Use and methods of drug conjugates in the treatment of tumor diseases

Abstract

The present invention relates to the use of a pharmaceutical in the therapeutic use of a drug conjugate and a method thereof. Specifically, the present invention provides the use of a bioactive molecular conjugate represented by formula (I) and a method thereof in the treatment of tumor diseases. Tumor diseases are particularly preferably unresectable locally advanced or metastatic solid tumors that are refractory to current standard treatments, in particular non-small cell lung cancer.

Description

Detailed description of the invention

[0001] This application is based on CN Application No. 202310579893.9 filed on 22 May 2023 (the entire disclosure thereof is incorporated herein by reference), and claims priority under that application.

[0002] Technical field This application relates to the use and method of drug conjugates in the treatment of tumor diseases, particularly unresectable locally advanced or metastatic solid tumors that are refractory to existing treatment criteria, such as tumors that have failed and / or recurred after first-line chemotherapy, tumors that have failed and / or recurred after radiotherapy, and / or tumors that have failed and / or recurred after targeted therapy, specifically non-small cell lung cancer.

[0003] Background technology Cancer (hereinafter referred to as "cancer") poses a significant burden on global public health. In the United States, cancer remains the second leading cause of death after cardiovascular disease. The number of cancer cases is also increasing in China. In 2019, there were approximately 4.4 million new cases of malignant tumors and approximately 2.624 million deaths in China. The increase in the number of cancer patients and deaths is leading to an overall expansion of the commercial activity in oncology treatment.

[0004] Chemotherapy is one of the primary means of treating cancer, but traditional chemotherapy is not specific in recognizing tumors, which can easily damage normal cells and cause serious adverse reactions in patients. To improve cancer patient survival rates, innovation in treatment methods is urgently needed in line with advances in detection and diagnosis. While significant progress has been made in numerous indications, mortality rates for some of the most refractory solid tumors have not significantly improved since the 1970s, and there is still a need for more effective treatments with fewer side effects. Molecularly targeted drugs are currently a key trend in drug design.

[0005] Monoclonal antibody drugs offer advantages such as potent targeting, high specificity, and a low incidence of serious adverse reactions. However, their large molecular weight limits their therapeutic effect when used alone. Antibody-drug conjugates (ADCs) are drugs in which a monoclonal antibody is coupled to a number of small molecule cytotoxins (effector molecules) via a chemical linker. After entering the body, ADC molecules bind to antigens on the surface of target cells via induction by the monoclonal antibody and enter the target cells. Once inside the cells, the ADC molecules release the effector molecules through chemical and / or enzymatic action, achieving the objective of destroying the target cells. ADC drugs combine the advantages of potent targeting of monoclonal antibodies and the high activity of small molecule toxins. This not only reduces the toxicity and side effects of small molecule cytotoxins but can also improve the efficacy of the drug.

[0006] Currently, various ADC drugs are commercially available worldwide, with indications including leukemia, lymphoma, and breast cancer. However, some pharmacokinetic and safety issues still exist with some ADC drugs, which can cause serious adverse reactions in patients after use. Furthermore, their response rates for some metastatic, recurrent, and / or refractory cancers still need further improvement. Therefore, there is still a need to develop the use or treatment methods of ADC drugs for these metastatic, recurrent, and / or refractory cancers to maximize their efficacy, minimize their toxicity, and meet the drug needs of cancer patients.

[0007] Summary of the Invention The present invention relates to the manufacture of a pharmaceutical product for treating individuals with tumor diseases, particularly individuals with recurrent or refractory locally advanced or metastatic non-small cell lung cancer, using formula (I). [ka] [In the formula, L1 is [ka] and; wherein, R1 and R2 are each independently hydrogen (e.g., protium or deuterium), halogen, carboxylate, sulfonate, cyano, C , 1-6 , 3-8 , , , , 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 consisting of 2 to 10 amino acids; x1 and x2 are each independently 0, 1, 2, 3, 4, 5 or 6; position 1 of L1 is bonded to D, and position of L1 is bonded to L2; L2 is

Chemical formula

[0008] In some embodiments, the tumor disease is an inoperable locally advanced or metastatic solid tumor that has failed standard treatment, or has no standard treatment regimen, or is not suitable for standard treatment at the current stage. In some embodiments, the standard treatment means the standard treatment regimen for tumor diseases recommended by the NCCN guidelines and CSCO guidelines for diagnosis and treatment.

[0009] In some embodiments, the tumor disease is a tumor that has failed treatment and / or relapsed after first-line chemotherapy. In some embodiments, the first-line chemotherapy means the first-line chemotherapy for tumor diseases recommended by the NCCN guidelines and CSCO guidelines for diagnosis and treatment.

[0010] In some embodiments, the tumor disease is a tumor that has failed to be treated and / or has recurred after radiotherapy. In some embodiments, radiotherapy means a radiotherapy regimen for tumor disease as recommended by the NCCN and CSCO guidelines for diagnosis and treatment.

[0011] In some embodiments, the tumor disease is a tumor that has failed to be treated and / or has recurred after targeted therapy or immunotherapy. In some embodiments, targeted therapy or immunotherapy means targeted therapy or immunotherapy for tumor disease as recommended by NCCN and CSCO guidelines for diagnosis and treatment.

[0012] In some embodiments, the tumor disease includes (but is not limited to) breast cancer, gastric cancer, lung cancer, ovarian cancer, urothelial carcinoma, esophageal cancer, liver cancer, colorectal cancer, cervical cancer, endometrial cancer, pancreatic cancer, bladder cancer, or brain tumor, preferably breast cancer (e.g., triple-negative breast cancer or Her2-positive breast cancer), ovarian cancer (e.g., ovarian epithelial carcinoma), gastric cancer, lung cancer, pancreatic cancer, bladder cancer, or urothelial carcinoma, more preferably the tumor disease is triple-negative breast cancer, Her2-positive breast cancer, ovarian cancer, gastric cancer, lung cancer, or pancreatic cancer, and even more preferably the tumor disease is triple-negative breast cancer, Her2-positive breast cancer, ovarian cancer, or gastric cancer.

[0013] In some embodiments, the tumor disease is breast cancer.

[0014] In some embodiments, breast cancer includes, but is not limited to, the following types: luminal A, luminal B, Her2-positive, triple-negative, or HR+ / Her2- breast cancer.

[0015] In some embodiments, breast cancer includes, but is not limited to, the following types: luminal A, luminal B, Her2-positive, and triple-negative breast cancer.

[0016] In some embodiments, the tumor disease is triple-negative breast cancer.

[0017] In some embodiments, the tumor disease is Her2-positive breast cancer.

[0018] In some embodiments, the tumor disease is HR+ / Her2- breast cancer.

[0019] In some embodiments, the tumorous disease is ovarian cancer.

[0020] In some embodiments, ovarian cancer includes, but is not limited to, the following types: platinum-sensitive and platinum-resistant.

[0021] In some embodiments, the tumor disease is gastric cancer.

[0022] In some embodiments, gastric cancer includes, but is not limited to, the following types: adenocarcinoma, adenosquamous carcinoma, squamous cell carcinoma, undifferentiated carcinoma, and neuroendocrine tumor.

[0023] In some embodiments, the tumor disease is pancreatic cancer.

[0024] In some embodiments, pancreatic cancer includes, but is not limited to, the following types: epithelial tumors, exocrine tumors, borderline tumors, tubular adenocarcinomas, endocrine tumors, mature teratomas, mesenchymal tumors, malignant lymphomas, and secondary tumors.

[0025] In some embodiments, the tumorous disease is bladder cancer.

