Treatment of solid tumors using antibody-drug conjugates targeting Claudin 18.2

Abstract

The present invention relates to a method for treating solid tumors by administering an antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof to subjects requiring treatment of solid tumors, as well as a kit of single-dose units, parts, etc., containing the same, and the use thereof.

Description

[Technical Field]

[0001] This invention relates to the field of disease treatment. Specifically, this invention relates to a method for treating solid tumors using an antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof. [Background technology]

[0002] Gastric cancer is one of the most common malignancies in the world and is a leading cause of cancer death worldwide. According to GLOBOCAN data, in 2020, gastric cancer ranked 5th in incidence and 4th in mortality, respectively, with a 5-year survival rate of less than 5% for patients with metastatic gastric cancer. Currently, surgical resection is the only curative treatment for gastric cancer, and the standard treatment for patients with advanced metastatic gastric cancer is chemotherapy in combination with fluoropyrimidines and platinum-based chemotherapy agents. The emergence of immunotherapies and targeted therapies such as trastuzumab and ramucirumab has increased treatment options for gastric cancer. However, the effectiveness of systematic treatment for advanced gastric cancer has been limited, with a median survival time of only about one year. Regarding immunotherapy, based on the results of the ATTRACTION-02 study, nivolumab has been approved for use in patients with advanced gastric cancer and gastroesophageal junction cancer who have received at least two types of systemic therapy but have not responded to treatment. In April 2021, based on the findings of the CheckMate-649 trial, the FDA approved nivolumab in combination with fluoropyrimidine and platinum-based chemotherapy as a first-line treatment for advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. This was also the first first-line immunotherapy approved by the FDA for gastric cancer. While these studies have yielded promising results, new treatments are still needed to benefit more gastric cancer patients.

[0003] Pancreatic cancer is one of the most common malignancies of the digestive system. In 2020, there were 496,000 new cases and 466,000 deaths worldwide, making it the seventh most common malignancy. Because pancreatic cancer is often advanced by the time it is diagnosed, the prognosis is poor. According to statistics from the US National Cancer Institute's SEER (Surveillance, Epidemiology, Final Outcome) database, the five-year survival rate for pancreatic cancer is only 8%, and only 28.6% of patients survive for more than one year after initial diagnosis. Furthermore, due to its high malignancy, pancreatic cancer patients still frequently experience recurrence despite surgical intervention, with the five-year survival rate after curative resection being only 18-27%. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, accounting for over 90% of all cases. Conventional treatments such as chemotherapy, surgery, and radiation therapy have been applied, but have not resulted in significant improvements in survival rates. Surgical resection and chemotherapy (a combination of gemcitabine, albumin-bound paclitaxel, and FOLFIRINOX) have been shown to improve survival rates in patients with early-stage pancreatic cancer, but they are not sufficient for treating patients with advanced pancreatic cancer.

[0004] Biliary tract cancer is divided into bile duct cancer and gallbladder cancer, and bile duct cancer can be further divided into extrahepatic and intrahepatic bile duct cancer based on anatomical structure. The incidence of bile duct cancer is extremely low in Western countries. However, in Southeast Asia and parts of China, the incidence of bile duct cancer is significantly increased due to infection with liver flukes and other parasites. Meanwhile, recent epidemiological studies have shown an increase in the incidence and mortality of intrahepatic bile duct cancer. Bile duct cancer is invasive and is usually diagnosed at an advanced stage. Most bile duct cancer patients are in an unresectable state at the time of initial definitive diagnosis, but even in the small number of patients for whom curative surgery is possible, the recurrence rate is high. According to the American Joint Committee on Cancer, the 5-year survival rates for stages I, II, III, and IV are 50%, 30%, 10%, and 0%, respectively. For most bile duct cancer patients, palliative chemotherapy is the only treatment option. The first-line standard treatment for patients with unresectable and metastatic bile duct cancer is a combination of gemcitabine and cisplatin. Studies of this combination therapy regimen have shown objective response rates of 19.5%–26.1%, median PFS of 5.8–8.0 months, and median OS of 11.2–11.7 months. Currently, there is no approved standard of treatment for biliary tract cancer patients whose disease has progressed after first-line systemic treatment. Pembrolizumab is approved for the treatment of MSI-H / dMMR solid tumors that have progressed after previous treatment, but since MSI-H / dMMR in advanced cholangiocarcinoma is rare, most patients are not suitable for this treatment.

[0005] Certain drugs targeting CLDN18.2 have entered clinical trials and demonstrated favorable efficacy and safety. Zolbetuximab (IMAB362, claudixmab, Astellas) was the first drug developed to target CLDN18.2. As a chimeric IgG1 monoclonal antibody, it specifically binds to CLDN18.2 on the surface of tumor cells, inducing antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cell-mediated cytotoxicity (CDC), apoptosis, and inhibition of cell proliferation. Several clinical trials have since been conducted to evaluate its efficacy and safety in patients with gastroesophageal cancer.

[0006] A Phase IIa trial (NCT01197885, MONO) was used to evaluate the efficacy and safety of zolbetuximab monotherapy in 54 patients with relapsed or refractory advanced gastric or lower esophageal adenocarcinoma who showed moderate or high CLDN18.2 expression in ≥50% of tumor cells. Of the 43 evaluable subjects, 10 showed clinical benefit, with 4 achieving partial response (PR) (objective response rate (ORR) 9%) and 6 achieving stable disease (SD) (14%). The median duration of response (DoR) for subjects who responded to zolbetuximab was 24.6 weeks (range: 13.1–156.1 weeks). Of the 10 patients who showed 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 nine subjects revealed that 4 (14%) achieved a partial response (PR) and 5 (17%) achieved stable disease (SD). Of all subjects, 52 (96%) experienced treatment-related adverse events (TEAEs) during the treatment period, most of which were grade 1 or 2. TEAEs occurring in more than 30% of subjects included nausea (63%), vomiting (57%), fatigue (43%), and decreased appetite (30%). Twelve subjects (22%) reported grade 3 vomiting, and eight subjects (15%) reported grade 3 nausea. Two subjects experienced grade 4 TEAEs (dyspnea and diarrhea) (one of each). 44 subjects (82%) experienced treatment-related adverse events (TRAEs), with nausea, vomiting, fatigue, and decreased appetite occurring in more than 10% of subjects. Only five subjects experienced serious TRAEs. Grade 3 and Grade 2 TEAEs (nausea and vomiting) occurred in one subject each. Additionally, one subject experienced Grade 2 hematemesis, and two experienced Grade 3 vomiting. With the exception of the one subject who experienced Grade 3 vomiting, all severe TRAEs were 600 mg / m². 2These TEAEs occurred in subjects who received the specified dose. These TEAEs could be mitigated by pausing or slowing down the infusion of zolbetuximab. Patients who had not previously undergone gastrectomy were more likely to report nausea and vomiting. The incidence of these TEAEs decreased over time as subjects received repeated injections of zolbetuximab.

[0007] Another phase II trial (NCT01630083, FAST) evaluating the efficacy and safety of zolbetuximab combined with EOX as first-line treatment for CLDN18.2-positive advanced gastric / gastroesophageal junction adenocarcinoma (G / GEJ AC) showed that compared to EOX monotherapy, median progression-free survival (PFS) improved from 5.3 months to 7.5 months (hazard ratio (HR) 0.44, 95% confidence interval 0.29–0.67, P<0.0005), and median overall survival (OS) increased from 8.3 months to 13.0 months (HR 0.55, 95% confidence interval 0.39–0.77, P<0.0005). The most frequently reported tetanic adverse events (TEAEs) in the zolbetuximab + EOX group were nausea (81.8%) and vomiting (67.5%). In patients who had previously undergone gastrectomy, the incidence of vomiting was low, and there was a dose-dependent relationship between the incidence and severity of vomiting and zolbetuximab. The most frequently reported serious adverse events (SAEs) in the zolbetuximab + EOX group were malignant tumor (3.9%), pneumonia (2.6%), and febrile neutropenia (2.6%). In the EOX group, the most frequently reported SAEs were malignant tumor (8.3%), gastric bleeding (3.6%), nausea, renal failure, pulmonary embolism, and febrile neutropenia (2.4% each). Currently, two Phase III clinical trials (NCT03504397 / NCT03653507) are underway evaluating the efficacy of zolbetuximab in combination with a different chemotherapy regimen (mFOLFOX6 or CAPOX) compared to placebo in the first-line treatment of locally advanced, unresectable or metastatic G / GEJ AC that is CLDN18.2-positive and HER2-negative. The results obtained will provide data on the safety and efficacy of CLDN18.2-targeted agents.

[0008] Gastric, pancreatic, and biliary tract cancers are characterized by their high malignancy and poor prognosis. The efficacy and benefits of systemic chemotherapy and immune checkpoint inhibitors for advanced gastric, pancreatic, and biliary tract cancers are very limited, making the exploration and development of new therapeutic targets and combination therapies an urgent necessity. CLDN18.2 is highly expressed in gastric and pancreatic cancer tissues, with an expression rate of 80% in gastric cancer patients and positive expression accounting for approximately 60% in pancreatic cancer, of which 54.6% are moderate to high expression. It has been reported that the CLDN18 positivity rate in extrahepatic cholangiocarcinoma tissue can reach 90%, and the CLDN18 positivity rate in intrahepatic cholangiocarcinoma can also reach 43%. Two Phase III clinical trials (NCT03504397 / NCT03653507) are underway to evaluate the efficacy of zolbetuximab combined with a different chemotherapy regimen (mFOLFOX6 or CAPOX) as a first-line treatment for CLDN18.2-positive, HER2-negative, locally advanced, unresectable, or metastatic G / GEJAC compared to placebo plus chemotherapy. Recent data have shown that both trials reached critical endpoints in PFS and OS, confirming the efficacy and safety of CLDN18.2-targeted therapy. However, zolbetuximab is only effective as a first-line treatment for gastric / gastroesophageal junction adenocarcinoma patients with high CLDN18.2 expression, and there are no effective treatment regimens for gastric / gastroesophageal junction adenocarcinoma with moderate / low CLDN18.2 expression and / or for patients who have failed standard treatment and / or other tumors expressing CLDN18.2. [Overview of the project]

[0009] The present invention satisfies the above needs by providing a method for treating solid tumors using an antibody-drug conjugate targeting Claudin 18.2.

[0010] To achieve the above objectives, the present invention first provides a method for preventing or treating solid tumors in a subject, the method comprising administering an effective amount of a Claudin18.2-targeting antibody-drug conjugate or a pharmaceutically acceptable salt thereof to a subject in need of prevention or treatment of solid tumors.

[0011] To achieve the above objectives, the present invention also provides a single-dose unit comprising an effective amount of the Claudin18.2-targeting antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to the present invention.

[0012] To achieve the above objectives, the present invention also provides a kit of parts comprising an effective amount of an antibody-drug conjugate targeting Claudin 18.2 according to the present invention or a pharmaceutically acceptable salt thereof.

[0013] The present invention also provides the use of a kit of single-dose units or parts according to the present invention in the manufacture of pharmaceuticals for the prevention or treatment of solid tumors.

[0014] This invention evaluates the safety and efficacy of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof in the treatment of solid tumors expressing CLDN18.2, and the correlation between the expression level of CLDN18.2 in tumor tissue and the efficacy of the Claudin18.2-targeting antibody-drug conjugate or a pharmaceutically acceptable salt thereof of this invention.

[0015] The antibody-drug conjugates targeting Claudin18.2 or a pharmaceutically acceptable salt thereof, as bystander-effect ADCs according to the present invention, exhibit significant tumor-suppressing effects in mouse tumor-carrying models with high and low expression of CLDN18.2. Clinical studies of the present invention have conducted exploratory administration regimen studies in subjects with various tumor types and different CLDN18.2 expression levels. Key evidence indicates that when CLDN18.2-high-expressing gastric / gastroesophageal junction adenocarcinoma was treated solely with the antibody-drug conjugates targeting Claudin18.2 according to the present invention, which had been refractory to previous second-line systemic therapies, an ORR of 25% or more was achieved, improving PFS and OS, and good tolerability was attained.

[0016] Other embodiments of the present invention will become apparent by referring to the following detailed description. [Modes for carrying out the invention]

[0017] Before describing the present invention in detail, it should be understood that since the methods and conditions can be changed, the present invention is not limited to the specific methods and experimental conditions described in this specification. Further, the terms used in this specification are for the purpose of describing particular embodiments only and are not limiting.

[0018] Definitions Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art. For the purposes of the present invention, the following terms are defined below. It should be understood that where appropriate, terms used in the singular may cover the plural and vice versa.

[0019] The term "about" when used in combination with a numerical value is intended to encompass numerical values in the range from a lower limit 5% lower than the specified value to an upper limit 5% higher than the specified value.

[0020] The term "and / or" used to connect two or more options is understood to mean any one of the options, or any two or more of the options. As used in this specification, the terms "comprise" or "include" are intended to mean that the recited element, component, or step is included, but not to exclude any other element, component, or step. The terms "comprise" or "include" as used in this specification also encompass situations consisting entirely of the recited elements, components, or steps, unless otherwise specified. For example, when referring to an antibody variable region "comprising" a particular sequence, it is intended to also encompass an antibody variable region consisting of the particular sequence.

