to disease recurrence / progression ≤ 6 months is counted as the first line of treatment;

[0372] b) If a drug in the previous combination therapy is discontinued due to AE, but any other combination therapy drug is still used, it is considered the same treatment plan;

[0373] c) If there is no disease progression, the change of the same drug dosage form is considered as the same treatment plan.

[0374] 12. CLDN18.2 expression is confirmed to be positive by pathological tissue testing in the central laboratory*. For subjects who have received any anti-CLDN18.2 treatment in the past, tumor samples should be collected again after the relevant anti-CLDN18.2 treatment is completed.

[0375] Remark:

[0376] *CLDN18.2 positive: Claudin18.2 immunohistochemical membrane staining intensity ≥2+ in ≥75% of tumor cells.

[0377] Additional inclusion criteria for the safety lead-in phase:

[0378] 13. Locally advanced unresectable or metastatic solid tumors confirmed by histopathology, which have failed or are intolerant to standard treatment or have no standard treatment.

[0379] Exclusion criteria

[0380] Subjects will not be included in this study if they meet any of the following criteria:

[0381] 1. HER2 positive (immunohistochemistry [IHC] 3+, or IHC2+ and in situ hybridization positive). HER2 positive subjects who have received anti-HER2 treatment in the past and whose HER-2 test results in tissue samples taken after anti-HER-2 treatment are negative do not meet this exclusion criteria. (For key research stages)

[0382] 2. Currently participating in another interventional clinical study, excluding observational (non-interventional) clinical studies or in the survival follow-up phase of an interventional study.

[0383] 3. Patients who have received previous treatment with antibody-drug conjugates based on topoisomerase inhibitors.

[0384] 4. The last anti-tumor treatment was received within 4 weeks before the first administration of the study drug or within 5 half-lives of the anti-tumor drug (including traditional Chinese medicine with clear indications for gastric cancer in the instructions, but herbal prescriptions are not included) (whichever is shorter) (drugs without a definite half-life require a 4-week washout period).

[0385] 5. Plan to receive other anti-tumor treatments during the treatment with this study drug [palliative radiotherapy for the purpose of relieving symptoms (such as pain) and not affecting the efficacy evaluation is allowed].

[0386] 6. Patients who have been treated with strong cytochrome P4503A4 (CYP3A4) inhibitors within 2 weeks or 5 half-lives (whichever is longer) before the first dose of study drug.

[0387] 7. Any live vaccine received within 4 weeks before the first dose of study drug or planned during the study.

[0388] 8. The patient had toxicity caused by previous anti-tumor therapy that had not recovered to Grade 0 or 1 in NCI CTCAE v5.0 before the first administration of the study drug (excluding alopecia, fatigue, pigmentation, and other conditions that the investigator judged to have no safety risks).

[0389] 9. Patients who have undergone major surgery (craniotomy, thoracotomy or laparotomy, laparoscopic resection of important tissues and organs, or other procedures defined by the investigator, excluding puncture biopsy) within 4 weeks before the first dose of study drug or have unhealed wounds, ulcers or fractures; or have undergone laparoscopic exploratory surgery within 2 weeks before the first dose of study treatment; or are planning to undergo major surgery during the study; Note: For the purpose of palliative treatment, local surgical treatment of isolated lesions is acceptable.

[0390] 10. Patients with bone metastasis who are at risk of paraplegia.

[0391] 11. Previously received whole pelvic radiotherapy.

[0392] 12. Subjects who have received radiotherapy within 3 weeks before the first dose. Subjects who have received radiotherapy within 3 weeks before the first dose must meet all of the following conditions to be included in the group: There are currently no radiotherapy-related toxic reactions (including but not limited to: no need to take glucocorticoids, radiation pneumonitis, radiation hepatitis, radiation enteritis, intestinal dysfunction, etc.), and no need to take glucocorticoids.