[0026] In some embodiments, bladder cancer includes, but is not limited to, the following types: urothelial (transitional cell) carcinoma, squamous cell carcinoma, and adenocarcinoma.

[0027] In some embodiments, the tumor disease is urothelial carcinoma.

[0028] In some embodiments, urothelial carcinoma includes, but is not limited to, the following types: basal, luminal, and wild-type urothelial carcinoma.

[0029] In some embodiments, the tumor disease is lung cancer.

[0030] In some embodiments, lung cancer includes, but is not limited to, the following types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).

[0031] In some embodiments, the lung cancer is recurrent or refractory locally advanced or metastatic non-small cell lung cancer.

[0032] In some embodiments, the lung cancer is EGFR wild-type non-small cell lung cancer.

[0033] In some embodiments, individuals with EGFR wild-type non-small cell lung cancer have previously received a median of two lines of treatment.

[0034] In some embodiments, individuals with EGFR wild-type non-small cell lung cancer have previously received treatment in combination with platinum-based chemotherapy and anti-PD-1 / L1 monoclonal antibody therapy.

[0035] In some embodiments, the lung cancer is EGFR-mutated non-small cell lung cancer.

[0036] In some embodiments, EGFR mutant NSCLC includes an exon 19 deletion or an exon 21 L858R mutation.

[0037] In some embodiments, individuals with EGFR-mutated NSCLC have previously been treated with first- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and have been confirmed to be negative for the exon 20 T790M mutation by tumor biopsy after treatment failure, or individuals with EGFR-mutated NSCLC have previously been treated with third-generation EGFR-TKIs (regardless of the T790M mutation status).

[0038] In some embodiments, EGFR-mutated non-small cell lung cancer is resistant to EGFR-TKI treatment.

[0039] In some embodiments, the conjugate has the following structure: L1 is [ka] Selected from, position 1 of L1 is connected to D, and position 2 of L1 is connected to L2; L2 is [ka] Here, y1 is 3, 4, 5, 6, 7, 8, 9 or 10, position 1 of L2 is connected to L1, position 2 of L2 is connected to L3; L3 is selected from a 5-6 membered heteroaromatic ring, such as pyrazole or triazole; L4 is [ka] And here, Z2 is C 1-3 Selected from alkylene, R3 is H and Z3 is C 1-3 Selected from alkylene, α is 0, L4 position 2 is bound to E, and L4 position 1 is bound to L3; E is [ka] Here, each R4 is independently hydrogen (e.g., protium or deuterium), β is 0, 1 or 2, position 2 of E is bonded to A (e.g., with a sulfhydryl on A), and position 1 of E is bonded to L4; m1, m2, and m3 are all 1; Bioactive molecules are [ka] A bioactive molecule is selected from, and preferably, is bound to position 1 of L1 via its own hydroxyl group; γ is selected from integers between 3 and 8 (for example, 3, 4, 5, 6, 7, or 8); A is sacituzumab or its antigen-binding fragment.

[0040] In some embodiments, the conjugate has the following structure: L1 is [ka] Selected from, position 1 of L1 is connected to D, and position 2 of L1 is connected to L2; L2 is [ka] And y1 is 3, 4, 5, 6, 7, 8, 9 or 10, position 1 of L2 is connected to L1, position 2 of L2 is connected to L3; L3 is selected from a 5-6 membered heteroaromatic ring, such as pyrazole or triazole; L4 is [ka] And here, Z2 is C 1-3 Selected from alkylene, R3 is H and Z3 is C 1-3Selected from alkylene, α is 1, position 2 of L4 is bound to E, position 1 of L4 is bound to L3, E is [ka] Here, each R4 is independently hydrogen (e.g., protium or deuterium), β is 0, 1 or 2, position 2 of E is bonded to A (e.g., with a sulfhydryl on A), and position 1 of E is bonded to L4; m1, m2, and m3 are all 1; Bioactive molecules are [ka] A bioactive molecule is selected from, and preferably, is bound to position 1 of L1 via its own hydroxyl group; γ is selected from integers between 3 and 8 (for example, 3, 4, 5, 6, 7, or 8); and A is sacituzumab or its antigen-binding fragment.

[0041] In some embodiments, D is [ka] Selected from.

[0042] In some technical solutions, the conjugate is expressed by the following formula: [ka] (In the formula, γ is an integer between 1 and 10, preferably selected from integers between 5 and 8.) Conjugate A has a structure represented by .

[0043] The present invention provides the use of compositions comprising a bioactive molecular conjugate of formula (I) as described herein. The compositions of bioactive molecular conjugates described herein are in subranges of about 1 to about 10, or any subrange in between, for example, about 1 to 2, about 1 to 3, about 1 to 4, about 1 to 5, about 1 to 6, about 1 to 7, about 1 to 8, about 1 to 9, about 1 to 10, about 2 to 3, about 2 to 4, about 2 to 5, about 2 to 6, about 2 to 7, about 2 to 8, about 2 to 9, about 2 to 10, about 3 to 4, about 3 to 5, has a DAR of approximately 3-6, 3-7, 3-8, 3-9, 3-10, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 5-6, 5-7, 5-8, 5-9, 5-10, 6-7, 6-8, 6-9, 6-10, 7-8, 7-9, 7-10, 8-9, 8-10, or 9-10.

[0044] In certain embodiments, the compositions of the bioactive molecule conjugates described herein are approximately 3 to 9, for example, approximately 3.0 to 3.5, approximately 3.0 to 4.0, approximately 3.0 to 4.5, approximately 3.0 to 5.0, approximately 3.0 to 6.0, approximately 3.5 to 4.0, approximately 3.5 to 4.5, approximately 3.5 to 5.0, approximately 3.5 to 5.5, approximately 3.5 to 6.0, approximately 3.5 to 6.5, approximately 4.0 to 4.5, approximately 4.0 to 5.0, approximately 4.0 to 5.5, approximately 4.0 to 6.0, approximately 4.0 to 6.5, approximately 4.0 to 7 It has DAR values ​​of 0.0, approximately 4.0-8.0, approximately 4.5-5.0, approximately 4.5-5.5, approximately 4.5-6.0, approximately 4.5-6.5, approximately 4.5-7.0, approximately 4.5-7.5, approximately 5.0-8.0, approximately 5.5-6.0, approximately 5.5-6.5, approximately 5.5-7.0, approximately 5.5-7.5, approximately 5.5-8.0, approximately 6.0-6.5, approximately 6.0-7.0, approximately 6.0-7.5, approximately 6.0-8.5, approximately 6.5-7.0, approximately 6.5-7.5, approximately 6.5-8.5, and approximately 7.0-7.5.

[0045] In some embodiments, the bioactive molecule conjugate compositions described herein have DAR values ​​of approximately 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, and 8.0.

[0046] In another embodiment, the present invention provides a method for treating a tumor disease, particularly recurrent or refractory non-small cell lung cancer, comprising the step of administering a therapeutically effective amount of a pharmaceutical composition comprising the bioactive molecular conjugate of formula (I) and / or the bioactive molecular conjugate of formula (I) to an individual in need.

[0047] In some embodiments, the tumor disease is an unresectable locally advanced or metastatic solid tumor that has failed standard treatment, does not have a standard treatment regimen, or is not suitable for standard treatment at this stage. In some embodiments, standard treatment means a standard treatment regimen for the tumor disease as recommended by the NCCN and CSCO guidelines for diagnosis and treatment.

[0048] In some embodiments, the tumor disease is a tumor that has failed to treat and / or recurred after first-line chemotherapy. In some embodiments, first-line chemotherapy means first-line chemotherapy for the tumor disease as recommended by the NCCN and CSCO guidelines for diagnosis and treatment.