[0021] As used herein, the terms "CLAUDIN" or "CLDN" refer to the most important backbone proteins that determine the structure of tight junctions between cells, are involved in adherens junctions, and play an important role in the metastasis and invasion of tumor cells. Claudin proteins are widely present in mammalian epithelial cells and endothelial cells, mainly on the lateral surface of epithelial cells and the cell membrane of basal cells. Different Claudin proteins are specifically expressed in different tissues. The Claudin18 (CLDN18) gene is located at 3q22.3, has a molecular weight of 24 kDa, contains 261 amino acid residues, and is a member of the Claudins superfamily. Its protein structure includes two extracellular loops and four 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), respectively. In the primary structure sequences of the two proteins, only the amino acid residues at some positions from the N-terminal signal peptide to the extracellular loop 1 (loop) structure are different. Particularly in extracellular loop 1, CLDN18.1 and CLDN18.2 differ by only eight amino acids. The sequence homology between and among species of the two subtypes of the CLDN18 protein is also very high. The sequence of the extracellular loop 1 of CLDN18.2 is completely identical in different species such as humans, mice, and rhesus monkeys. The homology between human and mouse CLDN18.2 proteins reaches 84%, indicating that the sequence of the CLDN18.2 protein is extremely conserved (O. Tureci. et al., Gene, 481: 83-92, 2011). CLDN18.2 or any of its variants and isoforms can be isolated from naturally expressed cells or tissues or recombinantly produced using techniques well known in the art and / or the techniques described herein. In one embodiment, the CLDN18.2 described herein is human CLDN18.2.

[0022] As used herein, the terms “antibody targeting CLDN18.2,” “antibody against CLDN18.2,” “antibody against CLDN18.2,” “CLDN18.2 antibody,” “antibody that binds to CLDN18.2,” “antibody that specifically binds to CLDN18.2,” or “antibody targeting CLDN18.2” refer to antibodies that can bind to (human) CLDN18.2 with sufficient affinity to be used as therapeutic agents 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 but not to cells expressing CLDN18.1. In some embodiments, binding is determined by, for example, radioimmunoassay (RIA), biolayer interferometry (BLI), MSD assay, surface plasmon resonance (SPR), or flow cytometry.

[0023] Intracellular CLDN18.2 expression can be determined by several methods, including the use of anti-CLDN18.2 antibodies. For example, the binding strength between "highly expressing CLDN18.2" cells and anti-CLDN18.2 antibodies (determined, e.g., by FACS) may be 500, 600, 700, 800, 900 times, or preferably more than 1000 times, e.g., more than 1100 times, more than 1200 times, more than 1300 times, more than 1400 times, or even higher than the binding strength between anti-CLDN18.2 antibodies and cells without CLDN18.2 expression. For example, the binding strength (determined, for example, by FACS) between cells with "moderate CLDN18.2 expression" and an anti-CLDN18.2 antibody is 5 to 500 times greater than the binding strength between the anti-CLDN18.2 antibody and cells without CLDN18.2 expression, for example, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100 times or more, but it may be less than 500 times.

[0024] In conventional quadruple-chain IgG antibodies, the full-length antibody heavy chain generally consists of a heavy chain variable region (abbreviated as VH herein) and a heavy chain constant region, the heavy chain constant region containing at least three domains CH1, CH2, and CH3. The full-length antibody light chain consists of a light chain variable region (abbreviated as VL herein) and a light chain constant region, the light chain constant region consisting of one domain CL. Each heavy chain variable region VH or each light chain variable region consists 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, and FR4.

[0025] The term "antibody fragment" includes a portion of the entire antibody. In preferred embodiments, the antibody fragment is an antigen-binding fragment.

[0026] An "antigen-binding fragment" is a molecule distinct from the entire antibody, containing a portion of the entire antibody, and refers to a molecule that binds to the antigen to which the entire antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2, dAb (domain antibodies), linear antibodies, single-chain antibodies (e.g., scFv), single-domain antibodies (e.g., VHH), bivalent or bispecific antibodies or their fragments, and Camelidae antibodies.

[0027] The term "antigen" refers to a molecule that triggers an immune response. This immune response may involve the production of antibodies, the activation of specific immune cells, or both. Technologists understand that virtually any macromolecule, including almost any protein or peptide, can be used as an antigen. Furthermore, antigens can also be generated from recombinant DNA 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.

[0028] A "complementarity-determining region," "CDR region," or "CDR" is a region within the antibody's variable domain where the sequence is highly variable, forming a structurally defined loop ("hypervariable loop") and / or containing an antigen contact residue ("antigen contact site"). CDRs are primarily responsible for binding to the antigen epitope. Heavy and light chain CDRs are generally called CDR1, CDR2, and CDR3, and are numbered sequentially from the N-terminus. CDRs located in the heavy chain variable domain of an antibody are called HCDR1, HCDR2, and HCDR3, while CDRs located in the light chain variable domain of an antibody are called LCDR1, LCDR2, and LCDR3.In a given amino acid sequence of the light chain variable region or heavy chain variable region, the precise amino acid sequence boundary of each CDR is determined by, for example, Chothia (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)) based on the 3D structure of the antibody and the topology of the CDR loop, Kabat (Kabat et al., Sequences of Proteins of Immunological Interest, 4th edition, US Department of Health and Human Services, National Institutes of Health (1987)) based on the variability of the antibody sequence, AbM (University of Bath), Contact (University College London), the International ImMunoGeneTics database (IMGT) (imgt.cines.fr / on the World Wide Web), and North based on affinity propagation clustering using numerous crystal structures. This can be determined using any one or a combination of many well-known antibody CDR numbering systems, including the CDR definition (North et al, “A New Clustering of Antibody CDR Loop Conformations”, Journal of Molecular Biology, 406, 228-256 (2011)).

[0029] The following is the scope of CDR as defined by the kabat, AbM, Chothia, Contact, and IMGT protocols. [Table 1]

[0030] Furthermore, the CDR may be determined based on having the same Kabat numbering position as a reference CDR sequence (e.g., any of the exemplary CDRs of the present invention).

[0031] Unless otherwise specified, the terms “CDR” or “CDR sequence” as used herein encompass CDR sequences determined by any of the methods described above.

[0032] Unless otherwise specified, the residue positions of the antibody variable region (including heavy chain variable region residues and light chain variable region residues) in this invention are positions numbered 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)).

[0033] In one embodiment, the heavy chain variable region (CDR) of the antibody of the present invention is determined according to the following scheme.

[0034] VH CDR1 is determined according to the AbM scheme, and VH CDR2 and 3 are determined according to the Kabat scheme.

[0035] In one embodiment, the light chain variable region (CDR) of the antibody of the present invention is determined according to the Kabat scheme.

[0036] In one embodiment, the heavy chain variable region CDR of the antibody of the present invention is determined according to the following scheme: VH CDR1 is determined according to the AbM scheme, VH CDR2 and 3 are determined according to the Kabat scheme, and the light chain variable region CDR is determined according to the Kabat scheme.

[0037] It should be noted that the CDR boundaries of the variable region of an antibody may differ based on different assignment systems. That is, the CDR sequences of the variable region of an antibody defined by different assignment systems will differ. Therefore, when defining an antibody having a specific CDR sequence as defined in this invention, the range of antibodies also includes antibodies whose variable region sequence contains a specific CDR sequence, but which, due to the different scheme applied (e.g., different assignment system schemes or combinations thereof), claim a different CDR boundary than the specific CDR boundary defined in this invention.

[0038] Antibodies with different specificities (i.e., different binding sites for different antigens) have different CDRs (under the same assignment system). However, although the CDR differs from antibody to antibody, only a limited number of amino acid positions within the CDR are directly involved in antigen binding. The smallest overlapping region can be determined using at least two of the Kabat, Chothia, AbM, Contact, and North methods, thereby providing the "minimum binding unit" for antigen binding. The minimum binding unit may be a subpart of the CDR. As will be apparent to those skilled in the art, the residues of the remaining CDR sequence can be determined by the antibody structure and protein folding. Therefore, any variant of the CDR described herein is also contemplated in the present invention. For example, in CDR variants, the amino acid residues within the minimum binding unit remain unchanged, while other CDR residues as defined by Kabat or Chothia may be substituted with conserved amino acid residues.

[0039] In this specification, the term “Fc region” is used to define the C-terminal region of an immunoglobulin heavy chain, which includes at least a portion of the constant region. This term includes both the Fc region of the natural sequence and mutant Fc regions. The “Fc domain” of a natural immunoglobulin includes two or three constant domains, namely the CH2 and CH3 regions, and optionally the CH4 region. For example, the immunoglobulin Fc domain of a natural antibody includes second and third constant domains (CH2 and CH3 regions) derived from two heavy chains of IgG, IgA, and IgD, or second, third, and fourth constant domains (CH2, CH3, and CH4 regions) derived from two heavy chains of IgM and IgE. Unless otherwise specified, the numbering of amino acid residues in the Fc region or constant region is based on the EU numbering system (also known as the EU index) described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991. In this invention, the “Fc region” does not include the heavy chain variable region VH and light chain variable region VL, as well as the heavy chain constant region CH1 and light chain constant region CL of immunoglobulins, but may in some cases include the N-terminal hinge region of the heavy chain constant region.

[0040] An "IgG-type antibody" refers to the IgG type to which the antibody's heavy chain constant region belongs. All antibodies of the same type have the same heavy chain constant region. Different types of antibodies have different heavy chain constant regions. For example, an IgG4-type antibody refers to one whose heavy chain constant region originates from IgG4, while an IgG1-type antibody refers to one whose heavy chain constant region originates from IgG1.

[0041] As used herein, the terms “binding” or “specific binding” mean that the binding interaction to an antigen is selective and can be distinguished from undesirable or nonspecific interactions. The ability of an antigen-binding site to bind to a particular antigen can be determined by enzyme immunosorbent assay (ELISA) or conventional binding assays known in the art (e.g., radioimmunoassay (RIA), thin-layer biomembrane interference assay, MSD assay, surface plasmon resonance (SPR), etc.).

[0042] As used herein, “antibody-drug conjugate (ADC)” refers to a compound obtained by linking an antibody and a drug via a linker.

[0043] As used herein, the term “site-directed binding” refers to a conjugation in which a drug / active substance specifically binds to a particular site on an antibody via a linker.

[0044] 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 is not biologically or otherwise undesirable. The ADC of the present invention may exist in the form of a pharmaceutically acceptable salt, including an acid-addition salt or a base-addition salt. In the present invention, a pharmaceutically acceptable non-toxic acid-addition salt refers to a salt formed with the ADC conjugate of the present invention and an organic or inorganic acid, and 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, and the like. A pharmaceutically acceptable, non-toxic base addition salt represents a salt formed with the ADC complex of the present invention and an organic or inorganic base, and includes, but is not limited to, alkali metal salts, such as lithium, sodium, or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts of organic bases, such as ammonium salts formed with N-group-containing organic bases.

[0045] The term “drug-to-antibody ratio” or “DAR” refers to the ratio of the small molecule drug moiety (D) bound to the Ab moiety to the Ab moiety, as described herein. For example, the DAR may be 1–20, 2–18, 4–16, 5–12, 6–10, 2–8, 3–8, 2–6, 4–6, 6–10, etc., e.g., 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 molecular population in the product, i.e., the overall ratio of the small molecule drug moiety (D) bound to the Ab moiety as described herein to the Ab moiety in the product, measured by a detection method (e.g., conventional methods such as mass spectrometry, ELISA assay, electrophoresis, and / or HPLC), and such a DAR is referred to as the average DAR in this context. It should be understood that the above overall ratio is a molar ratio. In some embodiments, the composite of the present invention has an average DAR value of 1 to 20, for example 2 to 18, 4 to 16, 5 to 12, 6 to 10, 2 to 8, 3 to 8, 2 to 6, 4 to 6, 6 to 10, for example 1.0 to 8.0, 2.0 to 6.0, for example 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. The range is 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, 7.9, 8, 8.1, 8.2, 8.3, 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, with two of these values ​​as the endpoints.

[0046] The term "effective dose" refers to the amount or dosage of the antibody-drug conjugate or its pharmaceutically acceptable salt, antibody, or fragment, composition, or combination of the present invention, which, after being administered to a patient or subject in a single or multiple dose, produces the expected effect in a patient or subject requiring treatment or prevention.

[0047] The "therapeutic dose" refers to the amount that effectively achieves the desired therapeutic outcome for the required duration and in the required dose. The therapeutic dose is also the amount in which the toxicity or adverse effects of the antibody-drug conjugate or its pharmaceutically acceptable salt, antibody, or antibody fragment, or composition, or combination, are less than the beneficial therapeutic effect. The "therapeutic dose" preferably inhibits a measurable parameter (e.g., tumor volume) by at least about 30%, and more preferably by at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 100% compared to an untreated subject.

[0048] The "prophylactic effective dose" refers to the amount that can effectively achieve the desired preventive outcome for the required period and in the required dosage. Generally, since prophylactic doses are administered before or in the early stages of the disease, the prophylactic effective dose is less than the therapeutic effective dose.

[0049] The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably and refer to cells into which exogenous nucleic acids have been introduced (including the offspring of such cells). Host cells include “transformed organisms” and “transformed cells,” which include primary transformed cells and their offspring, regardless of passage number. Offspring may not be exactly the same as parent cells in terms of nucleic acid content and may contain mutations. Mutant offspring having the same function or biological activity, sorted or selected from the initially transformed cells, are included herein.

[0050] As used herein, the term “label” refers to a compound or composition that is directly or indirectly bound or fused to a drug (such as a polynucleotide probe or antibody) to facilitate the detection of the bound or fused drug. The label itself may be detectable (e.g., a radioisotope label or a fluorescent label), or, in the case of an enzyme label, may catalyze a chemical change in a detectable substrate compound or composition. This term is intended to cover both direct labeling of a probe or antibody by binding (physically connecting) a detectable substance to the probe or antibody, and indirect labeling of a probe or antibody by reacting with another directly labeled reagent.

[0051] "Individual" or "Subject" includes mammals. Mammals include, but are not limited to, livestock (cattle, sheep, cats, dogs, horses, etc.), primates (humans and non-human primates, e.g., monkeys), rabbits, and rodents (mice and rats, etc.). In some embodiments, the individual or subject is a human.

[0052] An “isolated” antibody or other molecule (e.g., an ADC molecule) is an antibody or molecule that has been separated from the natural environment or components of the environment in which it is expressed. In some embodiments, the antibody or ADC molecule is purified to a purity of over 95% or over 99% by measurement, such as by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse-phase HPLC).