[0393] 13. The presence of cardia or pyloric obstruction affecting eating or gastric emptying, and / or persistent and recurrent vomiting (vomiting ≥ 3 times within 24 hours).

[0394] 14. Patients with a history of gastrointestinal perforation and / or fistula within 6 months before the first administration of study drug, which has not been cured by surgical treatment.

[0395] 15. Symptomatic central nervous system metastases, and / or manifestations of spinal compression. Subjects with asymptomatic brain metastases (i.e., no neurological symptoms, no need for glucocorticoid treatment, and brain metastasis lesions ≤1.5 cm in diameter) or brain metastases with stable symptoms after treatment must meet all of the following criteria to participate in this study: no midbrain, pons, cerebellum, meninges, medulla oblongata, or spinal cord metastases; clinical status remains stable for at least 4 weeks, clinical evidence confirms that there are no new or enlarged brain metastases, and corticosteroid and anticonvulsant treatment has been stopped for at least 2 weeks before the first dose of study drug. Note: The central nervous system is not a target lesion.

[0396] 16. History of interstitial lung disease, non-infectious pneumonia, severely impaired lung function or uncontrolled lung disease such as pulmonary fibrosis, severe radiation pneumonitis, acute lung injury, etc., or suspected of having the above diseases during the screening period.

[0397] 17. The presence of uncontrolled diseases, such as:

[0398] Active or poorly controlled serious infection requiring systemic anti-infective drugs (antibiotics, antivirals or antifungals) within 1 week before the first dose of study drug, including but not limited to respiratory tract, urinary system, biliary system, etc.

[0399] ·People infected with human immunodeficiency virus (HIV) (HIV 1 / 2 antibody positive).

[0400] · Subjects with acute or chronic active hepatitis B [subjects with positive hepatitis B surface antigen (HBsAg) and / or hepatitis B core antibody (HBcAb) need to undergo further hepatitis B virus (HBV) DNA testing. If the HBV DNA copy number is ≤104 copies / mL or ≤2000IU / mL or below the detection limit, they can be included in the study.] or acute or chronic active hepatitis C [positive hepatitis C virus antibody (HCVAb), HCV RNA>103 copies / mL]. Subjects with lower than the above standards after nucleotide antiviral treatment, as well as HCV antibody positive but RNA negative are allowed to be included.

[0401] Active pulmonary tuberculosis, currently receiving anti-tuberculosis treatment or having received anti-tuberculosis treatment within 1 year before the first dose of study drug.

[0402] Active syphilis or latent syphilis that requires treatment.

[0403] Symptomatic congestive heart failure (NYHA class II-IV), symptomatic or poorly controlled arrhythmias, QTc interval >480ms, or personal or family history of congenital long / short QT syndrome.

[0404] Poorly controlled hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg).

[0405] 18. Any arterial thromboembolic event within 6 months before the first dose of study drug, including myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, etc.

[0406] 19. History of deep vein thrombosis, pulmonary embolism, or any other serious venous thromboembolism within 3 months before the first dose of study drug (implanted venous port or catheter-derived thrombosis, or superficial vein thrombosis is not considered "serious" venous thromboembolism).

[0407] 20. The tumor invades surrounding important structures or organs (such as large blood vessels, trachea, etc.) or there is a risk of gastrointestinal / respiratory fistula.

[0408] 21. After stent implantation in the trachea or digestive tract [referring to the muscular tube from the mouth to the anal canal, including the mouth, pharynx, esophagus, stomach, small intestine (duodenum, jejunum, ileum), large intestine (cecum, appendix, colon, rectum) and anal canal, etc.].

[0409] 22. Pleural effusion, ascites, or pericardial effusion that is symptomatic and requires intervention (such as drainage, peritoneal shunt, or cell-free and concentrated ascites reinfusion therapy [CART]). Only patients with a small amount of pleural effusion, ascites, or pericardial effusion on imaging and no symptoms can be enrolled (drainage and CART treatment are not allowed within 2 weeks before the screening period).