[0049] In some embodiments, the tumor disease is a tumor that has failed to be treated and / or has recurred after targeted therapy or immunotherapy. In some embodiments, targeted therapy or immunotherapy means targeted therapy or immunotherapy for tumor disease as recommended by NCCN and CSCO guidelines for diagnosis and treatment.

[0050] In some embodiments, the tumor disease includes (but is not limited to) breast cancer, gastric cancer, lung cancer, ovarian cancer, urothelial carcinoma, esophageal cancer, liver cancer, colorectal cancer, cervical cancer, endometrial cancer, pancreatic cancer, bladder cancer, or brain tumor, preferably breast cancer (e.g., triple-negative breast cancer or Her2-positive breast cancer), ovarian cancer (e.g., ovarian epithelial carcinoma), gastric cancer, lung cancer, pancreatic cancer, bladder cancer, or urothelial carcinoma, more preferably the tumor disease is triple-negative breast cancer, Her2-positive breast cancer, ovarian cancer, gastric cancer, lung cancer, or pancreatic cancer, and even more preferably the tumor disease is triple-negative breast cancer, Her2-positive breast cancer, ovarian cancer, or gastric cancer.

[0051] In some embodiments, the tumor disease is breast cancer.

[0052] In some embodiments, breast cancer includes, but is not limited to, the following types: Luminal type A, Luminal type B, Her-2 positive type, and Triple-negative type.

[0053] In some embodiments, the tumor disease is triple-negative breast cancer.

[0054] In some embodiments, the tumor disease is Her2-positive breast cancer.

[0055] In some embodiments, breast cancer is HR-positive and Her2-negative (HR+ / Her2-) breast cancer.

[0056] In some embodiments, the tumorous disease is ovarian cancer.

[0057] In some embodiments, ovarian cancer includes, but is not limited to, the following types: platinum-sensitive and platinum-resistant.

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

[0059] In some embodiments, gastric cancer includes, but is not limited to, the following types: adenocarcinoma, adenosquamous carcinoma, squamous cell carcinoma, undifferentiated carcinoma, and neuroendocrine tumor.

[0060] In some embodiments, the tumor disease is pancreatic cancer.

[0061] In some embodiments, pancreatic cancer includes, but is not limited to, the following types: epithelial tumors, exocrine tumors, borderline tumors, tubular adenocarcinomas, endocrine tumors, mature teratomas, mesenchymal tumors, malignant lymphomas, and secondary tumors.

[0062] In some embodiments, the tumorous disease is bladder cancer.

[0063] In some embodiments, bladder cancer includes, but is not limited to, the following types: urothelial (transitional cell) carcinoma, squamous cell carcinoma, and adenocarcinoma.

[0064] In some embodiments, the tumor disease is urothelial carcinoma.

[0065] In some embodiments, urothelial carcinoma includes, but is not limited to, the following types: basal, luminal, and wild-type urothelial carcinoma.

[0066] In some embodiments, the tumor disease is lung cancer.

[0067] In some embodiments, lung cancer includes, but is not limited to, the following types: small cell lung cancer, non-small cell lung cancer.

[0068] In some embodiments, the lung cancer is recurrent or refractory locally advanced or metastatic non-small cell lung cancer.

[0069] In some embodiments, the lung cancer is EGFR wild-type non-small cell lung cancer.

[0070] In some embodiments, individuals with EGFR wild-type non-small cell lung cancer have previously received a median of two lines of treatment.

[0071] In some embodiments, individuals with EGFR wild-type non-small cell lung cancer have previously received combination therapy with platinum-based chemotherapy and anti-PD-1 / L1 monoclonal antibody therapy.

[0072] In some embodiments, the lung cancer is EGFR-mutated non-small cell lung cancer.

[0073] In some embodiments, EGFR mutant NSCLC includes an exon 19 deletion or an exon 21 L858R mutation.

[0074] In some embodiments, individuals with EGFR-mutated NSCLC have previously been treated with first- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and have been confirmed to be negative for the exon 20 T790M mutation by tumor biopsy after treatment failure, or individuals with EGFR-mutated NSCLC have previously been treated with third-generation EGFR-TKIs (regardless of the T790M mutation status).

[0075] In some embodiments, EGFR-mutated non-small cell lung cancer is resistant to EGFR-TKI treatment.

[0076] In some embodiments, the individual is one having recurrent or refractory locally advanced or metastatic non-small cell lung cancer and other tumors.

[0077] In some embodiments, the individual is either an individual with EGFR wild-type non-small cell lung cancer, or an individual with EGFR-mutated non-small cell lung cancer that is resistant to EGFR-TKI treatment.

[0078] In some embodiments, a method for treating a tumor disease further includes evaluating the tumor according to RECIST 1.1.

[0079] In some embodiments, the evaluation cycle is 6 to 8 weeks, for example, 8 weeks.

[0080] In some embodiments, the pharmaceutical composition comprises a bioactive molecular conjugate and a pharmaceutically acceptable carrier and / or excipient.

[0081] In some embodiments, the bioactive molecule conjugate or pharmaceutical composition is administered once every 7 to 35 days, preferably once every 7 to 28 days, for example, once every 7, 14, 21, 28, or 35 days.

[0082] In some embodiments, a bioactive molecule conjugate or pharmaceutical composition is administered once every 14 days.

[0083] In some embodiments, the route of administration of the conjugate or pharmaceutical composition is oral, transdermal, rectal, transmucosal, intramuscular, intrathecal, intravenous, or intraperitoneal, preferably intravenous.

[0084] In some embodiments, the dose of the bioactive molecule conjugate each time, based on the body weight of the individual, is 1 mg / kg to 30 mg / kg, preferably 1 mg / kg to 20 mg / kg, more preferably 2 mg / kg to 12 mg / kg, even more preferably 2 to 5 mg / kg, 4 to 7 mg / kg, 6 to 9 mg / kg, 8 to 11 mg / kg, 10 to 13 mg / kg, or 12 to 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.

[0085] In some embodiments, the dose of the bioactive molecule conjugate for each administration, based on the body weight of the individual, is 4 mg / kg or 5 mg / kg.

[0086] In some embodiments, the dose of the bioactive molecule conjugate or its composition in each administration is 1 mg / kg to 20 mg / kg, based on the body weight of the individual, and is administered once every 7 to 28 days.

[0087] In some embodiments, the lung cancer is EGFR wild-type non-small cell lung cancer or EGFR-mutated non-small cell lung cancer resistant to EGFR-TKI treatment.

[0088] In some embodiments, the lung cancer is EGFR wild-type non-small cell lung cancer or EGFR-mutated non-small cell lung cancer resistant to EGFR-TKI treatment, and the dose of the bioactive molecule conjugate or its composition in each dose, based on the individual's body weight, is 5 mg / kg and administered once every two weeks.

[0089] In some embodiments, the administration regimen of the bioactive molecule conjugate is divided into one or more administration stages (e.g., one, two, three, or four stages), and the administration cycle and dose at each stage are selected independently of the aforementioned administration cycle or dose.

[0090] In some embodiments, the use or method of the present invention results in tumor elimination or volume reduction.

[0091] In some embodiments, the use or method of the present invention results in a reduction of tumor volume of at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, or at least 40%.

[0092] On the other hand, the present invention provides a bioactive molecular conjugate or composition represented by formula (I) for treating tumor diseases, wherein the bioactive molecular conjugate or composition and the tumor disease are as described above.

[0093] definition Unless otherwise specified below, all scientific and technical terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. References to the art used herein are intended to be references to the art as commonly understood, including any technical modifications or substitutions of equivalent technologies that would be obvious to those skilled in the art. The following terms are expected to be well understood by those skilled in the art, but the following definitions are provided for the better explanation of the present invention.

