Method for combined treatment of cancer by antibody-drug conjugate targeting Claudin18.2

Abstract

The invention relates to a method for treating cancer by using an antibody-drug conjugate targeting Claudin18.2. The antibody-drug conjugate is used for treating cancer by using the antibody-drug conjugate targeting Claudin18.2. The antibody-drug conjugate targeting Claudin18.2 is combined with an antibody drug for treating cancer and / or a chemotherapeutic drug for treating various tumor types and subjects with different CLDN18.2 expression levels, so that the antibody-drug conjugate has a good curative effect on treating the subjects with various tumor types and different CLDN18.2 expression levels.

Description

Technical Field

[0001] The present invention relates to the field of disease treatment, and in particular to a method for treating cancer using an antibody-drug conjugate targeting Claudin18.2. Background Art

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

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

[0004] Some drugs targeting CLDN18.2 have entered clinical studies and have shown good efficacy and safety. Zolbetuximab (IMAB362, claudixmab, Astellas) is the first drug developed for the CLDN18.2 target. As a chimeric IgG1 monoclonal antibody, it can specifically bind to CLDN18.2 on the surface of tumor cells, causing antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), apoptosis and cell proliferation inhibition. Subsequently, several clinical trials have also evaluated its efficacy and safety in patients with gastroesophageal cancer. A phase IIa trial (NCT01197885, MONO) evaluated the efficacy and safety of zolbetuximab monotherapy in 54 patients with recurrent or refractory advanced gastric or lower esophageal adenocarcinoma who had moderate or high CLDN18.2 expression in ≥50% of tumor cells. The study showed that 10 of the 43 evaluable subjects had clinical benefit, of which 4 achieved partial response (PR) (objective response rate (ORR) 9%) and 6 (14%) achieved stable disease (SD). The median duration of response (DoR) for subjects who responded to zolbetuximab was 24.6 weeks (range: 13.1-156.1 weeks). Among the 10 subjects who achieved clinical benefit (complete response (CR) + PR + SD), 9 (90%) had moderate or high CLDN18.2 expression in ≥70% of tumor cells. Subgroup analysis of these 9 subjects found that 4 (14%) achieved PR and 5 (17%) achieved SD. Among all subjects, 52 (96%) experienced treatment-emergent adverse events (TEAEs), most of which were grade 1 or 2. TEAEs occurring in ≥30% of subjects included nausea (63%), vomiting (57%), fatigue (43%), and decreased appetite (30%). Grade 3 vomiting was reported in 12 subjects (22%) and Grade 3 nausea was reported in 8 subjects (15%). Grade 4 TEAEs occurred in 2 subjects: dyspnea and diarrhea (1 subject each).Treatment-related adverse events (TRAEs) occurred in 44 subjects (82%), of which nausea, vomiting, fatigue, and decreased appetite occurred in ≥10% of subjects. Only 5 subjects experienced serious TRAEs. Grade 3 and 2 TEAEs (nausea and vomiting) occurred in 1 subject each, grade 2 hematemesis in 1 subject, and grade 3 vomiting in 2 subjects. All serious TRAEs occurred in patients receiving 600 mg / m, except for 1 subject who experienced grade 3 vomiting. 2 These TEAEs were alleviated by pausing or slowing the zolbetuximab infusion. Patients without prior gastrectomy were more likely to report nausea and vomiting. The incidence of these TEAEs decreased over time as subjects received repeated zolbetuximab infusions.

[0005] Another phase II trial (NCT01630083, FAST) evaluated the efficacy and safety of zolbetuximab combined with EOX versus EOX in the first-line treatment of CLDN18.2-positive advanced gastric / gastroesophageal junction adenocarcinoma (G / GEJ AC). The results showed that the median progression-free survival (PFS) improved from 5.3 months to 7.5 months [hazard ratio (HR), 0.44; 95% CI, 0.29-0.67; P < 0.0005]; the median overall survival (OS) increased from 8.3 months to 13.0 months (HR, 0.55; 95% CI, 0.39-0.77; P < 0.0005). The most frequently reported TEAEs in the zolbetuximab plus EOX group were nausea (81.8%) and vomiting (67.5%). The incidence of vomiting was low in patients with previous gastrectomy, and the incidence and severity of vomiting were dose-dependent with zolbetuximab. The most frequently reported serious adverse events (SAEs) in the zolbetuximab plus EOX group were malignancy (3.9%), pneumonia (2.6%), and febrile neutropenia (2.6%). The most frequently reported SAEs in the EOX group were malignancy (8.3%), gastric hemorrhage (3.6%), and nausea, renal failure, pulmonary embolism, and febrile neutropenia (2.4% each). Two Phase III clinical studies (NCT03504397 / NCT03653507) are underway to evaluate the efficacy of zolbetuximab combined with different chemotherapy regimens (mFOLFOX6 or CAPOX) versus placebo combined with chemotherapy as first-line treatment for CLDN18.2-positive and HER2-negative locally advanced unresectable or metastatic G / GEJ AC. These data provide safety and efficacy data for drugs targeting CLDN18.2.

[0006] In addition to monoclonal antibodies targeting CLDN18.2, ADC drugs targeting CLDN18.2 are also being developed. The ADC drugs CMG901 and SYSA1801 targeting CLDN18.2, which are currently progressing faster, have shown good safety and tolerability in their Phase I studies, as well as preliminary efficacy in treating CLDN18.2-positive drug-resistant / refractory solid tumors.

[0007] There is growing evidence that ADCs may enhance the efficacy of immunotherapeutic agents. The mechanisms involved are diverse and include induction of immunogenic cell death, maturation of dendritic cells, increased T lymphocyte infiltration, and enhanced immune memory and expression of immunomodulatory proteins such as PD-L1 and MHC. Some ADCs have shown greater potency in preclinical models with intact immune systems, supporting the relevance of their immunomodulatory functions. Multiple HER2-targeted ADCs, including trastuzumab emtansine, trastuzumab deruxtecan, and disitamab vedotin, have been tested in combination with ICIs in vitro and in vivo, demonstrating synergistic activity associated with enhanced homing and activation of immune effectors.

[0008] ADC has been approved by regulatory authorities as a single drug for the treatment of a variety of solid and hematological malignancies, showing anti-tumor efficacy. ADC combined with immunotherapy, chemotherapy or anti-vascular therapy has shown better anti-tumor effects than single drugs in preclinical and clinical studies, and combination therapies with efficacy and safety recognized by regulatory authorities have been approved by the FDA for accelerated approval. However, no relevant exploration results have been disclosed in subjects with different tumor types that are positive for CLDN18.2 expression. SUMMARY OF THE INVENTION

[0010] In order to solve the above technical problems, the object of the present invention is to provide a method for treating cancer by using an antibody-drug conjugate targeting Claudin18.2.

[0011] In order to achieve the above object, the present invention provides the following aspects

[0012] A unit preparation, wherein the unit preparation contains: an effective amount (such as 1 mg-10000 mg, 5 mg-9000 mg, 3 mg-8000 mg, 10 mg-6000 mg, 50 mg-4000 mg, 100 mg-2500 mg, 200 mg-1000 mg, 300 mg-900 mg, 400 mg-800 mg, 500 mg-700 mg, 180 mg-550 mg, 200 mg-540 mg, 240 mg-480 mg, 300 mg-420 mg, 360 mg-420 mg or 360 mg-480 mg) of an antibody-drug conjugate targeting Claudin18.2.

[0013] A single drug dosage unit or kit comprising an effective amount (e.g., 1 mg-10000 mg, 5 mg-9000 mg, 3 mg-8000 mg, 10 mg-6000 mg, 50 mg-4000 mg, 100 mg-2500 mg, 200 mg-1000 mg, 300 mg-900 mg, 400 mg-800 mg, 500 mg-700 mg, 180 mg-550 mg, 200 mg-540 mg, 240 mg-480 mg, 300 mg-420 mg, 360 mg-420 mg or 360 mg-480 mg) of an anti-Claudin18.2 targeted The antibody-drug conjugate preferably also contains an effective amount (e.g., 1 mg-10000 mg, 5 mg-9000 mg, 3 mg-8000 mg, 10 mg-6000 mg, 50 mg-4000 mg, 100 mg-2500 mg, 200 mg-1000 mg, 300 mg-900 mg, 400 mg-800 mg, 500 mg-700 mg, 180 mg-550 mg, 200 mg-540 mg, 240 mg-480 mg, 300 mg-420 mg, 360 mg-420 mg or 360 mg-480 mg) of an antibody drug for treating cancer.

[0014] Use of an antibody-drug conjugate targeting Claudin18.2 for preparing a pharmaceutical composition or kit for treating cancer, wherein the pharmaceutical composition or kit comprises an effective amount of an antibody-drug conjugate targeting Claudin18.2 and component A, wherein component A is selected from antibody drugs and / or chemotherapeutic drugs for treating cancer.

[0015] In one or more embodiments of the present invention, the antibody-drug conjugate targeting Claudin18.2, the antibody drug for treating cancer and the chemotherapeutic drug are in a form suitable for injection (preferably intravenous or subcutaneous injection) or oral administration.

[0016] In one or more embodiments of the invention, the unit dosage form, the single pharmaceutical dosage unit, the pharmaceutical composition and the kit further comprise instructions.

[0017] In one or more embodiments of the present invention, the instructions record the dosage regimen of the drug, for example, the dosage of the antibody-drug conjugate targeting Claudin18.2 is 0.1 mg / kg-100 mg / kg, 0.2 mg / kg-50 mg / kg, 0.3 mg / kg-30 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 4.5 mg / kg, 6 mg / kg, 7.5 mg / kg, 8 mg / kg, 10mg / kg, 11mg / kg, 12mg / kg, 13.5mg / kg, 15mg / kg, 16mg / kg, 18mg / kg, 20mg / kg, 22mg / kg, 25mg / kg, 28mg / kg or 30mg / kg, with a dosing cycle of 2 weeks / 14 days (Q2W)-5 weeks / 35 days (Q5W), preferably a dosing cycle of 3 weeks / 21 days (Q3W) or 4 weeks / 28 days (Q4W), once on the first day of each cycle.

[0018] In one or more embodiments of the present invention, the effective amount of the antibody-drug conjugate targeting Claudin18.2 is selected from the group consisting of: 0.1 mg / kg-100 mg / kg, 0.2 mg / kg-50 mg / kg, 0.3 mg / kg-30 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, 12 mg / kg, 13.5 mg / kg, 15 mg / kg, 16 mg / kg, 18 mg / kg, 20 mg / kg, 22 mg / kg, 25 mg / kg, 28 mg / kg or 30 mg / kg.

[0019] In one or more embodiments of the present invention, the effective amount of the antibody-drug conjugate targeting Claudin18.2 is selected from the group consisting of: 1 mg-10000 mg, 5 mg-9000 mg, 3 mg-8000 mg, 10 mg-6000 mg, 50 mg-4000 mg, 100 mg-2500 mg, 200 mg-1000 mg, 300 mg-900 mg, 400 mg-800 mg, 500 mg-700 mg, 180 mg-550 mg, 200 mg-540 mg, 240 mg-480 mg, 300 mg-420 mg, 360 mg-420 mg or 360 mg-480 mg.

[0020] In order to achieve the above objectives, the present invention also provides a method for treating cancer with an antibody-drug conjugate targeting Claudin18.2, which comprises administering an effective amount of an antibody-drug conjugate targeting Claudin18.2, and an antibody drug and / or chemotherapeutic drug for treating cancer to an individual in need thereof, wherein the administration is preferably by injection (preferably intravenous injection or subcutaneous injection) or oral administration.

[0021] In one or more embodiments of the present invention, the antibody-drug conjugate targeting Claudin18.2 is selected from:

[0022]

[0023] wherein Ab is an antibody or an antigen-binding fragment thereof targeting Claudin18.2;

[0024] wherein y is an integer of 1 or 2; or,

[0025]

[0026] wherein Ab is an antibody or an antigen-binding fragment thereof targeting Claudin18.2;

[0027] Where q represents the average DAR, and q ranges from 2 to 11.

[0028] Wherein, the antibody or its antigen-binding fragment targeting Claudin18.2 comprises HCDR1, HCDR2, HCDR3 as shown in SEQ ID NO:1 (GFTFSSYVMS), SEQ ID NO:2 (TISHSGGSTYYADSVKG) and SEQ ID NO:3 (DAPYYDILTGYRY), and LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:6 (RASQSISSWLA), SEQ ID NO:7 (KASSLES) and SEQ ID NO:8 (QQYNSYSYT), respectively.

[0029] In one or more embodiments of the present invention, the antibody or antigen-binding fragment thereof targeting Claudin18.2 comprises a heavy chain variable region and / or a light chain variable region, wherein the heavy chain variable region

[0030] (i) comprises or consists of the amino acid sequence of SEQ ID NO: 4; or

[0031] (ii) comprises or consists of an amino acid sequence having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2 or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 4 (preferably, the amino acid changes do not occur in the CDR regions); or

[0032] an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 4; and / or

[0033] Light chain variable region

[0034] (i) comprises or consists of the amino acid sequence of SEQ ID NO: 9; or

[0035] (ii) comprises or consists of an amino acid sequence having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2 or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 9 (preferably, the amino acid changes do not occur in the CDR regions); or

[0036] An amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:9.

[0037] In one or more embodiments of the present invention, the antibody targeting Claudin18.2 further comprises a heavy chain constant region and / or a light chain constant region. In one or more embodiments of the present invention, the antibody targeting Claudin18.2 or the heavy chain constant region thereof is an IgG antibody.

[0038] In one or more embodiments of the present invention, the heavy chain constant region of the antibody targeting Claudin18.2 is selected from IgG1, IgG2, IgG3 or IgG4, preferably IgG1, more preferably human IgG1, such as (human) wild-type IgG1 heavy chain constant region.

[0039] In one or more embodiments, the antibody light chain constant region (LC) of the invention is a lambda or kappa light chain constant region.

[0040] In one or more embodiments, the heavy chain constant region (HC) of the present invention

[0041] (i) comprising or consisting of an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the amino acid sequence of SEQ ID NO:5;

[0042] (ii) comprises or consists of the amino acid sequence of SEQ ID NO: 5; or

[0043] (iii) comprises or consists of an amino acid sequence having one or more (preferably no more than 20 or 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 5.

[0044] In some preferred embodiments, the antibody light chain constant region (LC) of the present invention is

[0045] (i) comprising or consisting of an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the amino acid sequence of SEQ ID NO: 10;

[0046] (ii) comprises or consists of the amino acid sequence of SEQ ID NO: 10; or

[0047] (iii) comprises or consists of an amino acid sequence having one or more (preferably no more than 20, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 10.

