Use of conjugate in treating tumor disease and method

Abstract

Provided are a use of an antibody-drug conjugate represented by formula (I) in treating a tumor disease and a method. The tumor disease includes a digestive system tumor. {D-[L1-(L2)m1-(L3)m2-(L4)m3-E]}γ-A Formula (I)

Description

Use and method of conjugates in treating tumor diseases

[0001] This application is based on the application with CN application number 202410400329.0 and application date April 3, 2024, and claims its priority. The disclosed content of the CN application is hereby introduced as a whole into this application. Technical Field

[0002] The present application relates to the use and method of conjugates in treating tumor diseases, including but not limited to digestive tract tumor diseases. Background Art

[0003] Cancer continues to pose a serious threat to human health worldwide. Most digestive system cancers are diagnosed at an advanced stage, making treatment difficult and ineffective. In particular, patients with previously treated locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma have a poor prognosis, with a median overall survival of less than one year.

[0004] Antibody-drug conjugates (ADCs) are a new class of targeted therapeutics that couple targeting groups, such as monoclonal antibodies, to effector molecules to achieve targeted therapeutic effects. Compared to traditional drug therapies, ADCs offer advantages such as strong targeting and enhanced anti-tumor activity, reducing toxic side effects while improving drug efficacy.

[0005] Currently, numerous ADCs are marketed worldwide, covering indications for leukemia, lymphoma, and breast cancer. However, the efficacy and safety of treatments for some metastatic, recurrent, and / or refractory digestive system cancers still need to be further improved. Therefore, the development of more highly effective and safe antibody-drug conjugates (ADCs) is crucial to meet the increasingly urgent clinical demand. Summary of the Invention

[0006] The present invention provides the use of an antibody drug conjugate of formula (I) or a composition containing the antibody drug conjugate in the preparation of a medicament for treating advanced gastric cancer or carcinoma of the esophagogastric junction (CEGJ); {D-[L1-(L2) m1 -(L3) m2 -(L4) m3 -E]} γ -A formula (I)

[0007] in,

[0008] L1 is Each R1 and R2 are independently hydrogen (such as protium or deuterium), halogen, carboxylic acid group, sulfonic acid group, cyano group, C 1-6 Alkyl, halogenated C1-6 Alkyl, cyano substituted C 1-6 Alkyl (e.g. -CH2CN), C 1-6 Alkoxy, C 2-10 Alkenyl or C 2-10 Alkynyl; Z1 is an amino acid or a peptide composed of 2 to 10 amino acids; x1 and x2 are each independently 0, 1, 2, 3, 4, 5 or 6; and the 1 position of L1 is connected to D, and the 2 position of L1 is connected to L2;

[0009] L2 is Wherein, y1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and the 1 position of L2 is connected to L1, and the 2 position of L2 is connected to L3;

[0010] L3 is a 5- to 12-membered heteroaromatic ring;

[0011] L4 is Where Z2 is selected from C 1-6 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene, and C 3- 8 cycloalkylene; R3 is selected from H and C 1-6 Alkyl; Z3 does not exist or is C 1-6 Alkylene; or, R3 and Z3 together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic group; α is 0, 1, 2, 3, 4, 5 or 6, and the 2 position of L4 is connected to E, and the 1 position of L4 is connected to L3;

[0012] E is wherein each R4 is independently hydrogen (e.g., protium or deuterium), β is 0, 1, or 2, and the 2 position of E is connected to A (e.g., connected to the thiol group on A), and the 1 position of E is connected to L4;

[0013] m1, m2 and m3 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0014] D is a bioactive molecular fragment;

[0015] γ refers to {D-[L1-(L2) m1 -(L3) m2 -(L4) m3 -E]} number of moieties, which is selected from an integer between 1 and 10; preferably, γ is selected from an integer between 3 and 8 (e.g., 3, 4, 5, 6, 7 or 8);

[0016] A is an anti-Trop-2 monoclonal antibody or an antigen-binding fragment thereof.

[0017] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer is:

[0018] Standard treatment has failed, or there is no standard treatment option, or standard treatment is not applicable at this stage;

[0019] Unresectable;

[0020] Locally advanced; and / or

[0021] Transfer occurred.

[0022] In some embodiments, the advanced gastric cancer is advanced gastric cancer that has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0023] In some embodiments, the advanced gastric cancer is unresectable advanced gastric cancer.

[0024] In some embodiments, the advanced gastric cancer is locally advanced gastric cancer.

[0025] In some embodiments, the advanced gastric cancer is metastatic advanced gastric cancer.

[0026] In some embodiments, the advanced gastric cancer is unresectable advanced gastric cancer that has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0027] In some embodiments, the advanced gastric cancer is locally advanced gastric cancer that has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0028] In some embodiments, the advanced gastric cancer is metastatic advanced gastric cancer that has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0029] In some embodiments, the advanced gastric cancer is unresectable locally advanced gastric cancer.

[0030] In some embodiments, the advanced gastric cancer is unresectable metastatic advanced gastric cancer.

[0031] In some embodiments, the advanced gastric cancer is locally advanced gastric cancer with metastasis.

[0032] In some embodiments, the advanced gastric cancer is unresectable locally advanced gastric cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0033] In some embodiments, the advanced gastric cancer is advanced gastric cancer with metastasis that has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment and cannot be surgically removed.

[0034] In some embodiments, the advanced gastric cancer is locally advanced gastric cancer that has metastasized and has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0035] In some embodiments, the advanced gastric cancer is unresectable locally advanced gastric cancer with metastasis.

[0036] In some embodiments, the advanced gastric cancer is locally advanced gastric cancer that has metastasized and cannot be surgically resected and has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0037] In some embodiments, the gastroesophageal junction cancer is a gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0038] In some embodiments, the gastroesophageal junction cancer is unresectable gastroesophageal junction cancer.

[0039] In some embodiments, the gastroesophageal junction cancer is locally advanced gastroesophageal junction cancer.

[0040] In some embodiments, the gastroesophageal junction cancer is metastatic gastroesophageal junction cancer.

[0041] In some embodiments, the gastroesophageal junction cancer is unresectable gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0042] In some embodiments, the gastroesophageal junction cancer is locally advanced gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0043] In some embodiments, the gastroesophageal junction cancer is metastatic gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0044] In some embodiments, the gastroesophageal junction cancer is unresectable locally advanced gastroesophageal junction cancer.

[0045] In some embodiments, the gastroesophageal junction cancer is unresectable metastatic gastroesophageal junction cancer.

[0046] In some embodiments, the gastroesophageal junction cancer is locally advanced gastroesophageal junction cancer that has metastasized.

[0047] In some embodiments, the gastroesophageal junction cancer is unresectable locally advanced gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0048] In some embodiments, the gastroesophageal junction cancer is metastatic gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment and cannot be surgically removed.

[0049] In some embodiments, the gastroesophageal junction cancer is locally advanced gastroesophageal junction cancer with metastasis that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0050] In some embodiments, the gastroesophageal junction cancer is unresectable, locally advanced metastatic gastroesophageal junction cancer.