[0094] The drug-antibody ratio (DAR) represents the average loading of a small molecule toxin drug by the antibody in a conjugate. For a particular conjugate molecule, the binding ratio of the small molecule toxin drug portion to the antibody portion has a precise value. However, when used to describe a sample containing many molecules, this value is calculated according to the percentages of various specific conjugate molecules, and this average loading is referred to herein as the average coupling ratio or "DAR".

[0095] The term “subject” means a mammal, such as a primate mammal, such as a human. In some embodiments, an individual (e.g., a human) has or is at risk of having the tumor or cancer described herein.

[0096] NCCN guidelines refer to clinical practice guidelines for various malignancies published by the National Comprehensive Cancer Network.

[0097] The CSCO guidelines for diagnosis and treatment refer to the guidelines for the clinical diagnosis and treatment of various malignancies published by the Chinese Society of Clinical Oncology (CSCO).

[0098] The term "platinum-based chemotherapy" refers to chemotherapy using a platinum-based drug, where the platinum-based drug is selected from cisplatin, carboplatin, sulfatodiaminocyclohexaneplatin, nedaplatin, oxaliplatin, lovaplatin, satraplatin, miboplatin, enloplatin, iproplatin, or dicycloplatin.

[0099] "First-generation EGFR-TKI inhibitors" include, for example, erlotinib or gefitinib. "Second-generation EGFR-TKI inhibitors" include, for example, afatinib or Vizimpro (dacomitinib). "Third-generation EGFR-TKI inhibitors" include, for example, osimertinib, rosiletinib, olmutinib, or AC0010.

[0100] The objective response rate (ORR) refers to the percentage of patients whose tumor has shrunk to a certain extent and maintained that level over a period of time (including CR and PR cases). The objective response of the tumor is evaluated according to the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). Subjects must have a measurable tumor lesion at baseline. According to the RECIST 1.1 criteria, the evaluation criteria for efficacy are divided into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD).

[0101] Progressive disease (PD): The sum of the diameters of all measured target lesions increases by at least 20% relative to the minimum value in the sum of all measured diameters (the baseline is considered the baseline if the baseline measurement is the minimum); and the absolute value of the sum of the diameters must increase by at least 5 mm (the appearance of one or more new lesions is also considered progressive disease).

[0102] Stable disease (SD): Target lesion reduction does not reach partial reduction (PR), increase does not reach PD levels, symptoms are intermediate, and the minimum sum of diameters can be used as a criterion in studies.

[0103] Partial response (PR): The total size of the target lesions is reduced by at least 30% compared to baseline.

[0104] Complete response (CR): All target lesions must disappear, and the short diameter of all pathological lymph nodes (including target and non-target nodules) must be reduced to less than 10 mm.

[0105] Disease control rate (DCR): According to RECIST criteria, this is the percentage of evaluable patients with pathologically confirmed disease who show disease reduction (including complete response, partial response, PR+CR) or stable disease (SD) after treatment, with such response lasting for at least 4 weeks.

[0106] Duration of response (DoR): This refers to the time from the first evaluation of complete response (CR) or partial response (PR) to the first evaluation of progressive disease (PD) or death from any cause.

[0107] Progression-free survival (PFS): The time from randomization or first dose of the investigational drug to the first evidence of disease progression or death from any cause.

[0108] Dose-limiting toxicity (DLT): The toxic effects and side effects of a drug that are the primary reasons for limiting the continuous increase in the drug dose.

[0109] Adverse events (AEs) refer to harmful medical events that occur in patients or clinical research subjects after receiving a drug, but which are not necessarily causally related to the treatment.

[0110] Therapeutic adverse events (TEAEs) refer to any adverse events that occur or worsen during or after the first dose of the drug. [Brief explanation of the drawing]

[0111] [Figure 1]The drawings described herein are used to provide a further understanding of the invention and constitute part of this application. Exemplary embodiments of the invention and their descriptions are used to illustrate the invention and do not unduly limit the invention. In the drawings, Figure 1 shows the in vitro plasma stability of conjugate A and Trodelvy®, a commercially available drug.

[0112] Detailed explanation In the following, the technical solutions in the embodiments of the present invention will be described clearly and completely with reference to the drawings of the embodiments. Clearly, the embodiments described are only a part of, not all, of, the embodiments of the present invention. The following description of at least one exemplary embodiment is essentially illustrative and is not intended to limit in any way the present invention, its application or use. All other embodiments that can be obtained by those skilled in the art without creative work based on the embodiments of the present invention are included within the scope of the protection of the present invention.

[0113] Example 1. 4-((S)-2-(4-aminobutyl)-35-(4-((6-(2-(methylsulfonyl)pyrimidine-5-yl)hexane-5-amide)methyl)-1H-1,2,3-triazole-1-yl)-4,8-dioxo-6,12,15,18,21,24,27,30,33-nonanooxa-3,9-diazapentatricontaneamino)benzyl((S)-4-ethyl-11-(2-(N-isopropylmethylsulfonamide)ethyl)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)carbonate [ka]

[0114] Step 1: Synthesis of 6-(2-(methylsulfonyl)pyrimidine-5-yl)-N-(propan-2-alkyne-1-yl)hexa-5-alkyneamide At 25°C, propa-2-in-1-amine (189 mg, 3.4 mmol) and compound 3-4 (800 mg, 2.83 mmol) were dissolved in dichloromethane (10 mL). N,N-diisopropylethylamine (738 mg, 5.67 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.63 g, 4.25 mmol) were added sequentially, and the mixture was stirred and reacted for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column (ethyl acetate / petroleum ether = 3 / 1) to obtain the title compound (700 mg). ESI-MS (m / z): 306.1 [M+H]+.

[0115] 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-nonanoxa-3,9-diazapentatricontaneamino)benzyl((S)-4-ethyl-11-(2-(N-isopropylmethanesulfonamide)ethyl)-3,14-dioxo-3,4,12,14-tetrahydro-2H-pyrano[2,3-b]-1H-pyrano[3',4':6,7]indadino[1,2-b]quinoline-4-yl)carbonate Under nitrogen protection at 25°C, T-030 (250 mg, 0.49 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, then 4-dimethylaminopyridine (478 mg, 3.91 mmol) in dichloromethane (3 mL) was added, followed by the slow addition of triphosgene (72 mg, 0.24 mmol) in dichloromethane (10 mL). The mixture was then stirred at 0°C for 20 minutes, and nitrogen was blown into the reaction mixture for 20 minutes. (S)-2-(32-azido-5-oxo-3,9,12,15,18,21,24,27,30-nonaoxa-6-azatriacetamidyl)-N-(4-(hydroxymethyl)phenyl)-6(((4-methoxyphenyl)diphenylmethyl)amino)acetamide (518 mg, 0.49 mmol) in dichloromethane (7 mL) was added. The mixture was then stirred and reacted for 1 hour. The reaction mixture 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]+.

[0116] Step 3: Synthesis of (S)-4-ethyl-11-(2-(N-isopropylsulfonamide)ethyl)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indadino[1,2-b]quinoline-4-yl(4-((S)-2-(4-(((4-methoxyphenyl)diphenylmethyl)amino)butyl)-35-(4-((6-(2-(methylsulfonyl)pyrimidine-5-yl)hexane-5-amide)methyl)-1H-1,2,3-triazole-1-yl)-4,8-dioxo-6,12,15,18,21,24,27,30,33-nonoxy-3,9-diazapentatricontaneamino)benzyl)carbonate] At room temperature, compound 33-1 (14 mg, 0.05 mmol) was dissolved in dimethyl sulfoxide and water (2.0 mL:0.5 mL), and copper(I) bromide (11 mg, 0.08 mmol) was added. The mixture was stirred and reacted for 1 hour. The system was purified by preparative HPLC to obtain the title compound (30 mg). ESI-MS (m / z): 815.9[(M-273) / 2+H]+.