[0048] In one or more embodiments of the present invention, the antibody targeting Claudin18.2 comprises a heavy chain and a light chain, wherein the heavy chain

[0049] comprising or consisting of the amino acid sequence of SEQ ID NO: 11; or

[0050] comprising or consisting of an amino acid sequence having one or more (preferably no more than 20 or 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 11, or an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 11; and

[0051] Light chain

[0052] comprising or consisting of the amino acid sequence of SEQ ID NO: 12; or

[0053] The invention relates to an amino acid sequence of the present invention, comprising or consisting of an amino acid sequence having one or more (preferably no more than 20 or 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 12, or an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 12.

[0054] In one or more embodiments of the present invention, the method comprises administering 0.1 mg / kg-100 mg / kg of an antibody-drug conjugate targeting Claudin18.2 to an individual in need thereof.

[0055] In one or more embodiments of the present invention, the method comprises administering 0.2 mg / kg-50 mg / kg of an antibody-drug conjugate targeting Claudin18.2 to an individual in need thereof.

[0056] In one or more embodiments of the present invention, the method comprises administering 0.3 mg / kg-30 mg / kg of an antibody-drug conjugate targeting Claudin18.2 to an individual in need thereof.

[0057] In one or more embodiments of the invention, the method comprises administering 1 mg / kg, 3 mg / kg, 4.5 mg / kg, 6 mg / kg, 7.5 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 13.5 mg / kg, 15 mg / kg, 16 mg / kg, 18 mg / kg, 20 mg / kg, 22 mg / kg, 25 mg / kg, 28 mg / kg, 30 mg / kg of an antibody-drug conjugate targeting Claudin18.2 to an individual in need thereof.

[0058] In one or more embodiments of the present invention, the administration cycle of the antibody-drug conjugate targeting Claudin18.2 is 2 weeks / 14 days (Q2W) to 5 weeks / 35 days (Q5W). Further, the administration cycle is 2 weeks / 14 days (Q2W), 3 weeks / 21 days (Q3W), 4 weeks / 28 days (Q4W) or 5 weeks / 35 days (Q5W), and the drug is administered once on the first day of each cycle.

[0059] In one or more embodiments of the present invention, the administration cycle of the antibody-drug conjugate targeting Claudin18.2 is 3 weeks / 21 days (Q3W) or 4 weeks / 28 days (Q4W), and the drug is administered once on the first day of each cycle.

[0060] In one or more aspects of the present invention, the antibody drug for treating cancer is selected from one or a combination of PD-1 inhibitors, recombinant anti-VEGF monoclonal antibodies, and monoclonal antibodies that specifically bind to VEGFR-2.

[0061] In one or more embodiments of the present invention, the PD-1 inhibitor is selected from one or a combination of pembrolizumab, nivolumab, carrelizumab, sintilimab, toripalizumab, and tislelizumab.

[0062] In one or more embodiments of the present invention, the dosing regimen of the PD-1 inhibitor is the dosing regimen in the respective instructions of the PD-1 inhibitor.

[0063] In one or more embodiments of the present invention, the dosage of sintilimab is 200 mg, and preferably the administration cycle of sintilimab is 3 weeks / 21 days (Q3W), for example, administration on the first day.

[0064] In one or more embodiments of the present invention, the recombinant anti-VEGF monoclonal antibody is selected from one or a combination of sevastatin, bevacizumab and / or bevacizumab.

[0065] In one or more embodiments of the present invention, the dosage of bevacizumab is 15 mg / kg. Preferably, the administration cycle of bevacizumab is 3 weeks / 21 days (Q3W), for example, administration on the first day.

[0066] In one or more embodiments of the present invention, the monoclonal antibody that specifically binds to VEGFR-2 is ramucirumab.

[0067] In one or more embodiments of the present invention, the dosage of Ramucirumab is 8 mg / kg, and preferably the administration cycle of Ramucirumab is 4 weeks / 28 days (Q4W), for example, administration on the 1st day and the 15th day.

[0068] In one or more aspects of the present invention, the chemotherapy drug is selected from one or a combination of oxaliplatin, capecitabine, gemcitabine, albumin-paclitaxel and S-1.

[0069] In one or more embodiments of the present invention, the dosage of oxaliplatin is 130 mg / m 2 ; Preferably, the administration cycle of oxaliplatin is 3 weeks / 21 days (Q3W), for example, administration on the 1st day.

[0070] In one or more embodiments of the present invention, the dosage of capecitabine is 1000 mg / m 2 ; Preferably, the administration cycle of capecitabine is twice a day (BID).

[0071] In one or more embodiments of the present invention, the dosage of gemcitabine is 1000 mg / m 2 ; Preferably, the administration cycle of gemcitabine is 3 weeks / 21 days (Q3W), for example, administration on the 1st day and the 8th day.

[0072] In one or more embodiments of the present invention, the dosage of nab-paclitaxel is 125 mg / m 2 ; Preferably, the administration cycle of the albumin paclitaxel is 3 weeks / 21 days (Q3W), for example, administration on the 1st day and the 8th day.

[0073] In one or more embodiments of the present invention, the dosage of Tegafur is 40 mg-60 mg; preferably, the administration cycle of Tegafur is 3 weeks / 21 days (Q3W), twice a day (BID), for example, administration on days 1-14.

[0074] In one or more embodiments of the present invention, the cancer comprises a solid tumor including gastric / gastroesophageal junction adenocarcinoma, pancreatic ductal adenocarcinoma.

[0075] In one or more embodiments of the present invention, the administration of the method includes intravenous injection and oral administration.

[0076] The antibody-drug conjugate targeting Claudin18.2 of the present invention is an ADC with a bystander effect, and also has a significant tumor inhibitory effect in a mouse tumor-bearing model with low expression of CLDN18.2. In preclinical pharmacodynamic studies, whether used in combination with antibody drugs and / or chemotherapeutic drugs for treating cancer, it has shown a certain synergistic effect. Therefore, the antibody-drug conjugate targeting Claudin18.2 of the present invention combined with antibody drugs and / or chemotherapeutic drugs for treating cancer has a certain therapeutic effect in treating subjects with various tumor types and different CLDN18.2 expression levels, and can significantly improve PFS and OS.

[0077] Other embodiments of the present invention will become apparent by reference to the detailed description given hereinafter. DETAILED DESCRIPTION OF THE INVENTION

[0079] Before describing the present invention in detail, it should be understood that the present invention is not limited to the specific methods and experimental conditions in this specification, because the methods and conditions can be changed. In addition, the terms used herein are only for the purpose of describing specific embodiments and are not intended to be limiting.

[0080] definition

[0081] Unless defined otherwise, all technical and scientific terms used herein 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.

[0082] The term "about" when used in conjunction with a number is meant to encompass a range of values ​​having a lower limit that is 5% less than the specified number and an upper limit that is 5% greater than the specified number.

[0083] The term “and / or”, when used to connect two or more optional items, should be understood to mean any one of the optional items or any two or more of the optional items.

[0084] As used herein, the term "comprising" or "including" means including the stated elements, integers or steps, but does not exclude any other elements, integers or steps. In this article, when the term "comprising" or "including" is used, unless otherwise indicated, it also covers the situation consisting of the stated elements, integers or steps. For example, when referring to an antibody variable region "comprising" a specific sequence, it is also intended to cover the antibody variable region consisting of the specific sequence.

[0085] The term "CLAUDIN" or "Claudin" or "CLDN" used in this article is the most important skeletal protein that determines the tight junction structure between cells. It is involved in adhesion junctions and plays an important role in the metastasis and invasion of tumor cells. Claudin protein is widely present in mammalian epithelial and endothelial cells, and its distribution is mainly on the side of epithelial cells and on the plasma membrane of basal cells. Different Claudin proteins are specifically expressed in different tissues. Among them, the Claudin18 (CLDN18) gene is located at 3q22.3, with a molecular weight of 24kDa and 261 amino acid residues. It is a member of the Claudins superfamily, and its protein structure includes 2 extracellular loops and 4 transmembrane regions. The two subtypes of human CLDN18 or Claudin18 protein are Claudin18.1 or CLDN18.1 (UniProt ID: P56856-1), and Claudin18.2 or CLDN18.2 (UniProtID: P56856-2). In the primary structure sequences of the two proteins, there are only differences in the amino acid residues at certain positions from the N-terminal signal peptide to the extracellular loop 1 (Loop 1) structure, especially in the extracellular loop 1, where CLDN18.1 and CLDN18.2 differ by only 8 amino acids. The inter-species sequence homology of the two subtypes of CLDN18 is also very high, among which the extracellular loop 1 of CLDN18.2 is completely consistent in sequence in different species such as humans, mice, and macaques, and the homology of CLDN18.2 proteins between humans and mice reaches 84%, indicating that the CLDN18.2 protein sequence is extremely conservative (O. Tureci et al., Gene 481: 83-92, 2011). CLDN18.2 or any variants and isoforms thereof can be isolated from cells or tissues that naturally express them, or recombinantly produced using techniques well known in the art and / or those described herein. In one embodiment, the CLDN18.2 described herein is human CLDN18.2.

[0086] The terms "antibody targeting CLDN18.2", "anti-CLDN18.2 antibody", "anti-CLDN18.2", "CLDN18.2 antibody", or "antibody that binds to CLDN18.2" or "antibody that specifically binds to CLDN18.2" as used herein refer to an antibody that is capable of binding to (human) CLDN18.2 with sufficient affinity so that the antibody can be used as a therapeutic agent targeting (human) CLDN18.2. In one embodiment, the (human) CLDN18.2 antibody binds to (human) CLDN18.2 with high affinity in vitro or in vivo. In one embodiment, the (human) CLDN18.2 antibody does not bind to CLDN18.1. In one embodiment, the (human) CLDN18.2 antibody binds to cells expressing CLDN18.2 without binding to cells expressing CLDN18.1. In some embodiments, the binding is measured, for example, by radioimmunoassay (RIA), biofilm thin layer interferometry (BLI), MSD electrochemiluminescence detection technology assay, or surface plasmon resonance (SPR) or flow cytometry.

[0087] The expression of CLDN18.2 in cells can be determined in a variety of ways, such as anti-CLDN18.2 antibodies. For example, the binding strength of cells "highly expressing CLDN18.2" to anti-CLDN18.2 antibodies (e.g., determined by FACS) can be 500, 600, 700, 800, 900 or preferably 1000 times or more, such as 1100 times, 1200, 1300, 1400 times or more than the binding strength of anti-CLDN18.2 antibodies to cells that do not express CLDN18.2. For example, cells that "moderately express CLDN18.2" may bind to an anti-CLDN18.2 antibody with an intensity (e.g., as determined by FACS) that is 5-500 times, such as 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100 times or more, but not more than 500 times, as strongly as the anti-CLDN18.2 antibody binds to cells that do not express CLDN18.2.

[0088] For conventional four-chain IgG antibodies, the full-length antibody heavy chain is usually composed of a heavy chain variable region (abbreviated as VH herein) and a heavy chain constant region, wherein the heavy chain constant region comprises at least three domains CH1, CH2 and CH3. The full-length antibody light chain is composed of a light chain variable region (abbreviated as VL herein) and a light chain constant region, wherein the light chain constant region consists of one domain CL. Each heavy chain variable region VH and each light chain variable region are composed of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0089] The term "antibody fragment" includes a portion of an intact antibody. In a preferred embodiment, the antibody fragment is an antigen-binding fragment.

[0090] "Antigen-binding fragment" refers to a molecule that is different from an intact antibody, which comprises a portion of an intact antibody and binds to the antigen to which the intact antibody binds. Examples of antigen-binding fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; dAb (domain antibody); linear antibody; single-chain antibody (e.g., scFv); single-domain antibody such as VHH; bivalent antibody or fragment thereof; or camelid antibody.

[0091] The term "antigen" refers to a molecule that triggers an immune response. This immune response may involve antibody production or activation of specific immune cells, or both. The technician will understand that any macromolecule, including essentially all proteins or peptides, can be used as an antigen. In addition, antigens can be derived from recombinant or genomic DNA expression. As used herein, the term "epitope" refers to a portion of an antigen (e.g., CLDN18.2) that specifically interacts with an antibody molecule.

[0092] "Complementarity determining region" or "CDR region" or "CDR" is a region in an antibody variable domain that is highly variable in sequence and forms a structurally determined loop ("hypervariable loop") and / or contains antigen contact residues ("antigen contact points"). CDR is primarily responsible for binding to antigen epitopes. The CDRs of the heavy and light chains are usually referred to as CDR1, CDR2, and CDR3, and are numbered sequentially from the N-terminus. The CDRs located in the antibody heavy chain variable domain are referred to as HCDR1, HCDR2, and HCDR3, while the CDRs located in the antibody light chain variable domain are referred to as LCDR1, LCDR2, and LCDR3. In a given light chain variable region or heavy chain variable region amino acid sequence, the precise amino acid sequence boundaries of each CDR can be determined using any one or a combination of a number of well-known antibody CDR assignment systems, including, for example, Chothia based on the three-dimensional structure of the antibody and the topology of the CDR loops (Chothia et al. (1989) Nature 342:877-883, Al-Lazikani et al., "Standard conformations for the canonical structures of immunoglobulins", Journal of Molecular Biology, 273, 927-948 (1997)), Kabat based on antibody sequence variability (Kabat et al., Sequences of Proteins of Immunological Interest, 4th Edition, US Department of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath), Contact (University College London), International ImMunoGeneTics database (IMGT) (on the World Wide Web at imgt.cines.fr / ), and North's CDR definition based on affinity propagation clustering using a large number of crystal structures (North et al., "A New Clustering of Antibody CDR Loop Concepts", Journal of Molecular Biology, 406, 228-256 (2011)).

[0093] Table 1 below shows the regional ranges of CDRs defined using the Kabat, AbM, Chothia, Contact, and IMGT schemes.

[0094] Table 1:

[0095]

[0096]

[0097] A CDR can also be identified based on having the same Kabat numbering position as a reference CDR sequence (eg, any of the exemplary CDRs of the invention).

[0098] Unless otherwise specified, in the present invention, the term "CDR" or "CDR sequence" encompasses a CDR sequence determined in any of the above-mentioned ways.

[0099] Unless otherwise indicated, in the present invention, when referring to the residue positions in the antibody variable region (including heavy chain variable region residues and light chain variable region residues), it refers to the numbering position according to the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)).

[0100] In one embodiment, the heavy chain variable region CDR of the antibody of the present invention is determined according to the following rules:

[0101] VH CDR1 was determined according to the AbM rule; and VH CDR2 and 3 were both determined according to the Kabat rule.

[0102] In one embodiment, the light chain variable region CDR of the antibody of the present invention is determined according to the Kabat rule.