[0053] The term "antitumor effect" refers to a biological effect that can be demonstrated by various means, including but not limited to, a reduction in tumor volume, a reduction in the number of tumor cells, a reduction in tumor cell proliferation, or a reduction in tumor cell survival rate.

[0054] In this specification, the terms “tumor” and “cancer” may be used interchangeably to include solid tumors and hematological malignancies.

[0055] The terms “cancer” and “cancerous” refer to or describe a physiological disorder of mammals characterized by uncontrolled cell proliferation. In some embodiments, cancers suitable for treatment with the antibody-drug conjugates of the present invention include gastric cancer, pancreatic cancer, or gastroesophageal junction cancer (including metastatic forms of these cancers).

[0056] The term “tumor” refers to the growth and proliferation of all tumor cells, whether malignant or benign, and all precancerous and cancerous cells and tissues. The terms “cancer,” “cancerous,” and “tumor” as used herein are not mutually exclusive.

[0057] The term “solid tumor” includes advanced malignant solid tumors, tumors associated with Claudin 18.2, such as Claudin 18.2-positive tumors, selected from one or more of 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 tract cancer (biliary tract cancer is classified as bile duct cancer and gallbladder cancer). In some embodiments, the solid tumor may be primary (1L) gastric / gastroesophageal junction adenocarcinoma, secondary or subsequent gastric / gastroesophageal junction adenocarcinoma, preferably secondary or subsequent gastric / gastroesophageal junction adenocarcinoma being 2L or later, and more preferably secondary or subsequent gastric / gastroesophageal junction adenocarcinoma being 3L. In some embodiments, the solid tumor may be primary (1L) gastric cancer, secondary or subsequent gastric cancer, preferably secondary or subsequent gastric cancer being 2L or later, and more preferably gastric cancer being 3L. In some embodiments, the solid tumor is primary (1L) pancreatic ductal adenocarcinoma, secondary or subsequent pancreatic ductal adenocarcinomas, and preferably the secondary or subsequent pancreatic ductal adenocarcinoma is 2L pancreatic ductal adenocarcinoma. In this specification, gastric / gastroesophageal junction adenocarcinoma may refer to gastric cancer or gastroesophageal junction adenocarcinoma.

[0058] The terms "primary tumor," "1L tumor," or "primary (1L) tumor" refer to tumors that have not been treated with systemic antitumor therapy. For example, the term "primary (1L) gastric / gastroesophageal junction adenocarcinoma" refers to gastric / gastroesophageal junction adenocarcinoma that has not been treated with systemic antitumor therapy. The terms "primary (1L) gastric cancer" and "primary (1L) pancreatic ductal adenocarcinoma" refer to gastric cancer and pancreatic ductal adenocarcinoma, respectively, that have not been treated with systemic antitumor therapy.

[0059] The terms "secondary tumor" or "2L tumor" refer to tumors that have failed primary treatment (e.g., refractory or intolerant to primary treatment). For example, secondary pancreatic ductal adenocarcinoma or 2L pancreatic ductal adenocarcinoma refers to pancreatic ductal adenocarcinoma that has failed primary treatment, such as being refractory or intolerant to primary treatment.

[0060] The terms "tertiary tumor" or "3L tumor" refer to tumors that have failed second-line treatment (e.g., refractory or intolerant to second-line treatment). For example, "tertiary (3L) gastric / gastroesophageal junction adenocarcinoma" refers to gastric / gastroesophageal junction adenocarcinoma that has failed second-line treatment, such as being refractory or intolerant to second-line treatment.

[0061] The term "secondary or subsequent tumors" refers to tumors that have failed in primary and subsequent treatments (such as second-line or tertiary treatment) (e.g., those that are refractory or intolerant to treatment).

[0062] In the case of tumors, the meaning of first-line, second-line, and tertiary treatment or therapy, and their treatment regimens, should be understood to be obvious and well known to those skilled in the art. First-line treatment refers to the first treatment cycle after the diagnosis of the tumor; second-line treatment refers to when the patient's tumor has progressed after first-line treatment, has become resistant to the first-line treatment regimen, and requires treatment with a different treatment regimen; and tertiary treatment refers to treatment using another regimen after second-line treatment has failed (see, for example, https: / / www.medsci.cn / article / show_article.do?id=1901e9517635). Treatment regimens are approved or recommended by authoritative bodies such as the NMPA or FDA. For example, first-line treatment includes, but is not limited to, fluorouracil (fluorouracil or capecitabine) in combination with a platinum-based agent (oxaliplatin or cisplatin); second-line treatment includes, but is not limited to, the combination of paclitaxel and ramucirumab. Third-line treatment includes, but is not limited to, nivolumab, irinotecan, or trifluridine / tipiracil.

[0063] As used herein, “treatment” (or “to treat” or “to treat”) means slowing, interrupting, preventing, alleviating, stopping, reducing or reversing the progression or severity of an existing symptom, condition, state, or disease.

[0064] As used herein, “prevention” (or “preventive” or “preventive”) includes the suppression of disease or disorder, or the onset or progression of symptoms of a particular disease or disorder. In some embodiments, subjects with a family history of cancer are candidates for preventive therapy. Generally, in the context of cancer, the term “prevention” (or “preventive”) refers to administering a drug before signs or symptoms of cancer appear, particularly in subjects at risk of cancer.

[0065] As used herein, the term “vector” refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is bound. This term includes not only vectors that function as self-replicating nucleic acid structures, but also vectors that bind to the genome of the host cell to which they are introduced. Some vectors can induce the expression of the nucleic acid to which they are functionally bound. Such vectors are referred to herein as “expression vectors.”

[0066] "Subject / patient / individual sample" refers to a collection of cells or bodily fluids taken from a patient or subject. Sources of tissue or cell samples may include, for example, solid tissues such as fresh, frozen, and / or preserved organ or tissue samples, biopsy samples, or puncture samples; blood or any blood component; bodily fluids such as cerebrospinal fluid, amniotic fluid, ascites, or interstitial fluid; or cells from a subject at any point in time during pregnancy or development. Tissue samples may contain compounds that do not naturally mix with tissue, such as preservatives, anticoagulants, buffers, fixatives, nutrients, and antibiotics.

[0067] The term "freeze-dried formulation" refers to a composition obtained by a freeze-drying process of a liquid formulation. Preferably, it is a solid composition with a moisture content of less than 5%, more preferably less than 3%.

[0068] The term "buffer" refers to a pH buffer capable of maintaining a stable pH in a solution. Preferably, the buffer can maintain the pH of the liquid formulation of the present invention, or the liquid formulation obtained by reconstituting the lyophilized formulation of the present invention, at about 5.5 to 7.5, for example, about 6.0 to 6.5, about 5.5 to 7.2, about 6.0 to 7.0, or about 6.3 to 6.8. Preferably, the buffer is selected from one or more of histidine, citric acid, succinic acid, glutamic acid, phosphoric acid, acetic acid, or salts thereof. The salts include, but are not limited to, histidine hydrochloride or salts formed with acids such as sulfuric acid, and salts formed with alkali metals such as lithium, sodium, or potassium salts, for example, histidine hydrochloride.

[0069] The term “stabilizer” refers to a chemical substance that can maintain the stability of a formulation in a chemical, physical, and / or biological manner. Preferably, the stabilizer is selected from one or more carbohydrates and polyols. Carbohydrates may be selected from, but are not limited to, sucrose, trehalose, glucose, lactose, maltose, cyclodextrin, maltodextrin, and dextran. Polyols may be selected from, but are not limited to, mannitol, sorbitol, and xylitol. Carbohydrates or polyols may be in the form of hydrates.

[0070] 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 solution is, for example, about 0.05-1, about 0.05-2, about 0.1-0.5, about 0.1-0.4, about 0.1-0.3, or about 0.2-0.4 mg / ml. Preferably, the surfactant is a nonionic surfactant and includes, but is not limited to, alkyl poly(ethylene oxide), polysorbates (e.g., polysorbate-20, polysorbate-80, polysorbate-60, or polysorbate-40), Pluronic, or combinations thereof.

[0071] A “reconstituted” formulation means a liquid formulation obtained by dissolving and / or suspending a solid formulation (e.g., a lyophilized formulation) in a physiologically acceptable solution. In this specification, “reconstituted” and “redissolved,” etc., are used interchangeably in terms of formulation.

[0072] As used herein, "w / v" represents "weight / volume," for example, "1%w / v" means 1g / 100mL = 0.01g / mL = 10mg / mL.

[0073] Treatment method The present invention provides a method for preventing or treating solid tumors in a subject, the method comprising administering an effective amount of a Claudin18.2-targeting antibody-drug conjugate or a pharmaceutically acceptable salt thereof to a subject in need of prevention or treatment of solid tumors.

[0074] In one embodiment of the present invention, the antibody-drug conjugate targeting Claudin18.2 is selected from the following: [ka] In the formula, Ab is an antibody or its antigen-binding fragment that targets Claudin18.2. q represents the average DAR and is between 2 and 11, for example q is between 2 and 5, for example q is between 3 and 5, 3.5 and 4.5, 3.2 and 4.2, or between 3 and 4, and more specifically q is 2, 2.5, 3, 3.5, 4, 4.8, or 5.

[0075] Depending on the context, when the variable after the square brackets in an ADC structural formula is specified as the mean DAR (e.g., q in formula IA), it should be understood to represent the ratio of Ab to the drug portion (i.e., exatecan) as measured by conventional measurement methods, as described in the Definitions section of this specification. The mean DAR can be a decimal. For example, when we write "q is between 3 and 5" or "q is a number between 3 and 5" for the mean DAR, it means that q is any number selected from 3 to 5, including integers and decimals.

[0076] In one embodiment of the present invention, the antibody-drug conjugate targeting Claudin18.2 is selected from the following: [ka] In the formula, Ab is an antibody or its antigen-binding fragment that targets Claudin18.2. In the formula, y is an integer of either 1 or 2.

[0077] If the variable after the square brackets in an ADC structural formula is not specified as the average DAR (e.g., y in formula IB), it is important to understand that it does not represent the average DAR, but rather refers to the number of linker payloads (i.e., the structures within the square brackets in formula IB) attached to each Ab in that ADC molecule, unless otherwise specified or contradicted by the context. For example, if y is 2, it means that one Ab is attached to two linker payloads in the ADC molecule.

[0078] In further embodiments of the present invention, the antibody or antigen-binding fragment targeting Claudin 18.2 includes HCDR1, HCDR2, and HCDR3, each consisting of the amino acid sequences described in SEQ ID NO: 1 (GFTFSSYVMS), SEQ ID NO: 2 (TISHSGGSTYYADSVKG), and SEQ ID NO: 3 (DAPYYDILTGYRY), respectively, and LCDR1, LCDR2, and LCDR3, each consisting of the amino acid sequences described in SEQ ID NO: 6 (RASQSISSWLA), SEQ ID NO: 7 (KASSLES), and SEQ ID NO: 8 (QQYNSYSYT), respectively.

[0079] In a further embodiment of the present invention, an antibody targeting Claudin18.2 or its antigen-binding fragment comprises a heavy chain variable region and / or a light chain variable region, the heavy chain variable region (i) containing or consisting of the amino acid sequence described in Sequence ID No. 4, (ii) an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence described in Sequence ID No. 4, or comprising such an amino acid sequence, (iii) an amino acid sequence having one or more (preferably 10 or less, more preferably 5, 4, 3, 2, or 1 or less) amino acid modifications (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence described in Sequence ID No. 4, wherein the amino acid modifications do not occur in the CDR and / or The light chain variable region is, (i) containing or consisting of the amino acid sequence described in Sequence ID No. 9, or (ii) an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence described in Sequence ID No. 9, or comprising such an amino acid sequence, (iii) an amino acid sequence having one or more (preferably 10 or less, more preferably 5, 4, 3, 2, or 1 or less) amino acid modifications (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence described in Sequence ID No. 9, wherein the amino acid modifications do not occur in the CDR.

[0080] In a further embodiment of the present invention, an antibody targeting Claudin18.2 or its antigen-binding fragment comprises a heavy chain and a light chain. The heavy chain is, (i) Contains or consists of the amino acid sequence shown in Sequence ID No. 11 below: EVQLLDSGGGLVQPGGSLRLSCAASGFTFSSYVMSWVRQAPGKGLNWVSTISHSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIDAPYYDILTGYRYWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK, or (ii) an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acids described in SEQ ID NO: 11, or comprising such an amino acid sequence, (iii) an amino acid sequence having one or more (preferably 20 or 10 or less, more preferably 5, 4, 3, 2, or 1 or less) amino acid modifications (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence described in Sequence ID No. 11, or comprising such an amino acid sequence and / or Light chains are (i) containing or consisting of the amino acid sequence shown in Sequence ID No. 12 below: DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC, or (ii) an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence described in Sequence ID No. 12, or comprising such an amino acid sequence, (iii) an amino acid sequence having one or more (preferably 20 or 10 or less, more preferably 5, 4, 3, 2, or 1 or less) amino acid modifications (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence described in Sequence ID No. 12, or comprising such an amino acid sequence.

[0081] In one embodiment of the present invention, N-acetylglucosamine (GlcNAc) attached to Ab is present at the Asn 297 glycosylation site of both heavy chains of the antibody.

[0082] In one embodiment of the present invention, an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is formulated as a dosage form.

[0083] In one embodiment of the present invention, a formulation of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is An antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof, at a concentration of approximately 15-60 mg / mL, for example, approximately 20-40 mg / mL. Approximately 5-50 mM, for example, approximately 10-30 mM buffer solution. Approximately 50-100 mg / ml, for example, approximately 60-90 mg / ml of stabilizer, and It is a liquid preparation containing approximately 0.05 to 1 mg / ml of surfactant, for example, approximately 0.1 to 0.3 mg / ml. The pH of the formulation is approximately 5.5 to 7.5, preferably approximately 6.0 to 6.5, and more preferably approximately 6.5.

[0084] In one embodiment of the present invention, the buffer is a combination of histidine and histidine hydrochloride, or histidine. The stabilizer is sucrose. The surfactant is polysorbate 80.