[0117] Step 4: Synthesis of 4-((S)-2-(4-aminobutyl)-35-(4-((6-(2-(methylsulfonyl)pyrimidine-5-yl)hexane-5-amide)methyl)-1H-1,2,3-triazole-1-yl)-4,8-dioxo-6,12,15,18,21,24,27,30,33-nonanooxa-3,9-diazapentatricontaneamino)benzyl((S)-4-ethyl-11-(2-(N-isopropylmethylsulfonamide)ethyl)-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl)carbonate (compound IM-1) Compound 33-2 (30 mg, 0.02 mmol) was dissolved in dichloromethane (1.0 mL), and trifluoroacetic acid (0.2 mL) was added to the reaction mixture and the mixture was reacted at room temperature for 30 minutes. After purification by preparative high-performance liquid chromatography (Method C), the trifluoroacetate of the title compound was obtained (20.0 mg). Its structure is characterized as follows: 1H NMR(400 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.10 (s, 2H), 8.38 (t, J = 5.56 Hz, 1H),8.32 (d, J = 8.40 Hz, 1H), 8.22-8.20 (m, 2H), 8.09 (t, J = 5.68 Hz, 1H), 7.91-7.87(m, 2H), 7.82-7.78 (m, 1H),7.69 (brs, 3H), 7.61 (d, J =8.56 Hz, 2H), 7.32 (d, J = 8.56 Hz, 2H), 7.06 (s, 1H), 5.56 (d, J = 16.96 Hz,1H), 5.51 (d, J = 16.96 Hz, 1H), 5.47 (d, J = 19.28 Hz, 1H), 5.42 (d, J = 19.28Hz, 1H), 5.14 (d, J = 12.20 Hz, 1H), 5.07 (d, J = 12.16 Hz, 1H), 4.48 (t, J =5.24 Hz, 2H), 4.46-4.43 (m, 1H), 4.29 (d, J = 5.60 Hz, 2H), 4.08-3.95 (m, 5H),3.79 (t, J = 5.28 Hz, 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 = 7.08 Hz, 2H),2.29 (t, J = 7.36 Hz, 2H), 2.23-2.13 (m, 2H), 1.82 (p, J = 7.24 Hz, 2H), 1.78-1.63(m, 2H), 1.61-1.49 (m, 2H), 1.42-1.27 (m, 2H), 1.15 (d, J = 6.80 Hz, 3H) , 1.13(d, J = 6.76 Hz, 3H), 0.90 (t, J = 7.32 Hz, 3H). ESI-MS (m / z): 816.0[M / 2 + H] + . [α] D 20:-19.55° (c =1.000g / 100mL, CH3CN)

[0118] Example 2. Manufacturing of Conjugate A 0.3 mL of sacituzumab antibody (anti-Trop-2, 33.5 mg / mL) was taken and diluted with 0.25 mL of a solution (pH 7.6) containing 20 mM PB, 150 mM NaCl, and 20 mM sodium edetate. Then, 0.45 mL of a solution (pH 7.6) containing 20 mM PB and 150 mM NaCl was added, and the mixture was thoroughly mixed. The pH of the reaction mixture was adjusted to 7.4 with 1 M Na2HPO4 solution, and 10 mM TCEP (tris(2-carboxyethyl)phosphine) solution was added. The mixture was thoroughly mixed and left at room temperature for 30 minutes. 10x molar IM-1 trifluoroacetate dissolved in dimethyl sulfoxide was added to the solution system, and the system was thoroughly mixed and left at room temperature for 2 hours. Then, 6.1 μl of 100 mM cysteine ​​was added to stop the reaction. Finally, the buffer solution was replaced with a pH 6.5 PBS buffer solution using a G-25 gel column to obtain the IM-1 product coupled to the sacituzumab antibody, which was named Conjugate A. [ka]

[0119] The molecular weight of conjugate A was analyzed by LC-MS, and the measured molecular weights of the light and heavy chains of conjugate A were correlated with the theoretical molecular weights of the light and heavy chains coupled to different numbers of toxins. It was found that each antibody molecule in conjugate A was coupled to 1 to 10 toxins (i.e., γ was 1 to 10). The mean coupling ratio (DAR) was then calculated to be approximately 6.9, according to the respective proportions of conjugate molecules coupled to different numbers of toxins.

[0120] Referring to Example 2, batches of conjugate A samples having DAR values ​​in the range of 6 to 8 (e.g., 7.3 or 7.4) were prepared, and the following non-clinical and clinical trials were performed.

[0121] Example 3. Detection of the inhibitory effect of conjugates on the proliferation of pancreatic cancer cell lines. The effect of conjugate A on the proliferation of BxPC-3 cells (a pancreatic cancer cell line from ATCC, TROP2-positive cells) was detected by the CeLITiter-Glo® chemiluminescent cell viability assay (i.e., CTG). On the first day of the experiment, BxPC-3 cells in the logarithmic growth phase were collected, the cell suspension concentration was adjusted with culture medium, and the suspension was added to a 96-well cell culture plate to a final cell concentration of 2000 cells / well. The cells were cultured overnight in a 5% CO2 incubator at 37°C. On the second day of the experiment, conjugate A (final concentration 0.152–1000 nM) was diluted to a 10-fold dilution using a 1:3 gradient, and 10 μl of the corresponding 10-fold dilution was added to each well (three overlapping wells for each drug concentration). After drug addition, the cells were cultured for 72 hours at 37°C in a 5% CO2 incubator. On the fifth day of the experiment, 50 μl (half the culture volume) of pre-melted and room-temperature equilibrated CTG solution was added to each well, and the mixture was thoroughly mixed for 2 minutes using a microplate shaker. After standing at room temperature for 20 minutes, the fluorescence signal values ​​were measured using an Envision 2104 plate reader.

[0122] The result was that conjugate A was 14.3 nM IC 50 Furthermore, it demonstrated significant inhibition of the proliferation of TROP2-positive BxPC-3 cells, with a maximum inhibition rate of 95.3%. This indicates that conjugate A can inhibit the proliferation of TROP2-positive pancreatic cancer cells, suggesting that it has a therapeutic effect against pancreatic cancer.

[0123] Example 4. Detection of the effects of conjugates on cardiovascular and respiratory function Cynomolgus monkeys were divided into groups of 10 (half male and half female). Conjugate A was administered intravenously once every two weeks for a total of four doses at doses of 25 mg / kg, 50 mg / kg, and 75 mg / kg, respectively. To evaluate the effects of Conjugate A on the cardiovascular and respiratory function of the cynomolgus monkeys, lead II ECG and respiratory rate were detected using a large animal non-invasive physiological signaling telemetry system, and arterial blood pressure was measured using a non-invasive sphygmomanometer.

[0124] The results showed that in each group of monkeys that received Conjugate A before the first dose, 2-3 hours after the first dose, 24-25 hours after, 72-73 hours after, 7 days after, approximately 2-3 hours after the final dose, and before the end of the recovery period, no arrhythmias were observed in lead II ECG and other parameters of lead II electrocardiogram, including heart rate, RR interval, P wave duration, PR interval, QRS wave duration, QT interval, corrected QT interval, and other parameters of lead II electrocardiogram. No significant abnormalities were observed in systolic blood pressure, diastolic blood pressure, mean arterial pressure, or respiratory rate. These results indicate that Conjugate A does not affect the cardiovascular and respiratory systems of cynomolgus monkeys and that the drug has good clinical safety potential.