[0410] 23. Subjects with esophageal or gastric varices that require immediate intervention (e.g., banding or sclerotherapy) or who are considered at high risk of bleeding based on the investigator's opinion or consultation with a gastroenterologist or hepatologist, with evidence of portal hypertension (including splenomegaly on imaging examinations), or with a history of varicose bleeding must undergo endoscopic evaluation within 3 months before the first dose of study drug.

[0411] 24. Any life-threatening bleeding event or grade 3 or 4 gastrointestinal / variceal bleeding event requiring transfusion, endoscopic or surgical treatment within 3 months before the first dose of study drug.

[0412] 25. Hepatic encephalopathy, hepatorenal syndrome, Child-Pugh B or more severe cirrhosis.

[0413] 26. Complete or incomplete intestinal obstruction during the screening period, or a history of complete or incomplete intestinal obstruction within 3 months before the first dose, or a risk of intestinal perforation (including but not limited to acute diverticulitis, history of intra-abdominal abscess), or a history of the following diseases: inflammatory bowel disease or extensive intestinal resection (partial colectomy or extensive small bowel resection, complicated by chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea.

[0414] 27. Significant malnutrition (such as needing intravenous nutrition supplementation, weight loss of more than 5% within 1 month from the signing of the informed consent, weight loss of more than 15% within 3 months, or reduction of food intake by 1 / 2 or more within 1 week). Except for those whose significant malnutrition has been corrected for more than 4 weeks before the first administration of the study drug.

[0415] 28. Other acute or chronic diseases or abnormal laboratory tests may result in the following: increasing the risks associated with the subjects' participation in the study or administration of study drugs, interfering with the interpretation of study results, and the subjects are not eligible to participate in this study according to the judgment of the researchers.

[0416] 29. Uncontrolled metabolic disorders or other non-malignant organ or systemic diseases or secondary reactions to cancer (such as leukemoid reactions, etc.), which may lead to higher medical risks and / or uncertainty in survival assessment.

[0417] 30. Neurological, psychiatric, or social conditions that affect compliance with study requirements, significantly increase the risk of AEs, or affect the subject's ability to provide a written ICF.

[0418] 31. History of other primary malignant tumors, except for the following:

[0419] · Malignant tumors that have been cured, with no known active disease for ≥ 2 years before study entry and a very low risk of recurrence;

[0420] Adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease recurrence;

[0421] Adequately treated carcinoma in situ with no evidence of disease recurrence.

[0422] 32. Known history of immunodeficiency.

[0423] 33. History of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.

[0424] 34. Patients with a history of severe allergic reactions to other monoclonal antibodies and / or allergies to any of the ingredients of the antibody-drug conjugate targeting CLAUDIN18.2 of the present invention, irinotecan, or paclitaxel.

[0425] 35. Others deemed by the researchers to be ineligible to participate in this study.

[0426] 4. Drug administration method and process

[0427] The study plans to randomly enroll patients in the experimental group or the control group in a 1:1 ratio. Stratification factors include: region (Asian countries / regions excluding Japan vs. Japan vs. Europe and the United States), primary site of cancer (stomach vs. gastroesophageal junction), and primary lesion resection (yes vs. no). Subjects in the experimental group will receive an antibody-drug conjugate targeting CLAUDIN18.2 6mg / kg IV D1, Q3W, one cycle every three weeks. The control group will receive treatment selected by the investigator, including: irinotecan 125mg / m 2 IV D1, D8, Q3W every three weeks (Note: 150 mg / m 2 IV D1, Q2W, one cycle every two weeks), or paclitaxel 80 mg / m 2 IVD1, D8, D15, Q4W, one cycle every four weeks. The researcher needs to choose the treatment method before the subject is randomized.