[0085] In one embodiment of the present invention, a formulation of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof has the following composition or formula: 20 mg / mL of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof, 20 mM histidine buffer, 8% (w / v) sucrose, 0.02% (w / v) polysorbate 80, pH 6.5.

[0086] Unless otherwise specified, if the formulation of the present invention is a liquid formulation, it is understood that it further includes a vehicle, which includes, but is not limited to, purified water such as ultrapure water, water for injection, sterile water, and redistilled water. Vehicles that can be used to reconstitute the lyophilized formulation of the present invention include, but are not limited to, purified water such as ultrapure water, water for injection, sterile water, redistilled water, physiological saline, Ringer's solution, glucose injection, and the like.

[0087] In further embodiments of the present invention, the formulation of an antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof is a lyophilized formulation. The lyophilized formulation is prepared by lyophilizing the pharmaceutical formulation of the present invention. For example, the lyophilized formulation is prepared by lyophilizing the liquid pharmaceutical formulation described in the above embodiments.

[0088] In one embodiment of the present invention, the lyophilized formulation is reconstituted before being administered to the subject.

[0089] In one embodiment of the present invention, a method for preventing or treating a solid tumor in a subject according to the present invention, wherein the solid tumor is an advanced malignant solid tumor, and / or Solid tumors may be Claudin18.2-related tumors, such as Claudin18.2-positive tumors selected from one or more of 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 tract cancer (biliary tract cancer is classified as bile duct cancer and gallbladder cancer).

[0090] In one embodiment of the present invention, an advanced solid tumor is a tumor that has not received systemic antitumor therapy, a tumor that has failed at least one systemic antitumor therapy, a tumor that has failed first-line therapy (e.g., refractory or intolerant to first-line therapy), or a tumor that has failed second-line therapy (e.g., refractory or intolerant to second-line therapy).

[0091] In one embodiment of the present invention, the advanced malignant solid tumor is a locally advanced, unresectable or metastatic solid tumor.

[0092] In one embodiment of the present invention, the advanced solid tumor is gastric cancer or gastroesophageal junction adenocarcinoma.

[0093] The solid tumors are primary (1L) gastric / gastroesophageal junction adenocarcinoma and secondary / subsequent gastric / gastroesophageal junction adenocarcinoma, preferably secondary / subsequent gastric / gastroesophageal junction adenocarcinomas of 2L or higher, and more preferably secondary / subsequent gastric / gastroesophageal junction adenocarcinomas of 3L. The solid tumors are primary (1L) gastric cancer and secondary / subsequent gastric cancer, preferably secondary / subsequent gastric cancers of 2L or higher, and more preferably gastric cancers of 3L. The solid tumors are primary (1L) pancreatic ductal adenocarcinoma and secondary / subsequent pancreatic ductal adenocarcinoma, preferably secondary / subsequent pancreatic ductal adenocarcinomas of 2L.

[0094] In one embodiment of the present invention, the advanced malignant solid tumor is locally advanced, unresectable or metastatic gastric / gastroesophageal junction adenocarcinoma.

[0095] In one embodiment of the present invention, advanced malignant solid tumors are Her-2 negative.

[0096] In one embodiment of the present invention, the subject has previously received treatment for the above-mentioned solid tumor.

[0097] In one embodiment of the present invention, a method for preventing or treating advanced malignant solid tumors in the subject of the present invention comprises administering an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof to the subject at a dose of 0.1 mg / kg to 100 mg / kg, further comprising administering an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof to the subject at a dose of 0.2 mg / kg to 50 mg / kg, and further comprising administering an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof to the subject at a dose of 0.3 mg / kg to 30 mg / kg. For example, this method includes administering an antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof at doses of 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. Furthermore, this method includes administering an antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof at doses of 0.3 mg / kg to 10 mg / kg, for example, 2 mg / kg to 9 mg / kg, 4 mg / kg to 8 mg / kg, or 5 mg / kg to 7 mg / kg. For example, this method includes administering a pharmaceutically acceptable salt thereof targeting Claudin 18.2 at a dose of 6 mg / kg.

[0098] In one embodiment of the present invention, a method for preventing or treating advanced malignant solid tumors in a subject according to the present invention comprises administering to a subject an antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof in an amount of 10 mg to 1500 mg, for example, 50 mg to 1000 mg, 100 mg to 800 mg, 200 mg to 600 mg, or 300 mg to 500 mg.

[0099] In one embodiment of the present invention, an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is administered according to a dosing cycle.

[0100] In one embodiment of the present invention, the administration cycle of this method is 2 weeks / 14 days (Q2W) to 5 weeks / 35 days (Q5W), for example, 18 to 24 days, 16 to 28 days, or 15 to 30 days, for example, 19, 20, 21, 22, or 23 days, and is administered once per administration cycle. Furthermore, the administration cycle of this method is 2 weeks / 14 days (Q2W), 3 weeks / 21 days (Q3W), 4 weeks / 28 days (Q4W), or 5 weeks / 35 days (Q5W), and is administered once per administration cycle, i.e., once every 2 weeks, once every 3 weeks, once every 4 weeks, or once every 5 weeks, preferably once on day 1 of each administration cycle.

[0101] In a further embodiment of the present invention, the method comprises administering to a subject 6 mg / kg of an antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof, once every 3 weeks / 21 days (once on day 1 of each administration cycle).

[0102] In one embodiment of the present invention, the administration mode of the method of the present invention includes intravenous infusion such as intravenous drip or intravenous bolus, and the intravenous drip can be performed through a peripheral vein, a central venous catheter, or an infusion port.

[0103] Antibody-drug conjugates or their pharmaceutically acceptable salts for therapeutic use The present invention provides an antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of solid tumors in a subject. The antibody-drug conjugate targeting Claudin18.2 is selected from the antibody-drug conjugates of formula IA or formula IB as defined herein, for example, in the "Therapeutic Methods" section.

[0104] In one embodiment of the present invention, the antibody or antigen-binding fragment targeting Claudin18.2 is as defined herein, for example, in the "Therapeutic Methods" section.

[0105] In one embodiment of the present invention, a solid tumor is as defined herein, for example, in the “Therapeutic Method” section.

[0106] In one embodiment of the present invention, an antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof is administered to a subject in a dose as described herein, for example, in the “Therapeutic Methods” section.

[0107] In one embodiment of the present invention, an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is administered in a dosing regimen as described herein, for example, in the “Therapeutic Methods” section.

[0108] Pharmaceutical use The present invention provides the use of an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for the prevention or treatment of solid tumors in a subject. The antibody-drug conjugate targeting Claudin18.2 is selected from the antibody-drug conjugates of formula IA or formula IB as defined herein, for example, in the "Therapeutic Methods" section.

[0109] In one embodiment of the present invention, the antibody or antigen-binding fragment targeting Claudin18.2 is as defined herein, for example, in the "Therapeutic Methods" section.

[0110] In one embodiment of the present invention, a solid tumor is as defined herein, for example, in the “Therapeutic Method” section.

[0111] In one embodiment of the present invention, an antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof is administered to a subject in a dose as described herein, for example, in the “Therapeutic Methods” section.

[0112] In one embodiment of the present invention, an antibody-drug conjugate targeting Claudin18.2 or a pharmaceutically acceptable salt thereof is administered in a dosing regimen as described herein, for example, in the “Therapeutic Methods” section.

[0113] Single dose unit A single dose unit contains an effective amount of the Claudin18.2-targeting antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to the present invention. Preferably, it contains a fixed dose of 1 to 500 mg, for example, 100 to 500 mg, of the Claudin18.2-targeting antibody-drug conjugate or a pharmaceutically acceptable salt thereof. For example, it contains a fixed dose of 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, or 500 mg of the Claudin18.2-targeting antibody-drug conjugate or a pharmaceutically acceptable salt thereof.

[0114] In one embodiment of the present invention, the single-dose unit is in the form of a unit dose.

[0115] Parts kit The parts kit contains an effective amount of the Claudin18.2-targeting antibody-drug conjugate according to the present invention or a pharmaceutically acceptable salt thereof. Preferably, the product contains a fixed dose of 1 to 500 mg, for example, 100 to 500 mg, of an antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof. For example, it contains 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 Claudin 18.2 or a pharmaceutically acceptable salt thereof.

[0116] Preferably, the parts kit further includes a package insert with instructions for use of an antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof for the prevention or treatment of an advanced malignant solid tumor of interest.

[0117] Purpose Use of a kit of single-dose units or parts according to the present invention in the manufacture of pharmaceuticals for the prevention or treatment of advanced malignant solid tumors, including but 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 tract cancer (biliary tract cancer is classified as bile duct cancer and gallbladder cancer). [Examples]

[0118] Example 1: Preparation of an antibody-drug conjugate targeting Claudin 18.2 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 full-length monoclonal antibody form in HEK293 cells (Invitrogen, A14527).

[0119] Based on HB37A6, ADC(IEX019-02) was further designed and synthesized as follows. The specific synthesis steps can also be found in the preparation steps for IEX019-02 in PCT / CN2022 / 139637 (which is incorporated herein by reference in its entirety).

[0120] 1) Preparation of compound 6 [ka] Under an 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 with saturated NH4Cl aqueous solution (150 mL). After separation, the aqueous layer was extracted with DCM (150 mL). The combined organic layers were dried and concentrated with (Na2SO4). The residue was purified by column chromatography. Product 6 (2.06 g, 5.72 mmol, 57%) was obtained as a pale yellow, concentrated 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).

[0121] 2) Preparation of compound 7 [ka] CSI (11 μL, 18 mg, 0.13 mmol) was added to a stirred solution of 6 (47 mg, 0.13 mmol) in DCM (10 mL). 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 a further 4.5 hours, the reaction mixture was concentrated. The residue was purified by gradient column chromatography (33 → 66% Â / heptane (1% AcOH)) to obtain 7 (88 mg, 0.098 mmol, 75%) as a colorless oil. 11H NMR (400 MHz, CDCl3) δ (ppm) 8.28 - 8.23 (m, 4H), 7.42 - 7.35 (m, 4H), 4.52 (t, J = 5.4 Hz, 4H), 4.30 (d, J = 8.3 Hz, 2H), 4.27 - 4.22 (m, 2H), 3.86 (t, J = 5.3 Hz, 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 = 8.7 Hz, 1H), 1.04 - 0.92 (m, 2H).

[0122] 3) Preparation of Compound 9

Chemical Structure

[0123] 4) Preparation of Compound 1 A solution of Et3N (73 mg, 101 μL, 0.72 mmol) and Compound 7 (65 mg, 72 μmol) in DMF (1.4 mL) was added to a solution of Compound 9 (155 mg, 159 μmol) in DMF (1.6 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 obtain Compound 1 (94 mg, 44 μmol, 28%) as a pale 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.

[0124] 5) HB37A6 is enzymatically reconstituted into HB37A6-(GlcNAc(Fuc)1-6-N3-GalNAc)2. HB37A6 was expressed in HEK293 cells and purified. 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 (equivalents) compared to the antibody) disclosed in PCT / EP2016 / 059194 (in a solution of histidine (20 mM) + NaCl (150 mM) containing 6 mM MnCl2) for 16 hours at 30°C.

[0125] Subsequently, the resulting incubation mixture was purified using a 50 mL protA column (Hitrap Mabselect Sure, GE, 11-0034-95). The incubation mixture obtained above was introduced into the column and washed with TBS + 0.2% Triton and TBS. Next, the column was eluted with 0.1 M acetate buffer (pH 2.9) and neutralized with 2.5 M Tris-HCl (pH 7.2). After dialyzing three times with PBS, the obtained (modified) glycosylated antibody was concentrated to 32.6 mg / mL using a Vivaspin Turbo 15 ultrafiltration system (Sartorius).

[0126] The obtained glycosylated antibody was analyzed by mass spectrometry, with the main steps being as follows: The glycosylated antibody was treated with IdeS prior to mass spectrometry, and the Fc / 2 fragment was analyzed. 20 μg of (modified) glycosylated antibody solution was incubated with 10 μL total volume of IdeS (Fabricator®) (1.25 U / μL) in PBS (pH 6.6) at 37°C for 1 hour. The sample was diluted to 80 μL and analyzed by JEOL AccuTOF (ESI-TOF), and the deconvoluted spectrum was obtained using Magtran software. Mass spectrometry of the IdeS digested sample revealed that the main product corresponds to the obtained HB37A6-(GlcNAc(Fuc)1-6-N3-GalNAc)2, with an observed mass of 24,330.4.

[0127] Therefore, the above results demonstrate that HB37A6-(GlcNAc(Fuc)1-6-N3-GalNAc)2 was obtained in which the GlcNAc of Asn297 in both heavy chains was replaced with 6-azide-GalNAc (substituted at position 4).

[0128] 6) Preparation of HB37A6-SYNtecan E complex (IEX019-02) The bioconjugate IEX019-02 of the present invention was prepared by conjugating compound 1 (linker payload) as a linker complex to azide-modified HB37A6-(GlcNAc(Fuc)1-6-N3-GalNAc)2 as a biomolecule. Accordingly, 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), PBS pH 7.4 (808 μL), 1,2-propylene glycol (11.3 mL), and compound 1 (350 μL, 40 mM DMF solution) were added. The reaction mixture was incubated overnight at room temperature, then filtered and dialyzed to PBS pH 7.4. Charcoal (350 mg) was added, and the residual free payload was removed by rotation overnight at room temperature. The charcoal was removed by centrifugation and filtration. ADCs were purified using an AKTA Purifier-10 (GE Healthcare) equipped with a Superdex200 26 / 600 SEC (GE Healthcare) column.

[0129] Mass spectrometry of the IdeS digested sample revealed two main products corresponding to the obtained ADC, namely the HB37A6-SYNtecan E complex. The first peak: observed mass 26469 Da (calculated mass 26465 Da), corresponds to the bound Fc / 2 fragment (a blocked lactone form with twice the payload). The second peak: observed mass 26499 Da (calculated mass 26501 Da), corresponds to the bound Fc / 2 fragment (an open carboxylate form with twice the payload).

