Application of antibody-drug conjugate in prevention or treatment of diseases

Abstract

The present invention relates to an application of an antibody-drug conjugate in the prevention or treatment of diseases. In particular, the present invention relates to an application of an antibody-drug conjugate as represented by formula (I), and a composition thereof, in the treatment of patients with locally recurrent or metastatic triple negative breast cancer, and a related treatment method.

Description

Use of antibody drug conjugate in preventing or treating diseases

[0001] This application is based on and claims priority to Chinese Patent Application Nos. 202410639002.9, filed on May 22, 2024, 202411247212.X, filed on September 6, 2024, 202510115180.6, filed on January 24, 2025, and 202510596409.2, filed on May 9, 2025, the disclosures of which are incorporated herein in their entireties. TECHNICAL FIELD

[0002] The present application relates to the use of antibody drug conjugate in preventing or treating diseases, including but not limited to cancer diseases, in particular locally advanced, locally recurrent or metastatic triple negative breast cancer. BACKGROUND

[0003] Cancer is one of the major health challenges worldwide, especially in terms of treatment of advanced and metastatic cancer. Despite the progress in treatment techniques in recent years, the survival rate for patients with advanced, recurrent or metastatic cancer is still very low, and there is an urgent need for new treatment methods.

[0004] Antibody drug conjugates (ADC) are a class of drugs that couple monoclonal antibodies and other small molecule cytotoxins (effector molecules) of different numbers through chemical linkers. After entering the body, the ADC molecule can bind to the target cell surface antigen through the guidance of the monoclonal antibody, enter the target cell, and the ADC molecule in the cell can release the effector molecule through chemical and / or enzymatic action to achieve the purpose of eliminating the target cell, combining the advantages of strong targeting of monoclonal antibodies and high activity of small molecule toxins.

[0005] Currently, there are several ADC drugs on the market worldwide, covering indications such as leukemia, lymphoma, breast cancer, etc. However, for some metastatic, recurrent, and / or refractory cancers, especially triple negative breast cancer, the treatment efficiency and safety still need to be further improved.

[0006] Therefore, there is a need for a new treatment method and therapeutic use that can more effectively utilize antibody drug conjugates to improve treatment efficacy and improve the survival rate of patients with advanced, recurrent or metastatic triple negative breast cancer. SUMMARY

[0007] The present application provides the use of an antibody drug conjugate represented by formula (I) in the preparation of a medicament for treating locally recurrent or metastatic triple negative breast cancer in a patient;

[0008] {D-[L1-(L2) m1 -(L3) m2 -(L4) m3 -E]} γ -A

[0009] Formula (I)

[0010] wherein,

[0011] L1 is each R1and R2is independently hydrogen (e.g., protium or deuterium), halogen, carboxylic acid group, sulfonic acid group, cyano, C 1-6 alkyl, haloC 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; Z1is an amino acid or a peptide consisting of 2-10 amino acids; x1and x2are each independently 0, 1, 2, 3, 4, 5, or 6; and D is attached at the 1 -position of L1and L2is attached at the 2-position of L1;

[0012] L2 is wherein y1is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and L2is attached at the 1 -position of L1and L3is attached at the 2-position of L2;

[0013] L3 is a 5-12 membered heteroaromatic ring;

[0014] L4 is wherein Z2is selected from the group consisting of C 1-6 alkylene, C 2-10 alkenylene, C 2-10 alkynylene, and C 3- 8cycloalkylene; R3is selected from the group consisting of H and C 1-6 alkyl; Z3is absent or C 1-6 alkylene; or, R3and Z3together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl; a is 0, 1, 2, 3, 4, 5, or 6, and E is attached at the 2-position of L4and L3is attached at the 1 -position of L4;

[0015] E is wherein each R4is independently hydrogen (e.g., protium or deuterium), b is 0, 1, or 2, and E is attached at the 2-position to A (e.g., to a thiol group on A) and L4is attached at the 1 -position of E;

[0016] m1, m2, and m3 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0017] D is a biologically active molecule fragment;

[0018] Y denotes the number of {D-[L1-(L2) m1 -(L3) m2 -(L4) m3 -E]} moieties attached to A (preferably via a thioether linkage), which is selected from an integer between 1 and 10; preferably, Y is selected from an integer between 3 and 8 (e.g., 3, 4, 5, 6, 7, or 8);

[0019] A is an anti-Trop-2 antibody or antigen-binding fragment thereof.