[0428] Subjects will continue to receive treatment until disease progression and / or the investigator assesses that the subject is no longer benefiting, toxicity is intolerable, informed consent is withdrawn, other reasons for stopping study treatment occur, or the treatment duration reaches 24 months (whichever occurs first), see Section 4.5.1 for details. Subject termination criteria. After termination of treatment, the subject will be followed up for safety and survival. Subjects in the control group are not allowed to cross over to the antibody-drug conjugate group targeting CLAUDIN18.2 for treatment after disease progression.

[0429] This study has an Independent Data Monitoring Committee (IDMC). The IDMC will review the accumulated safety data of the study to ensure the safety of the subjects and the scientific nature of the trial, and make recommendations to the sponsor on whether to continue, revise, or stop the trial based on the safety data. For the interim analysis, the IDMC will review the interim analysis results of the safety data and efficacy data, make a judgment on whether the trial is effective according to the preset effective threshold of the trial, and make recommendations to the sponsor. The responsibilities of IDMC members and related procedures will be defined separately in the IDMC Charter. The final version of the IDMC Charter must be approved by the IDMC and the sponsor before analysis.

[0430] For Japan and the United States, a safety introduction phase will be set up before entering the key clinical trial. Each country will enroll 3 to 6 subjects to evaluate safety and PK characteristics. In the safety introduction phase, 3 subjects will be enrolled first and treated with 6 mg / kg of antibody-drug conjugate targeting CLAUDIN18.2. The DLT observation period is 21 days after the first dose of the first cycle. If none of the 3 subjects develops DLT during the DLT observation period, enrollment for the key clinical trial will begin. If one of the first 3 subjects develops DLT, 3 more subjects will be included in the safety introduction phase; if no DLT occurs in the 3 additional subjects, enrollment for the key clinical trial will begin.

[0431] Antibody-drug conjugate targeting CLAUDIN18.2 of the present invention

[0432] Dosage form: Lyophilized preparation for injection

[0433] Specification: 100mg / bottle

[0434] Dosage: 6 mg / kg, D1, Q3W, intravenous infusion (Intravenously, IV).

[0435] Irinotecan

[0436] Dosage:

[0437] 125 mg / m 2 , D1, D8, Q3W, IV

[0438] 150 mg / m 2 , D1, Q2W, IV (only for EU and Japanese research centers).

[0439] Paclitaxel

[0440] Dosage: 80 mg / m 2 , D1, D8, D15, Q4W, IV.

[0441] 5 Experimental results analysis

[0442] Efficacy evaluation

[0443] ·OS.

[0444] The efficacy of solid tumors was evaluated by IRRC and researchers according to RECIST v1.1. Evaluation indicators included: PFS, ORR, DCR, DOR, and TTR.

[0445] Quality of Life

[0446] EORTC QLQ-C30 score, EORTC QLQ-OG25 score, EQ-5D-5L score.

[0447] Safety Assessment

[0448] The incidence, relevance to study drug, and severity of all TEAEs, AESIs, and SAEs.

[0449] ·Study the changes in vital signs, ECG physical examination and laboratory test results before, during and after drug treatment.

[0450] Immunogenicity: Subjects will be tested for ADA, and ADA-positive serum samples will be tested for NAb (if necessary).

[0451] PK evaluation

[0452] PK parameters, including but not limited to: AUC, Ctrough, Cmax, CL, V and t1 / 2.

[0453] Biomarker Assessment

[0454] To evaluate the relationship between CLDN18.2 expression level in tumor tissues before treatment and efficacy.

[0455] Hypothesis Testing:

[0456] The primary efficacy endpoints of this study were PFS and OS. The type I error was controlled at 0.025 on one side and assigned to two endpoints: PFS (α = 0.005) and OS (α = 0.02). The hypothesis test was first performed on PFS. If a statistically significant difference was achieved at the level of α = 0.005 on one side, α was recovered and passed to OS in its entirety. Otherwise, OS was analyzed at α = 0.0199 on one side. At the final analysis of PFS, an OS non-binding futility interim analysis will be performed, and an α of 0.0001 will be assigned to the OS futility interim analysis.