[0130] 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 over 99%, and the concentration was 6.12 mg / ml. [ka] In the formula, q represents the average DAR, for example, 3 to 5, 3.2 to 4.8, or 3.5 to 4.5 (e.g., 3.52). In the formula, Ab is HB37A6.

[0131] It is important to understand that the average DAR is the DAR measured for the prepared ADC product, and the average DAR of products from different batches may differ.

[0132] Example 2. Manufacturing of the formulation A solution of 20 mg / mL IEX019-02 ADC, 20 mM histidine, 8% (w / v) sucrose, and 0.02% (w / v) polysorbate 80, pH 6.5, was freeze-dried (the freeze-drying process can be prepared according to conventional processes in the art), and the freeze-drying process parameters are shown in Table 1. [Table 2]

[0133] Example 3: Phase Ia and Phase Ib Clinical Trials 1. Test antibodies and other pharmaceuticals Investigational drug: The Claudin 18.2-targeting antibody-drug conjugate of the present invention (IEX019-02) Active ingredient content: 100 mg / vial

[0134] 2. Selection / Exclusion Criteria for Targets Selection criteria: To qualify, applicants must meet all of the following conditions.

[0135] Selection criteria required for both Phase Ia and Phase Ib: 1. I am willing and capable to sign the Informed Consent Form (ICF) and to follow the visits and related procedures outlined in the plan. 2. Dose escalation phase in Phase Ia: According to the RECIST v1.1 response evaluation criteria for solid tumors, at least one evaluable lesion must be present. Dose expansion phases in Phases Ia and Ib: According to the RECIST v1.1 response evaluation criteria for solid tumors, at least one measurable lesion must be present. 3. Regardless of gender, all participants were 18 years of age or older. 4. According to the Eastern Cooperative Oncology Group Performance Status (ECOG PS), the score is 0 or 1. 5. The predicted survival time was 12 weeks or longer. 6. Bone marrow and organ function are adequate. • Blood test: ANC ≥ 1.5 × 10 9 / L, platelet count ≥100×10 9 The patient must not have received any transfusions of blood products (including red blood cell suspensions, platelet components, cryoprecipitations, etc.), erythropoietin (EPO), G colony-stimulating factor (G-CSF), or granulocyte-macrophage colony-stimulating factor (GM-CSF) within 7 days prior to blood collection. • Liver function: TBIL ≤ 1.5 × ULN (TBIL ≤ 3 × ULN is acceptable in patients with Gilbert's syndrome), ALT and AST ≤ 2.5 × ULN in patients without liver metastases, ALT and AST ≤ 5 × ULN and albumin ≥ 28 g / L in patients with liver metastases. • Renal function: Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL / min (using the Cockcroft-Gault formula), urinary protein < 2+ or 24-hour total urinary protein < 1 g. • Coagulation function: International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN (subjects receiving anticoagulation therapy and with coagulation function within the above range were accepted). 7. Women of childbearing age, or men whose partners are of childbearing age, were required to use effective contraception throughout the entire treatment period and within six months after the end of the treatment period.

[0136] Selection criteria for the Phase Ia dose escalation stage: 1. Patients with unresectable, locally advanced, or metastatic G / GEJ AC, PDAC, BTC, or other solid tumors diagnosed histopathologically as refractory or intolerant to standard treatment, or not receiving standard treatment. 2. Histopathological examination confirmed CLDN18.2 positivity (**Subjects with high CLDN18.2 expression were preferred to be registered with G / GEJ AC, and **Subjects with moderate and high CLDN18.2 expression were preferred to be registered with PDAC).

[0137] Selection criteria for cohort A in phase Ib: 1. Histopathologically confirmed unresectable, locally advanced, or metastatic G / GEJ AC. 2. The patient has received at least two systemic therapies (anti-PD-(L)1 therapy + platinum-based chemotherapy, fluorouracil, paclitaxel / docetaxel, or irinotecan; patients with HER2 overexpression (defined as immunohistochemical results of 3+ or 2+ and ISH+) must have received anti-HER2 therapy, and patients who have not previously received anti-PD-(L)1 therapy or anti-HER2 therapy must have a valid reason for contraindication or lack of benefit) and is experiencing disease progression. 3. Histopathological examination confirmed high expression of CLDN18.2.

[0138] Selection criteria for cohort B in phase Ib: 1. Unresectable, locally advanced, or metastatic G / GEJ AC diagnosed histopathologically. 2. Disease progression was observed after first-line standard treatment (individuals with HER2 overexpression should receive anti-HER2 therapy unless there is a reasonable reason for it to be contraindicated or not beneficial). 3. Histopathological examination confirmed positivity for *CLDN18.2.

[0139] Selection criteria for cohort C in phase Ib: 1. Unresectable, locally advanced, or metastatic PDAC diagnosed histopathologically. 2. Disease progression occurred after at least one systemic treatment.

[0140] Selection criteria for cohort D in phase Ib: 1. Unresectable, locally advanced, or metastatic BTC diagnosed histopathologically. 2. Disease progression occurred after at least one systemic treatment. 3. Histopathological examination confirmed positivity for *CLDN18.2.

[0141] Note: *CLDN18.2 positive: Defined as a condition in which the degree of membrane staining in tumor tissue detected by immunohistochemistry indicates that the percentage of tumor cells is 1% or more, and previous test results, research center test results, and central laboratory test results are within acceptable limits. **High CLDN18.2 expression: The intensity of Claudin18.2 immunohistochemical membrane staining was 2+ or higher in more than 75% of tumor cells.** ***Moderate and high CLDN18.2 expression: The intensity of Claudin18.2 immunohistochemical membrane staining was 2+ or higher in more than 50% of tumor cells.

[0142] Exclusion criteria: Participants who met any of the following criteria were not selected for this clinical trial.

[0143] Common exclusion criteria for Phase Ia and Phase Ib: 1. You are participating in another interventional clinical trial, excluding observational (non-interventional) clinical trials, or you are in the survival follow-up phase of an interventional clinical trial. 2. The patient received their last antitumor treatment within 4 weeks prior to the first dose of the investigational drug, or within 5 half-lives of the antitumor drug (whichever is shorter). 3. Patients are expected to receive other antitumor treatments while undergoing treatment with the investigational drug [to enable palliative radiotherapy aimed at alleviating symptoms (such as pain) without affecting efficacy evaluation]. 4. The patient has received treatment with a potent cytochrome P450 3A4 (CYP3A4) inhibitor within two weeks or five half-lives prior to the first dose of the investigational drug (whichever is longer). 5. The participant has received any live vaccine within four weeks prior to the first dose of the investigational drug, or is scheduled to receive any live vaccine during the clinical trial period. 6. Prior to the first dose of the investigational drug, the patient had prior treatment-induced toxicity that had not been reduced to level 0 or 1 on the NCI CTCAE v5.0 scale (excluding hair loss, fatigue, hyperpigmentation, and other conditions that the principal investigator determined did not pose a safety risk). 7. Within four weeks prior to the first dose of the investigational drug, you have undergone major surgery (craniotomy, thoracotomy, or laparotomy, or any other surgery as defined by the principal investigator, excluding biopsies), or you have an unhealed wound, ulcer, or fracture, or you are scheduled to undergo major surgery during the study period. Note: Local surgical treatment for isolated lesions is acceptable for palliative purposes. 8. I previously received whole-pelvis radiation therapy. 9. Presence of pyloric obstruction and / or persistent recurrent vomiting (three or more episodes of vomiting within a 24-hour period). 10. The patient had a history of gastrointestinal perforation and / or fistula that did not heal with surgical treatment within six months prior to the first dose of the investigational drug. 11. Symptomatic metastases to the central nervous system. Patients with asymptomatic brain metastases (i.e., no neurological symptoms, no need for glucocorticoid treatment, and all brain metastases ≤ 1.5 cm) or patients whose symptoms are stable after treatment for brain metastases must meet all of the following criteria to be enrolled in this trial: A stable clinical state with clinical evidence confirming the absence of metastases to the midbrain, pons, cerebellum, meninges, medulla oblongata, or spinal cord, and the absence of new or expanding brain metastases, and discontinuation of corticosteroid and anticonvulsant therapy at least two weeks prior to the first dose of the investigational drug. Note: The central nervous system is not a target lesion. 12. A history of pneumonia requiring hormone therapy, or a history of poorly controlled lung disease such as interstitial lung disease, non-infectious pneumonia, severe pulmonary dysfunction or pulmonary fibrosis, severe radiation pneumonitis, or acute lung injury, or suspected of having any of the aforementioned diseases at the time of screening. 13. There is an uncontrollable illness, for example, • Within four weeks prior to the first dose of the investigational drug, the patient has an uncontrolled infection requiring systemic anti-infective therapy (antibiotics, antiviral drugs, or antifungal drugs). • Individuals infected with human immunodeficiency virus (HIV) (HIV 1 / 2 antibody positive). • Acute or chronic active hepatitis B (defined as positive for hepatitis B surface antigen (HBsAg) and / or hepatitis B core antibody (HBcAb), and a hepatitis B virus DNA copy number of 104 copies / mL or greater, or 2000 IU / mL or greater, or exceeding the detection limit) or acute or chronic active hepatitis C [positive for hepatitis C virus antibody (HCVAb), and HCV RNA greater than 103 copies / mL]. Patients receiving nucleotide antiviral therapy and meeting the above criteria, as well as those who are HCV antibody positive but RNA test negative, were permitted to register. ·Active COVID-19 infection. • The patient has active pulmonary tuberculosis and is receiving anti-tuberculosis treatment, or has received anti-tuberculosis treatment within one year prior to the first dose of the investigational drug. Active syphilis or latent syphilis requires treatment. • A personal or family history of symptomatic congestive heart failure (New York Heart Association NYHA grade II-IV), symptomatic or uncontrolled arrhythmias, QTc interval > 480 ms, or congenital long / short QT syndrome. • Hypertension that is poorly controlled with standardized treatment (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg). 14. Within six months prior to the first dose of the investigational drug, the patient has experienced any of the following arterial thromboembolic events: myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack. 15. The tumor may have infiltrated surrounding vital structures (such as major blood vessels or the trachea), or there may be a risk of developing a gastrointestinal or respiratory fistula. 16. After stent placement surgery in the trachea or gastrointestinal tract. 17. Symptomatic pleural effusion, ascites, or pericardial effusion requiring intervention (such as drainage). 18. Patients with esophageal or gastric varices requiring emergency intervention (such as bandaging or sclerotherapy), or those with evidence of portal hypertension (including splenomegaly detected on imaging) or a history of variceal bleeding, based on the opinion of the principal investigator or in consultation with a gastroenterologist or hepatologist, must undergo endoscopy within three months prior to the first dose of the investigational drug. 19. A life-threatening bleeding event, or a Grade 3 or 4 gastrointestinal / variceal bleeding event requiring transfusion, endoscopy, or surgical treatment, occurring within 3 months prior to the first dose of the investigational drug. 20. A history of deep vein thrombosis, pulmonary embolism, or other severe venous thromboembolism within three months prior to the first dose of the investigational drug (thrombosis related to implanted venous access ports or catheters, or superficial venous thrombosis, was not considered “severe” venous thromboembolism). 21. Hepatic encephalopathy, hepatorenal syndrome, or severe cirrhosis of the liver, classified as Child-Pugh class B or higher. 22. There is a risk of bowel obstruction or perforation (including, but not limited to, a history of acute diverticulitis and intra-abdominal abscess), or a history of inflammatory bowel disease or extensive bowel resection (partial colectomy or extensive small bowel resection complicated with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea. 23. If intravenous nutritional supplementation is required, malnutrition is severe. This excludes patients whose malnutrition had improved for more than 4 weeks prior to the first dose of the investigational drug. 24. The principal investigator determined that the subject was ineligible to participate in this clinical trial because other acute or chronic diseases, or abnormal clinical test values, could increase the risk of participating in the clinical trial or receiving the investigational drug, or could interfere with the interpretation of the clinical trial results. 25. Neurological, mental, or social conditions that meet any of the following criteria: affecting compliance with clinical trial requirements, significantly increasing the risk of adverse events, or affecting the subject's ability to provide written ICF. 26. History of other primary malignancies, excluding those listed below: • Cured malignant tumors with no active disease in at least two years prior to clinical trial enrollment and with a very low risk of recurrence. • Non-melanoma skin cancer or malignant lentigo that has been properly treated and shows no evidence of disease recurrence. • Carcinoma in situ that has received adequate treatment and shows no evidence of disease recurrence. 27. History of immunodeficiency. 28. History of allogeneic organ transplantation and history of allogeneic hematopoietic stem cell transplantation. 29. A history of severe allergic reactions to other monoclonal antibodies and / or allergic reactions to any formulation component of the antibody-drug conjugate targeting Claudin 18.2 of the present invention. 30. For pregnant or breastfeeding women. 31. Any other condition that, in the judgment of the principal investigator, makes the participant ineligible to participate in this clinical trial.

[0144] 3. Method and Procedure of Administration Dosage: 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 4.5 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg. The actual dose (mg) is calculated based on the subject's body weight (kg). The initial dose was calculated based on the subject's baseline body weight. If the subject's body weight changes by less than ±10% from baseline (body weight at the time of the first dose during the study period), the baseline body weight is used for dose calculation. Otherwise, the actual dose is calculated based on the pre-determined dose date or the day before dose.

[0145] Method of administration: Intravenous infusion (peripheral vein, central venous catheter, or infusion port). If indicated, an infusion pump may be used.

[0146] Dosage frequency: The administration cycle was 3 weeks / 21 days (Q3W), with one dose administered on the first day of each cycle.

[0147] 4. Experimental Results Safety evaluation • Incidence, correlation with investigational drug, and severity of all TEAEs, AESIs, and SAEs. Changes in vital signs, physical examination results, and clinical test results before, during, and after treatment with the investigational drug. • Immunogenicity: ADA assays are performed on all subjects, and neutralizing antibody (NAb) assays are performed on ADA-positive serum samples (if necessary).