[0020] In some embodiments, the present application provides use of a composition comprising an antibody drug conjugate as described above in the manufacture of a medicament for preventing or treating locally recurrent or metastatic triple-negative breast cancer in a patient.

[0021] In some embodiments, the patient has previously received more than one chemotherapy treatment, or more than two chemotherapy treatments, or more than three chemotherapy treatments, or more than four chemotherapy treatments; and / or

[0022] The patient has previously received more than one chemotherapy treatment, or more than two chemotherapy treatments, or more than three chemotherapy treatments, or more than four chemotherapy treatments, and wherein at least one of the chemotherapies was performed in the context of metastasis of the triple-negative breast cancer.

[0023] In some specific embodiments, the patient has previously received two or more chemotherapy treatments, wherein at least one of the chemotherapies was performed in the context of metastasis of the triple-negative breast cancer, and the triple-negative breast cancer has a visceral metastasis, e.g., a liver metastasis.

[0024] In some specific embodiments, the use is further characterized by one or more of the following:

[0025] (1) the triple-negative breast cancer has a visceral metastasis, e.g., a liver metastasis;

[0026] (2) the triple-negative breast cancer has a lymph node metastasis;

[0027] (3) the triple-negative breast cancer has a TROP-2 expression H-score of 0, 0-10, 10-100, 100-200, or greater than 200; preferably, the TROP-2 expression H-score is greater than 200;

[0028] (4) the triple-negative breast cancer is HER2 non-expressing;

[0029] (5) the triple-negative breast cancer is HER2 low-expressing;

[0030] (6) the patient has received two treatments or three treatments previously;

[0031] (7) the patient has received more than three treatments previously;

[0032] (8) the patient has received more than three chemotherapy treatments or more than four chemotherapy treatments previously, and the chemotherapy treatments were performed in the case of advanced triple-negative breast cancer;

[0033] (9) the patient has received targeted drug treatment previously; preferably, the targeted drug is a PD-1 inhibitor or a PD-L1 inhibitor drug;

[0034] (10) the triple-negative breast cancer is primary triple-negative breast cancer;

[0035] (11) the triple-negative breast cancer is non-primary triple-negative breast cancer.