[0051] In some embodiments, the gastroesophageal junction cancer is unresectable, metastatic, locally advanced gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0052] In some embodiments, the standard treatment refers to the standard treatment regimen for the cancer recommended by the NCCN guidelines and the CSCO diagnosis and treatment guidelines.

[0053] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer has failed and / or recurred after first-line treatment. The drugs used in the first-line treatment refer to first-line chemotherapy drugs, immunotherapy, and / or targeted therapy drugs recommended by the NCCN guidelines and CSCO diagnosis and treatment guidelines for the cancer.

[0054] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer has failed and / or relapsed after first-line chemotherapy. In some embodiments, the first-line chemotherapy refers to a first-line chemotherapy for the cancer recommended by the NCCN Guidelines and the CSCO Diagnosis and Treatment Guidelines.

[0055] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer has failed and / or recurred after radiotherapy. In some embodiments, the radiotherapy refers to the radiotherapy regimen for the cancer recommended by the NCCN guidelines and the CSCO diagnosis and treatment guidelines.

[0056] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer has failed and / or recurred after treatment with targeted drugs or immunotherapy. In some embodiments, the targeted drugs or immunotherapy refer to targeted drugs or immunotherapy for the cancer recommended by the NCCN guidelines and the CSCO diagnosis and treatment guidelines.

[0057] In some embodiments, the gastric cancer includes but is not limited to the following types: adenocarcinoma, adenosquamous carcinoma, squamous cell carcinoma, undifferentiated carcinoma, and neuroendocrine tumor.

[0058] In some embodiments, the gastric cancer is gastric adenocarcinoma.

[0059] In some embodiments, the gastroesophageal junction cancer is gastroesophageal junction adenocarcinoma.

[0060] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer has been previously treated with chemotherapy, such as fluorouracil-based, platinum-based, taxane-based, or camptothecin-based chemotherapy.

[0061] In some embodiments, the chemotherapy treatment is a platinum-based chemotherapy, such as cisplatin and / or oxaliplatin.

[0062] In some embodiments, the chemotherapy treatment is a camptothecin chemotherapy, such as irinotecan.

[0063] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer has been previously treated with immunotherapy.

[0064] In some embodiments, the immunotherapy is PD-1 / L1 therapy.

[0065] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer has been previously treated with more than one treatment; for example, more than one, more than two, more than three, more than four, or more than five treatments.

[0066] In some embodiments, the conjugate has the following structure:

[0067] L1 is selected from And the 1 position of L1 is connected to D, and the 2 position of L1 is connected to L2;

[0068] L2 is wherein y1 is 3, 4, 5, 6, 7, 8, 9 or 10; and the 1 position of L2 is connected to L1, and the 2 position of L2 is connected to L3;

[0069] L3 is selected from a 5- to 6-membered heteroaromatic ring, such as pyrazole or triazole;

[0070] L4 is Where Z2 is selected from C 1-3 Alkylene; R3 is H; Z3 is selected from C 1-3 Alkylene; α is 0, and the 2-position of L4 is connected to E, and the 1-position of L4 is connected to L3;

[0071] E is wherein each R4 is independently hydrogen (e.g., protium or deuterium), β is 0, 1, or 2, and the 2 position of E is connected to A (e.g., connected to the thiol group on A), and the 1 position of E is connected to L4;

[0072] m1, m2, and m3 are all 1;

[0073] The bioactive molecule is selected from Preferably, the bioactive molecule is linked to the 1 position of L1 via its own hydroxyl group;

[0074] γ is selected from an integer between 3 and 8 (e.g., 3, 4, 5, 6, 7 or 8);

[0075] A is sacituzumab or an antigen-binding fragment thereof.

[0076] In some embodiments, the conjugate has the following structure:

[0077] L1 is selected from And the 1 position of L1 is connected to D, and the 2 position of L1 is connected to L2;

[0078] L2 is wherein y1 is 3, 4, 5, 6, 7, 8, 9 or 10; and the 1 position of L2 is connected to L1, and the 2 position of L2 is connected to L3;

[0079] L3 is selected from a 5- to 6-membered heteroaromatic ring, such as pyrazole or triazole;

[0080] L4 is Where Z2 is selected from C 1-3 Alkylene; R3 is H; Z3 is selected from C 1-3 Alkylene; α is 1, and the 2 position of L4 is connected to E, and the 1 position of L4 is connected to L3;

[0081] E is wherein each R4 is independently hydrogen (e.g., protium or deuterium), β is 0, 1, or 2, and the 2 position of E is connected to A (e.g., connected to the thiol group on A), and the 1 position of E is connected to L4;

[0082] m1, m2, and m3 are all 1;

[0083] The bioactive molecule is selected from Preferably, the bioactive molecule is linked to the 1 position of L1 via its own hydroxyl group;

[0084] γ is selected from an integer between 3 and 8 (e.g., 3, 4, 5, 6, 7 or 8);

[0085] A is sacituzumab or an antigen-binding fragment thereof.

[0086] In some embodiments, D is selected from

[0087] In some technical solutions, the conjugate is a conjugate A having the structure shown in the following formula:

[0088] Wherein, γ is an integer between 1 and 10; preferably, γ is an integer selected from 5 to 8.

[0089] In some embodiments, the composition contains a plurality of the conjugates. In some embodiments, the conjugate or composition has a DAR value of 1 to 12; preferably 1 to 10; more preferably a DAR value of 5 to 8; for example, a DAR value of 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.

[0090] In some embodiments, the composition is a pharmaceutical composition.

[0091] In some embodiments, the medicament or pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient.

[0092] In some embodiments, the conjugate or composition is formulated into a preparation suitable for administration. In some preferred embodiments, the conjugate or composition is formulated into an injection.

[0093] In another aspect, the present application provides an antibody-drug conjugate of formula (I) and / or the composition as described above for use in treating advanced gastric cancer or gastroesophageal junction cancer in an individual.

[0094] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer is:

[0095] Standard treatment has failed, or there is no standard treatment option, or standard treatment is not applicable at this stage;

[0096] Unresectable;

[0097] Locally advanced; and / or

[0098] Transfer occurred.

[0099] In some embodiments, the advanced gastric cancer is advanced gastric cancer that has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0100] In some embodiments, the advanced gastric cancer is unresectable advanced gastric cancer.

[0101] In some embodiments, the advanced gastric cancer is locally advanced gastric cancer.

[0102] In some embodiments, the advanced gastric cancer is metastatic advanced gastric cancer.

[0103] In some embodiments, the advanced gastric cancer is unresectable advanced gastric cancer that has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0104] In some embodiments, the advanced gastric cancer is locally advanced gastric cancer that has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0105] In some embodiments, the advanced gastric cancer is metastatic advanced gastric cancer that has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0106] In some embodiments, the advanced gastric cancer is unresectable locally advanced gastric cancer.

[0107] In some embodiments, the advanced gastric cancer is unresectable metastatic advanced gastric cancer.