[0148] PK rating • PK properties of the drug in the human body after single and multiple doses. AUC, Tmax, Ctrough, Cmax, CL, V, t 1 / 2 The main PK parameters, including those mentioned above, are determined.

[0149] Effectiveness evaluation • Efficacy evaluation for solid tumors was based on RECIST v1.1, and evaluation indices included ORR, DoR, DCR, TTR, and PFS. • OS.

[0150] Biomarker evaluation • Evaluate the relationship between the expression level of CLDN18.2 in tumor tissue before treatment and the therapeutic effect.

[0151] Sample size To accurately assess the dose escalation phase (Phase Ia), we planned to enroll approximately 14-30 subjects eligible for DLT evaluation.

[0152] Dose escalation phase (Phase Ia): For each tumor type, 2 to 4 doses were planned to be selected for escalation. Approximately 6 to 60 subjects were enrolled for each escalation dose, resulting in a total of approximately 40 to 140 cases being enrolled.

[0153] Phase Ib: Approximately 261 participants were planned to be enrolled.

[0154] Cohort A: According to the primary estimation goal of this cohort, assuming that the ORR after monotherapy with an antibody-drug conjugate targeting Claudin 18.2 reaches 25%, with a one-sided level of 0.025, using 100 samples, we can observe with approximately 90% confidence that the lower limit of the 95% confidence interval for ORR after treatment with the antibody-drug conjugate therapy targeting Claudin 18.2 of the present invention was 12%. Assuming an exclusion rate of 10%, 111 subjects needed to be enrolled.

[0155] Cohort B: Approximately 50 subjects were planned to be enrolled to evaluate the efficacy of monotherapy with the Claudin 18.2-targeting antibody-drug conjugate of the present invention.

[0156] Cohorts C and D: To evaluate the efficacy of monotherapy with the Claudin 18.2-targeting antibody-drug conjugate of the present invention, approximately 50 subjects were planned to be enrolled in each cohort (including subjects who received RP2D during the dose escalation phase (Phase Ia)).

[0157] statistical methods Descriptive statistics were used to summarize all safety, PK, immunogenicity, and efficacy data. For continuous variables, descriptive statistics (such as number of cases, mean, standard deviation, median, minimum, and maximum; for PK indices, geometric mean and geometric coefficient of variation) were used for summarization, while for discrete variables, frequency and percentages were used for summarization. The indicators of antitumor effect included the following: - Best overall efficacy [complete response (CR), partial response (PR), stable disease (SD), or disease progression (PD)] -ORR(CR+PR) and DCR(CR+PR+SD) -DoR or TTR -PFS -OS Where permitted by the data, ORR and DCR and their 95% CIs are provided, and the percentage of subjects showing the best response of CR, PR, SD, or PD is also calculated. The Kaplan-Meier method is used to calculate the median time and 95% CI of DoR, TTR, PFS, OS, and the ratio and 95% CI at specified time points (if applicable, e.g., 6 months, 12 months, and every 6 months thereafter).

[0158] The Claudin18.2-targeting antibody-drug conjugate of the present invention, as a bystander ADC, demonstrated significant tumor suppression in mouse tumor models with high and low CLDN18.2 expression. To verify the above conclusions, drug therapy exploration experiments were conducted in clinical trials of the present invention on subjects with multiple tumor types and different levels of CLDN18.2 expression. Monotherapy with the Claudin18.2-targeting antibody-drug conjugate of the present invention was estimated to achieve an ORR of 25% in gastric / gastroesophageal junction adenocarcinoma with high CLDN18.2 expression that had failed previous second-line systemic therapy, improving PFS and OS, and demonstrating good tolerability.

[0159] Eligible patients (pt) with advanced solid tumors refractory to or intolerant of standard treatment were enrolled. During dose escalation, six dose levels of the Claudin 18.2-targeted antibody-drug conjugate (0.3 / 1 / 3 / 6 / 8 / 10 mg / kg intravenous Q3W) were evaluated. The selected dose levels were expanded in patients with CLDN18.2-positive gastric / gastroesophageal junction adenocarcinoma (G / GEJ AC), defined as ≥1% tumor cells with immunohistochemical membrane staining intensity (1+ / 2+ / 3+). 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), as assessed by the investigator according to RECIST v1.1.

[0160] As of January 15, 2024, 159 patients were enrolled in China and Australia (male: 61.0%, median age: 58.0 years, ECOG PS 1: 82.4%, Stage IV: 96.8%, median number of prior treatment lines: 2, G / EJ AC: 66.7%), with 79 patients receiving 6 mg / kg and 51 patients receiving 8 mg / kg. The median treatment duration was 13.7 weeks (range: 3.0-40.6). Dose-limiting toxicities (DLTs) were observed in 2 out of 6 patients at a dose of 10 mg / kg (1 case of G4 myelosuppression, 1 case of G4 neutropenia and 1 case of G3 febrile neutropenia). Of all patients, treatment-related adverse events (TEAEs) occurred in 149 patients (93.7%), and TEAEs of G3 or higher occurred in 79 patients (49.7%). The most common TEAEs were anemia (54.7%), leukopenia (47.8%), and neutropenia (46.4%). The incidence of Grade 3 or higher gastrointestinal toxicity, such as vomiting (1.9%), nausea (1.3%), and decreased appetite (1.3%), was low. Hypoalbuminemia occurred in 24.5% of patients, but no patients experienced Grade 3 or higher events. Two treatment-induced adverse events (TRAEs) that led to treatment discontinuation occurred (1.3%). There were no TRAEs resulting in death. As of February 2, 2024, efficacy was evaluable in CLDN18.2-positive (1+ / 2+ / 3+≧1%) patients (n=95) with G / GEJ AC. 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 levels (2+ / 3+≧75%), the ORR was 43.5% (95% CI: 23.2~65.5) at 6 mg / kg (n=23) and 47.1% (95% CI: 23.0~72.2) at 8 mg / kg (n=17). In patients with high CLDN18.2 expression levels who received 6 mg / kg, the median PFS was 6.8 months (95% CI: 4.2~NC), with events occurring in 13 patients. PFS and DoR in other patients were immature.

[0161] Eligible patients who were refractory to or unable to tolerate standard treatment were enrolled. Claudin 18.2-targeted antibody-drug conjugates were administered intravenously at 6 mg / kg or 8 mg / kg Q3W. In dose escalation, patients were enrolled regardless of CLDN18.2 expression. For dose expansion, patients needed to have CLDN18.2 expression of ≥40% (immunohistochemical staining intensity 1+ / 2+ / 3+). The primary endpoint was safety. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and progression-free survival (PFS), as assessed by the investigator according to RECIST v1.1.

[0162] As of December 19, 2023, 35 patients (1 dose escalation, 34 dose expansion) from China and Australia were enrolled (male: 57.1%, median age: 58.0 years, ECOG PS 1: 71.4%, Stage IV: 91.4%, median number of prior treatment lines: 2), of which 28 were PDAC patients and 7 were BTC patients. Patients were administered an antibody-drug conjugate targeting Claudin 18.2 at 6 mg / kg (n=17) or 8 mg / kg (n=18). The median treatment duration was 7.0 weeks (range: 3.0-23.6), and 23 patients (65.7%) were still undergoing treatment. Treatment-related adverse events (TRAEs) occurred in 28 patients (80.0%), of which 9 patients (25.7%) experienced grade 3 or higher TRAEs. Common TRAEs (≥20%) included anemia (42.9%), neutropenia (28.6%), nausea (25.7%), vomiting (25.7%), and leukopenia (22.9%). Four serious TRAEs occurred (11.4%). TRAEs leading to treatment interruption and discontinuation occurred in seven patients (20.0%) and one patient (2.9%), respectively. No TRAEs resulted in death. The safety profiles of the Claudin 18.2-targeting antibody-drug conjugates in PDAC and BTC were comparable to those of the overall study cohort, and no new safety signals were observed. As of January 15, 2024, 25 patients receiving 6 mg / kg and 8 mg / kg were available for efficacy evaluation. Partial responses (PRs) were observed in seven patients (5 in PDAC and 2 in BTC). The ORR was 28.0% (95% CI: 12.1–49.4), and the DCR was 80.0% (95% CI: 59.3–93.2). Of the evaluable patients (1+ / 2+ / 3+, n=13) with CLDN18.2 expression of 60% or higher who received 6 mg / kg, 5 achieved a 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). Among the 10 PDAC patients in this subgroup, the ORR was 40% (95% CI: 12.2–73.8). DoR and PFS data were immature.

[0163] 5. Study of administration regimens Based on a comprehensive analysis of clinical safety, efficacy, and PK data of the CLAUDIN18.2-targeting antibody-drug conjugate of the present invention, a dose of 6 mg / kg Q3W was selected as the recommended dosing regimen for the main clinical trial of the CLAUDIN18.2-targeting antibody-drug conjugate of the present invention.

[0164] Pharmacokinetics The antibody-drug conjugate targeting CLAUDIN18.2 of the present invention has a half-life of approximately 2 weeks (NCA method) in tumor patients, and a 3-week dosing interval was supported.

[0165] clinical safety Exposure safety analysis revealed that, in the dose range of 1–10 mg / kg, the clinical safety risk of the antibody-drug conjugate targeting CLAUDIN18.2 of the present invention increased with increasing dose. In the dose range of 1–6 mg / kg, the relationship between exposure and safety was relatively flat, and the overall safety at 6 mg / kg was good. Above 6 mg / kg, the safety risk increased significantly.

[0166] Clinical effectiveness Exposure effect analysis revealed no clear exposure-dependent trend in the PR rate within the dose range of 3–6 mg / kg, indicating that the PR rate reached a consistent level. A significant exposure-dependent trend was observed in DC (disease control, SD+PR), and the DCR plateaued at a dose of 6 mg / kg. 6 mg / kg was the optimal effective dose.

[0167] In summary, the 6 mg / kg Q3W dosing regimen was the optimal regimen, offering a good balance of clinical benefit and safety.

[0168] Example 4: Phase III Clinical Trial 1. Investigational drug The present invention relates to an injectable antibody-drug conjugate targeting Claudin 18.2 (IEX019-02). Irinotecan Paclitaxel

[0169] 2. Test Objectives 2.1. Main Examination Objectives This study compares progression-free survival (PFS), overall survival (OS), and other efficacy indicators between monotherapy with the CLAUDIN18.2-targeting antibody-drug conjugate of the present invention (experimental group) and a treatment selected by the investigators (control group) as subsequent treatment for patients with gastric cancer or gastroesophageal junction adenocarcinoma.

[0170] 2.2 Other Test Objectives For patients with gastric cancer or gastroesophageal junction adenocarcinoma, the present invention's CLAUDIN18.2-targeting antibody-drug conjugate (test group) will be compared with a treatment chosen by the principal investigator (control group) using other efficacy indicators (including ORR, DCR, DoR, and TTR).

[0171] The quality of life will be assessed for two control groups.

[0172] The safety and tolerability of the antibody-drug conjugate (test group) targeting CLAUDIN18.2 of the present invention will be further evaluated in the subjects.

[0173] The overall pharmacokinetic (PK) characteristics of the CLDN18.2 antibody-drug conjugate and exatecan will be evaluated.

[0174] The immunogenicity of the antibody-drug conjugate targeting CLAUDIN18.2 according to the present invention will be evaluated.

[0175] 3. Selection / Exclusion Criteria for Targets Selection criteria: To qualify, applicants must meet all of the following conditions.

[0176] Common selection criteria for the safety introduction phase and the early clinical trial phase: 1. I am willing and capable to sign the Informed Consent Form (ICF) and to follow the visits and related procedures outlined in the plan. 2. Regardless of gender, the age at which the ICF was signed must meet the definition of adulthood according to local regulations (e.g., 18 years or older in the United States). 3. According to the Eastern Cooperative Oncology Group Performance Status (ECOG PS), the score was 0 or 1. 4. The predicted survival time was 12 weeks or longer. 5. Bone marrow and organ function are adequate. • Blood test: ANC ≥ 1.5 × 10 9 / L, platelet count ≥100×10 9 The subject must not have received any transfusions of blood products (red blood cell suspension, platelet component, cryoprecipitation, etc.), erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), or granulocyte-macrophage colony-stimulating factor (GM-CSF) within 7 days prior to blood collection. • Liver function: TBIL ≤ 1.5 × ULN (TBIL ≤ 3 × ULN was acceptable in patients with Gilbert's syndrome), ALT and AST ≤ 2.5 × ULN in patients without liver metastases, ALT and AST ≤ 5 × ULN in patients with liver metastases, albumin ≥ 28 g / L (the subjects were not permitted to receive treatment with human serum albumin infusion in the 7 days prior to blood collection). • Renal function: Creatinine clearance ≥ 60 mL / min (using the Cockcroft-Gault formula), urinary protein < 2+ or 24-hour total urinary protein < 1 g. • Coagulation function: International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN (the subjects were permitted to receive anticoagulation therapy, and their coagulation function was within the above range). 6. Female participants must agree not to breastfeed from the time of screening until 6 months after the last dose. 7. Women of childbearing age, or men whose partners are of childbearing age, were required to use effective contraception from the time of screening through the entire treatment period, and within six months after the end of the treatment period. Male participants must agree not to provide sperm from the screening stage through the entire trial period and within six months after the last dose. • Female participants must agree not to donate eggs during the screening period, throughout the entire trial period, and within 6 months after the last dose. • Female patients must agree not to breastfeed from the screening stage through the entire treatment period, and within six months after the last dose.