[0125] Example 5. Detection of the toxic metabolic behavior of conjugates in animals Cynomolgus monkeys were divided into four groups according to different doses: a control group, a 25 mg / kg dose group, a 50 mg / kg dose group, and a 75 mg / kg dose group. Each group consisted of 5 males and 5 females. The monkeys were intravenously injected with Conjugate A at dose levels of 25 mg / kg and 50 mg / kg, once every two weeks for four consecutive doses. Blood samples were collected from each group of monkeys at 1 hour before and immediately after the first and last doses (0-1 minute after the end of administration), as well as 4 hours, 24 hours, 48 ​​hours, 96 hours, and 168 hours after the last dose, before and immediately after the second and third doses (0-1 minute after the end of administration), and 336 hours after the last dose. For monkeys in the 75 mg / kg dose group, blood samples were further collected at 4, 24, 48, 96, and 168 hours after the third dose to detect the toxicological behavior of the conjugate and the toxin molecules released in vivo.

[0126] Table 1 below shows the peak plasma concentrations (C) of conjugate A and the toxin molecules released by conjugate A in male and female monkeys after administration by the method described above. max The results show the exposure (AUC) to the toxin molecules and their respective effects. The results indicate that the maximum dose (HNSTD) of conjugate A that does not cause serious toxicity is 50 mg / kg, and that after the final dose at this level, the exposure to the toxin molecules in female and male monkeys was 3.85 h, respectively. * μg / mL and 5.86h * The concentration was μg / mL, and exposure to conjugate A in female and male monkeys was 45.8 hours, respectively. * mg / mL and 64.2h * This indicates that the concentration was mg / mL.

[0127] [Table 1]

[0128] According to the experimental results, exposure to ADC and toxins or C in all animal groups maxIt can be observed that the data were similar after the first dose and after the final dose. This indicates that conjugate A did not show significant toxicity accumulation after continuous intravenous administration, was well tolerated in animals, and therefore has good potential regarding the safety of the clinical drug.

[0129] Example 6. Metabolic stability of conjugates in vitro In this experiment, Conjugate A and Trodelvy® were first formulated into 3.4 mg / mL working solutions in physiological saline. These working solutions were then added to human blank plasma to obtain 0.05 mg / mL human plasma samples. The plasma samples were incubated at 37°C, and the release of toxin molecules was measured at 1, 3, 24, 48, 72, and 144 hours. Conjugate A and the commercially available drug Trodelvy® were compared in terms of differences in in vitro plasma stability. The results are shown in Figure 1.

[0130] As shown in Figure 1 of this specification, the yield of free toxins in human plasma increased with increasing incubation time. After 24 hours of incubation, the release rates of toxin molecules of conjugate A and the commercially available ADC drug Trodelvy® in human plasma were 28.5% and 93.4%, respectively. After 48 hours of incubation, the release rates of toxin molecules of conjugate A and the commercially available ADC drug Trodelvy® in human plasma were 44.6% and 109.1%, respectively. After 72 hours of incubation, the release rates of toxin molecules of conjugate A and the commercially available ADC drug Trodelvy® in human plasma were 53.7% and 100.6%, respectively. After 144 hours of incubation, the release rates of toxin molecules of conjugate A and the commercially available ADC drug Trodelvy® in human plasma were 65.3% and 104.8%, respectively.

[0131] The results showed that the release rate of toxin molecules from conjugate A in human plasma was significantly lower than that of Trodelvy®. This indicates that conjugate A is relatively stable in human plasma, exhibits minimal toxin release in the plasma, and effectively achieves the goal of toxin release after reaching the target tumor site. Furthermore, compared to the commercially available drug Trodelvy®, conjugate A may reduce the risk of serious side effects caused by rapid and excessive toxin release in plasma.

[0132] Example 7. Clinical Trial I. Protocol Patients with epithelial malignancies diagnosed by histological examination were treated with conjugate A. All patients had unresectable locally advanced or metastatic solid tumors that had failed standard treatment, lacked a standard treatment regimen, or were unsuitable for standard treatment at this stage. Based on patient body weight, a dose-escalation design was adopted with five dose cohorts of 2, 4, 6, 9, and 12 mg / kg, administered intravenously every two weeks in 28-day cycles, until disease progression or unacceptable toxic reactions occurred. Toxicity in all planned dose groups and several intermediate dose groups was assessed by BLRM. Based on model analysis, the sponsor and researchers jointly made dose-escalation decisions.

[0133] II. Pharmacokinetic Studies In the PK analysis of the dose-escalation cohort, exposure to conjugate A increased proportionally with dose within the test dose range of 2–6 mg / kg. No accumulation of conjugate A was observed after repeated administration. Under a two-week dosing schedule, the half-lives of conjugate A and free payload were approximately 36 hours and 49 hours, respectively. In the first four-week cycle, plasma exposure to free payload (peak plasma concentration (C)) was observed. maxThe pharmacokinetic parameters and plasma exposure (expressed as AUC) of the total antibody (referring to conjugated, partially unconjugated, and fully unconjugated antibodies) were similar to those of conjugated A, while the AUC and AUC were approximately 6% and 5% of those of conjugated A. These results indicate that the linker of conjugated A was stable in systemic circulation and that most of the payload molecules were delivered to tumor tissue by the targeted antibody.

[0134] III. Safety Results During the dose escalation study, no grade 3 or higher TEAEs occurred in the 2 mg / kg dose group; grade 3 TEAEs, including oral mucositis and anemia, occurred in the 4 mg / kg dose group; and grade 3 or higher TEAEs, including neutropenia and leukopenia, occurred in the 6 mg / kg dose group. Of the 28 patients (93.9%) enrolled in the dose escalation cohort, 17 patients (56.7%) experienced grade 3 or higher TRAEs. The most common (incidence ≥ 5%) were anemia (26.7%), neutropenia (23.3%), leukopenia (16.7%), stomatitis (16.7%), and thrombocytopenia (13.3%). The aforementioned grade 3 or higher TEAEs were reversible after symptomatic treatment, administration could be continued, and there were no TRAEs resulting in death. Therefore, the results of the dose escalation study demonstrated that Conjugate A is safe and well-tolerated.

[0135] In a subsequent dose-expansion study, 211 patients received at least one dose of conjugate A. Of these, 23 and 188 patients with different types of advanced solid tumors received treatment with conjugate A at dose levels of 4 mg / kg Q2W and 5 mg / kg Q2W, respectively. 202 patients (95.7%) reported TRAEs. 110 patients (52.1%) reported grade 3 or higher TRAEs, most of which resolved after supportive care or dose adjustment. Treatment-related serious adverse events (TRSAEs) occurred in 51 patients (24.2%), but no TRAEs resulting in death were reported. This further suggests that conjugate A monotherapy is tolerable and manageable.

[0136] The TRAEs for the 4 mg / kg Q2W and 5 mg / kg Q2W dose levels are summarized in Table 2 below.