[0108] In some embodiments, the advanced gastric cancer is locally advanced gastric cancer with metastasis.

[0109] In some embodiments, the advanced gastric cancer is unresectable locally advanced gastric cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0110] In some embodiments, the advanced gastric cancer is advanced gastric cancer with metastasis that has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment and cannot be surgically removed.

[0111] In some embodiments, the advanced gastric cancer is locally advanced gastric cancer that has metastasized and has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0112] In some embodiments, the advanced gastric cancer is unresectable locally advanced gastric cancer with metastasis.

[0113] In some embodiments, the advanced gastric cancer is locally advanced gastric cancer that has metastasized and cannot be surgically resected and has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0114] In some embodiments, the gastroesophageal junction cancer is a gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0115] In some embodiments, the gastroesophageal junction cancer is unresectable gastroesophageal junction cancer.

[0116] In some embodiments, the gastroesophageal junction cancer is locally advanced gastroesophageal junction cancer.

[0117] In some embodiments, the gastroesophageal junction cancer is metastatic gastroesophageal junction cancer.

[0118] In some embodiments, the gastroesophageal junction cancer is unresectable gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0119] In some embodiments, the gastroesophageal junction cancer is locally advanced gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0120] In some embodiments, the gastroesophageal junction cancer is metastatic gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0121] In some embodiments, the gastroesophageal junction cancer is unresectable locally advanced gastroesophageal junction cancer.

[0122] In some embodiments, the gastroesophageal junction cancer is unresectable metastatic gastroesophageal junction cancer.

[0123] In some embodiments, the gastroesophageal junction cancer is locally advanced gastroesophageal junction cancer that has metastasized.

[0124] In some embodiments, the gastroesophageal junction cancer is unresectable locally advanced gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0125] In some embodiments, the gastroesophageal junction cancer is metastatic gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment and cannot be surgically removed.

[0126] In some embodiments, the gastroesophageal junction cancer is locally advanced gastroesophageal junction cancer with metastasis that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0127] In some embodiments, the gastroesophageal junction cancer is unresectable, locally advanced metastatic gastroesophageal junction cancer.

[0128] In some embodiments, the gastroesophageal junction cancer is unresectable, metastatic, locally advanced gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0129] In some embodiments, the standard treatment refers to the standard treatment regimen for the cancer recommended by the NCCN guidelines and the CSCO diagnosis and treatment guidelines.

[0130] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer has failed and / or recurred after first-line treatment. The drugs used in the first-line treatment refer to first-line chemotherapy drugs, immunotherapy, and / or targeted therapy drugs recommended by the NCCN guidelines and CSCO diagnosis and treatment guidelines for the cancer.

[0131] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer has failed and / or recurred after radiotherapy. In some embodiments, the radiotherapy refers to the radiotherapy regimen for the cancer recommended by the NCCN guidelines and the CSCO diagnosis and treatment guidelines.

[0132] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer has failed and / or recurred after treatment with targeted drugs or immunotherapy. In some embodiments, the targeted drugs or immunotherapy refer to targeted drugs or immunotherapy for the cancer recommended by the NCCN guidelines and the CSCO diagnosis and treatment guidelines.

[0133] In some embodiments, the gastric cancer includes but is not limited to the following types: adenocarcinoma, adenosquamous carcinoma, squamous cell carcinoma, undifferentiated carcinoma, and neuroendocrine tumor.

[0134] In some embodiments, the gastric cancer is gastric adenocarcinoma.

[0135] In some embodiments, the gastroesophageal junction cancer is gastroesophageal junction adenocarcinoma.

[0136] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer has been previously treated with chemotherapy, such as fluorouracil-based, platinum-based, taxane-based, or camptothecin-based chemotherapy.

[0137] In some embodiments, the chemotherapy treatment is a platinum-based chemotherapy, such as cisplatin and / or oxaliplatin.

[0138] In some embodiments, the chemotherapy treatment is a camptothecin chemotherapy, such as irinotecan.

[0139] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer has been previously treated with immunotherapy.

[0140] In some embodiments, the immunotherapy is PD-1 / L1 therapy.

[0141] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer has been previously treated with more than one treatment; for example, more than one, more than two, more than three, more than four, or more than five treatments.

[0142] In another aspect, the present invention provides a method for treating advanced gastric cancer or gastroesophageal junction cancer, comprising the step of administering to an individual in need thereof a therapeutically effective amount of the antibody drug conjugate of formula (I) and / or the composition as described above.

[0143] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer is:

[0144] Standard treatment has failed, or there is no standard treatment option, or standard treatment is not applicable at this stage;

[0145] Unresectable;

[0146] Locally advanced; and / or

[0147] Transfer occurred.

[0148] In some embodiments, the advanced gastric cancer is advanced gastric cancer that has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0149] In some embodiments, the advanced gastric cancer is unresectable advanced gastric cancer.

[0150] In some embodiments, the advanced gastric cancer is locally advanced gastric cancer.

[0151] In some embodiments, the advanced gastric cancer is metastatic advanced gastric cancer.

[0152] In some embodiments, the advanced gastric cancer is unresectable advanced gastric cancer that has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0153] In some embodiments, the advanced gastric cancer is locally advanced gastric cancer that has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0154] In some embodiments, the advanced gastric cancer is metastatic advanced gastric cancer that has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0155] In some embodiments, the advanced gastric cancer is unresectable locally advanced gastric cancer.

[0156] In some embodiments, the advanced gastric cancer is unresectable metastatic advanced gastric cancer.

[0157] In some embodiments, the advanced gastric cancer is locally advanced gastric cancer with metastasis.

[0158] In some embodiments, the advanced gastric cancer is unresectable locally advanced gastric cancer that has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0159] In some embodiments, the advanced gastric cancer is advanced gastric cancer with metastasis that has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment and cannot be surgically removed.

[0160] In some embodiments, the advanced gastric cancer is locally advanced gastric cancer that has metastasized and has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0161] In some embodiments, the advanced gastric cancer is unresectable locally advanced gastric cancer with metastasis.

[0162] In some embodiments, the advanced gastric cancer is locally advanced gastric cancer that has metastasized and cannot be surgically resected and has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0163] In some embodiments, the gastroesophageal junction cancer is a gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0164] In some embodiments, the gastroesophageal junction cancer is unresectable gastroesophageal junction cancer.

[0165] In some embodiments, the gastroesophageal junction cancer is locally advanced gastroesophageal junction cancer.

[0166] In some embodiments, the gastroesophageal junction cancer is metastatic gastroesophageal junction cancer.

[0167] In some embodiments, the gastroesophageal junction cancer is unresectable gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0168] In some embodiments, the gastroesophageal junction cancer is locally advanced gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0169] In some embodiments, the gastroesophageal junction cancer is metastatic gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0170] In some embodiments, the gastroesophageal junction cancer is unresectable locally advanced gastroesophageal junction cancer.

[0171] In some embodiments, the gastroesophageal junction cancer is unresectable metastatic gastroesophageal junction cancer.

[0172] In some embodiments, the gastroesophageal junction cancer is locally advanced gastroesophageal junction cancer that has metastasized.