[0177] Additional selection criteria in the early stages of clinical trials: 8. Histopathologically diagnosed, unresectable, locally advanced, or metastatic gastric / gastroesophageal junction adenocarcinoma (G / GEJA). 9. Advanced, locally advanced, or metastatic gastric / gastroesophageal junction adenocarcinoma confirmed by imaging studies. 10. The patient has a disease lesion (measurable and / or unmeasurable disease) that can be evaluated by radiographic imaging according to RECIST 1.1 criteria. If a patient has only one radiologically evaluable lesion, and that lesion has been previously treated with local radiotherapy, the progression of the disease after radiotherapy must be clearly explained. 11. The patient has received at least two systemic treatments (previous treatments must include fluorouracil, platinum-based chemotherapy, paclitaxel / docetaxel, irinotecan, or a taxane) and has experienced disease progression. The number of previous systemic treatment lines was four or less. a) If the period from the end of the previous (new) systemic adjuvant therapy to disease recurrence / progression is within 6 months, it is considered primary treatment. b) If a specific drug was discontinued due to an adverse event in a previous combination therapy, but the other drugs in the combination continued to be used, it is considered the same treatment regimen. c) No progression of the disease was observed, and the dosage form was changed to the same one, so it was considered the same treatment plan. 12. Positive expression of CLDN18.2* was confirmed by histopathological examination in the central laboratory. For subjects who have previously received any anti-CLDN18.2 treatment, tumor samples should be collected again after completion of the relevant anti-CLDN18.2 treatment. Note: *CLDN18.2 positive: The degree of Claudin18.2 immunohistochemical staining was 2+ or higher in more than 75% of tumor cells.

[0178] Additional selection criteria during the safe implementation phase: 13. Histopathologically confirmed locally advanced, unresectable or metastatic solid tumor, failure or intolerance of standard treatment, or lack of standard treatment.

[0179] Exclusion criteria: Participants who met any of the following criteria were not selected for this clinical trial. 1. HER2-positive (immunohistochemistry [IHC] 3+, or IHC 2+ and positive in situ hybridization). HER2-positive subjects who had previously received anti-HER2 therapy did not meet the exclusion criteria if HER-2 detection was negative in tissue samples taken after anti-HER2 therapy. (For early-stage clinical trials) 2. You are participating in another interventional clinical trial, excluding observational (non-interventional) clinical trials, or you are in the survival follow-up phase of an interventional clinical trial. 3. The patient has previously received antibody-drug conjugate therapy based on a topoisomerase inhibitor. 4. The patient has received their last antitumor treatment within 4 weeks prior to the first dose of the investigational drug, or within 5 half-lives of the antitumor drug (this includes herbal medicines that are indicated for gastric cancer in the prescription, but does not include crude drug preparations) (whichever is shorter) (a 4-week drug-free period is required for drugs that do not have an exact half-life). 5. Patients are expected to receive other antitumor treatments while undergoing treatment with the investigational drug [to enable palliative radiotherapy aimed at alleviating symptoms (such as pain) without affecting efficacy evaluation]. 6. The patient has received treatment with a potent cytochrome P450 3A4 (CYP3A4) inhibitor within two weeks or five half-lives prior to the first dose of the investigational drug (whichever is longer). 7. You have received any live vaccine within four weeks prior to the first dose of the investigational drug, or you are scheduled to receive any live vaccine during the clinical trial period. 8. Prior to the first dose of the investigational drug, the patient had prior treatment-induced toxicity that had not been reduced to level 0 or 1 on the NCI CTCAE v5.0 scale (excluding hair loss, fatigue, hyperpigmentation, and other conditions that the principal investigator determined did not pose a safety risk). 9. Within four weeks prior to the first dose of the investigational drug, the patient has undergone major surgery (craniotomy, thoracotomy, or laparotomy, or any other surgery as defined by the principal investigator, excluding biopsies), has an unhealed wound, ulcer, or fracture, or has undergone laparoscopic exploratory surgery within two weeks prior to the first dose of the investigational drug, or is scheduled to undergo major surgery during the study period. Note: Local surgical treatment for isolated lesions was permitted for palliative purposes. 10. Patients with bone metastases at risk of lower body paralysis. 11. I previously underwent whole-pelvis radiation therapy. 12. The patient received radiotherapy within three weeks prior to the first dose. Patients who received radiotherapy within three weeks prior to the first dose must meet all of the following conditions before registration: Currently, there are no radiation-related toxic reactions (including, but not limited to, not requiring glucocorticoids, but excluding radiation pneumonitis, radiation hepatitis, radiation enteritis, intestinal dysfunction, etc.), and they do not require glucocorticoids. 13. Obstruction of the cardia and pylorus affecting eating or gastric emptying, and / or persistent recurrent vomiting (three or more episodes of vomiting within a 24-hour period). 14. The patient had a history of gastrointestinal perforation and / or fistula that did not heal with surgical treatment within six months prior to the first dose of the investigational drug. 15. Symptomatic metastases to the central nervous system and / or spinal compression symptoms. For subjects with asymptomatic brain metastases (i.e., no neurological symptoms, no need for glucocorticoid treatment, and all brain metastases ≤ 1.5 cm) or subjects whose symptoms are stable after treatment for brain metastases, all of the following criteria must be met to enroll in this trial: A stable clinical state with clinical evidence confirming the absence of metastases to the midbrain, pons, cerebellum, meninges, medulla oblongata, or spinal cord, and the absence of new or expanding brain metastases, and discontinuation of corticosteroid and anticonvulsant treatment at least two weeks prior to the first dose of the investigational drug. Note: The central nervous system was not a target lesion. 16. You have a history of interstitial lung disease, non-infectious pneumonia, severe pulmonary dysfunction, or poorly controlled lung disease such as pulmonary fibrosis, severe radiation pneumonitis, or acute lung injury, or you are suspected of having any of the aforementioned diseases at the time of screening. 17. There is an uncontrollable illness, for example, • Within one week prior to the first dose of the investigational drug, the patient has had a severe infection that is active or clinically uncontrolled and requires treatment with a systemic anti-infective agent (antibiotic, antiviral, or antifungal) including but not limited to the respiratory, urinary, or biliary systems. • Individuals infected with human immunodeficiency virus (HIV) (HIV 1 / 2 antibody positive). • Acute or chronic active hepatitis B [Participants who are positive for hepatitis B surface antigen (HBsAg) and / or hepatitis B core antibody (HBcAb) must undergo further hepatitis B virus (HBV) DNA testing. Participants can participate in the clinical trial if their HBV DNA copy count is 10⁴ copies / mL or less, or 2000 IU / mL or more, or below the detection limit.] or acute or chronic active hepatitis C [positive for hepatitis C virus antibody (HCVAb), HCV RNA > 10⁧ copies / mL]. Participants receiving nucleotide antiviral therapy and meeting the above criteria, as well as those who are HCV antibody positive but RNA test negative, were permitted to enroll. • The patient has active pulmonary tuberculosis and is receiving anti-tuberculosis treatment, or has received anti-tuberculosis treatment within one year prior to the first dose of the investigational drug. • Active syphilis or latent syphilis required treatment. • A personal or family history of symptomatic congestive heart failure (New York Heart Association NYHA grade II-IV), symptomatic or uncontrolled arrhythmias, QTc interval > 480 ms, or congenital long / short QT syndrome. • Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg). 18. Within six months prior to the first dose of the investigational drug, the patient has experienced any of the following arterial thromboembolic events: myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack. 19. A history of deep vein thrombosis, pulmonary embolism, or other severe venous thromboembolism within three months prior to the first dose of the investigational drug (thrombosis related to an implanted intravenous infusion port or catheter, or superficial venous thrombosis, was not considered “severe” venous thromboembolism). 20. The tumor may have infiltrated surrounding vital structures or organs (such as major blood vessels or the trachea), or there may be a risk of developing a gastrointestinal or respiratory fistula. 21. Post-stent placement surgery in the trachea or digestive tract [referring to the muscular tract from the oral cavity to the anal canal, including the oral cavity, pharynx, esophagus, stomach, small intestine (duodenum, jejunum, ileum), large intestine (cecum, appendix, colon, rectum), anal canal, etc.]. 22. Symptomatic pleural effusion, ascites, or pericardial effusion requiring intervention (such as drainage, peritoneal shunt, or cell-free concentrated ascites reinfusion therapy [CART]). Only asymptomatic patients with small amounts of pleural effusion, ascites, or pericardial effusion on imaging were selected (drainage and CART treatment were not permitted in the two weeks prior to screening). 23. Patients with esophageal or gastric varices requiring emergency intervention (such as bandaging or sclerotherapy), or those with evidence of portal hypertension (including splenomegaly detected on imaging) or a history of variceal bleeding, based on the opinion of the principal investigator or consultation with a gastroenterologist or hepatologist, must undergo endoscopy within three months prior to the first dose of the investigational drug. 24. A life-threatening bleeding event, or a Grade 3 or 4 gastrointestinal / variceal bleeding event requiring transfusion, endoscopy, or surgical treatment, occurring within three months prior to the first dose of the investigational drug. 25. Hepatic encephalopathy, hepatorenal syndrome, or severe cirrhosis of the liver, Child-Pugh classification B or higher. 26. During screening, the patient had complete or incomplete bowel obstruction, or a history of complete or incomplete bowel obstruction or risk of bowel perforation (including, but not limited to, a history of acute diverticulitis and abdominal abscess), or a history of any of the following conditions within three months prior to the first dose: inflammatory bowel disease or extensive bowel resection (partial colectomy or extensive small bowel resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea. 27. Severe malnutrition (e.g., requiring intravenous nutritional support, weight loss exceeding 5% within one month of ICF signing, weight loss exceeding 15% within three months, or a reduction of more than half in food intake within one week). Excluding those whose malnutrition had improved more than four weeks prior to the first dose of the investigational drug. 28. The principal investigator determined that the subject was ineligible to participate in this clinical trial because other acute or chronic diseases, or abnormal clinical test values, could increase the risk of participating in the clinical trial or receiving the investigational drug, or could interfere with the interpretation of the clinical trial results. 29. Poorly controlled metabolic disorders, other non-malignant organ diseases or systemic diseases, or secondary reactions to cancer (such as leukemoid reactions) may lead to increased medical risk and uncertainty in survival assessments. 30. Neurological, mental, or social conditions that meet any of the following criteria: affecting compliance with clinical trial requirements, significantly increasing the risk of adverse events, or affecting the subject's ability to provide a written ICF. 31. History of other primary malignancies, excluding those listed below: • Cured malignant tumors with no active disease in at least two years prior to clinical trial enrollment and with a very low risk of recurrence. • Non-melanoma skin cancer or malignant lentigo that has been properly treated and shows no evidence of disease recurrence. • Carcinoma in situ that has received adequate treatment and shows no evidence of disease recurrence. 32. History of immunodeficiency. 33. History of allogeneic organ transplantation and history of allogeneic hematopoietic stem cell transplantation. 34. Past severe allergic reactions to other monoclonal antibodies, and / or allergic reactions to any of the formulation components of the present invention: the Claudin 18.2-targeting antibody-drug conjugate, irinotecan, and paclitaxel. 35. Any other condition that, in the judgment of the principal investigator, makes the participant ineligible to participate in this clinical trial.

[0180] 4. Method and Procedure of Administration According to the research program, participants were randomly assigned to a test group and a control group in a 1:1 ratio. Stratification factors included region (Asian countries / regions excluding Japan vs. Japan vs. Europe / America), primary site of cancer (stomach vs. gastroesophageal junction), and primary tumor resection (with vs. without). Participants in the test group received an antibody-drug conjugate targeting CLAUDIN18.2 at a dose of 6 mg / kg IV D1, Q3W, every 3 weeks for one cycle. The control group received treatment of their choice, which was irinotecan 125 mg / m². 2 IV is administered every three weeks on D1, D8, and Q3W as one cycle (Note: 150 mg / m² in Europe and Japan). 2 IV D1, Q2W (administered every two weeks as one cycle), or paclitaxel 80 mg / m² 2 This includes administration of IV on D1, D8, D15, and Q4W, in cycles of four weeks. The principal investigator must select the treatment method before randomly assigning subjects.

[0181] Participants will continue treatment until the disease progresses and / or the investigator determines that the participant is no longer benefiting from the treatment, toxicity becomes unbearable, the ICF is discontinued, other reasons for discontinuing the investigational treatment occur, or the treatment period reaches 24 months (whichever comes first). Participants completed standard treatment. After treatment completion, safety and survival follow-up studies will be conducted for the participants. After disease progression, participants in the control group were not permitted to transfer to the group receiving the antibody-drug conjugate targeting CLAUDIN18.2 for treatment.

[0182] In this clinical trial, an Independent Data Monitoring Committee (IDMC) was established to review the accumulated safety data of the trial in order to ensure the safety of the subjects and the scientific validity of the experiment. Furthermore, based on the safety data, the IDMC provides recommendations to the sponsor regarding the continuation, modification, or discontinuation of the experiment. In the interim analysis, the IDMC reviews the results of the safety and efficacy data, determines the validity of the trial based on a pre-defined validity threshold, and provides recommendations to the sponsor. The responsibilities of IDMC members and related procedures are defined separately in the IDMC Charter. The final version of the IDMC Charter required approval from the IDMC and the sponsor before the analysis.

[0183] In Japan and the United States, a safety induction phase is established before commencing critical clinical practice. Each country enrolls 3 to 6 subjects to evaluate safety and PK characteristics. In the safety induction phase, three subjects are initially enrolled and treated with an antibody-drug conjugate targeting CLAUDIN18.2 at 6 mg / kg. The DLT observation period is 21 days from the first dose of the first cycle. If all three subjects do not experience DLT during the DLT observation period, critical clinical enrollment is initiated. If one of the initial three subjects experiences DLT, three additional subjects are included in the safety induction phase. If the additional three subjects do not develop DLT, critical clinical enrollment is initiated.

[0184] The present invention relates to an antibody-drug conjugate targeting CLAUDIN18.2. Dosage form: Lyophilized injection Active ingredient content: 100 mg / vial Method of administration: 6 mg / kg, D1, Q3W, intravenous infusion (IV). Irinotecan Method of administration: 125 mg / m² 2 D1, D8, Q3W, IV 150 mg / mm³ 2 D1, Q2W, IV (applicable only to research centers in the European Union and Japan). Paclitaxel Dosage method: 80 mg / m² 2 , D1, D8, D15, Q4W, IV.