[0103] In one embodiment, the heavy chain variable region CDRs of the antibodies of the invention are determined according to the following rules: VH CDR1 is determined according to the AbM rule; and VH CDR2 and 3 are both determined according to the Kabat rule; and the light chain variable region CDRs are determined according to the Kabat rule.

[0104] It should be noted that the boundaries of the CDRs of the variable regions of the same antibody obtained based on different assignment systems may be different. That is, the CDR sequences of the variable regions of the same antibody defined under different assignment systems are different. Therefore, when it comes to defining antibodies using specific CDR sequences defined in the present invention, the scope of the antibodies also covers antibodies whose variable region sequences contain the specific CDR sequences, but whose claimed CDR boundaries are different from the specific CDR boundaries defined in the present invention due to the application of different schemes (e.g., different assignment system rules or combinations).

[0105] Antibodies with different specificities (i.e., different binding sites for (same or different) antigens) have different CDRs (under the same assignment system). However, although CDRs differ from antibody to antibody, only a limited number of amino acid positions within a CDR are directly involved in antigen binding. Using at least two of the Kabat, Chothia, AbM, Contact, and North methods, the minimum overlapping region can be determined, thereby providing a "minimum binding unit" for antigen binding. The minimum binding unit can be a sub-portion of a CDR. As will be apparent to those skilled in the art, the residues of the remainder of the CDR sequence can be determined by the structure of the antibody and protein folding. Therefore, the present invention also contemplates variants of any CDR given herein. For example, in a variant of a CDR, the amino acid residues of the minimum binding unit can remain unchanged, while the remaining CDR residues defined according to Kabat or Chothia can be replaced by conservative amino acid residues.

[0106] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain containing at least a portion of a constant region. The term includes native sequence Fc regions and variant Fc regions. A natural immunoglobulin "Fc domain" comprises two or three constant domains, i.e., a CH2 domain, a CH3 domain, and an optional CH4 domain. For example, in a natural antibody, an immunoglobulin Fc domain comprises the second and third constant domains (CH2 domain and CH3 domain) of two heavy chains derived from IgG, IgA, and IgD class antibodies; or comprises the second, third, and fourth constant domains (CH2 domain, CH3 domain, and CH4 domain) of two heavy chains derived from IgM and IgE class antibodies. Unless otherwise indicated herein, the numbering of amino acid residues in the Fc region or heavy chain constant region is numbered according to the EU numbering system (also referred to as the EU index) as described in Kabat et al., Sequences of Proteins of Immunological Interes, 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD, 1991. Herein, the term "Fc region" does not include the heavy chain variable region VH and the light chain variable region VL and the heavy chain constant region CH1 and the light chain constant region CL of an immunoglobulin, but may include the hinge region at the N-terminus of the heavy chain constant region in some cases.

[0107] An "IgG-type antibody" refers to an IgG-type antibody to which the heavy chain constant region belongs. The heavy chain constant region of all antibodies of the same type is the same, and the heavy chain constant region of antibodies of different types is different. For example, an IgG4-type antibody means that its heavy chain constant region is from IgG4, or an IgG1-type antibody means that its heavy chain constant region is from IgG1.

[0108] As used herein, the term "binding" or "specific binding" means that the binding is selective for the antigen and can be distinguished from unwanted or non-specific interactions. The ability of an antigen binding site to bind to a specific antigen can be determined by enzyme-linked immunosorbent assay (ELISA) or conventional binding assays known in the art such as by radioimmunoassay (RIA) or thin-layer interferometry or MSD assays or surface plasmon resonance (SPR).

[0109] As used herein, "antibody-drug conjugate (ADC)" refers to a structure obtained by linking an antibody and a drug.

[0110] The term "drug: antibody ratio" or "DAR" refers to the ratio of the small molecule drug moiety (D) coupled to the antibody (Ab) moiety described herein to the Ab moiety. In some embodiments described herein, the DAR can be determined by p and r in Formula I, for example, the DAR can be 1 to 20, such as 2-18, 4-16, 5-12, 6-10, 2-8, 3-8, 2-6, 4-6 or 6-10, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. The DAR can also be calculated as the average DAR of the population of molecules in the product, i.e., the overall ratio of the small molecule drug moiety (D) (e.g., exatecan) coupled to the Ab moiety described herein to the Ab moiety in the product measured by a detection method (e.g., by conventional methods such as mass spectrometry, ELISA assay, electrophoresis and / or HPLC), and this DAR is referred to as the average DAR herein. In some embodiments, the average DAR value of the conjugate of the invention is 1 to 20, such as 2-18, 4-16, 5-12, 6-10, 2-8, 3-8, 2-6, 4-6, or 6-10, such as 1.0-8.0 or 2.0-6.0, such as 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5. 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10, or a range defined with any two of these values ​​as endpoints, for example, q is 2-5, for example, q is 3-5 or 3.5-4.5. More specifically, q is 2, 2.5, 3, 3.5, 4, 4.8 or 5; or q is 5-11, such as 7-9 or 7.5-8.5.

[0111] The term "effective amount" refers to an amount or dosage of an antibody or antibody fragment (eg, antigen binding fragment) or composition or combination of the invention that produces the desired effect in a patient in need of treatment or prevention after administration in single or multiple doses to the patient.

[0112] A "therapeutically effective amount" refers to an amount effective to achieve the desired therapeutic outcome at the desired dosage and for the desired period of time. A therapeutically effective amount is also an amount in which any toxic or deleterious effects of the antibody or antibody fragment (e.g., antigen binding fragment) or composition or combination are outweighed by the therapeutically beneficial effects. A "therapeutically effective amount" preferably inhibits a measurable parameter (e.g., tumor volume) by at least about 30%, even more preferably by at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or even 100%, relative to an untreated subject.

[0113] The term "prophylactically effective amount" refers to an amount effective to achieve the desired preventive result at the required dosage and for the required period of time. Typically, since a prophylactic dose is used in a subject prior to or at an earlier stage of the disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0114] The term "single drug dosage unit" refers to a single drug dosage form, such as an injection, containing a therapeutically active ingredient (such as the antibody-drug conjugate targeting Claudin18.2 and / or antibody drug and / or chemotherapeutic drug described in the present invention) to be administered to a subject at the time of the dosing regimen (preferably per kg body weight of the subject), for example, placed in an ampoule (or vial).

[0115] The term "unit dosage form" refers to the smallest dosing unit or the smallest packaging unit that can be divided in a drug. For example, in the case where 200 mg of a drug needs to be administered to an individual, the unit dosage form of the drug may be a packaging unit of 10 mg, thereby administering 20 packaging units of the drug to the individual, or a packaging unit of 100 mg, thereby administering 2 packaging units of the drug to the individual. The packaging units such as 10 mg or 100 mg exemplified herein are for illustrative purposes only, not for limiting purposes.

[0116] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid is introduced, including progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and progeny derived therefrom, without regard to the number of passages. Progeny may not be completely identical to the parent cell in nucleic acid content, and may contain mutations. The terms described herein include mutant progeny screened or selected for the same function or biological activity in the initially transformed cell.

[0117] The term "label" as used herein refers to a compound or composition that is directly or indirectly conjugated or fused to a reagent (such as a polynucleotide probe or antibody) and facilitates the detection of the reagent to which it is conjugated or fused. The label itself can be detectable (e.g., a radioisotope label or a fluorescent label) or can catalyze a chemical change in a detectable substrate compound or composition in the case of an enzymatic label. The term is intended to encompass direct labeling of a probe or antibody by coupling (i.e., physically connecting) a detectable substance to the probe or antibody and indirect labeling of a probe or antibody by reacting with another reagent that is directly labeled.

[0118] "Individuals" or "subjects" or "objects" include mammals. Mammals include, but are not limited to, domestic animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the individual or subject or object is a human.

[0119] An "isolated" antibody or other molecule (e.g., ADC molecule) is an antibody or molecule that has been separated from a component of its natural environment or the environment in which it is expressed and synthesized. In some embodiments, the antibody or ADC molecule is purified to greater than 95% or 99% purity, as determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC).

[0120] The term "anti-tumor effect" refers to a biological effect that can be exhibited by a variety of means, including but not limited to, for example, a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in tumor cell proliferation, or a decrease in tumor cell survival.

[0121] The terms "tumor" and "cancer" are used interchangeably herein and encompass both solid tumors and hematological tumors.

[0122] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. In certain embodiments, cancers suitable for treatment by the antibodies of the invention include gastric cancer, pancreatic cancer, or gastroesophageal junction cancer, including metastatic forms of those cancers.

[0123] The term "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. The terms "cancer," "cancerous," and "tumor" are not mutually exclusive when referred to herein.

[0124] As used herein, "treat," ...

[0125] As used herein, "prevention" includes inhibition of the occurrence or development of a disease or condition or symptoms of a particular disease or condition. In some embodiments, subjects with a family history of cancer are candidates for preventive regimens. Generally, in the context of cancer, the term "prevention" refers to the administration of a drug before signs or symptoms of cancer occur, particularly before signs or symptoms of cancer occur in a subject at risk for cancer.

[0126] The term "vector" as used herein refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes vectors that are self-replicating nucleic acid structures as well as vectors that are incorporated into the genome of a host cell into which they have been introduced. Some vectors are capable of directing the expression of nucleic acids to which they are operably linked. Such vectors are referred to herein as "expression vectors."

[0127] "Subject / patient / individual sample" refers to a collection of cells or fluids obtained from a patient or subject. The source of the tissue or cell sample can be solid tissue, such as an organ or tissue sample or a biopsy sample or a puncture sample from fresh, frozen and / or preserved; blood or any blood component; body fluids, such as cerebrospinal fluid, amniotic fluid (amniotic fluid), peritoneal fluid (ascites), or interstitial fluid; cells from any time of pregnancy or development of the subject. Tissue samples may contain compounds that are not naturally mixed with tissues in nature, such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, etc.

[0128] Treatment

[0129] The present invention provides a method for treating cancer by combining an antibody-drug conjugate targeting Claudin18.2, which comprises administering an effective amount of an antibody-drug conjugate targeting Claudin18.2 and an antibody drug and / or a chemotherapeutic drug for treating cancer to an individual in need.

[0130] In some embodiments of the present invention, the antibody-drug conjugate targeting Claudin18.2 is selected from:

[0131]

[0132] wherein Ab is an antibody or an antigen-binding fragment thereof targeting Claudin18.2;

[0133] Wherein y is an integer of 1 or 2.

[0134] In some embodiments of the present invention, the antibody-drug conjugate targeting Claudin18.2 is selected from:

[0135]

[0136] wherein Ab is an antibody or an antigen-binding fragment thereof targeting Claudin18.2;

[0137] q represents the average DAR, and q is 2-11; wherein q is 2-5, for example, q is 3-5 or 3.5-4.5, more specifically, q is 2, 2.5, 3, 3.5, 4, 4.8 or 5; or q is 5-11, for example, 7-9 or 7.5-8.5.

[0138] In some embodiments of the present invention, the antibody or antigen-binding fragment thereof targeting Claudin18.2 comprises HCDR1, HCDR2, HCDR3 as shown in the amino acid sequences of SEQ ID NO:1 (GFTFSSYVMS), SEQ ID NO:2 (TISHSGGSTYYADSVKG) and SEQ ID NO:3 (DAPYYDILTGYRY), and LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:6 (RASQSISSWLA), SEQ ID NO:7 (KASSLES) and SEQ ID NO:8 (QQYNSYSYT), respectively.

[0139] In some embodiments of the present invention, the antibody or antigen-binding fragment thereof targeting Claudin18.2 comprises a heavy chain variable region and / or a light chain variable region, wherein the heavy chain variable region

[0140] (i) comprises or consists of the amino acid sequence of SEQ ID NO: 4; or

[0141] (ii) an amino acid sequence comprising one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 4, consisting of said amino acid sequence, preferably, said amino acid changes do not occur in the CDR regions; or

[0142] (iii) comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the amino acid sequence of SEQ ID NO: 4; and / or

[0143] Light chain variable region

[0144] (i) comprises or consists of the amino acid sequence of SEQ ID NO: 9; or

[0145] (ii) an amino acid sequence comprising one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 9, consisting of said amino acid sequence, preferably, said amino acid changes do not occur in the CDR regions; or

[0146] (iii) comprises or consists of an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the amino acid sequence of SEQ ID NO:9.

[0147] In some embodiments of the present invention, the antibody or antigen-binding fragment thereof targeting Claudin18.2 of the present invention comprises a heavy chain constant region. In some embodiments, the antibody or antigen-binding fragment thereof targeting Claudin18.2 of the present invention comprises a light chain constant region. In some embodiments, the antibody or antigen-binding fragment thereof targeting Claudin18.2 of the present invention further comprises a heavy chain constant region and a light chain constant region.

[0148] In some embodiments of the present invention, the heavy chain constant region (HC) of the present invention is a heavy chain constant region of IgG1, IgG2, IgG3 or IgG4, preferably a heavy chain constant region of IgG1, such as a wild-type IgG1 heavy chain constant region. In some embodiments, the antibody light chain constant region (LC) of the present invention is a lambda or kappa light chain constant region.

[0149] In some preferred embodiments, the heavy chain constant region (HC) of the present invention

[0150] (i) comprising or consisting of an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the amino acid sequence of SEQ ID NO:5;

[0151] (ii) comprises or consists of the amino acid sequence of SEQ ID NO: 5; or

[0152] (iii) comprises or consists of an amino acid sequence having one or more (preferably no more than 20 or 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 5.

[0153] In some preferred embodiments, the antibody light chain constant region (LC) of the present invention is

[0154] (i) comprising or consisting of an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the amino acid sequence of SEQ ID NO: 10;

[0155] (ii) comprises or consists of the amino acid sequence of SEQ ID NO: 10; or

[0156] (iii) comprises or consists of an amino acid sequence having one or more (preferably no more than 20, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 10.

[0157] In some embodiments of the present invention, the antibody or antigen-binding fragment thereof targeting Claudin18.2 of the present invention comprises a heavy chain and a light chain, wherein the heavy chain comprises or consists of the amino acid sequence of SEQ ID NO: 11 as shown below:

[0158] EVQLLDSGGGLVQPGGSLRLSCAASGFTFSSYVMSWVRQAPGKGLNWVSTISHSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAIDAPYYDILTGYRYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:11);

[0159] or

[0160] An amino acid sequence comprising or consisting of an amino acid sequence having one or more (preferably no more than 20 or 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 11,

[0161] or

[0162] comprising or consisting of an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 11; and

[0163] The light chain comprises or consists of the amino acid sequence of SEQ ID NO: 12 shown below:

[0164] DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSYTFGQGTKLEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:12);

[0165] or

[0166] An amino acid sequence comprising or consisting of an amino acid sequence having one or more (preferably no more than 20 or 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 12,

[0167] or

[0168] Comprising or consisting of an amino acid sequence that is at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the amino acid sequence of SEQ ID NO:12.