[0036] In some more specific embodiments, the use is further characterized by (1) and (3), (1) and (4), (1) and (5), (1) and (6), (1) and (7), (1) and (8), (1) and (9), (1) and (10), (1) and (11), (2) and (3), (2) and (4), (2) and (5), (2) and (6), (2) and (7), (2) and (8), (2) and (9), (2) and (10), (2) and (11), (3) and (4), (3) and (5), (3) and (6), (3) and (7), (3) and (8), (3) and (9), (3) and (10), (3) and (11), (4) and (6), (4) and (7), (4) and (8), (4) and (9), (4) and (10), (4) and (11), (5) and (6), (5) and (7), (5) and (8), (5) and (9), (5) and (10), (5) and (11), (6) and (9), (6) and (9), (6) and (11), (7) and (8), (7) and (9), (7) and (10), (7) and (11), (8) and (9), (8) and (10), (8) and (11), (1), (3) and (4), (1), (3) and (5), (1), (3) and (6), (1), (3) and (7), (1), (3) and (8), (1), (3) and (9), (1), (3) and (10), (1), (3) and (11), (1), (4) and (6), (1), (4) and (7), (1), (4) and (8), (1), (4) and (9), (1), (4) and (10), (1), (4) and (11), (1), (5) and (6), (1), (5) and (7), (1), (5) and (8), (1), (5) and (9), (1), (5) and (10), (1), (5) and (11), (1), (6) and (9), (1), (6) and (10), (1), (6) and (11), (1), (7) and (8), (1), (7) and (9), (1), (7) and (10), (1), (7) and (11), (1), (8) and (9), (1), (8) and (10), (1), (8) and (11), (2), (3) and (4), (2), (3) and (5), (2), (3) and (6), (2), (3) and (7), (2), (3) and (8), (2), (3) and (9), (2), (3) and (10), (2), (3) and (11), (2), (4) and (6), (2), (4) and (7), (2), (4) and (8), (2), (4) and (9), (2), (4) and (10), (2), (4) and (11), (2), (5) and (6), (2), (5) and (7),(2), (5) and (8), (2), (5) and (9), (2), (5) and (10), (2), (5) and (11), (2), (6) and (9), (2), (7) and (8), (2), (7) and (9), (2), (7) and (10), (2), (7) and (11), (2), (8) and (9), (2), (8) and (10), (2), (8) and (11), (3), (4) and (6), (3), (4) and (7), (3), (4) and (8), (3), (4) and (9), (3), (4) and (10), (3), (4) and (11), (3), (5) and (6), (3), (5) and (7), (3), (5) and (8), (3), (5) and (9), (3), (5) and (10), (3), (5) and (11), (3), (6) and (9), (3), (6) and (10), (3), (6) and (11), (3), (7) and (8), (3), (7) and (9), (3), (7) and (10), (3), (7) and (11), (3), (8) and (9), (3), (8) and (10), (3), (8) and (11), (4), (6) and (9), (4), (6) and (10), (4), (6) and (11), (4), (7) and (8), (4), (7) and (9), (4), (7) and (10), (4), (7) and (11), (4), (8) and (9), (4), (8) and (10), (4), (8) and (11), (5), (6) and (9), (5), (6) and (10), (5), (6) and (11), (5), (7) and (8), (5), (7) and (9), (5), (7) and (10), (5), (7) and (11), (5), (8) and (9), (5), (8) and (10), (5), (8) and (11), (7), (8) and (9), (1), (3), (4) and (6), (1), (3), (4) and (7), (1), (3), (4) and (8), (1), (3), (4) and (9), (1), (3), (4) and (10), (1), (3), (4) and (11), (1), (3), (5) and (6), (1), (3), (5) and (7), (1), (3), (5) and (8), (1), (3), (5) and (9), (1), (3), (5) and (10), (1), (3), (5) and (11), (1), (3), (6) and (9), (1), (3), (6) and (10), (1), (3), (6) and (11), (1), (3), (7) and (8), (1), (3), (7) and (9), (1), (3), (8) and (9), (1), (4), (6) and (9),(1), (5), (6), and (9), (1), (7), (8), and (9), (2), (3), (4), and (6), (2), (3), (4), and (7), (2), (3), (4), and (8), (2), (3), (4), and (9), (2), (3), (5), and (6), (2), (3), (5), and (7), (2), (3), (5), and (8), (2), (3), (5), and (9), (2), (3), (6), and (9), (2), (3), (7), and (8), (2), (3), (7), and (9), (2), (3), (8), and (9), (2), (4), (6), and (9), (2), (5), (6), and (9), (2), (7), (8), and (9), (3), (4), (6), and (9), (3), (5), (6), and (9), (3), (7), (8), and (9), (4), (7), (8), and (9), (5), (7), (8), and (9), (1), (3), (4), (6), and (9), (1), (3), (4), (7), and (8), (1), (3), (4), (7), and (9), (1), (3), (5), (6), and (9), (1), (3), (5), (7), and (8), (1), (3), (5), (7), and (9), (1), (4), (7), (8), and (9), (1), (5), (7), (8), and (9), (2), (3), (4), (6), and (9), (2), (3), (4), (7), and (8), (2), (3), (4), (7), and (9), (2), (3), (5), (6), and (9), (2), (3), (5), (7), and (8), (2), (3), (5), (7), and (9), (2), (4), (7), (8), and (9), (2), (5), (7), (8), and (9), (3), (4), (7), (8), and (9), (3), (5), (7), (8), and (9), (1), (3), (4), (7), (8), and (9), (1), (3), (5), (7), (8), and (9), (2), (3), (4), (7), (8), and (9), (2), (3), (5), (7), (8), and (9), (1), (3), (4), (6), (9), and (10), (1), (3), (4), (7), (8), and (10), (1), (3), (4), (7), (9), and (10), (1), (3), (5), (6), (9), and (10), (1), (3), (5), (7), (8), and (10), (1), (3), (5), (7), (9), and (10), (1), (4), (7), (8), (9), and (10),(1), (5), (7), (8), (9), and (10), (2), (3), (4), (6), (9), and (10), (2), (3), (4), (7), (8), and (10), (2), (3), (4), (7), (9), and (10), (2), (3), (5), (6), (9), and (10), (2), (3), (5), (7), (8), and (10), (2), (3), (5), (7), (9), and (10), (2), (4), (7), (8), (9), and (10), (2), (5), (7), (8), (9), and (10), (3), (4), (7), (8), (9), and (10), (3), (5), (7), (8), (9), and (10), (1), (3), (4), (7), (8), (9), and (10), (1), (3), (5), (7), (8), (9), and (10), (2), (3), (4), (7), (8), (9), and (10), (2), (3), (5), (7), (8), (9), and (10), (1), (3), (4), (6), (9), and (11), (1), (3), (4), (7), (8), and (11), (1), (3), (4), (7), (9), and (11), (1), (3), (5), (6), (9), and (11), (1), (3), (5), (7), (8), and (11), (1), (3), (5), (7), (9), and (11), (1), (4), (7), (8), (9), and (11), (1), (5), (7), (8), (9), and (11), (2), (3), (4), (6), (9), and (11), (2), (3), (4), (7), (8), and (11), (2), (3), (4), (7), (9), and (11), (2), (3), (5), (6), (9), and (11), (2), (3), (5), (7), (8), and (11), (2), (3), (5), (7), (9), and (11), (2), (4), (7), (8), (9), and (11), (2), (5), (7), (8), (9), and (11), (3), (4), (7), (8), (9), and (11), (3), (5), (7), (8), (9), and (11), (1), (3), (4), (7), (8), (9), and (11), (1), (3), (5), (7), (8), (9), and (11), (2), (3), (4), (7), (8), (9), and (11), (2), (3), (5), (7), (8), (9), and (11).