[0137] [Table 2]

[0138] In a Phase 1 / 2 multicenter dose-escalation / expansion study in patients with relapsed or refractory locally advanced / metastatic NSCLC and other tumor types, all NSCLC patients received 5 mg / kg of conjugate A intravenously over Q2W. Tumor assessments based on RECIST 1.1 were performed by investigators every 8 weeks. Of the 43 enrolled patients (63% male, 88% with ECOG ps1, median age 58 years [44–74]), 67.4% (29 / 43) experienced grade ≥3 TRAEs. The most common grade ≥3 TRAEs (incidence ≥5%) were neutropenia (32.6%), anemia (30.2%), leukopenia (23.3%), stomatitis (9.3%), rash (7.0%), and lymphopenia (7.0%). Grade 4 TRAEs occurred only in the case of neutropenia and leukopenia. Most hematological toxicities occurred within the first two months of treatment and resolved after administration of granulocyte colony-stimulating factor or erythropoietin without blood transfusion. Dose reduction due to TRAEs occurred in 23.3% (10 / 43) of patients. No neurological disorders or drug-related ILD / pneumonitis were reported. No TRAEs resulted in treatment discontinuation or death.

[0139] IV. Results of effectiveness The treatment outcomes for various indications are as follows:

[0140] 1. Triple-negative breast cancer (TNBC) In all patients with triple-negative breast cancer, some patients showed a partial response.

[0141] In patients with progressive disease following prior adriamycin / cyclophosphamide / paclitaxel neoadjuvant chemotherapy, left mastectomy, and left chest radiotherapy, conjugate A was administered intravenously at a dose of 4 mg / kg based on the patient's body weight, according to the aforementioned administration cycle. After 18 weeks, a partial response was observed, lasting for 6 weeks. In several efficacy evaluations, the total volume of the target lesion was reduced by 40%. Patients did not experience any serious adverse events.

[0142] 2. Ovarian cancer In all patients with ovarian cancer, some patients showed a partial response.

[0143] In patients with ovarian cancer who had previously undergone hysterectomy, oophorectomy, or failed treatment with carboplatin / paclitaxel, rucaparib, or carboplatin / docetaxel / bevacizumab, Conjugate A was administered intravenously at a dose of 4 mg / kg based on the patient's body weight, according to the aforementioned administration cycle. After 21 weeks, a partial response was observed, which lasted for 15 weeks. In several efficacy evaluations, the total volume of the target lesions was reduced by 64.8%, and one of the target lesions completely disappeared. No patients experienced serious adverse events.

[0144] 3.HER2 positive breast cancer In patients with HER2-positive breast cancer who had failed prior treatment with modified radical mastectomy, epirubicin / paclitaxel, HER2 monoclonal antibody / docetaxel, and capecitabine, conjugate A was administered intravenously at a dose of 6 mg / kg based on the patient's body weight, according to the aforementioned administration cycle. After 8 weeks, a partial response was observed. In several efficacy evaluations, the total volume of the target lesion was reduced by 49.6%.

[0145] 4. Stomach cancer In patients with gastric cancer who had previously undergone total gastrectomy and failed treatment with paclitaxel / tegafur, anlotinib / tegafur, anlotinib / capecitabine, oxaliplatin / fluorouracil, and oxaliplatin / larcitrexed, Conjugate A was administered intravenously at a dose of 4 mg / kg based on the patient's body weight, according to the aforementioned administration cycle. After 15 weeks, a partial response was observed, lasting for 10 weeks and still showing benefit. In several efficacy evaluations, the total volume of the target lesions was reduced by 62.8%, and one of the target lesions completely disappeared. No serious adverse events occurred in the patients.

[0146] 5. Pancreatic cancer In patients with pancreatic cancer who had failed prior distal pancreatic resection, radiotherapy, or multiple-line therapy with gemcitabine / capecitabine, gemcitabine / irinotecan / fluorouracil, gemcitabine / albumin-paclitaxel / oxaliplatin / fluorouracil, and nivolumab / kabilalizumab, conjugate A was administered intravenously at a dose of 4 mg / kg based on the patient's body weight, according to the aforementioned administration cycle. Stable disease was observed after 7 weeks, which lasted for 30.3 weeks. In several efficacy evaluations, the total volume of the target lesion was reduced by 8.8%, and no serious adverse events occurred in the patients.

[0147] 6.HR+ / Her2- breast cancer Thirty-nine patients were enrolled and treated with conjugate A. In the 28 patients who were evaluable for response (those who underwent at least one tumor evaluation after baseline), the ORR was 42.9% (12 / 28, 2 cases awaiting confirmation), the DCR was 85.7% (24 / 28), and the median PFS was 7.6 months.

[0148] 7. Non-small cell lung cancer (NSCLC) In a phase 1 / 2 multicenter dose-escalation / expansion study involving patients with relapsed or refractory locally advanced / metastatic NSCLC and other tumor subtypes, all NSCLC patients received conjugate A intravenously at a dose of 5 mg / kg every two weeks. Tumor assessments based on RECIST 1.1 were performed by investigators every eight weeks.

[0149] Of the 43 patients enrolled (63% male, 88% with ECOG PS 1, median age 58 years [44–74]), the median follow-up period was 11.5 months (mo; 95% CI, 10.4–12.2). The median treatment duration was 5.7 months (range 0.5–14.1). In the 39 patients whose response was evaluable, the ORR was 44% (17 / 39, 15 confirmed, 2 pending), the median DoR was 9.3 months (range, 1.3+ to 11.2+), and the 6-month DoR rate was 77%. In the EGFR wild-type subgroup (who had previously received a median of 2 lines of treatment, including anti-PD-1 / L1 monoclonal antibody therapy), the ORR was 26% (5 / 19), the DCR was 89% (17 / 19), the median PFS was 5.3 months, and the 9-month OS rate was 80.4%. In the TKI-resistant EGFR-mutated NSCLC subgroup (50% were unresponsive to at least one line of chemotherapy), the ORR was 60% (12 / 20), the DCR was 100% (20 / 20), the median PFS was 11.1 months, and the 9-month PFS rate was 66.7%.

[0150] In summary, clinical trials demonstrated that conjugate A has good efficacy against the aforementioned unresectable locally advanced or metastatic solid tumors that have failed standard treatment, without inducing serious toxicity that could hinder its clinical use. These results demonstrate that conjugate A has good safety and efficacy in the treatment of tumor diseases, and that conjugate A with DAR values ​​ranging from 6 to 8 (e.g., DAR value 7.3 or DAR value 7.4) produced in various batches exhibits essentially consistent efficacy and safety.

[0151] Various modifications of the present invention other than those described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to be included in the scope of the appended claims. All references cited herein (including all patents, patent applications, journal articles, books and any other publications) are incorporated herein by reference.

Claims

1. Formula (I) in the manufacture of a pharmaceutical product for the treatment of individuals with recurrent or refractory locally advanced or metastatic non-small cell lung cancer. 【Chemistry 1】 [In the formula, L １ teeth 【Chemistry 2】 and; where R １ and R ２ are each independently hydrogen (e.g., protium or deuterium), halogen, carboxylic acid group, sulfonic acid group, cyano, C １－６ alkyl, halogenated C １－６ alkyl, cyano-substituted C １－６ alkyl (e.g., -CH ２ CN), C １－６ alkoxy, C ２－１０ alkenyl or C ２－１０ alkynyl; Z １ is an amino acid or a peptide consisting of 2 to 10 amino acids; x １ and x ２ are each independently 0, 1, 2, 3, 4, 5 or 6; L １ is bonded to D at position 1 and to L ２ at position 2; L ２ teeth 【Transformation 3】 And; where y1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; L ２ L is at position 1 １ It is coupled and L at position 2. ３ connect; L ３ It is selected from 5- to 12-membered heteroaromatic rings; L ４ teeth 【Chemistry 4】 And here, Z ２ is C １－６ Alkylene, C ２－１０ Alkenylene, C ２－１０ Alkynylene and C ３－８ Selected from the group consisting of cycloalkylenes; R ３ H and C １－６ Selected from Alkylene; Z ３ It does not exist, or C １－６ Selected from alkylenes; or R ３ and Z ３ These, together with the nitrogen atom to which they are bonded, form a 4- to 8-membered heterocycline; α is 0, 1, 2, 3, 4, 5 or 6, L ４ Position 2 is connected to E, L ４ Position 1 is L ３ connect; E is 【Transformation 5】 And here, each R ４ β is independently hydrogen (e.g., protium or deuterium), β is 0, 1 or 2, position 2 of E is bonded to A (e.g., bonded to a thiol group on A), and position 1 of E is L ４ It is connected to; I understand １ , m ２ and m ３ Each of these is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; D is a bioactive molecular fragment; γ is selected from integers 1 to 10, preferably from integers 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8); and A is an anti-Trop-2 monoclonal antibody or its antigen-binding fragment. The use of a bioactive molecule conjugate represented by [the specified symbol].