[0457] The superiority hypothesis test for PFS and OS is:

[0458] Null hypothesis H0: HR≥1; alternative hypothesis Ha: HR<1

[0459] Sample size calculation:

[0460] The log-rank test will be used to compare differences between the groups, and the subjects will be randomized to the two treatment groups in a 1:1 ratio. Assuming that PFS and OS in each treatment group are exponentially distributed, assuming a PFS HR of 0.5 (median PFS in the control group is 3.5 months and median PFS in the experimental group is 7.0 months), at a one-sided test level of α = 0.005, approximately 98% power is required to observe a total of approximately 179 PFS events at the final analysis. Assuming a HR of 0.71 (median OS in the control group is 6.5 months and median OS in the experimental group is 9.2 months), at a one-sided test level of α = 0.0199, approximately 88% power is required to observe a total of approximately 371 OS events at the final analysis. Assuming the following enrollment rates: 29 patients per month in the first 4 months, 37 patients per month from 5 to 8 months, 46 patients per month from 9 to 12 months, and 17 patients per month thereafter, and assuming the annual dropout rates of PFS and OS in each group were 15% and 5%, respectively, it is expected that 179 PFS events will be observed in the 450 subjects at the 11th month after the first randomization of the first subject, and 371 OS events will be observed at the 27th month after the first randomization of the first subject.

[0461] Interim analysis:

[0462] This study is planned to conduct 1 final analysis of PFS, 2 interim analyses of OS, and 1 final analysis of OS. The first interim analysis of OS futility will be conducted at the same time as the final analysis of PFS (179 PFS events). The interim analysis time is driven by the number of events required for the final analysis of PFS. It is expected that approximately 37% (138) OS events will occur at the interim analysis (HR futility margin ≥ 1.005); the second interim analysis of OS futility will be conducted at 75% (278) events, with an OS minimum detectable difference (MDD) of HR = 0.745 and a one-sided test level of 0.0072. The final analysis of OS is expected to be conducted at 100% (371 cases) of events, with an OS minimum detectable difference (MDD) of HR = 0.804 and a one-sided test level of approximately 0.0177. The overall significance level of OS will be adjusted as follows: The first interim analysis of OS futility will be conducted with two groups of non-bound futility tests based on the Gamma Family consumption function with a parameter of -2. The α boundary values ​​for the second interim analysis and final analysis of OS were approximated by the Lan-Demets method to approximate the O'brien-Fleming boundary distribution and the final analysis results of PFS (determining whether to recover the α of PFS).

[0463] Statistical methods:

[0464] The descriptive summary of continuous variables will include the number, mean, standard deviation, median, minimum, and maximum. The descriptive summary of categorical variables will include the number and percentage.

[0465] Key analysis:

[0466] The primary analysis of the PFS and OS comparison between the two groups was performed using the stratified log-rank test. The Kaplan-Meier method was used to estimate the median PFS and OS and their 95% confidence intervals (CI), and survival curves were drawn. The stratified Cox proportional hazard model was used to estimate the HR and its 95% CI between the two groups, and the stratification factors were random stratification factors.

[0467] Secondary analysis:

[0468] The primary analysis of ORR and DCR between groups was tested by the CMH method with stratification factors, and the ORR and DCR rate differences and their CIs between groups were estimated by the Miettinen & Nurminen method with stratification factors. The median DoR and TTR and their 95% CIs were estimated by the Kaplan-Meier method, and survival curves were drawn.

[0469] Descriptive statistical analysis was performed on the quality of life scale scores.

[0470] Safety and tolerability are summarized descriptively. No formal hypothesis-testing analyses of the safety and tolerability data will be performed unless otherwise stated.

[0471] Descriptive statistical analysis was performed on drug concentrations and related PK parameter indicators.

[0472] Baseline CLDN18.2 expression levels were summarized descriptively. If data were available, the relationship between CLDN18.2 expression levels and efficacy, safety, and PK (if applicable) indicators was analyzed exploratoryly.