[0173] In some embodiments, the gastroesophageal junction cancer is unresectable locally advanced gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0174] In some embodiments, the gastroesophageal junction cancer is metastatic gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment and cannot be surgically removed.

[0175] In some embodiments, the gastroesophageal junction cancer is locally advanced gastroesophageal junction cancer with metastasis that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0176] In some embodiments, the gastroesophageal junction cancer is unresectable, locally advanced metastatic gastroesophageal junction cancer.

[0177] In some embodiments, the gastroesophageal junction cancer is unresectable, metastatic, locally advanced gastroesophageal junction cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0178] In some embodiments, the standard treatment refers to the standard treatment regimen for the cancer recommended by the NCCN guidelines and the CSCO diagnosis and treatment guidelines.

[0179] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer has failed and / or recurred after first-line treatment. The drugs used in the first-line treatment refer to first-line chemotherapy drugs, immunotherapy, and / or targeted therapy drugs recommended by the NCCN guidelines and CSCO diagnosis and treatment guidelines for the cancer.

[0180] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer has failed and / or relapsed after first-line chemotherapy. In some embodiments, the first-line chemotherapy refers to a first-line chemotherapy for the cancer recommended by the NCCN Guidelines and the CSCO Diagnosis and Treatment Guidelines.

[0181] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer has failed and / or recurred after radiotherapy. In some embodiments, the radiotherapy refers to the radiotherapy regimen for the cancer recommended by the NCCN guidelines and the CSCO diagnosis and treatment guidelines.

[0182] In some embodiments, the advanced gastric cancer or gastroesophageal junction cancer has failed and / or recurred after treatment with targeted drugs or immunotherapy. In some embodiments, the targeted drugs or immunotherapy refer to targeted drugs or immunotherapy for the cancer recommended by the NCCN guidelines and the CSCO diagnosis and treatment guidelines.

[0183] In some embodiments, the gastric cancer includes but is not limited to the following types: adenocarcinoma, adenosquamous carcinoma, squamous cell carcinoma, undifferentiated carcinoma, and neuroendocrine tumor.

[0184] In some embodiments, the gastric cancer is gastric adenocarcinoma.

[0185] In some embodiments, the gastroesophageal junction cancer is gastroesophageal junction adenocarcinoma.

[0186] In some embodiments of any of the aforementioned aspects, the individual has previously received chemotherapy, such as fluorouracil-based, platinum-based, taxane-based, or camptothecin-based chemotherapy.

[0187] In some embodiments, the chemotherapy treatment is a platinum-based chemotherapy, such as cisplatin and / or oxaliplatin.

[0188] In some embodiments, the individual has previously received camptothecin chemotherapy, such as irinotecan.

[0189] In some embodiments of any of the aforementioned aspects, the individual has previously received immunotherapy.

[0190] In some embodiments, the immunotherapy is PD-1 / L1 therapy.

[0191] In some embodiments of any of the above aspects, the individual has previously received more than one treatment; for example, the individual has previously received more than one, more than two, more than three, more than four, or more than five treatments.

[0192] In some embodiments, the antibody drug conjugate or the composition is administered once every 7 to 35 days, preferably once every 7 to 28 days, for example, once every 7 days, 14 days, 21 days, 28 days, or 35 days.

[0193] In some embodiments, the antibody drug conjugate or the composition is administered once every 1-5 weeks, preferably once every 1-3 weeks, for example, once every 1 week, every 2 weeks, or every 3 weeks.

[0194] In some embodiments, the antibody drug conjugate or the composition is administered once every three weeks.

[0195] In some embodiments, the antibody drug conjugate or the composition is administered once every 2 weeks.

[0196] In some embodiments, the administration routes of the conjugate or composition include, but are not limited to, oral administration, transdermal injection, rectal administration, transmucosal administration, intramuscular injection, intramedullary injection, intravenous injection, or intraperitoneal injection, preferably intravenous injection.

[0197] In some embodiments, the dosage of the antibody drug conjugate per administration is 1 mg / kg to 30 mg / kg based on the individual's body weight; preferably 1 mg / kg to 20 mg / kg; more preferably 2 mg / kg to 12 mg / kg; further preferably 2-5 mg / kg, 4-7 mg / kg, 6-9 mg / kg, 8-11 mg / kg, 10-13 mg / kg, or 12-15 mg / kg; for example: 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 8.5 mg / kg, 9 mg / kg, 9.5 mg / kg, 10 mg / kg, 11 mg / kg or 12 mg / kg.

[0198] In some embodiments, the dosage of the antibody drug conjugate administered per administration is 5 mg / kg based on the individual's body weight.

[0199] In some embodiments, the antibody drug conjugate or the pharmaceutical composition is administered once every three weeks, and the dose of the antibody drug conjugate per administration is 5 mg / kg based on the individual's body weight.

[0200] In some embodiments, the antibody drug conjugate or the pharmaceutical composition is administered once every 2 weeks, and the dose of the antibody drug conjugate per administration is 5 mg / kg based on the individual's body weight.

[0201] In some embodiments, the administration regimen of the antibody drug conjugate is divided into one or more administration phases (e.g., one phase, two phases, three phases, or four phases), and the administration cycle and administration dose of each phase are independently selected from the administration cycles or doses described above.

[0202] In some embodiments, the uses or methods of the present invention result in the elimination or reduction of tumor size.

[0203] In some embodiments, the uses or methods of the present invention result in a reduction in tumor volume of at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, or at least 40%.

[0204] definition

[0205] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0206] The drug-antibody conjugation ratio (DAR) refers to the average loading of the antibody to the small molecule toxin drug in the conjugate. Although the ratio of the small molecule toxin drug portion to the antibody portion has a specific value for a specific conjugate molecule, it should be understood that when used to describe a sample containing many molecules, this value refers to the average calculated based on the percentage of different specific conjugate molecules, and this loading average is referred to herein as the average conjugation ratio or "DAR".

[0207] The NCCN guidelines refer to the clinical practice guidelines for various malignant tumors issued by the National Comprehensive Cancer Network of the United States.

[0208] CSCO diagnosis and treatment guidelines refer to the clinical diagnosis and treatment guidelines for various malignant tumors issued by the Chinese Society of Clinical Oncology (CSCO).

[0209] The objective response rate (ORR) refers to the proportion of patients whose tumors shrink to a certain degree and for a certain period of time, including both complete response (CR) and partial response (PR). Objective response was assessed using the response evaluation criteria in solid tumors version 1.1 (RECIST 1.1). Patients must have measurable tumor lesions at baseline. Efficacy was assessed according to RECIST 1.1 as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD).

[0210] Disease progression (PD): The minimum value of the sum of all target lesion diameters measured during the entire study is used as a reference, and the relative increase in the sum of diameters is at least 20% (if the baseline measurement value is the minimum, the baseline value is used as a reference); in addition, the absolute value of the sum of diameters must increase by at least 5 mm (the appearance of one or more new lesions is also considered disease progression).