[0169] In some embodiments of the present invention, in the method of the present invention, it includes administering 0.1 mg / kg-100 mg / kg of an antibody-drug conjugate targeting Claudin18.2 to an individual; further, the method includes administering 0.2 mg / kg-50 mg / kg of an antibody-drug conjugate targeting Claudin18.2 to an individual; further, the method includes administering 0.3 mg / kg-30 mg / kg of an antibody-drug conjugate targeting Claudin18.2 to an individual. For example: the method includes administering 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, 15 mg / kg of an antibody-drug conjugate targeting Claudin18.2 to an individual. Furthermore, the method comprises administering 1 mg / kg-30 mg / kg of an antibody-drug conjugate targeting Claudin18.2 to an individual. For example, the method comprises administering 1 mg / kg, 3 mg / kg, 4.5 mg / kg, 6 mg / kg, 7.5 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 13.5 mg / kg, 15 mg / kg, 16 mg / kg, 18 mg / kg, 20 mg / kg, 22 mg / kg, 25 mg / kg, 28 mg / kg or 30 mg / kg of an antibody-drug conjugate targeting Claudin18.2 to an individual.

[0170] In some embodiments of the present invention, the dosing cycle of the method is 2 weeks / 14 days (Q2W) to 5 weeks / 35 days (Q5W); further, the dosing cycle of the method is 2 weeks / 14 days (Q2W), 3 weeks / 21 days (Q3W), 4 weeks / 28 days (Q4W) or 5 weeks / 35 days (Q5W), and the drug is administered once on the first day of each cycle.

[0171] In some embodiments of the present invention, the antibody drug for treating cancer is selected from one or a combination of PD-1 inhibitors, recombinant anti-VEGF monoclonal antibodies, and monoclonal antibodies that specifically bind to VEGFR-2.

[0172] In some embodiments, the PD-1 inhibitor is selected from one or a combination of pembrolizumab, nivolumab, carrelizumab, sintilimab, toripalizumab, and tislelizumab.

[0173] In one embodiment of the present invention, the method comprises administering 200 mg of sintilimab to an individual in need thereof. In one embodiment of the present invention, the administration cycle of sintilimab is 3 weeks / 21 days (Q3W), for example, administration on day 1.

[0174] In some embodiments of the present invention, the recombinant anti-VEGF monoclonal antibody is selected from one or a combination of sevalizumab and bevacizumab.

[0175] In one embodiment of the present invention, the method comprises administering 15 mg / kg of bevacizumab to an individual in need thereof. In one embodiment of the present invention, the administration cycle of bevacizumab is 3 weeks / 21 days (Q3W), for example, administration on day 1.

[0176] In some embodiments of the present invention, the monoclonal antibody that specifically binds to VEGFR-2 comprises ramucirumab.

[0177] In some embodiments of the present invention, the method comprises administering 8 mg / kg of ramucirumab to an individual in need thereof. In some embodiments of the present invention, the administration cycle of ramucirumab is 4 weeks / 28 days (Q4W), for example, administration on the 1st day and the 15th day.

[0178] In some embodiments of the present invention, the chemotherapy drug is selected from one or a combination of oxaliplatin, capecitabine, gemcitabine, albumin-paclitaxel and S-1.

[0179] In some embodiments, the dosage of oxaliplatin is 130 mg / m 2 ; The dosing cycle of oxaliplatin is 3 weeks / 21 days (Q3W), for example, it is administered on the 1st day.

[0180] In some embodiments, the dosage of capecitabine is 1000 mg / m 2 ; Capecitabine is administered twice daily.

[0181] In some embodiments, the dosage of gemcitabine is 1000 mg / m 2 ; The dosing cycle of gemcitabine is 3 weeks / 21 days (Q3W), for example, administration on the 1st and 8th days.

[0182] In some embodiments, the dosage of nab-paclitaxel is 125 mg / m 2 ; The dosing cycle of albumin paclitaxel is 3 weeks / 21 days (Q3W), for example, administration on the 1st day and the 8th day.

[0183] In some specific embodiments, the dosage of Tegafur is 40 mg-60 mg; the administration cycle of Tegafur is 3 weeks / 21 days (Q3W), twice a day, for example, administration on days 1-14.

[0184] In some embodiments, the method of treating cancer by combining an antibody-drug conjugate targeting Claudin18.2 of the present invention comprises:

[0185] Mode 1: 4 mg / kg-10 mg / kg (preferably 6 mg / kg) of the antibody-drug conjugate targeting Claudin18.2 of the present invention is administered on the first day of every 21-day cycle; 8 mg / kg of Ramucirumab is administered on the first and 15th days of every 28-day cycle.

[0186] Mode 2: 4 mg / kg-10 mg / kg (preferably 6 mg / kg) of the antibody-drug conjugate targeting Claudin18.2 of the present invention, administered on the first day of a 21-day cycle; 15 mg / kg of bevacizumab, administered on the first day of a 21-day cycle.

[0187] Mode 3: 4 mg / kg-10 mg / kg (preferably 6 mg / kg) of the antibody-drug conjugate targeting Claudin18.2 of the present invention, administered on the first day of each cycle for a 21-day cycle; 200 mg of sintilimab, administered on the first day of each 21-day cycle.

[0188] Mode 4: 4 mg / kg-10 mg / kg (preferably 6 mg / kg) of the antibody-drug conjugate targeting Claudin18.2 of the present invention, administered on the first day of each 21-day cycle; 200 mg of sintilimab, administered on the first day of each 21-day cycle; 130 mg / m 2 Each 21-day cycle was administered on day 1. Each subject received up to 6 cycles of oxaliplatin treatment.

[0189] Mode 5: 4 mg / kg-10 mg / kg (preferably 6 mg / kg) of the antibody-drug conjugate targeting Claudin18.2 of the present invention, administered on the first day of each 21-day cycle; 200 mg of sintilimab, administered on the first day of each 21-day cycle; 1000 mg / m 2 , twice daily, 21 days per cycle, on days 1-14; oxaliplatin 130 mg / m 2 , each cycle is 21 days, and the drug is given on the first day (oxaliplatin can be received for a maximum of 6 cycles).

[0190] Mode 6: 4 mg / kg-10 mg / kg (preferably 6 mg / kg) of the antibody-drug conjugate targeting Claudin18.2 of the present invention, administered on the first day of each cycle for a 21-day cycle; 40 mg-60 mg of S-1a, twice a day, administered on days 1-14 for a 21-day cycle.

[0191] Mode 7: 4 mg / kg-10 mg / kg (preferably 6 mg / kg) of the antibody-drug conjugate targeting Claudin18.2 of the present invention, one cycle of 21 days, administered on the first day of each cycle; 1000 mg / m 2 , every 21 days as a cycle, administration on day 1 and day 8; albumin paclitaxel 125 mg / m 2 , each cycle is 21 days, with medication given on the 1st and 8th days.

[0192] In some preferred embodiments of the present invention, the method of treating cancer by combining an antibody-drug conjugate targeting Claudin18.2 of the present invention may include the methods shown in Table 2:

[0193] Table 2

[0194]

[0195]

[0196]

[0197] In some embodiments of the present invention, in the method of combining the antibody-drug conjugate targeting Claudin18.2 to treat cancer of the present invention, the cancer is a solid tumor, and further, the solid tumor can be a tumor associated with Claudin18.2, such as gastric cancer, breast cancer, liver cancer, colon cancer, lung cancer, gallbladder cancer, esophageal cancer, gastric / gastroesophageal junction adenocarcinoma, pancreatic ductal adenocarcinoma, biliary tract cancer (biliary tract cancer is divided into cholangiocarcinoma and gallbladder cancer). In some preferred embodiments, the antibody-drug conjugate targeting Claudin18.2 of the present invention is combined to treat gastric / gastroesophageal junction adenocarcinoma. In a preferred embodiment of the present invention, the antibody-drug conjugate targeting Claudin18.2 of the present invention is combined to treat pancreatic ductal adenocarcinoma.

[0198] In some specific embodiments, the antibody-drug conjugate targeting Claudin18.2 of the present invention is combined with sintilimab, ramucirumab, and bevacizumab to treat gastric / gastroesophageal junction adenocarcinoma. In some preferred embodiments, the antibody-drug conjugate targeting Claudin18.2 of the present invention is combined with sintilimab, ramucirumab, and bevacizumab to treat advanced gastric / gastroesophageal junction adenocarcinoma that has failed or is intolerant to first-line standard treatment and is CLDN18.2 positive.

[0199] In some specific embodiments, the antibody-drug conjugate targeting Claudin18.2 of the present invention is combined with sintilimab and / or capecitabine and / or oxaliplatin to treat gastric / gastroesophageal junction adenocarcinoma. In some preferred embodiments, the antibody-drug conjugate targeting Claudin18.2 of the present invention is combined with sintilimab and / or capecitabine and / or oxaliplatin to treat HER2-negative, CLDN18.2-positive gastric / gastroesophageal junction adenocarcinoma that has not been previously treated with systemic therapy.

[0200] In some specific embodiments, the antibody-drug conjugate targeting Claudin18.2 of the present invention is combined with Segao to treat pancreatic ductal adenocarcinoma. In some preferred embodiments, the antibody-drug conjugate targeting Claudin18.2 of the present invention is combined with Segao to treat pancreatic ductal adenocarcinoma that has failed or is intolerant to gemcitabine-based treatment and is CLDN18.2 positive.

[0201] In some specific embodiments, the antibody-drug conjugate targeting Claudin18.2 of the present invention is combined with gemcitabine and nab-paclitaxel to treat pancreatic ductal adenocarcinoma. In some preferred embodiments, the antibody-drug conjugate targeting Claudin18.2 of the present invention is combined with gemcitabine and nab-paclitaxel to treat CLDN18.2-positive pancreatic ductal adenocarcinoma that has not been previously treated with systemic therapy.

[0202] In some embodiments of the present invention, the administration of the method of the present invention includes intravenous injection and oral administration. In some embodiments, the antibody-drug conjugate targeting Claudin18.2, sintilimab, ramucirumab, bevacizumab, oxaliplatin, albumin paclitaxel, and gemcitabine of the present invention are administered by intravenous injection. In some embodiments, the administration of capecitabine and 1-tetracycline is oral administration.

[0203] In some embodiments of the present invention, the active ingredient of the antibody-drug conjugate targeting Claudin18.2 of the present invention is a recombinant anti-tight junction protein 18.2 monoclonal antibody-ixitecan conjugate, and the dosage form is a lyophilized preparation for injection, with a specification of 100 mg / bottle. In some embodiments of the present invention, the finished product of the antibody-drug conjugate targeting Claudin18.2 of the present invention contains 20 mg / mL of the antibody-drug conjugate targeting Claudin18.2 of the present invention, histidine, histidine hydrochloride, sucrose and polysorbate 80. The antibody-drug conjugate targeting Claudin18.2 of the present invention should be prepared by professional health personnel using aseptic technology. In some embodiments of the present invention, the finished product should be diluted with 5% glucose injection. In some embodiments of the present invention, the final concentration of the antibody-drug conjugate targeting Claudin18.2 of the present invention should be maintained at 1 mg / mL-6 mg / mL. The administration of the antibody-drug conjugate targeting Claudin18.2 of the present invention should be performed through an intravenous infusion tube equipped with a 0.2 μm-5 μm online filter. BRIEF DESCRIPTION OF THE DRAWINGS

[0204] Figure 1 The anti-tumor efficacy of an antibody-drug conjugate targeting CLAUDIN18.2 combined with an anti-PD-1 antibody in the EMT6-hClaudin18.2 tumor-bearing mouse model.

[0205] Figure 2 Effect of antibody-drug conjugate targeting CLAUDIN18.2 combined with anti-PD-1 antibody on body weight changes in mice.

[0206] Figure 3 The anti-tumor efficacy of an antibody-drug conjugate targeting CLAUDIN18.2 combined with capecitabine and oxaliplatin in the HCT15-Claudin 18.2 tumor-bearing mouse model.

[0207] Figure 4 Effect of antibody-drug conjugate targeting CLAUDIN18.2 combined with capecitabine and oxaliplatin on the body weight of HCT15-Claudin 18.2 tumor-bearing mice. DETAILED DESCRIPTION

[0208] The embodiments of the present invention will be described in detail below in conjunction with examples. It will be appreciated by those skilled in the art that the following examples are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. In the examples, if no specific techniques or conditions are indicated, the techniques or conditions described in the literature in this area or the product specifications are used. If the manufacturer is not indicated for reagents or instruments used, it is a conventional product that can be purchased from the market.

[0209] Example

[0210] Example 1 Preparation of Antibody-Drug Conjugate Targeting Claudin18.2

[0211] The anti-CLDN18.2 monoclonal antibody HB37A6 (heavy chain sequence as shown in SEQ ID NO: 11, light chain sequence as shown in SEQ ID NO: 12; see CN202010570517.X) and the control antibody zolbetuximab (abbreviated as Zmab, sequence derived from International Nonproprietary Names for Pharmaceutical Substances (INN) 117) were expressed in HEK293 cells (Invitrogen, A14527) in the form of full-length monoclonal antibodies.

[0212] Based on HB37A6, a synthetic ADC was further designed. The specific synthesis steps refer to the preparation steps of IEX019-02 in PCT / CN2022 / 139637 (Example 2.1.1), the contents of which are incorporated into the present invention by reference.

[0213] Example 2

[0214] 20 mg / mL IEX019-02 ADC, 20 mM histidine solution, 8% (w / v) sucrose, 0.02% (w / v) polysorbate 80, pH 6.5 were freeze-dried (the freeze-drying process can be prepared according to conventional processes in the art), and the freeze-drying process parameters are shown in Table 3.

[0215] Table 3

[0216]

[0217] Example 3

[0218] 1. Test antibodies and other drugs

[0219] Study drug: Antibody-drug conjugate targeting Claudin18.2 (formulation of Example 2).

[0220] Specification: 100mg / bottle

[0221] Drug source: Innovent Biologics (Suzhou) Co., Ltd.

[0222] Administration: Intravenous infusion (IV)

[0223] Sintilimab

[0224] Specification: 100mg (10ml) / bottle

[0225] Dosage: 200 mg Q3W intravenous infusion

[0226] Drug source: Innovent Biologics (Suzhou) Co., Ltd.

[0227] Ramucirumab

[0228] Specifications: 100mg (10ml) / bottle, 500mg (50ml) / bottle

[0229] Dosage: 8 mg / kg, every 28 days as a cycle, administered on the 1st and 15th day of each cycle, intravenous infusion

[0230] Drug source: Innovent Biologics (Suzhou) Co., Ltd.