[0037] In some embodiments, the treatment is selected from one or more of surgery, chemotherapy, radiotherapy, targeted therapy, endocrine therapy, and immunotherapy.

[0038] In some embodiments, the triple-negative breast cancer is a locally advanced or metastatic triple-negative breast cancer that is refractory to standard treatment, or has no standard treatment regimen, or is not suitable for standard treatment at the present stage. In some embodiments, the standard treatment refers to the standard treatment regimen recommended by the NCCN guideline and CSCO diagnosis and treatment guideline for the tumor disease.

[0039] In some embodiments, the triple-negative breast cancer is a triple-negative breast cancer that is refractory to and / or relapsed after first-line chemotherapy drug treatment. In some embodiments, the first-line chemotherapy drug refers to the first-line chemotherapy drug recommended by the NCCN guideline and CSCO diagnosis and treatment guideline for the triple-negative breast cancer.

[0040] In some embodiments, the triple-negative breast cancer is a triple-negative breast cancer that is refractory to and / or relapsed after radiotherapy. In some embodiments, the chemotherapy, radiotherapy, targeted therapy, endocrine therapy, or immunotherapy refers to the chemotherapy, radiotherapy, targeted therapy, endocrine therapy, or immunotherapy regimen recommended by the NCCN guideline and CSCO diagnosis and treatment guideline for the triple-negative breast cancer.

[0041] In some embodiments, the triple-negative breast cancer is a tumor that is refractory to and / or relapsed after targeted drug or immunotherapy treatment. In some embodiments, the targeted drug or immunotherapy refers to the targeted drug or immunotherapy recommended by the NCCN guideline and CSCO diagnosis and treatment guideline for the triple-negative breast cancer.

[0042] In some embodiments, the triple-negative breast cancer is a locally advanced, locally recurrent, or metastatic triple-negative breast cancer.

[0043] In some embodiments, the triple-negative breast cancer is a locally recurrent triple-negative breast cancer.

[0044] In some embodiments, the triple-negative breast cancer is a metastatic triple-negative breast cancer.

[0045] In some embodiments, the triple-negative breast cancer is a locally advanced recurrent triple-negative breast cancer.

[0046] In some embodiments, the triple-negative breast cancer is a locally recurrent and metastatic triple-negative breast cancer.

[0047] In some embodiments, the triple-negative breast cancer is a locally advanced and metastatic triple-negative breast cancer.

[0048] In some embodiments, the triple-negative breast cancer has received prior treatment.

[0049] In some embodiments, the triple-negative breast cancer has received more than two treatments.

[0050] In some embodiments, the triple-negative breast cancer has received more than two systemic treatments.

[0051] In some embodiments, the triple-negative breast cancer has received more than two treatments, and wherein at least one treatment was performed in the case of inoperable locally advanced or in the case of metastasis of the triple-negative breast cancer.

[0052] In some embodiments, the triple-negative breast cancer has received first-line treatment.