[0211] Stable disease (SD): The target lesion has not decreased to the level of PR, nor increased to the level of PD, but is somewhere in between. The minimum sum of the diameters can be used as a reference for research.

[0212] Partial response (PR): at least a 30% reduction in the sum of target lesions compared to baseline.

[0213] Complete remission (CR): All target lesions disappear and the short diameter of all pathological lymph nodes (including target nodules and non-target nodules) must be reduced to <10mm.

[0214] Dose-limiting toxicities (DLT) are side effects of drugs that are the main reason for limiting further increase in drug dose.

[0215] Adverse Event (AE): refers to any untoward medical event that occurs in patients or clinical research subjects after receiving a drug, but is not necessarily causally related to the treatment.

[0216] Treatment-emergent adverse event (TEAE) refers to any AE that occurs or worsens during or after the first dose of the drug.

[0217] “Advanced” usually refers to a malignant tumor whose pathological stage reaches stage III or IV of the American Joint Committee on Cancer (AJCC) cancer staging system (or equivalent cancer staging system).

[0218] Gastric cancer: A malignant tumor originating from the gastric epithelial cells. First-line treatment for gastric cancer is categorized as either HER2-positive or HER2-negative based on biomarker expression, with targeted therapy, immunotherapy, and / or chemotherapy used accordingly. Second- and third-line treatments primarily utilize targeted therapy and / or chemotherapy.

[0219] Adenocarcinoma of the esophagogastric junction (AEG) is defined as adenocarcinoma whose tumor center is within 5 cm above or below the esophagogastric anatomical junction and spans or contacts the esophagogastric junction (EGJ). First-line treatment for AEG is categorized as either HER2-positive or HER2-negative based on biomarker expression, with appropriate targeted therapy, immunotherapy, and / or chemotherapy selected. Second- and third-line treatments primarily include targeted therapy and / or chemotherapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0220] The drawings described herein are used to provide a further understanding of the present invention and constitute a part of this application. The exemplary embodiments of the present invention and the drawings thereof are used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0221] Figure 1 shows the conjugate A and the marketed drug Trodelvy TM In vitro plasma stability. DETAILED DESCRIPTION

[0222] The present invention will be described clearly and completely below with reference to the embodiments. It is apparent that the embodiments described are merely illustrative and are not intended to limit the scope of protection of the present invention. All other alternatives derived by those of ordinary skill in the art based on the embodiments without creative effort are intended to fall within the scope of protection of the present invention.

[0223] Example 1. 4-((S)-2-(4-aminobutyl)-35-(4-((6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-ynamido)methyl)-1H-1,2,3-triazol-1-yl)-4,8-dioxo-6,12,15,18,21,24,27,30,33-nonaoxa-3,9-diazapentatriacontamido)benzyl((S)-4-ethyl-11-(2-(N-isopropylmethylsulfonamido)ethyl)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbonate (Compound IM-1)

[0224] Step 1: Synthesis of 6-(2-(methylsulfonyl)pyrimidin-5-yl)-N-(prop-2-yn-1-yl)hex-5-ynamide (Compound 3-5)

[0225] Prop-2-yn-1-amine (189 mg, 3.4 mmol) and compound 3-4 (800 mg, 2.83 mmol) were dissolved in dichloromethane (10 mL) at 25°C. N,N-diisopropylethylamine (738 mg, 5.67 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.63 g, 4.25 mmol) were added sequentially. The mixture was stirred for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was purified on a flash silica gel column (ethyl acetate / petroleum ether = 3 / 1) to obtain the title compound, 700 mg. ESI-MS (m / z): 306.1 [M+H].

[0226] Step 2: Synthesis of 4-((S)-35-azido-2-(4-(((4-methoxyphenyl)diphenylmethyl)amino)butyl)-4,8-dioxo-6,12,15,18,21,24,27,30,33-nonaoxa-3,9-diazapentatriacontamido)benzyl((S)-4-ethyl-11-(2-(N-isopropylmethanesulfonamido)ethyl)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbonate (Compound 33-1)

[0227] At 25°C, under nitrogen protection, T-030 (250 mg, 0.49 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, and a solution of 4-dimethylaminopyridine (478 mg, 3.91 mmol) in dichloromethane (3 mL) was added. Then, a solution of triphosgene (72 mg, 0.24 mmol) in dichloromethane (10 mL) was slowly added dropwise. After the addition was complete, the reaction was stirred at 0°C for 20 min, and the reaction solution was purged with nitrogen for 20 min. A solution of (S)-2-(3,2-azido-5-oxo-3,9,12,15,18,21,24,27,30-nonaoxa-6-azatriacontamide)-N-(4-(hydroxymethyl)phenyl)-6-(((4-methoxyphenyl)diphenylmethyl)amino)hexanamide (518 mg, 0.49 mmol) in dichloromethane (7 mL) was added. The reaction mixture was stirred at 0°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title compound, 500 mg. ESI-MS (m / z): 1597.5 [M+H].

[0228] Step 3: Synthesis of (S)-4-ethyl-11-(2-(N-isopropylmethylsulfonyl)ethyl)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl(4-((S)-2-(4-(((4-methoxyphenyl)diphenylmethyl)amino)butyl)-35-(4-((6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-ynamido)methyl)-1H-1,2,3-triazol-1-yl)-4,8-dioxo-6,12,15,18,21,24,27,30,33-nonoxa-3,9-diazapentatriacontamido)benzyl)carbonate (Compound 33-2)

[0229] Compound 33-1 (14 mg, 0.05 mmol) was dissolved in dimethyl sulfoxide and water (2.0 mL:0.5 mL) at room temperature. Cuprous bromide (11 mg, 0.08 mmol) was added and the mixture was stirred for 1 h. Purification by preparative HPLC afforded the title compound (30 mg). ESI-MS (m / z): 815.9 [(M-273) / 2+H]+.

[0230] Step 4: Synthesis of 4-((S)-2-(4-aminobutyl)-35-(4-((6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-ynamido)methyl)-1H-1,2,3-triazol-1-yl)-4,8-dioxo-6,12,15,18,21,24,27,30,33-nonaoxa-3,9-diazapentatriacontamido)benzyl((S)-4-ethyl-11-(2-(N-isopropylmethylsulfonamido)ethyl)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbonate (Compound IM-1)

[0231] Compound 33-2 (30 mg, 0.02 mmol) was dissolved in dichloromethane (1.0 mL). Trifluoroacetic acid (0.2 mL) was added to the reaction mixture and allowed to react at room temperature for 30 min. Purification by preparative HPLC afforded the trifluoroacetate salt of the title compound (20.0 mg). Its structural characterization is as follows:

[0232] 1H NMR (400MHz, DMSO-d6) δ10.18(s,1H),9.10(s,2H),8.38(t,J=5.56Hz,1H),8.32(d,J=8.40Hz,1H),8.22-8. 20(m,2H),8.09(t,J=5.68Hz,1H),7.91-7.87(m,2H),7.82-7.78(m,1H),7.69(brs,3H),7.61(d,J=8.56Hz,2 H),7.32(d,J=8.56Hz,2H),7.06(s,1H),5.56(d,J=16.96Hz,1H),5.51(d,J=16.96Hz,1H),5.47(d,J=19.28 Hz,1H),5.42(d,J=19.28Hz,1H),5.14(d,J=12.20Hz,1H),5.07(d,J=12.16Hz,1H),4.48(t,J=5.24Hz,2H),4 .46-4.43(m,1H),4.29(d,J=5.60Hz,2H),4.08-3.95(m,5H),3.79(t,J=5.28Hz,2H),3.51-3.43(m,32H),3. 40(s,3H),3.39-3.35(m,2H),3.30-3.26(m,2H),3.00(s,3H),2.82-2.74(m,2H),2.56(t,J=7.08Hz,2H),2.2 9(t,J=7.36Hz,2H),2.23-2.13(m,2H),1.82(p,J=7.24Hz,2H),1.78-1.63(m,2H),1.61-1.49(m,2H),1.42-1 .27(m,2H),1.15(d,J=6.80Hz,3H),1.13(d,J=6.76Hz,3H),0.90(t,J=7.32Hz,3H).ESI-MS(m / z):816.0[M / 2 + H] + . [α] D 20 The value is -19.55° (c = 1.000 g / 100 mL, CH3CN).

[0233] Example 2. Preparation of Conjugate A

[0234] 0.3 mL of Sacituzumab antibody (anti-Trop-2, 33.5 mg / mL) was diluted with 0.25 mL of a solution containing 20 mM PB, 150 mM NaCl, and 20 mM sodium edetate (pH 7.6). 0.45 mL of a solution containing 20 mM PB and 150 mM NaCl (pH 7.6) was added and mixed thoroughly. The pH was adjusted to 7.4 with 1 M Na2HPO4 solution. 10 mM TCEP (tris(2-carboxyethyl)phosphine) solution was added and mixed thoroughly. The mixture was allowed to stand at room temperature for 30 minutes. A 10-fold amount of IM-1 trifluoroacetate dissolved in dimethyl sulfoxide was added to the above solution, mixed thoroughly, and allowed to stand at room temperature for 2 hours. After completion, 6.1 μL of 100 mM cysteine ​​was added to terminate the reaction. Finally, the buffer solution was replaced with a PBS buffer solution at pH 6.5 using a G-25 gel column to obtain a product of IM-1 and Sacituzumab antibody conjugation, which was named conjugate A.

[0235] The molecular weight of conjugate A was analyzed by LCMS, and the measured molecular weights of the light and heavy chains of conjugate A were correlated with the theoretical molecular weights of light and heavy chains conjugated with different numbers of toxins. It was determined that each antibody molecule in conjugate A was conjugated with 1 to 10 toxins (i.e., γ was 1 to 10). The average coupling ratio (DAR) of approximately 6.9 was calculated based on the percentages of conjugate molecules conjugated with different numbers of toxins.

[0236] With reference to Example 2, conjugate A samples with DAR values ​​ranging from 6 to 8 (eg, 7.3 or 7.4) were prepared in batches, and the following non-clinical and clinical studies were performed.

[0237] Experimental Example 1. Detection of the effects of conjugates on cardiovascular and respiratory function

[0238] The cynomolgus monkeys were divided into 10 groups (half male and half female) and the conjugate A was administered intravenously at doses of 25 mg / kg, 50 mg / kg, and 75 mg / kg, respectively, once every 2 weeks for a total of 4 times. The large animal non-invasive physiological signal telemetry system was used to detect the lead II electrocardiogram and respiratory rate, and the arterial blood pressure was measured with a non-invasive sphygmomanometer to evaluate the effects of conjugate A on the cardiovascular and respiratory function of the cynomolgus monkeys.

[0239] Results showed no arrhythmias in lead II electrocardiograms (ECGs) of monkeys treated with conjugate A before the first dose, 2-3 hours, 24-25 hours, 72-73 hours, and 7 days after dosing, approximately 2-3 hours after the final dose, and before the end of the recovery period. No significant abnormalities were observed in lead II ECG parameters, including heart rate, RR interval, P wave duration, PR interval, QRS duration, QT interval, and corrected QT interval, as well as in systolic blood pressure, diastolic blood pressure, mean arterial pressure, and respiratory rate. These findings suggest that conjugate A has no effects on the cardiovascular and respiratory systems of cynomolgus monkeys and has a promising clinical safety profile.

[0240] Experimental Example 2. Detection of toxic metabolic behavior of conjugates in animals

[0241] Cynomolgus monkeys were divided into four groups according to the dose level: control, 25 mg / kg, 50 mg / kg, and 75 mg / kg, with five males and five females in each group. Cynomolgus monkeys were administered conjugate A intravenously every two weeks for four consecutive doses at the 25 mg / kg and 50 mg / kg dose levels. Blood samples were collected from monkeys in each group before the first and last doses, immediately after the dose (0 to 1 minute after the dose), 4 hours, 24 hours, 48 ​​hours, 96 hours, and 168 hours after the first and last doses, within 1 hour before the second and third doses, immediately after the dose (0 to 1 minute after the dose), and 3 to 36 hours after the last dose. Blood samples were also collected from monkeys in the 75 mg / kg group 4, 24 hours, 48 ​​hours, 96 hours, and 168 hours after the third dose to assess the toxicokinetics of the conjugate and its released toxin.

[0242] The following table records the peak blood concentrations (C max ) and exposure (AUC). The results showed that the highest no-serious-toxicity dose (HNSTD) of conjugate A was 50 mg / kg. After the last dose of this dose, the exposure of the toxin molecule in female and male monkeys was 3.85 h*μg / mL and 5.86 h*μg / mL, respectively. The exposure of female and male monkeys to conjugate A was 45.8 h*mg / mL and 64.2 h*mg / mL, respectively.

[0243] According to the test results, the exposure of ADC and toxin or C max The data are relatively close, indicating that there is no obvious toxic accumulation after continuous intravenous administration of conjugate A, and it is well tolerated in animals, with good prospects for clinical drug safety.

[0244] Experimental Example 3. In vitro metabolic stability of conjugates

[0245] In this experiment, conjugate A and Trodelvy were first TM Use physiological saline to prepare 3.4 mg / mL working solution, conjugate A and Trodelvy TM The working solution was added to human blank plasma to obtain human plasma samples with a concentration of 0.05 mg / ml. The plasma samples were incubated at 37°C and the release of toxin molecules was measured at 1h, 3h, 24h, 48h, 72h and 144h to compare the release of conjugate A with the marketed drug Trodelvy. TM The results are shown in Figure 1.