[0231] Bevacizumab

[0232] Specification: 100mg (4ml) / bottle

[0233] Dosage: 15 mg / kg, Q3W, intravenous infusion

[0234] Drug source: Innovent Biologics (Suzhou) Co., Ltd.

[0235] Chemotherapy drugs

[0236] The specifications and administration methods of oxaliplatin, capecitabine, gemcitabine, nab-paclitaxel, and S-1 are detailed in the protocol.

[0237] 2. Research objectives

[0238] To evaluate the efficacy and safety of antibody-drug conjugates targeting Claudin18.2 combined with antibody drugs or chemotherapy drugs in the treatment of cancer subjects.

[0239] The pharmacokinetic (PK) characteristics of antibody-drug conjugates targeting claudin18.2, anti-tight junction protein 18.2 (CLDN18.2) antibodies, and exatecan were evaluated.

[0240] Evaluation of the immunogenicity of antibody-drug conjugates targeting Claudin18.2.

[0241] 3. Dose-limiting toxicity

[0242] Toxicity evaluation was performed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. DLT was defined as any of the following adverse events (AEs) related to the study drug: antibody-drug conjugate targeting Claudin18.2 within 21 days after the first dose in the dose-finding phase:

[0243] 1. Hematological toxicity

[0244] Grade 4 neutrophil count decrease lasting for >7 days

[0245] ≥ Grade 3 febrile neutropenia [absolute neutrophil count (ANC) <1×10 9 / L and single temperature >38.3℃ or temperature ≥38.0℃ for more than 1 hour】

[0246] Grade 4 anemia that cannot be explained by underlying disease

[0247] Grade 4 decreased platelet count

[0248] ≥Grade 3 platelet count decrease lasting for >7 days

[0249] ≥ Grade 3 decreased platelet count with bleeding

[0250] Grade 4 lymphocyte count decrease lasting ≥ 14 days

[0251] 2. Hepatotoxicity

[0252] Grade 4 elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT)

[0253] AST or ALT > 5× Upper Limit of Normal Value (ULN) with ≥ Grade 2 elevation of total bilirubin (TBIL)

[0254] In subjects without liver metastases, AST or ALT > 5×ULN for > 7 days after optimal treatment

[0255] In subjects with liver metastases, if baseline levels are ≤3×ULN, AST or ALT >5×ULN for >7 days after optimal treatment

[0256] In subjects with liver metastases, if baseline levels are >3×ULN, AST or ALT >8×ULN, persisting for >7 days after optimal treatment

[0257] 3. Non-hematological and non-hepatotoxicity

[0258] 1) Any non-hematologic, non-major hepatotoxicity of grade 3 or higher (except for laboratory abnormalities), except for the following:

[0259] Grade 3 joint pain

[0260] Grade 3 myalgia

[0261] Grade 3 rash

[0262] ·Level 3 hair loss

[0263] Grade 3 fatigue / asthenia

[0264] Grade 3 hypertension or hypotension

[0265] Grade 3 nausea, vomiting, diarrhea, or anorexia that resolves to ≤ Grade 2 within 3 days with best supportive care

[0266] 2) Any non-hematologic, non-major hepatotoxic laboratory abnormality of grade 3 or higher that requires treatment or leads to hospitalization, except for the following:

[0267] Grade 3 electrolyte abnormalities

[0268] Grade 3 elevated Gamma-Glutamyl Transferase (GGT)

[0269] Asymptomatic laboratory abnormalities, including grade 3 / 4 elevated alkaline phosphatase, hyperuricemia, elevated serum amylase, and elevated lipase

[0270] 4. Any 5th level AE

[0271] 5. Other AEs that are determined to be DLTs after discussion between the investigator and the sponsor

[0272] Remark:

[0273] Grade 3 or 4 infusion related reactions (IRR) are not considered DLTs. However, if a grade 3 or 4 IRR occurs, the subject needs to stop the study treatment and be replaced by a new subject. If ≥ 2 subjects in a dose group experience a grade 3 or 4 IRR, enrollment must be suspended and the sponsor needs to review the safety data of the study to determine whether to continue enrollment.

[0274] Throughout the trial, the above criteria will be used to assess whether subjects require dosing delays or discontinuations. However, only DLTs that occur during the DLT observation period after the first dose will be used to determine dose escalation and tolerability.

[0275] If any of the above toxicities occur during the DLT observation period, the investigator and the sponsor will determine whether the toxicity is a DLT after consultation. In addition, for other toxicities that affect the study drug treatment, the investigator and the sponsor will determine whether the toxicity is a DLT after consultation.

[0276] 4. Inclusion / Exclusion Criteria

[0277] Subjects must meet all of the following conditions to participate in the study:

[0278] 1. Sign the written informed consent form (ICF), and be willing and able to comply with the visits and related procedures specified in the protocol.

[0279] 2. According to RECIST v1.1, the patient must have at least one measurable lesion (who has not received radiotherapy before). (Baseline accurate measurement by computed tomography (CT) or magnetic resonance imaging (MRI) (preferably intravenous contrast agent) shows that its long diameter is ≥10 mm (except for lymph nodes, the short axis of the lymph nodes must be ≥15 mm), the target lesion diameter is ≥2 times the image layer thickness, and the lesion is suitable for repeated accurate measurement. If the lesion located in the previously irradiated area clearly proves that it has progressed in accordance with the RECIST V1.1 criteria, the lesion can be regarded as a measurable lesion).

[0280] 3. Age ≥ 18 years old, no gender restrictions.

[0281] 4. The Eastern Cooperative Oncology Group Performance Status (ECOGPS) score is 0 or 1.

[0282] 5. Expected survival period ≥ 12 weeks.

[0283] 6. Have adequate bone marrow and organ function:

[0284] a. Routine blood test: ANC ≥ 1.5 × 10 9 / L; platelet count ≥100×10 9 / L; hemoglobin content ≥9.0g / dL. The subjects must not have received blood product transfusion (including red blood suspension, single platelet, cryoprecipitate, etc.), erythropoietin (EPO), G-colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) treatment within 7 days before blood sample collection;

[0285] b. Liver function: TBIL ≤ 1.5 × ULN (TBIL ≤ 3 × ULN is allowed for Gilbert syndrome subjects); ALT and AST ≤ 2.5 × ULN for subjects without liver metastasis, ALT and AST ≤ 5 × ULN for subjects with liver metastasis; albumin ≥ 28 g / L;

[0286] c. Renal function: creatinine clearance ≥ 60 mL / min (using Cockcroft-Gault formula); urine protein < 2+ or total urine protein in 24 hours < 1 g;

[0287] d. Coagulation function: International Normalized Ratio (INR) ≤ 1.5 and Activated Partial Thromboplastin Time (APTT) ≤ 1.5 × ULN (subjects who are allowed to receive anticoagulation therapy and whose coagulation function is within the above range).

[0288] 7. Female subjects of childbearing age or male subjects whose partners are female subjects of childbearing age must take effective contraceptive measures throughout the treatment period and for 6 months after the treatment.

[0289] 8. Pathological tissue testing confirmed that *CLDN18.2 was positive.

[0290] Queue A:

[0291] 9. Histopathologically confirmed unresectable locally advanced, recurrent or metastatic G / GEJ AC.

[0292] 10. Patients who have failed or are intolerant to first-line systemic standard treatment.

[0293] Queue B:

[0294] 11. Histopathologically confirmed unresectable locally advanced, recurrent or metastatic HER2-negative G / GEJ AC.

[0295] 12. Subjects must not be suitable for radical treatments, such as radical chemoradiotherapy and / or surgery; for subjects who have previously received (neo)adjuvant chemotherapy / adjuvant (radio)chemotherapy / radical chemoradiotherapy, the time from the last treatment to disease recurrence must be greater than 6 months.

[0296] 13. Patients in the locally advanced or metastatic stage have not received any systemic treatment (including chemotherapy, targeted therapy, tumor immunotherapy, etc.).

[0297] Cohort C:

[0298] 14. Histopathologically confirmed unresectable locally advanced, recurrent or metastatic PDAC.

[0299] 15. Patients who have failed or are intolerant to at least one line of gemcitabine-based systemic standard treatment;

[0300] Queue D:

[0301] 16. Histopathologically confirmed unresectable locally advanced, recurrent or metastatic PDAC.

[0302] 17. Subjects must not be suitable for radical treatments, such as radical chemoradiotherapy and / or surgery; for subjects who have previously received (neo)adjuvant chemotherapy / adjuvant (radio)chemotherapy / radical chemoradiotherapy, the time from the last treatment to disease recurrence must be greater than 6 months.

[0303] 18. Patients who have not received any systemic treatment (including chemotherapy, targeted therapy, tumor immunotherapy, etc.) in the locally advanced or recurrent stage.

[0304] Remark:

[0305] *CLDN18.2 positive: defined as Claudin18.2 immunohistochemical membrane staining intensity ≥2+ in ≥40% of tumor cells, accepting previous test results, research center test results, and central laboratory test results. The sponsor can dynamically adjust the proportion of CLDN18.2 expression according to new data during the study.

[0306] Subjects will not be included in this study if they meet any of the following criteria:

[0307] 1. Currently participating in another interventional clinical study, excluding observational (non-interventional) clinical studies or in the survival follow-up phase of an interventional study.

[0308] 2. Patients receiving treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors within 2 weeks or 5 half-lives (whichever is longer) before the first dose of study drug.

[0309] 3. Received the last anti-tumor treatment within 4 weeks before the first dose of study drug or within 5 half-lives of the anti-tumor drug (whichever is shorter).

[0310] 4. Patients who have received therapeutic or palliative radiotherapy within 2 weeks before the first dose of study drug.

[0311] 5. Patients who received biliary stent implantation within 7 days before the first use of study drug.

[0312] 6. Plan to receive other anti-tumor treatment during the treatment with this study drug [palliative radiotherapy for the purpose of relieving symptoms (such as pain) and not affecting the efficacy evaluation is allowed].

[0313] 7. Any live vaccine received within 4 weeks before the first dose of study drug or planned during the study.

[0314] 8. Patients who have undergone major surgery (craniotomy, thoracotomy or laparotomy or other surgery defined by the investigator, excluding puncture biopsy) within 4 weeks before the first administration of the study drug, or have unhealed wounds, ulcers or fractures; or are planning to undergo major surgery during the study. Local surgical treatment for isolated lesions is acceptable for the purpose of palliative treatment.

[0315] 9. The patient had toxicity caused by previous treatment that had not recovered to Grade 0 or 1 in NCI CTCAE v5.0 before the first dose of the study drug (excluding alopecia, fatigue, pigmentation, and other conditions judged by the investigator to have no safety risks).

[0316] 10. Patients with a history of gastrointestinal perforation and / or fistula within 6 months before the first administration of study drug, which has not been cured by surgical treatment.

[0317] 11. The presence of pyloric obstruction and / or persistent recurrent vomiting (vomiting ≥ 3 times within 24 hours).

[0318] 12. After the implantation of a stent in the digestive tract [referring to the muscular tube from the mouth to the anal canal, including the mouth, pharynx, esophagus, stomach, small intestine (duodenum, jejunum, ileum), large intestine (cecum, appendix, colon, rectum) and anal canal] or endotracheal stent.

[0319] 13. Symptomatic central nervous system metastases. Subjects with asymptomatic brain metastases (i.e., no neurological symptoms, no need for glucocorticoid treatment, and brain metastases ≤1.5 cm) or brain metastases with stable symptoms after treatment must meet all of the following criteria to participate in this study: no midbrain, pons, cerebellum, meninges, medulla oblongata, or spinal cord metastases; clinical status remains stable for at least 4 weeks, clinical evidence confirms that there are no new or enlarged brain metastases, and corticosteroid and anticonvulsant treatment is stopped for at least 2 weeks before the first dose of study drug. Note: The central nervous system is not a target lesion.

[0320] 14. Bone metastasis with risk of paraplegia.

[0321] 15. Interstitial lung disease requiring steroid hormone treatment, or a history of interstitial lung disease, non-infectious pneumonia, severely impaired lung function or uncontrolled lung disease such as pulmonary fibrosis, severe radiation pneumonitis, acute lung injury, etc., or suspected of having the above diseases during the screening period.

[0322] 16. The presence of uncontrolled diseases, such as:

[0323] a. Infection that was poorly controlled and required systemic anti-infective drugs (antibiotics, antivirals, or antifungals) within one week before the first dose of study drug.

[0324] b. People infected with human immunodeficiency virus (HIV) (HIV 1 / 2 antibody positive).

[0325] c. Acute or chronic active hepatitis B (defined as positive hepatitis B surface antigen (HBsAg) and / or hepatitis B core antibody (HBcAb) and hepatitis B virus DNA copy number ≥ 10 4 copies / mL or ≥2000 IU / mL or acute or chronic active hepatitis C [Hepatitis C Virus antibody (HCVAb) positive, HCV RNA>10 3 copies / mL]. Subjects whose test results were lower than the above standards after nucleotide antiviral treatment and those with positive HCV antibodies but negative RNA tests were allowed to be enrolled.

[0326] d. Active COVID-19 infection.

[0327] e. Active pulmonary tuberculosis, currently receiving anti-tuberculosis treatment or having received anti-tuberculosis treatment within 1 year before the first dose of study drug.

[0328] f. Active syphilis or latent syphilis requires treatment.

[0329] g. Symptomatic congestive heart failure (New York Heart Association classification NYHA II-IV), symptomatic or poorly controlled arrhythmias, QTc interval >480ms or personal or family history of congenital long / short QT syndrome.

[0330] h. Hypertension that is poorly controlled by standardized treatment (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg).

[0331] i. The tumor invades or compresses surrounding important structures (such as large blood vessels, trachea, etc.) or there is a risk of gastrointestinal / respiratory tract fistula.

[0332] j. Pleural effusion, ascites, or pericardial effusion that is symptomatic and requires intervention (eg, drainage).

[0333] k. Subjects with esophageal or gastric varices requiring immediate intervention (e.g., banding or sclerotherapy) or who are considered at high risk for bleeding based on the investigator's opinion or consultation with a gastroenterologist or hepatologist, with evidence of portal hypertension (including splenomegaly on imaging studies), or with a history of variceal bleeding must undergo endoscopic evaluation within 3 months prior to the first dose of study drug.

[0334] l. Any life-threatening bleeding event or grade 3 or 4 gastrointestinal / variceal bleeding event requiring transfusion, endoscopic or surgical treatment within 3 months before the first dose of study drug.

[0335] m. Any arterial thromboembolic event within 6 months before the first administration of study drug, including myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, etc.

[0336] n. History of new or uncontrolled deep vein thrombosis, pulmonary embolism, or any other serious venous thromboembolism within 3 months prior to the first dose of study drug (thrombosis of implanted venous port or catheter, or superficial vein thrombosis is not considered "serious" venous thromboembolism).