[0185] 5. Analysis of experimental results Effectiveness evaluation • OS. • Efficacy evaluation for solid tumors was conducted in accordance with RECIST v1.1 and assessed by the IRRC and the principal investigator, with evaluation metrics including: PFS, ORR, DCR, DOR, and TTR.

[0186] Quality of life • EORTC QLQ-C30 score, EORTC QLQ-OG25 score, EQ-5D-5L score.

[0187] Safety evaluation • Incidence, correlation with investigational drug, and severity of all TEAEs, AESIs, and SAEs. Changes in vital signs, ECG, physical examination, and clinical test results before, during, and after treatment with the investigational drug. • Immunogenicity: The ADA assay is performed on all subjects, and the NAb assay is performed on ADA-positive serum samples (if necessary).

[0188] PK rating • PK parameters included, but were not limited to, AUC, Ctrough, Cmax, CL, V, and t1 / 2.

[0189] Biomarker evaluation • Evaluate the relationship between the expression level of CLDN18.2 in tumor tissue before treatment and the therapeutic effect.

[0190] Hypothesis testing: The primary efficacy endpoints of this clinical trial were PFS and OS. A one-sided error of 0.025 was controlled and allocated to two endpoints: PFS (α=0.005) and OS (α=0.02). First, a hypothesis test was performed for PFS. If a statistically significant difference was reached at the level of one-sided α=0.005, α was restored and all was allocated to OS. Otherwise, OS was analyzed with one-sided α=0.0199. During the final analysis of PFS, an OS-unbound futility interim analysis was performed, to which α=0.0001 was allocated.

[0191] The hypothesis tests regarding the superiority of PFS and OS were as follows: Null hypothesis H0: HR ≥ 1, Alternative hypothesis Ha: HR < 1

[0192] Calculating sample size: Rank tests were used to compare differences between groups, and subjects were randomly assigned to two treatment groups in a 1:1 ratio. Assuming that PFS and OS in each treatment group were exponentially distributed, and that the PFS HR was 0.5 (median PFS of the control group was 3.5 months, median PFS of the treatment group was 7.0 months), a confidence level of approximately 98% for the final analysis required observing a total of approximately 179 PFS events at a one-sided level α=0.005. Assuming an HR of 0.71 (median OS of the control group was 6.5 months, median OS of 9.2 months for the treatment group), a confidence level of approximately 88% for the final analysis required observing a total of approximately 371 OS events at a one-sided level α=0.0199. The following enrollment rates were assumed: 29 events per month for the first 4 months, 37 events per month from months 5 to 8, 46 events per month from months 9 to 12, and 17 events per month thereafter. Assuming that the 1-year dropout rates for PFS and OS are 15% and 5% respectively in each group, it is expected that 179 PFS events will be observed in 450 subjects 11 months after the initial subjects were randomized, and 371 OS events will be observed 27 months after the initial subjects were randomized.

[0193] Interim analysis In this clinical trial, it is planned to conduct one final analysis of PFS, two interim analyses of OS, and one final analysis of OS. The first interim futility analysis of OS will be conducted simultaneously with the final analysis of PFS (179 PFS events). The interim analysis time is determined by the number of events required for the final analysis of PFS, and it is expected that approximately 37% (138 events) of OS events will occur during the interim analysis (HR futility boundary ≥ 1.005). The second interim analysis of OS validity will be conducted with 75% (278 events), and the minimum detectable difference (MDD) will be HR = 0.745 and the one-sided level will be 0.0072. The final analysis of OS will be conducted with 100% (371 events), and the minimum detectable difference (MDD) is expected to be HR = 0.804 and the one-sided level will be approximately 0.0177. The overall significance level of OS is adjusted as follows. The first interim futility analysis of OS is performed by two sets of uncoupled futility tests based on the gamma family cost function with parameter -2. The α margins for the second interim validity analysis and the final analysis of OS are approximated by the Lan-Demets method to the O'Brien-Fleming boundary allocation and the results of the final analysis of PFS (to determine whether to recover the α of PFS).

[0194] Statistical methods: Descriptive summaries of continuous variables include the number of cases, mean, standard deviation, median, minimum, and maximum values. Descriptive summaries of categorical variables include the number of cases and percentages.

[0195] Primary analysis: The primary analysis for comparing the PFS group and the OS group was performed using the stratified log-rank test. The Kaplan-Meier method was used to estimate the median of PFS and OS and their 95% confidence intervals (CIs), and the survival curves were plotted. At the same time, the stratified Cox proportional hazard model was used to estimate the HR between groups and its 95% CI, and the stratification factor was a random stratification factor.

[0196] Minority analysis: A primary analysis comparing ORR and DCR groups was performed using a CMH test with added stratification factors, and the difference in ORR and DCR rates between groups and their CIs were estimated using the Miettinen & Nurminen method with added stratification factors. The Kaplan-Meier method was used to estimate DoR, TTR, and the median of their 95% CIs, and survival curves were plotted.

[0197] A descriptive statistical analysis was conducted on quality of life scale scores.

[0198] Descriptive summaries were performed regarding safety and tolerability. Unless otherwise specified, formal hypothesis testing was not conducted on the safety and tolerability data.

[0199] Descriptive statistical analysis was performed on PK parameter indicators related to drug concentration.

[0200] A descriptive summary was prepared regarding baseline expression levels of CLDN18.2. Where applicable, exploratory analyses were performed on the relationship between CLDN18.2 expression levels and efficacy, safety, and PK (where applicable) indicators.

[0201] A descriptive summary of the safety implementation phase will be provided separately.

[0202] The data currently available, as confirmed by Phase Ia and Phase Ib trials, demonstrate that the CLAUDIN18.2-targeting antibody-drug conjugate of the present invention has good safety and excellent therapeutic efficacy, as indicated by, for example, PFS, OS, ORR, and / or DCR. [Table 3-1] [Table 3-2] [Table 4-1] [Table 4-2]

[0203] Although exemplary embodiments of the present invention have been described above, these disclosures are merely illustrative, and it will be understood by those skilled in the art that various other substitutions, adaptations, and modifications are possible within the scope of the invention. Therefore, the present invention is not limited to the specific embodiments described herein.

Claims

1. A method for preventing or treating solid tumors in a subject, comprising administering an effective amount of a Claudin 18.2-targeting antibody-drug conjugate or a pharmaceutically acceptable salt thereof to a subject in need of prevention or treatment of solid tumors. The antibody-drug conjugate targeting Claudin 18.2 is selected from antibody-drug conjugates of formula IA. 【Chemistry 1】 In the formula, Ab is an antibody or antigen-binding fragment that targets Claudin 18.

2. The method wherein q represents the average DAR and is a number from 2 to 11, for example, a number from 2 to 5, preferably a number from 3 to 5, more preferably a number from 3 to 4.

2. A method for preventing or treating solid tumors in a subject, comprising administering an effective amount of a Claudin 18.2-targeting antibody-drug conjugate or a pharmaceutically acceptable salt thereof to a subject in need of prevention or treatment of solid tumors. The antibody-drug conjugate targeting Claudin 18.2 is selected from antibody-drug conjugates of formula IB. 【Chemistry 2】 In the formula, Ab is an antibody or antigen-binding fragment that targets Claudin 18.

2. The method wherein y is an integer of 1 or 2.

3. The method according to claim 1 or 2, wherein the antibody or antigen-binding fragment targeting Claudin 18.2 comprises HCDR1, HCDR2, and HCDR3, each consisting of the amino acid sequences described in SEQ ID NOs: 1, 2, and 3, and LCDR1, LCDR2, and LCDR3, each consisting of the amino acid sequences described in SEQ ID NOs: 6, 7, and 8.

4. The antibody or antigen-binding fragment targeting Claudin 18.2 includes a heavy chain variable region and / or a light chain variable region, the heavy chain variable region is (i) containing or consisting of the amino acid sequence described in Sequence ID No. 4, (ii) an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence described in Sequence ID No. 4, or comprising such an amino acid sequence, (iii) an amino acid sequence having one or more (preferably 10 or less, more preferably 5, 4, 3, 2, or 1 or less) amino acid modifications (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence described in Sequence ID No. 4, wherein the amino acid modifications do not occur in the CDR, and / or The aforementioned light chain variable region is (i) containing or consisting of the amino acid sequence described in Sequence ID No. 9, (ii) an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence described in Sequence ID No. 9, or comprising such an amino acid sequence, (iii) The method according to any one of claims 1 to 3, comprising or consisting of an amino acid sequence having one or more (preferably 10 or less, more preferably 5, 4, 3, 2, or 1 or less) amino acid modifications (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence described in Sequence ID No. 9, wherein preferably the amino acid modifications do not occur in the CDR.

5. The antibody or antigen-binding fragment targeting Claudin 18.2 comprises a heavy chain and a light chain, the heavy chain being (i) containing or consisting of the amino acid sequence described in Sequence ID No. 11, or (ii) an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence described in Sequence ID No. 11, or comprising such an amino acid sequence, (iii) an amino acid sequence having one or more (preferably 20 or 10 or less, more preferably 5, 4, 3, 2, or 1 or less) amino acid modifications (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence described in Sequence ID No. 11, or comprising such an amino acid sequence and / or The aforementioned light chain is (i) containing or consisting of the amino acid sequence described in Sequence ID No. 12, (ii) an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence described in Sequence ID No. 12, or comprising such an amino acid sequence, (iii) The method according to any one of claims 1 to 4, comprising or consisting of an amino acid sequence having one or more (preferably 20 or 10 or less, more preferably 5, 4, 3, 2, or 1 or less) amino acid modifications (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence described in Sequence ID No.

12.

6. The solid tumor is an advanced malignant solid tumor 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 received systemic antitumor therapy, a tumor for which at least one systemic antitumor therapy has failed, a tumor for which primary therapy has failed (e.g., refractory or intolerant to primary therapy), a tumor for which secondary therapy has failed (e.g., refractory or intolerant to secondary therapy), and / or Preferably, the advanced malignant solid tumor is a locally advanced, unresectable or metastatic solid tumor, according to any one of claims 1 to 5.

7. The solid tumors are secondary or subsequent gastric cancers or gastroesophageal junction adenocarcinomas. Preferably, the secondary or subsequent gastric cancer or gastroesophageal junction adenocarcinoma is gastric cancer or gastroesophageal junction adenocarcinoma of stage 2L or later, according to claim 6.

8. The method according to claim 7, wherein the secondary or subsequent gastric cancer or gastroesophageal junction adenocarcinoma is a 3L gastric cancer or gastroesophageal junction adenocarcinoma.

9. The method according to any one of claims 1 to 8, comprising administering to the subject 0.1 mg / kg to 100 mg / kg of the antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof.

10. The method according to claim 9, comprising administering to the subject 0.2 mg / kg to 50 mg / kg of the antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof.

11. The method according to claim 10, comprising administering to the subject 0.3 mg / kg to 30 mg / kg of the antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof.

12. The method according to any one of claims 1 to 11, comprising administering to the subject 4 mg / kg to 8 mg / kg of the antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof.

13. The method according to any one of claims 1 to 12, comprising administering to the subject 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 the antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof.

14. The method according to any one of claims 1 to 13, wherein the administration cycle of the method is 2 weeks to 5 weeks, for example 18 to 24 days, for example 19, 20, 21, 22 or 23 days, and the dose is administered once per administration cycle.

15. The method according to any one of claims 1 to 14, wherein the administration cycle of the method is 3 weeks, and the dose is administered once on the first day of each administration cycle.

16. The method according to any one of claims 1 to 15, comprising administering to the subject 6 mg / kg of the antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof once every three weeks.

17. The method according to any one of claims 1 to 16, wherein the antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof is administered by intravenous infusion.

18. A single dose unit comprising an effective amount of an antibody-drug conjugate targeting Claudin 18.2 according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

19. A kit of parts comprising an effective amount of an antibody-drug conjugate targeting Claudin 18.2 as described in any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, Preferably, the kit of parts also includes a package insert printed with instructions for use of the antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof for the prevention or treatment of advanced malignant solid tumors in a subject.

20. A kit of a single-dose unit according to claim 18 or a kit of parts according to claim 19, for the manufacture of a pharmaceutical product for preventing or treating advanced malignant solid tumors.

21. A Claudin 18.2-targeted antibody-drug conjugate or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of solid tumors in a subject, The antibody-drug conjugate targeting Claudin 18.2 is selected from the antibody-drug conjugate of formula IA as defined in claim 1, or from the antibody-drug conjugate of formula IB as defined in claim 2, wherein the antibody-drug conjugate targeting Claudin 18.2 is selected from the antibody-drug conjugate of formula IB as defined in claim 2, or a pharmaceutically acceptable salt thereof.

22. The antibody or antigen-binding fragment thereof that targets Claudin 18.2 is as defined in any one of claims 3 to 5, and / or The solid tumor is as defined in any one of claims 6 to 8, and / or The antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof is administered to the subject in a dose defined in any one of claims 9 to 13, and / or The antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof according to claim 21, wherein the antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof is administered according to a dosing regimen defined in any one of claims 14 to 17.

23. The use of an antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for the prevention or treatment of solid tumors in a subject, The antibody-drug conjugate targeting Claudin 18.2 is selected from the antibody-drug conjugates of formula IA as defined in claim 1, or from the antibody-drug conjugates of formula IB as defined in claim 2, as used.

24. The antibody or antigen-binding fragment thereof that targets Claudin 18.2 is as defined in any one of claims 3 to 5, and / or The solid tumor is as defined in any one of claims 6 to 8, and / or The antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof is administered to the subject in a dose defined in any one of claims 9 to 13, and / or The use according to claim 23, wherein the antibody-drug conjugate targeting Claudin 18.2 or a pharmaceutically acceptable salt thereof is administered according to a dosing regimen defined in any one of claims 14 to 17.

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