[0473] Safety run-in period data will be summarized descriptively separately.

[0474] The data currently obtained show that, as confirmed by Phase Ia and Ib experiments, the antibody-drug conjugate targeting CLAUDIN18.2 of the present invention has a good safety profile and excellent therapeutic efficacy as shown by, for example, PFS, OS, ORR and / or DCR.

[0475] Glossary of abbreviations and definitions

[0476]

[0477]

[0478]

[0479] Sequence information

[0480]

[0481] The exemplary embodiments of the present invention are described above, and it should be understood by those skilled in the art that these disclosures are only exemplary, and various other substitutions, adaptations and modifications can be made within the scope of the present invention. Therefore, the present invention is not limited to the specific embodiments listed herein.

Claims

1. A method for preventing or treating solid tumors in an individual, the method comprising administering to an individual in need thereof an effective amount of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof; in, The antibody-drug conjugate targeting Claudin18.2 is selected from the antibody-drug conjugate of Formula IA: wherein Ab is an antibody or an antigen-binding fragment thereof targeting Claudin18.2; wherein q represents the average DAR, and is a value of 2-11, for example, a value of 2 to 5, preferably a value of 3 to 5, and more preferably a value of 3 to 4.

2. A method for preventing or treating solid tumors in an individual, the method comprising administering to an individual in need thereof an effective amount of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof; in, The antibody-drug conjugate targeting Claudin18.2 is selected from the antibody-drug conjugate of formula IB: wherein Ab is an antibody or an antigen-binding fragment thereof targeting Claudin18.2; Wherein y is an integer of 1 or 2.

3. The method according to claim 1 or 2, in, The antibody or antigen-binding fragment thereof targeting Claudin18.2 comprises HCDR1, HCDR2, HCDR3 as shown in the following amino acid sequences: SEQ ID NOs: 1, 2 and 3, respectively, and LCDR1, LCDR2 and LCDR3 as shown in the following amino acid sequences: SEQ ID NOs: 6, 7 and 8, respectively.

4. The method according to any one of claims 1 to 3, in, The antibody or antigen-binding fragment thereof targeting Claudin18.2 comprises a heavy chain variable region and / or a light chain variable region, wherein the heavy chain variable region (i) comprises or consists of the amino acid sequence of SEQ ID NO: 4; or (ii) comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid of SEQ ID NO:4; or (iii) comprises or consists of an amino acid sequence having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 4, preferably, the amino acid changes do not occur in the CDR regions; and / or Light chain variable region (i) comprises or consists of the amino acid sequence of SEQ ID NO: 9; or (ii) comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid of SEQ ID NO:9; or (iii) comprises or consists of an amino acid sequence having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 9, preferably, the amino acid changes do not occur in the CDR regions.

5. The method according to any one of claims 1 to 4, in, The antibody or antigen-binding fragment thereof targeting Claudin18.2 comprises a heavy chain and a light chain, wherein the heavy chain (i) comprises or consists of the amino acid sequence of SEQ ID NO: 11; or (ii) comprises or consists of an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acids of SEQ ID NO: 11; or (iii) comprises or consists of an amino acid sequence having one or more (preferably no more than 20 or 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 11; and / or Light chain (i) comprises or consists of the amino acid sequence of SEQ ID NO: 12; or (ii) comprises or consists of an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acids of SEQ ID NO: 12; or (iii) comprises or consists of an amino acid sequence having one or more (preferably no more than 20 or 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO:

12.

6. The method according to any one of claims 1 to 5, in, The solid tumor is an advanced malignant solid tumor, and the advanced solid tumor is selected from one or more of the following: gastric cancer, breast cancer, liver cancer, colon cancer, lung cancer, gallbladder cancer, esophageal cancer, gastroesophageal junction adenocarcinoma, pancreatic ductal adenocarcinoma and biliary tract cancer; Preferably, the advanced solid tumor is a tumor that has not been treated with systemic anti-tumor therapy, a tumor that has failed at least one systemic anti-tumor therapy, a tumor that has failed first-line therapy (e.g., is ineffective or intolerant to first-line therapy), a tumor that has failed second-line therapy (e.g., is ineffective or intolerant to second-line therapy); and / or Preferably, the advanced malignant solid tumor is a locally advanced unresectable or metastatic solid tumor.