[0337] o. Hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh class B or worse cirrhosis.

[0338] p. Risk of intestinal obstruction or intestinal perforation (including but not limited to history of acute diverticulitis, abdominal abscess) or history of the following diseases: inflammatory bowel disease or extensive intestinal resection (partial colectomy or extensive small bowel resection, complicated by chronic diarrhea), Crohn's disease, ulcerative colitis, etc.

[0339] q. Significant malnutrition (such as needing intravenous nutrition supplementation, weight loss of 5% within 1 month or more than 15% within 3 months from the signing of the informed consent, or a reduction of 1 / 2 or more in food intake within 1 week). Except for those whose malnutrition has been corrected for more than 4 weeks before the first administration of the study drug.

[0340] r. Other acute or chronic illnesses or laboratory abnormalities that could increase the risks associated with study participation or study drug administration, or interfere with the interpretation of study results and, in the investigator's judgment, render the subject ineligible for participation in this study.

[0341] s. Neurological, psychiatric, or social conditions that affect compliance with study requirements, significantly increase the risk of AEs, or affect the subject's ability to provide a written ICF.

[0342] 17. History of other primary malignant tumors, except for the following:

[0343] · Malignant tumors that have been cured, with no known active disease for ≥ 2 years before study entry and a very low risk of recurrence;

[0344] Adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease recurrence;

[0345] Adequately treated carcinoma in situ with no evidence of disease recurrence.

[0346] 18. Known history of immunodeficiency.

[0347] 19. History of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation.

[0348] 20. Queue A3, Queue B:

[0349] Long-term use of systemic hormones or immunosuppressive drugs, which have not been reduced to physiological doses or discontinued 4 weeks before the first dose, excluding: intranasal inhaled local steroid treatment or local steroid injection (such as intra-articular injection); systemic corticosteroid treatment not exceeding 10 mg / day of prednisone or its equivalent physiological dose; glucocorticoids as prophylactic medication for allergic reactions (such as pre-CT medication), and vomiting prevention medication specified in the protocol. Long-term systemic hormone or any other immunosuppressive drug treatment is required, excluding inhaled hormone treatment.

[0350] Patients with active autoimmune or inflammatory diseases [including inflammatory bowel disease (such as ulcerative colitis, Crohn's disease, etc.), celiac disease, systemic lupus erythematosus, Sarcoidosis syndrome or Wegener syndrome (granulomatosis with polyangiitis), Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.], or a history of the disease in the past 2 years. Subjects with vitiligo, psoriasis, alopecia or Grave's disease who do not require systemic treatment in the past 2 years, hypothyroidism who only require thyroid hormone replacement therapy, and type 1 diabetes who only require insulin replacement therapy can be enrolled. Subjects with only positive autoimmune antibodies need to confirm whether they have autoimmune diseases based on the researcher's judgment.

[0351] 21. Patients who have received previous treatment with antibody-drug conjugates based on topoisomerase inhibitors.

[0352] 22. Subjects receiving drug treatment have a history of allergy to the corresponding drugs or preparations.

[0353] 23. For subjects receiving drug treatment, there are contraindications to the corresponding drugs.

[0354] 24. For subjects receiving drug treatment, there is a history of corresponding drug-related adverse reactions leading to permanent discontinuation of medication.

[0355] 25. Pregnant or lactating female subjects.

[0356] 26. Others deemed by the researchers as not meeting the conditions for participating in this study.

[0357] 5. Study Design

[0358] This study is a Phase II study to evaluate the safety, tolerability, pharmacokinetics and efficacy of the antibody-drug conjugate targeting Claudin18.2 of the present invention in the combined treatment of subjects with advanced malignant solid tumors, including Part 1 (safety introduction phase) and Part 2 (POC trial phase).

[0359] In the Part 1 stage, each cohort plans to enroll 3-6 subjects to receive the combined treatment of the antibody-drug conjugate targeting Claudin18.2 of the present invention. The preset safe introduction dose of the antibody-drug conjugate targeting Claudin18.2 of the present invention is 6 mg / kg Q3W, and the administration method is intravenous infusion (Intravenous, IV) Q3W. The DLT observation period is within 21 days (3 weeks) after the first administration. During the DLT observation period, the antibody-drug conjugate targeting Claudin18.2 of the present invention is only administered once. If ≥1 / 3 of the subjects have a DLT event during the DLT observation period, 3-6 subjects are allowed to be enrolled to receive 4.5 mg / kg Q3W treatment of the antibody-drug conjugate targeting Claudin18.2 of the present invention; if the 4.5 mg / kg dose group is not tolerated, 3-6 subjects are allowed to be enrolled to receive 3 mg / kg Q3W treatment of the antibody-drug conjugate targeting Claudin18.2 of the present invention; if it is still not tolerated, the exploration of combined treatment will be terminated. If the antibody-drug conjugate targeting Claudin18.2 of the present invention is well tolerated at 6 mg / kg Q3W, the sponsor will decide whether to safely introduce 8 mg / kg Q3W according to the above principles based on the previous research data.

[0360] The sponsor is allowed to adjust the safe introduction dose of the antibody-drug conjugate targeting Claudin18.2 of each cohort according to the results of the previous study. After completing the safe introduction phase and determining the dose and safety of the antibody-drug conjugate combination therapy targeting CLAUDIN18.2, the Part 2 phase will be entered.

[0361] The design of the study cohorts and Part 2 (POC trial phase) is as follows. Whether each cohort will be initiated and when to initiate it will be determined by the sponsor:

[0362] Cohort A: Subjects with advanced gastric / gastro-Esophageal Junction Adenocarcinoma (G / GEJ AC) who have failed or are intolerant to first-line standard treatment and are CLDN18.2 positive will be divided into 3 groups, with a planned enrollment of approximately 49 patients in each group (including patients in the same dose group in the safety lead-in phase):

[0363] A1: receiving the antibody-drug conjugate targeting Claudin18.2 of the present invention + ramucirumab 8 mg / kg d1, d15, Q4W treatment (d means day, the same below).

[0364] A2: receiving the antibody-drug conjugate targeting Claudin18.2 of the present invention + bevacizumab 15 mg / kg Q3W treatment.

[0365] A3: Receive the Claudin18.2-targeting antibody-drug conjugate of the present invention + sintilimab 200 mg IVQ3W treatment (if the safety introduction of cohort B2 has been completed before the start of this cohort, there is no need to repeat it).

[0366] Cohort B: Subjects with HER2-negative, CLDN18.2-positive advanced G / GEJ AC who have not received systemic treatment before will be randomly assigned to the following groups after the safety run-in phase, with approximately 40 patients in each group. Stratification factors include CPS (≥5 vs. <5) and cancer site (stomach vs. gastroesophageal junction):

[0367] B1: receiving the antibody-drug conjugate targeting Claudin18.2 of the present invention + sintilimab 200 mg IVQ 3W + oxaliplatin 130 mg / m 2 IV Q3W treatment. Each subject received up to 6 cycles of oxaliplatin treatment.

[0368] B2: Received the Claudin18.2-targeting antibody-drug conjugate of the present invention + sintilimab 200 mg IVQ3W treatment.

[0369] B3: receive sintilimab 200 mg IV Q3W + capecitabine 1000 mg / m 2 BID PO × 14 days Q3W + oxaliplatin 130 mg / m 2 Treatment was IV Q3W (maximum 6 cycles of oxaliplatin).

[0370] B4: (if B1 is well tolerated) receiving the antibody-drug conjugate targeting Claudin18.2 of the present invention + sintilimab 200 mg IV Q3W + capecitabine 1000 mg / m 2 BID PO × 14d Q3W + oxaliplatin 130 mg / m 2 IV Q3W treatment (oxaliplatin for up to 6 cycles). The sponsor will decide whether to include this combination treatment group based on preliminary data.

[0371] Cohort C: Subjects with pancreatic ductal adenocarcinoma (PDAC) who have failed or are intolerant to gemcitabine-based treatment and are CLDN18.2-positive. It is planned to enroll approximately 44 subjects (including cases in the same dose group in the safety lead-in phase) to receive an antibody-drug conjugate targeting CLAUDIN18.2 + S-1 40mg-60mg, twice daily, d1-d14, Q3W.

[0372] Cohort D: CLDN18.2-positive advanced PDAC subjects who have not received systemic treatment before. After the safety lead-in phase, approximately 80 subjects are planned to be enrolled and randomized 1:1 to D1 / D2. Stratification factors include liver metastasis (yes vs. no) and primary lesion resection (yes vs. no):

[0373] Cohort D1: receiving the antibody-drug conjugate targeting Claudin18.2 of the present invention + gemcitabine 1000 mg / m 2 Q3W + nab-paclitaxel 125 mg / m 2 Treatment on d1, d8, Q3W.

[0374] Cohort D2: received gemcitabine 1000 mg / m 2 Q3W + nab-paclitaxel 100 mg / m 2 , d1, d8, Q3W treatment.

[0375] The sponsor is allowed to adjust the requirements for the CLDN18.2 expression level of the subjects in the above-mentioned cohorts based on the research results of other trials of antibody-drug conjugates targeting Claudin18.2 of the present invention. The subjects will receive continuous treatment until disease progression, intolerable toxicity, withdrawal of informed consent, loss of follow-up, death, or other reasons for stopping the study treatment (whichever occurs first). After termination of the study treatment, the subjects will undergo safety follow-up and survival follow-up. During the study, the researchers will perform imaging assessments on the subjects according to RECIST v1.1.

[0376] The study drug dosages and treatment regimens are shown in Table 4 below.

[0377] Table 4

[0378]

[0379]

[0380]

[0381] 6. Evaluation Indicators

[0382] Safety Assessment

[0383] The incidence, relevance to study drug, and severity of all TEAEs, AESIs, and SAEs were analyzed.

[0384] Changes in vital signs, electrocardiogram, physical examination, and laboratory test results before, during, and after study drug treatment.

[0385] Immunogenicity: All subjects will be tested for ADA, and ADA-positive serum samples will be tested for neutralizing antibodies (NAb) if necessary.

[0386] PK evaluation

[0387] PK characteristics of drugs after single and multiple administration in humans, determine key PK parameters, including but not limited to: AUC, Tmax, Ctrough, Cmax, CL, V and t1 / 2.

[0388] Efficacy evaluation

[0389] The researchers evaluated tumor efficacy according to RECIST v1.1. The evaluation indicators included: objective response rate (ORR), duration of response (DoR), disease control rate (DCR), time to response (TTR), and progression-free survival (PFS).

[0390] Overall Survival (OS).

[0391] Biomarker Assessment

[0392] CLDN18.2 expression level in tumor tissues before treatment.

[0393] 7. Statistical methods

[0394] Sample size

[0395] The sample size of each cohort in Part 1 is not based on statistical hypothesis testing. Each combination treatment regimen is planned to enroll 3-6 subjects at each dose level, for a total of approximately 21-84 subjects.

[0396] Part 2 is to evaluate the efficacy and safety of the antibody-drug conjugate targeting CLAUDIN18.2 of the present invention in the combined treatment of subjects with advanced malignant solid tumors. It includes four cohorts and will enroll approximately 431 subjects: Cohort A contains 3 cohorts, 49 subjects in each group (including subjects in the same dose group as Part 1), for a total of 147 subjects; Cohort B contains up to four treatment groups, 40 subjects in each group, for a total of 160 subjects; Cohort C contains 44 subjects (including subjects in the same dose group as Part 1); Cohort D contains two treatment groups, 40 subjects in each group, for a total of 80 subjects. The sample size of each cohort is calculated as follows:

[0397] Cohort A includes advanced G / GEJ AC subjects who have failed or are intolerant to first-line standard treatment and are CLDN18.2 positive. According to the safety results of Part 1, three trial groups are planned: the antibody-drug conjugate targeting CLAUDIN18.2 of the present invention is combined with sintilimab, ramucirumab, and bevacizumab. Assuming that the ORR of each combination drug is 45% and the dropout rate is 20%, the sample size of 49 subjects will have a 70% confidence level to ensure that the lower limit of the 90% confidence interval is >26.5%.

[0398] Cohort B includes HER2-negative, CLDN18.2-positive advanced G / GEJ AC subjects who have not received systemic treatment before. A randomized controlled trial with equal ratios is planned: B1, B2, and B4 (if included) are experimental groups, and B3 is the control group. B1: Three-drug combination (antibody-drug conjugate targeting CLAUDIN18.2 of the present invention + sintilimab + oxaliplatin). B2: Two-drug combination (antibody-drug conjugate targeting CLAUDIN18.2 of the present invention + sintilimab). B3: Standard control treatment (sintilimab + capecitabine + oxaliplatin). B4: Four-drug combination (antibody-drug conjugate targeting CLAUDIN18.2 of the present invention + sintilimab + capecitabine + oxaliplatin, if included). 40 subjects are planned for each group, for a total of 160 subjects (if B4 group is included) or 120 subjects (if B4 group is not included). Assuming an ORR of 78% in each trial group and 58% in the control group, a one-sided significance level of 0.1 for the intergroup comparison, and a dropout rate of 10%, 80 subjects would have approximately 70% power to detect that the ORR in B1 / B2 / B4 was higher than that in the B3 group.

[0399] Cohort C includes PDAC subjects who have failed or are intolerant to gemcitabine-based treatment and are CLDN18.2 positive, and receive the antibody-drug conjugate targeting CLAUDIN18.2 of the present invention + Tegafur two-drug combination therapy. Assuming the ORR of the combined drug is 35% and the dropout rate is 20%, the sample size of 44 subjects will have 70% power to ensure that the lower limit of the 90% confidence interval is >17%.

[0400] Cohort D includes subjects with CLDN18.2-positive advanced pancreatic ductal adenocarcinoma (PDAC) who have not received previous systemic treatment. A 1:1 randomized controlled trial is planned: the antibody-drug conjugate targeting CLAUDIN18.2 of the present invention + gemcitabine + albumin-bound paclitaxel (experimental group), gemcitabine + albumin-bound paclitaxel (control group). 40 subjects are planned in each group, for a total of 80 subjects. Assuming that the ORR of the experimental group is 43%, the ORR of the control group is 23%, the one-sided significance level of the inter-group comparison is 0.1, and the dropout rate is 10%, 80 subjects will have approximately 70% confidence to detect that the ORR of the experimental group is higher than that of the control group.

[0401] Statistical methods

[0402] Unless otherwise specified, the data of subjects with the same tumor type / dose / combination treatment regimen in Part 1 and Part 2 (non-randomized cohorts A and C) will be combined for statistical analysis, and the DLT data of Part 1 will be analyzed separately according to tumor type / dose level / combination treatment regimen.