2. The use according to claim 1, wherein the non-small cell lung cancer is unresectable locally advanced or metastatic non-small cell lung cancer that has failed standard treatment, for which there are no standard treatment options, or which is not suitable for standard treatment at this stage.

3. The use according to claim 1 or 2, wherein the non-small cell lung cancer is EGFR wild-type non-small cell lung cancer.

4. The use according to claim 3, wherein the individual has previously received a median of two lines of treatment.

5. The use according to claim 3, wherein the individual has previously received combination therapy with platinum-based chemotherapy and anti-PD-1 / L1 monoclonal antibody therapy.

6. The use according to claim 1 or 2, wherein non-small cell lung cancer has an EGFR mutation, preferably the EGFR mutation comprises an exon 19 deletion or an exon 21 L858R mutation.

7. The use according to claim 6, wherein an individual having EGFR mutation NSCLC has previously been treated with a first-generation or second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), and after treatment failure, it has been confirmed by tumor biopsy that the exon 20 T790M mutation is negative, or an individual having EGFR mutation NSCLC has previously been treated with a third-generation EGFR-TKI, regardless of whether the T790M mutation is present or not.

8. The use according to claim 6 or 7, wherein the non-small cell lung cancer is resistant to EGFR-TKI treatment.

9. The use according to any one of claims 6 to 8, wherein the individual is receiving first-line treatment, preferably the first-line treatment is platinum-based chemotherapy.

10. The conjugate has the following structure, namely, L １ but 【Transformation 6】 Selected from the group consisting of L １ Position 1 is connected to D, L １ Position 2 is L ２ Combine, L ２ but 【Transformation 7】 And here, y １ is 3, 4, 5, 6, 7, 8, 9 or 10, L ２ Position 1 is L １ It is connected to L ２ Position 2 is L ３ It is connected, L ３ This is selected from a 5-6 member heteroaromatic ring, for example, pyrazole or triazole. L ４ but 【Transformation 8】 And here, Z ２ is C １－３ Selected from alkylene, R ３ H is Z ３ is C １－３ Selected from alkylenes, α is 1, L ４ Position 2 is connected to E, L ４ Position 1 is L ３ It is connected, E is 【Chemistry 9】 And here, each R ４ β is independently hydrogen (e.g., protium or deutherium), β is 0, 1 or 2, position 2 of E is bonded to A (e.g., bonded to a thiol group on A), and position 1 of E is L ４ It is connected, I understand １ , m ２ and m ３ All of them are 1, Bioactive molecules 【Chemistry 10】 Selected from the group consisting of, preferably, the bioactive molecule via its own hydroxyl group L １ It is connected to position 1, γ is selected from integers between 3 and 8 (for example, 3, 4, 5, 6, 7, or 8), The use according to any one of claims 1 to 9, wherein A is sacituzumab or its antigen-binding fragment.

11. The structure of the conjugate 【Chemistry 11】 (In the formula, γ is an integer from 1 to 10, preferably selected from an integer from 5 to 8.) The use according to any one of claims 1 to 10.

12. A method for treating recurrent or refractory locally advanced or metastatic non-small cell lung cancer, comprising the step of administering to an individual in need of such treatment a therapeutically effective amount of a bioactive molecular conjugate according to any one of claims 1, 10, and 11, and / or a pharmaceutical composition comprising a bioactive molecular conjugate according to any one of claims 1, 10 to 11.

13. The method according to claim 12, wherein the non-small cell lung cancer is unresectable locally advanced or metastatic non-small cell lung cancer that has failed standard treatment, for which there are no standard treatment regimen options, or which is not suitable for standard treatment at this stage.

14. The method according to claim 12 or 13, wherein the non-small cell lung cancer is EGFR wild-type non-small cell lung cancer.

15. The use according to claim 14, wherein the individual has previously received a median of two lines of treatment.

16. The individual had previously received platinum-based chemotherapy and anti-PD-1 / L １ The method according to claim 14, wherein the patient is receiving combination therapy with monoclonal antibody therapy.

17. The method according to claim 12 or 13, wherein the non-small cell lung cancer has an EGFR mutation, preferably the EGFR mutation comprises an exon 19 deletion or an exon 21 L858R mutation.

18. The method according to claim 17, wherein an individual having EGFR mutation NSCLC has previously been treated with a first-generation or second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), and after treatment failure, it has been confirmed by tumor biopsy that the exon 20 T790M mutation is negative, or an individual having EGFR mutation NSCLC has previously been treated with a third-generation EGFR-TKI, regardless of whether the T790M mutation is present or not.

19. The method according to claim 17 or 18, wherein the non-small cell lung cancer is resistant to EGFR-TKI treatment.

20. The method according to claim 19, wherein the individual is receiving first-line treatment, preferably the first-line treatment is platinum-based chemotherapy.

21. The method according to any one of claims 12 to 20, wherein the pharmaceutical composition comprises the bioactive molecule conjugate and a pharmaceutically acceptable carrier and / or excipient.

22. The method according to any one of claims 12 to 21, comprising administering a bioactive molecule conjugate or pharmaceutical composition once every 7 to 35 days, preferably once every 7 to 28 days, for example, once every 7, 14, 21, 28, or 35 days.

23. The method according to any one of claims 12 to 22, comprising administering a bioactive molecular conjugate or pharmaceutical composition once every 14 days.

24. The method according to any one of claims 12 to 23, wherein the route of administration of the conjugate or pharmaceutical composition is oral administration, transdermal injection, rectal administration, transmucosal administration, intramuscular injection, intrathecal injection, intravenous injection, or intraperitoneal injection, preferably intravenous injection.

25. The method according to any one of claims 12 to 24, wherein the dose of the bioactive molecule conjugate each time based on the body weight of the individual is 1 mg / kg to 30 mg / kg, preferably 1 mg / kg to 20 mg / kg, more preferably 2 mg / kg to 12 mg / kg, even more preferably 2 to 5 mg / kg, 4 to 7 mg / kg, 6 to 9 mg / kg, 8 to 11 mg / kg, 10 to 13 mg / kg, or 12 to 15 mg / kg.

26. The method according to any one of claims 12 to 25, wherein the dose of the bioactive molecule conjugate each time, based on the body weight of the individual, is 4 mg / kg or 5 mg / kg.

27. The method according to any one of claims 12 to 26, wherein the dose of the bioactive molecule conjugate or composition each time, based on the body weight of the individual, is 1 mg / kg to 20 mg / kg, and the administration is performed once every 7 to 28 days.

28. The method according to any one of claims 12 to 27, wherein the method is divided into one or more administration stages (for example, 1, 2, 3, or 4 stages), the administration cycle in each stage is as described in any one of claims 22, 23, or 27, and / or the dose administered in each stage is as described in any one of claims 25 to 27.

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