[0246] Figure 1 shows that as the incubation time increases, the amount of free toxin generated in human plasma increases. After 24 hours of incubation, the amount of conjugate A and the marketed ADC drug Trodelvy in human plasma TM The percentages of toxin molecule release were 28.5% and 93.4%, respectively. After 48 hours of incubation, the concentrations of conjugate A and the marketed ADC drug Trodelvy in human plasma were significantly increased. TM The percentages of toxin molecule release were 44.6% and 109.1%, respectively. After 72 hours of incubation, the concentrations of conjugate A and the marketed ADC drug Trodelvy in human plasma were significantly increased. TM The percentages of toxin molecule release were 53.7% and 100.6%, respectively. After 144 hours of incubation, conjugate A and the marketed ADC drug Trodelvy in human plasma TM The percentages of released toxin molecules were 65.3% and 104.8%, respectively.

[0247] The results showed that the release rate of toxin molecules of conjugate A in human plasma was significantly lower than that of Trodelvy TM This indicates that conjugate A is relatively stable in human plasma, with a small amount of toxin released in plasma, effectively achieving the purpose of targeting the tumor site and then releasing the toxin. At the same time, it is similar to the marketed drug Trodelvy. TM In comparison, conjugate A can reduce the risk of serious adverse reactions caused by excessive and rapid release of toxins in plasma.

[0248] Test Example 1. Phase I clinical study

[0249] 1. Experimental Plan

[0250] Conjugate A is used to treat patients with histologically confirmed epithelial malignancies. All patients have unresectable locally advanced or metastatic solid tumors that have failed standard treatment, have no standard treatment options, or are not currently suitable for standard treatment. Based on patient weight, the study designed five dose levels of 2, 4, 6, 9, and 12 mg / kg, administered intravenously once every 2 weeks, with a cycle of 28 days, until disease progression or unacceptable toxicity. The BLRM method was used to evaluate the toxicity of all planned dose groups and some intermediate dose groups. Based on model analysis, the dose escalation decision was jointly made by the sponsor and the investigator.

[0251] 2. Safety Results

[0252] During the treatment process, no "Treatment Emergent Adverse Events (TEAEs)" of grade 3 or above were observed in the 2 mg / kg dose group; grade 3 TEAEs, including oral mucositis and anemia, were observed in the 4 mg / kg dose group; and grade 3 or above TEAEs, including decreased neutrophil count and decreased white blood cell count, were observed in the 6 mg / kg dose group. The above-mentioned grade 3 or above TEAEs were recoverable after symptomatic treatment and can be continued, indicating that conjugate A has good clinical safety.

[0253] 3. Effectiveness Results

[0254] A patient with gastric cancer who had previously failed total gastrectomy, paclitaxel / Tegafur, anlotinib / Tegafur, anlotinib / capecitabine, oxaliplatin / fluorouracil, and oxaliplatin / raltitrexed received intravenous infusion of Conjugate A at a weight-based dose of 4 mg / kg, according to the aforementioned dosing schedule. A partial response was observed after 15 weeks, which has persisted for 10 weeks and is currently benefiting. Multiple efficacy assessments demonstrated a 62.8% reduction in the total volume of target lesions, with one target lesion disappearing. No serious adverse events were reported.

[0255] In summary, the Phase I clinical trial showed that Conjugate A showed, at least initially, good efficacy in gastric cancer, without inducing severe toxicities that could preclude clinical use. These results demonstrate that Conjugate A has a favorable safety and efficacy profile for the treatment of tumors, and that different batches of Conjugate A with DAR values ​​ranging from 6 to 8 (e.g., DAR values ​​of 7.3 or 7.4) exhibited essentially consistent efficacy and safety.

[0256] Experimental Example 2. Phase II Clinical Study

[0257] In a Phase II clinical study, patients with previously treated inoperable advanced gastric adenocarcinoma or gastroesophageal junction adenocarcinoma were enrolled in a single-agent treatment program of 5 mg / kg Q2W of conjugate A until disease progression or unacceptable toxicity. Enrolled patients included patients with gastric adenocarcinoma or gastroesophageal junction adenocarcinoma who had received standard 1 or more lines of treatment, including chemotherapy alone (e.g., platinum-based chemotherapy) or chemotherapy combined with anti-PD-1 / L1 therapy.

[0258] A total of 48 patients were enrolled and followed for at least 9 weeks. Of these, 24 patients (50.0%) had received one prior therapy (2nd line of therapy), and 24 patients (50.0%) had received ≥2 prior therapies (3rd or higher line of therapy). Forty patients (83.3%) had previously received an anti-PD-1 / L1 inhibitor. Thirteen patients (27.1%) had previously received irinotecan.

[0259] Among 41 efficacy-evaluable patients (defined as ≥1 study scan), the objective response rate (ORR) was 22.0%, the disease control rate (DCR) was 80.5%, and the median duration of response (DOR) was 7.5 months.

[0260] In the subset of patients who had received more than three lines of treatment and had more mature follow-up (median follow-up time of 14.6 months) (n=24, of whom 54.2% had received ≥4 prior therapies), the median progression-free survival (mPFS) was 3.7 months (95% CI: 2.6, 5.4); the median overall survival (mOS) was 7.6 months (95% CI: 5.3, 15.5).

[0261] The most common grade ≥ 3 TRAEs were anemia, decreased neutrophil count, leukopenia, and neutropenia. No treatment-related adverse events (TRAEs) leading to treatment discontinuation or death occurred during treatment. No neuropathy or drug-related interstitial lung disease (ILD) / pneumonitis were reported. Most TRAEs resolved with supportive care or dose adjustments.

[0262] The above results show that monotherapy with conjugate A can achieve durable remission in patients with advanced gastric adenocarcinoma or gastroesophageal junction adenocarcinoma who have received second-line and third-line treatment or above, with controllable safety.

[0263] Various modifications of the present invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited herein (including all patents, patent applications, journal articles, books, and any other publications) is incorporated herein by reference in its entirety.

Claims

1. Use of an antibody-drug conjugate of formula (I) or a composition containing the antibody-drug conjugate in the preparation of a medicament for treating advanced gastric cancer or carcinoma of the esophagogastric junction (CEGJ); {D-[L1-(L2) m1 -(L3) m2 -(L4) m3 -E]} γ -A formula (I) in, L1 is wherein each R1 and R2 are independently hydrogen (e.g., protium or deuterium), halogen, carboxylic acid, sulfonic acid, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, cyano substituted C 1-6 Alkyl (e.g. -CH2CN), C 1-6 Alkoxy, C 2-10 Alkenyl or C 2-10 Alkynyl; Z1 is an amino acid or a peptide composed of 2 to 10 amino acids; x1 and x2 are each independently 0, 1, 2, 3, 4, 5 or 6; and the 1 position of L1 is connected to D, and the 2 position of L1 is connected to L2; L2 is Wherein, y1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and the 1 position of L2 is connected to L1, and the 2 position of L2 is connected to L3; L3 is selected from a 5- to 12-membered heteroaromatic ring; L4 is Where Z2 is selected from C 1-6 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene, and C 3- 8 cycloalkylene; R3 is selected from H and C 1-6 Alkyl; Z3 is absent or selected from C 1-6 Alkylene; or, R3 and Z3 together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic group; α is 0, 1, 2, 3, 4, 5 or 6, and the 2 position of L4 is connected to E, and the 1 position of L4 is connected to L3; E is wherein each R4 is independently hydrogen (e.g., protium or deuterium), β is 0, 1, or 2, and the 2 position of E is connected to A (e.g., connected to the thiol group on A), and the 1 position of E is connected to L4; m1, m2 and m3 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; D is a bioactive molecular fragment; γ is selected from an integer between 1 and 10; preferably, γ is selected from an integer between 3 and 8 (e.g., 3, 4, 5, 6, 7 or 8); A is an anti-Trop-2 monoclonal antibody or an antigen-binding fragment thereof.