[0403] Descriptive statistics were used to summarize all safety, PK, immunogenicity, and efficacy data. For continuous variables, descriptive statistics (including number of cases, mean, standard deviation, median, minimum and maximum values; PK indicators also included geometric mean and geometric coefficient of variation) were used for summary; for discrete variables, frequencies and percentages were used for summary.

[0404] Anti-tumor efficacy indicators include:

[0405] - Best overall response [complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD)]

[0406] -ORR (CR+PR) and DCR (CR+PR+SD)

[0407] -DoR and TTR

[0408] -PFS

[0409] -OS

[0410] If data permit, ORR and DCR and their confidence intervals will be provided, and the proportion of subjects with best response of CR, PR, SD or PD will also be calculated. For the randomized cohort in Part 2, the chi-square test will be used to compare the differences in ORR and DCR between groups, and the ORR rate difference between groups and its confidence interval will be estimated; the Kaplan-Meier method will be used to calculate the median time of DoR, TTR, PFS and OS and their confidence intervals, as well as the rates and confidence intervals at specified time points (if applicable, such as the 6th and 12th months and every 6 months thereafter). For the randomized cohort in Part 2, the log-rank test will also be used to compare the differences between groups, and the Cox model will be used to calculate the HR and its confidence interval.

[0411] Safety data: All AEs will be coded and classified according to the Medical Dictionary for Respiratory Diseases (MedDRA), and the incidence and severity of each type of adverse event will be summarized. Vital signs, laboratory tests, and 12-lead electrocardiograms will be analyzed using descriptive statistical methods to analyze their observed values ​​and changes relative to baseline.

[0412] Immunogenicity data: Summary of the positive rates of anti-drug antibodies and neutralizing antibodies

[0413] PK data: Descriptive statistical analysis of PK measurement data and its parameters, including but not limited to AUC, Cmax, CL, V and t1 / 2.

[0414] Biomarker data: Descriptive statistics were used to analyze the expression level of CLDN18.2 in tumor tissues before treatment, and to explore the relationship between the expression level of CLDN18.2 before treatment and the efficacy.

[0415] 8. Experimental Results

[0416] 1) In this experiment, EMT6-hClaudin18.2 cells were inoculated into Balb / c mice to determine the anti-tumor effect of IEX019-02 (i.e., an antibody-drug conjugate targeting CLAUDIN18.2) combined with anti-PD-1 antibody

[0417] Balb / c mice:

[0418] Female Balb / c mice were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd., and the grade was SPF. The mice were started 3 days after arrival and acclimation.

[0419] cell:

[0420] EMT6-hClaudin18.2 cells (Innovent Biologics (Suzhou) Co., Ltd.) were cultured according to the instructions for subsequent in vivo experiments. Cells were collected by centrifugation, resuspended in sterile PBS and adjusted to a cell density of 15 × 10 6 On day 0, 0.2 mL of cell suspension was subcutaneously inoculated into the right abdominal area of ​​Balb / c mice to establish the EMT6-hClaudin18.2 tumor-bearing mouse model.

[0421] Dosage:

[0422] Seven days after tumor cell inoculation, the tumor volume of each mouse was measured with a vernier caliper, and mice with tumor volumes of approximately 97-137 mm were selected. 3 The mice between 1 and 2 were divided into groups according to tumor volume (7 mice per group). The dosage and method of administration are shown in Table 5. hIgG (purchased from EQUITECH-BIO) was used as a negative control, and αPD-1 was a mouse PD-1 monoclonal antibody (sequence see PCT / CN2016 / 094122). The antibody-drug conjugate targeting CLAUDIN18.2 was administered once a week for a total of three times, i.e., on the 7th, 14th, and 21st days after inoculation, and αPD-1 was administered twice a week for a total of 5 times, i.e., on the 7th, 10th, 14th, 17th, and 21st days after inoculation. The tumor volume and body weight of the mice were monitored twice a week. The body weight and tumor volume were measured before each administration, and the relative tumor inhibition rate (TGI%) was calculated on the 24th day after inoculation. The calculation formula is as follows: TGI% = 100% * (tumor volume of the control group - tumor volume of the treatment group) / (tumor volume of the control group - tumor volume of the control group before administration). Tumor volume measurement: The maximum long axis (L) and maximum wide axis (W) of the tumor were measured with a vernier caliper, and the tumor volume was calculated according to the following formula: V = L × W2 / 2. Body weight was measured with an electronic balance.

[0423] Table 5. Experimental design

[0424]

[0425] The tumor inhibition rate results are shown in Table 6 and Figure 1 As shown: the tumor inhibition rate of the antibody-drug conjugate group targeting CLAUDIN18.2 was 54%, the tumor inhibition rate of the αPD-1 group was 44%, and the tumor inhibition rate of the antibody-drug conjugate group targeting CLAUDIN18.2 + αPD-1 group was 86%. The tumor inhibition effect of the antibody-drug conjugate group targeting CLAUDIN18.2 + αPD-1 group was stronger than that of the antibody-drug conjugate group targeting CLAUDIN18.2 and the αPD-1 group. At the same time, we monitored the weight of the mice, and the results are as follows Figure 2As shown, there was no significant difference in the weight of mice. Therefore, compared with the antibody-drug conjugate targeting CLAUDIN18.2 and αPD-1 alone, the antibody-drug conjugate targeting CLAUDIN18.2 combined with αPD-1 has a more obvious inhibitory effect on tumors.

[0426] Table 6. Tumor inhibition rate on day 24

[0427]

[0428] 2) Antitumor efficacy of IEX019-02 (antibody-drug conjugate targeting CLAUDIN18.2) combined with capecitabine and oxaliplatin in HCT15-Claudin 18.2 tumor-bearing CB17-SCID mice

[0429] In this experiment, HCT15-Claudin 18.2 cells were inoculated into CB17-SCID mice to determine the anti-tumor effect of IEX019-02 (i.e., an antibody-drug conjugate targeting CLAUDIN18.2) combined with capecitabine and oxaliplatin.

[0430] CB17-SCID mice:

[0431] Female CB17-SCID mice were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd., with SPF grade, quality inspection unit is Beijing Weitonglihua Experimental Animal Technology Co., Ltd., and the certificate number is NO.110011231104500063. The mice were acclimated for 3 days after arrival, and then the study began.

[0432] cell:

[0433] HCT15-Claudin 18.2 cells (Innovent Biologics (Suzhou) Co., Ltd.) were cultured according to the instructions for subsequent in vivo experiments. Cells were collected by centrifugation, resuspended in sterile PBS and the cell density was adjusted to 10 × 10 6 On day 0, 0.2 mL of cell suspension was subcutaneously inoculated into the right abdominal area of ​​CB17-SCID mice to establish the HCT15-Claudin 18.2 tumor-bearing mouse model.

[0434] Dosage:

[0435] Six days after tumor cell inoculation, the tumor volume of each mouse was measured, and mice with tumor volumes within a certain range (89.91 mm 3 -138.27mm 3) were divided into 4 groups according to tumor volume, including Vehicle group, Capecitabine + Oxaliplatin, 180mg / kg + 5mg / kg group, Antibody-drug conjugate targeting CLAUDIN18.2, 1mg / kg group, Antibody-drug conjugate targeting CLAUDIN18.2 + Capecitabine + Oxaliplatin, 1mg / kg + 180mg / kg + 5mg / kg group, with 7 mice in each group. Antibody-drug conjugate targeting CLAUDIN18.2 was administered by intravenous injection, single dose; Capecitabine was administered by gavage, once a day, for 7 consecutive days; Oxaliplatin was injected intraperitoneally, once every 4 days, for 2 consecutive times. Tumor volume was monitored until 17 days. After the experiment, the relative tumor inhibition rate of each group of mice was calculated. The tumor volume of mice was measured on the 6th, 10th, 13th, and 17th days after tumor inoculation, and the tumor was measured twice a week. The tumor was weighed during measurement and gavage. The relative tumor inhibition rate (TGI%) was calculated on the 17th day after inoculation, and the calculation formula was as follows: TGI% = 100% * (tumor volume of the control group - tumor volume of the treatment group) / (tumor volume of the control group - tumor volume of the control group before administration). Tumor volume measurement: The maximum long axis (L) and the maximum wide axis (W) of the tumor were measured with a vernier caliper, and the tumor volume was calculated according to the following formula: V = L × W2 / 2. Body weight was measured using an electronic balance. The experimental design is shown in Table 7.

[0436] Table 7. Experimental design

[0437]

[0438] The tumor inhibition rate results are shown in Table 8 and Figure 3 As shown: the tumor inhibition rate of the capecitabine + oxaliplatin group was 62%, the tumor inhibition rate of the antibody-drug conjugate targeting CLAUDIN18.2 group was 99%, and the tumor inhibition rate of the antibody-drug conjugate targeting CLAUDIN18.2 + capecitabine + oxaliplatin group was 111%. The tumor inhibition effect of the antibody-drug conjugate targeting CLAUDIN18.2 + capecitabine + oxaliplatin group was stronger than that of the capecitabine + oxaliplatin group and the antibody-drug conjugate targeting CLAUDIN18.2 alone group. Therefore, the antibody-drug conjugate targeting CLAUDIN18.2 combined with capecitabine and oxaliplatin showed a certain synergistic effect compared with the antibody-drug conjugate targeting CLAUDIN18.2 alone and the combination of capecitabine + oxaliplatin, and the TGI% increased by 12% and 49% respectively. At the same time, we monitored the weight of the mice, and the results are as follows Figure 4As shown, there was no significant difference in the body weight of mice in the antibody-drug conjugate group targeting CLAUDIN18.2, while the body weight of mice in the capecitabine + oxaliplatin group and the antibody-drug conjugate group targeting CLAUDIN18.2 + capecitabine + oxaliplatin group decreased severely. The combination of 180 mg / kg capecitabine and 5 mg / kg oxaliplatin caused the weight of mice to decrease.

[0439] Table 8. Tumor inhibition rate on day 17

[0440]

[0441]

[0442] The antibody-drug conjugate targeting Claudin18.2 of the present invention is an ADC with a bystander effect, and also has a significant tumor inhibitory effect in a mouse tumor-bearing model with low expression of CLDN18.2. In preclinical pharmacodynamic studies, whether used in combination with an antibody drug for treating cancer and / or a chemotherapeutic drug, it has shown a certain synergistic effect and has shown a significant inhibitory effect on tumor volume. Therefore, the antibody-drug conjugate targeting Claudin18.2 of the present invention has a good therapeutic effect in combination with an antibody drug for treating cancer and / or a chemotherapeutic drug to treat subjects with various tumor types and different CLDN18.2 expression levels.

[0443] Antibody-drug conjugates targeting Claudin18.2 combined with sintilimab, ramucirumab, and bevacizumab for the treatment of advanced gastric / gastroesophageal junction adenocarcinoma with CLDN18.2 positive and failure of first-line standard treatment or intolerance can achieve an ORR of more than 45%, improve PFS and OS, and have good tolerability.

[0444] The ORR of the antibody-drug conjugate targeting Claudin18.2 combined with sintilimab and / or capecitabine and / or oxaliplatin for the treatment of HER2-negative, CLDN18.2-positive gastric / gastroesophageal junction adenocarcinoma that has not received previous systemic treatment can reach more than 78%, improve PFS and OS, and have good tolerability.

[0445] The ORR of an antibody-drug conjugate targeting Claudin18.2 combined with Segalovirus for the treatment of CLDN18.2-positive pancreatic ductal adenocarcinoma who have failed or are intolerant to gemcitabine-based regimens can reach more than 35%, improving PFS and OS while having good tolerability.

[0446] The ORR of an antibody-drug conjugate targeting Claudin18.2 combined with gemcitabine + albumin-paclitaxel for the treatment of CLDN18.2-positive pancreatic ductal adenocarcinoma that has not received previous systemic treatment can reach more than 43%, improving PFS and OS while having good tolerability.

[0447] Sequence information

[0448]

[0449]

[0450] The exemplary embodiments of the present invention are described above, and those skilled in the art should understand that these disclosures are only exemplary, and various other replacements, adaptations and modifications can be made within the scope of the present invention. Therefore, the present invention is not limited to the specific embodiments listed herein.

Claims

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

2. A method for treating cancer with an antibody-drug conjugate targeting Claudin18.2, the method comprising administering an effective amount of an antibody-drug conjugate targeting Claudin18.2, and an antibody drug and / or a chemotherapeutic drug for treating cancer to an individual in need; in, The antibody-drug conjugate targeting Claudin18.2 is selected from: wherein Ab is an antibody or an antigen-binding fragment thereof targeting Claudin18.2; Wherein q represents the average DAR, and q is 2-11, for example, a value of 2 to 5, preferably a value of 3 to 5, and more preferably a value of 3 to 4.

3. The method according to claim 1 or 2, wherein: The antibody or antigen-binding fragment targeting Claudin18.2 comprises HCDR1, HCDR2, HCDR3 as shown in the amino acid sequences of SEQ ID NO:1, 2 and 3, respectively, and LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:6, 7 and 8, respectively; or the antibody or antigen-binding fragment targeting Claudin18.2 comprises HCDR1-3 contained in the heavy chain variable region as shown in SEQ ID NO:4 and LCDR1-3 contained in the light chain variable region as shown in SEQ ID NO:9; preferably, the heavy chain variable region CDR and light chain variable region CDR of the antibody or antigen-binding fragment targeting Claudin18.2 are determined according to the rules of Kabat, AbM, Chothia, Contact and / or IMGT schemes.

4. The method according to any one of claims 1 to 3, wherein: The antibody or antigen-binding fragment thereof targeting Claudin18.2 comprises a heavy chain variable region and / or a light chain variable region, wherein the heavy chain variable region (i) comprises or consists of the amino acid sequence of SEQ ID NO: 4; or (ii) an amino acid sequence comprising one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 4, consisting of said amino acid sequence, preferably, said amino acid changes do not occur in the CDR regions; or an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 4; and / or Light chain variable region (i) comprises or consists of the amino acid sequence of SEQ ID NO: 9; or (ii) an amino acid sequence comprising one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 9, consisting of said amino acid sequence, preferably, said amino acid changes do not occur in the CDR regions; or An amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:

9.

5. The method according to any one of claims 1 to 4, wherein: The antibody or antigen-binding fragment thereof targeting Claudin18.2 further comprises a heavy chain constant region and / or a light chain constant region.

6. The method according to claim 5, wherein: The heavy chain constant region of the antibody or antigen-binding fragment thereof targeting Claudin18.2 is an IgG antibody.

7. The method according to claim 6, wherein: The heavy chain constant region of the antibody or antigen-binding fragment thereof targeting Claudin18.2 is selected from IgG1, IgG2, IgG3 or IgG4, preferably IgG1.