7. The method according to claim 6, in, The solid tumor is posterior line gastric cancer or gastroesophageal junction adenocarcinoma; Preferably, the posterior line gastric cancer or gastroesophageal junction adenocarcinoma is 2L or later gastric cancer or gastroesophageal junction adenocarcinoma.

8. The method according to claim 7, in, The posterior line gastric cancer or gastroesophageal junction adenocarcinoma is 3L gastric cancer or gastroesophageal junction adenocarcinoma.

9. The method according to any one of claims 1 to 8, in, The method comprises administering 0.1 mg / kg to 100 mg / kg of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof to the individual.

10. The method according to claim 9, in, The method comprises administering 0.2 mg / kg to 50 mg / kg of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof to the individual.

11. The method according to claim 10, in, The method comprises administering 0.3 mg / kg to 30 mg / kg of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof to the individual.

12. The method according to any one of claims 1 to 11, in, The method comprises administering 4 mg / kg to 8 mg / kg of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof to the individual.

13. The method according to any one of claims 1 to 12, in, The method comprises administering to the individual 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 4.5 mg / kg, 6 mg / kg, 7.5 mg / kg, 8 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13.5 mg / kg, or 15 mg / kg of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof.

14. The method according to any one of claims 1 to 13, in, The administration cycle of this method is 2 weeks to 5 weeks, such as 18 to 24 days, such as 19, 20, 21, 22 or 23 days, and the drug is administered once in each administration cycle.

15. The method according to any one of claims 1 to 14, in, The administration cycle of this method is 3 weeks, with one administration on the first day of each cycle.

16. The method according to any one of claims 1 to 15, in, The method comprises administering 6 mg / kg of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof to the individual once every 3 weeks.

17. The method according to any one of claims 1 to 16, in, The antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is administered by intravenous infusion.

18. A single dose unit, include: An effective amount of the antibody-drug conjugate targeting Claudin18.2 according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

19. A complete kit comprising an effective amount of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17; Preferably, the invention further comprises a package insert printed with instructions for using the antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof in an individual to prevent or treat an advanced malignant solid tumor in the individual.

20. Use of the single dose unit of claim 18 or the kit of parts of claim 19 in the preparation of a medicament for preventing or treating advanced malignant solid tumors.

21. An antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof, for use in preventing or treating individual solid tumors; in, The antibody-drug conjugate targeting Claudin18.2 is selected from the antibody-drug conjugate of formula IA defined in claim 1 or the antibody-drug conjugate of formula IB defined in claim 2.

22. The antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof according to claim 21, wherein the antibody or antigen-binding fragment thereof targeting Claudin18.2 is as defined in any one of claims 3 to 5, and / or wherein the solid tumor is as defined in any one of claims 6 to 8; and / or wherein the antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is administered to an individual at a dose as defined in any one of claims 9 to 13; and / or The antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is administered according to the dosage regimen as described in any one of claims 14-17.

23. Use of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating individual solid tumors; in, The antibody-drug conjugate targeting Claudin18.2 is selected from the antibody-drug conjugate of formula IA defined in claim 1 or the antibody-drug conjugate of formula IB defined in claim 2.

24. The use according to claim 23, wherein the antibody or antigen-binding fragment thereof targeting Claudin18.2 is as defined in any one of claims 3 to 5, and / or wherein the solid tumor is as defined in any one of claims 6 to 8; and / or wherein the antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is administered to an individual at a dose as defined in any one of claims 9 to 13; and / or The antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is administered according to the dosage regimen as described in any one of claims 14-17.

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