2. The use according to claim 1, wherein the advanced gastric cancer or gastroesophageal junction cancer is: Standard treatment has failed, or there is no standard treatment option, or standard treatment is not applicable at this stage; Unresectable; Locally advanced; and / or Transfer occurred.

3. The use according to claim 1 or 2, wherein the gastric cancer is selected from gastric adenocarcinoma, gastric adenosquamous carcinoma, gastric squamous cell carcinoma, undifferentiated gastric carcinoma, and gastric neuroendocrine tumor; preferably, the gastric cancer is gastric adenocarcinoma.

4. The use according to claim 1 or 2, wherein the gastroesophageal junction cancer is gastroesophageal junction adenocarcinoma.

5. The use according to any one of claims 1 to 4, wherein the advanced gastric cancer or gastroesophageal junction cancer has been previously treated with chemotherapy, such as fluorouracil, platinum, taxane or camptothecin chemotherapy.

6. The use according to claim 5, wherein the chemotherapy is platinum chemotherapy, such as cisplatin and / or oxaliplatin.

7. The use according to claim 5, wherein the chemotherapy is camptothecin chemotherapy, such as irinotecan.

8. The use according to any one of claims 1 to 7, wherein the advanced gastric cancer or gastroesophageal junction cancer has been previously treated with immunotherapy, such as anti-PD-1 / L1 therapy.

9. The use according to any one of claims 5-8, wherein the advanced gastric cancer or gastroesophageal junction cancer has been previously treated with chemotherapy combined with anti-PD-1 / L1 therapy.

10. The use according to any one of claims 1 to 9, wherein the advanced gastric cancer or gastroesophageal junction cancer has been previously treated with more than one treatment; for example, has been treated with more than one, more than two, more than three, more than four or more than five treatments.

11. The use according to any one of claims 1 to 10, wherein the conjugate has the following structure: L1 is selected from And the 1 position of L1 is connected to D, and the 2 position of L1 is connected to L2; L2 is in, y1 is 3, 4, 5, 6, 7, 8, 9 or 10; and the 1 position of L2 is connected to L1, and the 2 position of L2 is connected to L3; L3 is selected from a 5- to 6-membered heteroaromatic ring, such as pyrazole or triazole; L4 is Where Z2 is selected from C 1-3 Alkylene; R3 is H; Z3 is selected from C 1-3 Alkylene; α is 1, and the 2 position of L4 is connected to E, and the 1 position of L4 is connected to L3; E is wherein each R4 is independently hydrogen (e.g., protium or deuterium), β is 0, 1, or 2, and the 2 position of E is connected to A (e.g., connected to the thiol group on A), and the 1 position of E is connected to L4; m1, m2, and m3 are all 1; The bioactive molecule is selected from Preferably, the bioactive molecule is linked to the 1 position of L1 via its own hydroxyl group; γ is selected from an integer between 3 and 8 (e.g., 3, 4, 5, 6, 7 or 8); A is sacituzumab or an antigen-binding fragment thereof.

12. The use according to any one of claims 1 to 11, wherein the conjugate has the following structure: in, γ is an integer from 1 to 10; preferably, γ is an integer selected from 5 to 8.

13. The use according to any one of claims 1 to 12, wherein the drug-antibody coupling ratio (DAR) of the composition is 1 to 12; preferably 1 to 10; more preferably 5 to 8; for example, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 or 8.0; Preferably, the drug further comprises a pharmaceutically acceptable carrier and / or excipient.

14. A method for treating advanced gastric cancer or gastroesophageal junction cancer, comprising administering to an individual in need thereof a therapeutically effective amount of the antibody drug conjugate or composition of any one of claims 1 and 11 to 13; the advanced gastric cancer or gastroesophageal junction cancer is as described in any one of claims 1 to 10.

15. The method according to claim 14, wherein the composition is a pharmaceutical composition; preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient.

16. The method according to claim 14 or 15, wherein the antibody drug conjugate or the composition is administered once every 1-5 weeks, preferably once every 1-3 weeks, for example, once every 1 week, every 2 weeks, or every 3 weeks; more preferably, once every 2 weeks.

17. The method according to any one of claims 14 to 16, wherein the administration route of the conjugate or composition includes but is not limited to oral administration, transdermal injection, rectal administration, transmucosal administration, intramuscular injection, intramedullary injection, intravenous injection, intraperitoneal injection, preferably intravenous injection.

18. The method according to any one of claims 14 to 17, wherein the dosage of the antibody drug conjugate per administration is 1 mg / kg to 30 mg / kg based on individual body weight; preferably 1 mg / kg to 20 mg / kg; more preferably 2 mg / kg to 12 mg / kg; and even more preferably 5 mg / kg.

19. The method according to any one of claims 14 to 18, wherein the antibody drug conjugate or the pharmaceutical composition is administered once every two weeks, and the dose of the antibody drug conjugate per administration is 5 mg / kg based on the individual's body weight.

20. The method according to any one of claims 14-18, which is divided into one or more administration phases (e.g., one, two, three or four phases), the administration cycle of each phase is as described in claim 16, and / or the administration dosage of each phase is as described in claim 18.

21. The method of any one of claims 14-20, wherein the individual has previously received chemotherapy, such as fluorouracil-based, platinum-based, taxane-based, or camptothecin-based chemotherapy.

22. The method of claim 21, wherein the chemotherapy treatment is a platinum-based chemotherapy, such as cisplatin and / or oxaliplatin.

23. The method of claim 21, wherein the chemotherapy treatment is a camptothecin chemotherapy, such as irinotecan.

24. The method according to any one of claims 14-23, wherein the individual has previously received immunotherapy, such as anti-PD-1 / L1 therapy.

25. The method according to any one of claims 21-24, wherein the individual has previously received chemotherapy combined with anti-PD-1 / L1 therapy.

26. The method of any one of claims 14-25, wherein the individual has previously received more than one treatment; for example, has previously received more than one, more than two, more than three, more than four, or more than five treatments.

27. The antibody drug conjugate or composition according to any one of claims 1, 11 to 13, for use in treating advanced gastric cancer or gastroesophageal junction cancer in an individual.

28. The antibody drug conjugate or composition of claim 27, wherein the advanced gastric cancer or gastroesophageal junction cancer is as described in any one of claims 1-10.

29. The antibody drug conjugate or composition of claim 27 or 28, wherein the subject is as described in any one of claims 21-26.

30. The antibody drug conjugate or composition of any one of claims 27-29, administered to the individual according to any one of claims 16-21.

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