8. The method according to any one of claims 1 to 7, wherein: The antibody or antigen-binding fragment thereof targeting Claudin18.2 comprises a heavy chain and a light chain, wherein the heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 11; or Contains the following sequence, or consists of the following sequence Composition: an amino acid sequence having one or more (preferably no more than 20 or 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 11, or an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 11; and Light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 12; or Contains the following sequence, or consists of the following sequence Composition: an amino acid sequence having one or more (preferably no more than 20 or 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 12, or an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:

12.

9. The method according to any one of claims 1 to 8, wherein: The method comprises administering 0.1 mg / kg to 100 mg / kg of an antibody-drug conjugate targeting Claudin18.2 to an individual in need thereof.

10. The method according to any one of claims 1 to 9, wherein: The method comprises administering 0.2 mg / kg to 50 mg / kg of an antibody-drug conjugate targeting Claudin18.2 to an individual in need thereof.

11. The method according to any one of claims 1 to 10, wherein: The method comprises administering 0.3 mg / kg to 30 mg / kg of an antibody-drug conjugate targeting Claudin18.2 to an individual in need thereof.

12. The method according to claim 11, wherein: The method comprises administering 1 mg / kg, 3 mg / kg, 4.5 mg / kg, 6 mg / kg, 7.5 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 13.5 mg / kg, 15 mg / kg, 16 mg / kg, 18 mg / kg, 20 mg / kg, 22 mg / kg, 25 mg / kg, 28 mg / kg, 30 mg / kg of an antibody-drug conjugate targeting Claudin18.2 to an individual in need thereof.

13. The method according to any one of claims 1 to 12, wherein: The administration cycle of the antibody-drug conjugate targeting Claudin18.2 is 2 weeks / 14 days (Q2W) to 5 weeks / 35 days (Q5W).

14. The method according to claim 13, wherein: The administration cycle of the antibody-drug conjugate targeting Claudin18.2 is 2 weeks / 14 days (Q2W), 3 weeks / 21 days (Q3W), 4 weeks / 28 days (Q4W) or 5 weeks / 35 days (Q5W), and the drug is administered once on the first day of each cycle.

15. The method according to any one of claims 1 to 14, wherein: The antibody drug for treating cancer is selected from one or a combination of PD-1 inhibitors, recombinant anti-VEGF monoclonal antibodies, and monoclonal antibodies specifically binding to VEGFR-2.

16. The method according to claim 15, wherein: The PD-1 inhibitor is selected from one or a combination of pembrolizumab, nivolumab, carrelizumab, sintilimab, toripalizumab, and tislelizumab.

17. The method according to claim 16, wherein: The method comprises administering 200 mg of sintilimab to an individual in need thereof.

18. The method according to claim 16 or 17, wherein: The administration cycle of Sintilimab is 3 weeks / 21 days (Q3W), for example, administration on the 1st day.

19. The method according to claim 15, wherein: The recombinant anti-VEGF monoclonal antibody is selected from one or a combination of sevastatin and bevacizumab.

20. The method according to claim 19, wherein: The method comprises administering 15 mg / kg of bevacizumab to an individual in need thereof.

21. The method according to claim 20, wherein: The administration cycle of bevacizumab is 3 weeks / 21 days (Q3W), for example, administration on the first day.

22. The method according to claim 15, wherein: The monoclonal antibody specifically binding to VEGFR-2 includes ramucirumab.

23. The method according to claim 22, wherein: The method comprises administering 8 mg / kg of ramucirumab to an individual in need thereof.

24. The method according to claim 23, wherein: The administration cycle of ramucirumab is 4 weeks / 28 days (Q4W), for example, administration on the 1st day and the 15th day.

25. The method according to any one of claims 1 to 24, wherein: The chemotherapy drug is selected from one or a combination of oxaliplatin, capecitabine, gemcitabine, albumin-paclitaxel and S-1.

26. The method according to claim 25, wherein: The dosage of oxaliplatin is 130 mg / m 2 ; The administration cycle of oxaliplatin is 3 weeks / 21 days (Q3W), for example, it is administered on the 1st day.

27. The method according to claim 25, wherein: The dosage of capecitabine is 1000 mg / m 2 ; The administration cycle of capecitabine is twice a day.

28. The method according to claim 25, wherein: The dosage of gemcitabine is 1000 mg / m 2 ; The administration cycle of gemcitabine is 3 weeks / 21 days (Q3W), for example, administration on the 1st day and the 8th day.

29. The method according to claim 25, wherein: The dosage of nab-paclitaxel is 125 mg / m 2 ; The administration cycle of the albumin paclitaxel is 3 weeks / 21 days (Q3W), for example, administration on the 1st day and the 8th day.

30. The method of claim 25, wherein: The dosage of Tegafur is 40 mg-60 mg; the administration cycle of Tegafur is 3 weeks / 21 days (Q3W), twice a day, for example, administration on days 1-14.

31. The method according to any one of claims 1 to 30, wherein: The cancer includes solid tumors, including gastric / gastroesophageal junction adenocarcinoma and pancreatic ductal adenocarcinoma.

32. The method according to any one of claims 1 to 31, wherein: The administration methods of this method include intravenous injection and oral administration.

33. The method of any one of claims 1-31, wherein the dosing regimen for the subject is selected from the group consisting of: (1) Administering 4 mg / kg-10 mg / kg (preferably 6 mg / kg) of an antibody-drug conjugate targeting claudin18.2 on day 1 of a 21-day cycle; administering 8 mg / kg of ramucirumab on days 1 and 15 of a 28-day cycle; (2) Administering an antibody-drug conjugate targeting Claudin18.2 at 4 mg / kg-10 mg / kg (preferably 6 mg / kg) on ​​day 1 of a 21-day cycle; and administering bevacizumab at 15 mg / kg on day 1 of a 21-day cycle; (3) Administering 4 mg / kg-10 mg / kg (preferably 6 mg / kg) of an antibody-drug conjugate targeting Claudin18.2 on the first day of each 21-day cycle; administering 200 mg of sintilimab on the first day of each 21-day cycle; (4) Administer 4 mg / kg-10 mg / kg (preferably 6 mg / kg) of an antibody-drug conjugate targeting claudin18.2 on the first day of each 21-day cycle; 200 mg of sintilimab on the first day of each 21-day cycle; 130 mg / m 2 , each 21-day cycle, the drug is administered on day 1, and each subject receives a maximum of 6 cycles of oxaliplatin treatment; (5) Administer 4 mg / kg-10 mg / kg (preferably 6 mg / kg) of an antibody-drug conjugate targeting claudin18.2 on the first day of each 21-day cycle; 200 mg of sintilimab on the first day of each 21-day cycle; 1000 mg / m2 of capecitabine 2 , twice daily, 21 days per cycle, 1-14 days; oxaliplatin 130 mg / m 2 , each 21-day cycle, with medication given on day 1 (oxaliplatin can be given for a maximum of 6 cycles); (6) administering 4 mg / kg-10 mg / kg (preferably 6 mg / kg) of an antibody-drug conjugate targeting Claudin18.2 on day 1 of each 21-day cycle; and 40 mg-60 mg of S-1a, twice daily on days 1-14 of each 21-day cycle; and (7) Administer 4 mg / kg-10 mg / kg (preferably 6 mg / kg) of an antibody-drug conjugate targeting claudin18.2 on the first day of each 21-day cycle; gemcitabine 1000 mg / m 2 , every 21 days as a cycle, administration on day 1 and day 8; albumin paclitaxel 125 mg / m 2 , each cycle is 21 days, with medication given on the 1st and 8th days.

34. A unit dosage form, wherein: The unit preparation comprises: an effective amount (such as 1 mg-10000 mg, 5 mg-9000 mg, 3 mg-8000 mg, 10 mg-6000 mg, 50 mg-4000 mg, 100 mg-2500 mg, 200 mg-1000 mg, 300 mg-900 mg, 400 mg-800 mg, 500 mg-700 mg, 180 mg-550 mg, 200 mg-540 mg, 240 mg-480 mg, 300 mg-420 mg, 360 mg-420 mg or 360 mg-480 mg) of an antibody-drug conjugate targeting Claudin18.2 as defined in any one of claims 1 to 8, preferably the antibody-drug conjugate targeting Claudin18.2 is in a form suitable for injection (preferably intravenous or subcutaneous injection) or oral administration, and preferably the unit preparation also comprises instructions.

35. A single drug dosage unit or kit comprising an effective amount (e.g., 1 mg-10000 mg, 5 mg-9000 mg, 3 mg-8000 mg, 10 mg-6000 mg, 50 mg-4000 mg, 100 mg-2500 mg, 200 mg-1000 mg, 300 mg-900 mg, 400 mg-800 mg, 500 mg-700 mg, 180 mg-550 mg, 200 mg-540 mg, 240 mg-480 mg, 300 mg-420 mg, 360 mg-420 mg or 360 mg-480 mg) of an antibody-drug conjugate targeting Claudin18.2 as defined in any one of claims 1 to 8, preferably the kit further comprises an effective amount (e.g., 1 to 10000 mg) of The invention relates to an antibody drug for treating cancer and / or a chemotherapeutic drug (preferably an antibody-drug conjugate targeting Claudin18.2) with a dosage of 200-3000 mg, 100-2500 mg, 200-1000 mg, 300-900 mg, 400-800 mg, 500-700 mg, 180 mg-550 mg, 200 mg-540 mg, 240 mg-480 mg, 300 mg-420 mg, 360 mg-420 mg or 360 mg-480 mg), preferably an antibody-drug conjugate targeting Claudin18.2, the antibody drug for treating cancer and / or the chemotherapeutic drug are in a form suitable for injection (preferably intravenous or subcutaneous injection) or oral administration, and preferably the single drug dosage unit or kit also comprises instructions.

36. Use of an antibody-drug conjugate targeting Claudin18.2 as defined in any one of claims 1 to 8 for preparing a pharmaceutical composition or kit for treating cancer, wherein the pharmaceutical composition or kit comprises an effective amount of an antibody-drug conjugate targeting Claudin18.2 and instructions, and preferably the kit further comprises component A, which is selected from antibody drugs and / or chemotherapeutic drugs for treating cancer.

37. The unit formulation according to claim 34, or the single drug dosage unit or kit according to claim 35, or the use according to claim 36, wherein the instructions record a dosing regimen, for example, the dosage of the antibody-drug conjugate targeting Claudin18.2 is 0.1 mg / kg-100 mg / kg, 0.2 mg / kg-50 mg / kg, 0.3 mg / kg-30 mg / kg, 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, 15 mg / kg, 16 mg / kg, 18 mg / kg, 20 mg / kg, 22 mg / kg, 25 mg / kg, 28 mg / kg or 30 mg / kg, Or the dosage of the antibody-drug conjugate targeting Claudin18.2 is 1 mg-10000 mg, 5 mg-9000 mg, 3 mg-8000 mg, 10 mg-6000 mg, 50 mg-4000 mg, 100 mg-2500 mg, 200 mg-1000 mg, 300 mg-900 mg, 400 mg-800 mg, 500 mg-700 mg, 180 mg-550 mg, 200 mg-540 mg, 240 mg-480 mg, 300 mg-420 mg, 360 mg-420 mg or 360 mg-480 mg, The administration cycle is 2 weeks / 14 days (Q2W) to 5 weeks / 35 days (Q5W), preferably 3 weeks / 21 days (Q3W) or 4 weeks / 28 days (Q4W), and the drug is administered once on the first day of each cycle; Preferably, the dosage regimen is selected from the group consisting of: (1) Administering 4 mg / kg-10 mg / kg (preferably 6 mg / kg) of an antibody-drug conjugate targeting claudin18.2 on day 1 of a 21-day cycle; administering 8 mg / kg of ramucirumab on days 1 and 15 of a 28-day cycle; (2) Administering an antibody-drug conjugate targeting Claudin18.2 at 4 mg / kg-10 mg / kg (preferably 6 mg / kg) on ​​day 1 of a 21-day cycle; and administering bevacizumab at 15 mg / kg on day 1 of a 21-day cycle; (3) Administering 4 mg / kg-10 mg / kg (preferably 6 mg / kg) of an antibody-drug conjugate targeting Claudin18.2 on the first day of each 21-day cycle; administering 200 mg of sintilimab on the first day of each 21-day cycle; (4) Administer 4 mg / kg-10 mg / kg (preferably 6 mg / kg) of an antibody-drug conjugate targeting claudin18.2 on the first day of each 21-day cycle; 200 mg of sintilimab on the first day of each 21-day cycle; 130 mg / m 2 , each 21-day cycle, the drug is administered on day 1, and each subject receives a maximum of 6 cycles of oxaliplatin treatment; (5) Administer 4 mg / kg-10 mg / kg (preferably 6 mg / kg) of an antibody-drug conjugate targeting claudin18.2 on the first day of each 21-day cycle; 200 mg of sintilimab on the first day of each 21-day cycle; 1000 mg / m2 of capecitabine 2 , twice daily, 21 days per cycle, 1-14 days; oxaliplatin 130 mg / m 2 , each 21-day cycle, with medication given on day 1 (oxaliplatin can be given for a maximum of 6 cycles); (6) administering 4 mg / kg-10 mg / kg (preferably 6 mg / kg) of an antibody-drug conjugate targeting Claudin18.2 on day 1 of each 21-day cycle; and 40 mg-60 mg of S-1a, twice daily on days 1-14 of each 21-day cycle; and (7) Administer 4 mg / kg-10 mg / kg (preferably 6 mg / kg) of an antibody-drug conjugate targeting claudin18.2 on the first day of each 21-day cycle; gemcitabine 1000 mg / m 2 , every 21 days as a cycle, administration on day 1 and day 8; albumin paclitaxel 125 mg / m 2 , each cycle is 21 days, with medication given on the 1st and 8th days.

38. The unit formulation according to claim 34, or the single drug dosage unit or kit according to claim 35, or the use according to claim 36, wherein the effective amount of the antibody-drug conjugate targeting Claudin18.2 is selected from the group consisting of: 1 mg-10000 mg, 5 mg-9000 mg, 3 mg-8000 mg, 10 mg-6000 mg, 50 mg-4000 mg, 100 mg-2500 mg, 200 mg-1000 mg, 300 mg-900 mg, 400 mg-800 mg, 500 mg-700 mg, 180 mg-550 mg, 200 mg-540 mg, 240 mg-480 mg, 300 mg-420 mg, 360 mg-420 mg or 360 mg-480 mg.

39. The unit formulation according to claim 34, or the single pharmaceutical dosage unit or kit according to claim 35, or the use according to claim 36, wherein the antibody-drug conjugate targeting Claudin18.2 is as defined in any one of claims 1 to 8.

40. A single pharmaceutical dosage unit or kit according to claim 35, or a use according to claim 36, wherein the antibody drug for treating cancer is as defined in any one of claims 15-24, or the chemotherapeutic drug is as defined in any one of claims 25-30.

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