[0053] In some embodiments, the triple-negative breast cancer has received second- or third-line treatment.

[0054] In some embodiments, the triple-negative breast cancer has received more than third-line treatment.

[0055] In some embodiments, the first-line treatment, the second- or third-line treatment, and the more than third-line treatment are each independently selected from one or more of chemotherapy, targeted therapy, immunotherapy, or combination therapy.

[0056] In some embodiments, the triple-negative breast cancer has received more than one chemotherapy treatment, or more than two chemotherapy treatments, or more than three chemotherapy treatments, or more than four chemotherapy treatments. In some embodiments, the triple-negative breast cancer has received more than one chemotherapy treatment, or more than two chemotherapy treatments, or more than three chemotherapy treatments, or more than four chemotherapy treatments, and at least one chemotherapy was performed in the case of metastasis of the disease. In some embodiments, the triple-negative breast cancer has received more than three chemotherapy treatments, or more than four chemotherapy treatments, and the chemotherapy treatments were performed in the case of advanced triple-negative breast cancer.

[0057] In some embodiments, the triple-negative breast cancer has received targeted drug treatment.

[0058] In some embodiments, the triple-negative breast cancer has received treatment with a PD-1 inhibitor or a PD-L1 inhibitor.

[0059] In some embodiments, the triple-negative breast cancer has not received treatment with a PD-1 inhibitor or a PD-L1 inhibitor.

[0060] In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor is selected from nivolumab, cemiplimab, dostarlimab, pidilizumab, tislelizumab, and pembrolizumab. In some embodiments, the triple-negative breast cancer has visceral metastasis, e.g., bone, brain, liver, or lung metastasis.

[0061] In some embodiments, the triple-negative breast cancer has not received late-line treatment.

[0062] In some embodiments, the triple-negative breast cancer has liver metastasis.

[0063] In some embodiments, the triple-negative breast cancer has lymph node metastasis.

[0064] In some embodiments, the triple-negative breast cancer has low HER2 expression.

[0065] In some embodiments, the triple-negative breast cancer does not express HER2.

[0066] In some embodiments, the triple-negative breast cancer has a H-score of TROP-2 expression of 0, 0-10, 10-100, 100-200, or greater than 200.

[0067] In some embodiments, the triple-negative breast cancer has a H-score of TROP-2 expression of greater than 200.

[0068] In some embodiments, the patient is an adult. In some specific embodiments, the patient is 20-70 years old, e.g., 25-65 years old, 30-60 years old, 35-55 years old, 40-55 years old, 40 years old, 41 years old, 42 years old, 43 years old, 44 years old, 45 years old, 46 years old, 47 years old, 48 years old, 49 years old, 50 years old, 51 years old, 52 years old, 53 years old, 54 years old, or 55 years old.

[0069] In some embodiments, the triple-negative breast cancer is a locally advanced triple-negative breast cancer.

[0070] In some embodiments, the triple-negative breast cancer is a late-stage triple-negative breast cancer. In some specific embodiments, the use is further characterized by one or more of the following:

[0071] (1) the patient has an ECOG score of 0-2, e.g., 0, 1, or 2; preferably, the patient has an ECOG score of 1;

[0072] (2) the triple-negative breast cancer has a PD-L1 CPS < 10;

[0073] (3) the triple-negative breast cancer has a visceral metastasis;

[0074] (4) the triple-negative breast cancer is a primary metastatic triple-negative breast cancer;

[0075] (5) the patient has a disease free interval (DFI) of 6 months or more, for example, 6-12 months, and further for example, > 12 months.

[0076] In some embodiments, the triple-negative breast cancer is a late-stage triple-negative breast cancer and has a PD-L1 CPS < 10.

[0077] In specific embodiments, the triple-negative breast cancer patient is a locally advanced stage TNBC patient who is not amenable to curative surgery or a metastatic TNBC patient who has not received treatment for advanced disease.

[0078] In some more specific embodiments, the late-stage triple-negative breast cancer is characterized by (1) and (2), (1) and (3), (1) and (4), (1) and (5), (2) and (3), (2) and (4), (2) and (5), (3) and (4), (3) and (5), (4) and (5), (1), (3) and (4), (1), (3) and (5), (1), (4) and (5), (2), (3) and (4), (2), (3) and (5), (2), (4) and (5), (3), (4) and (5), (1), (2), (3) and (4), (1), (2), (3) and (5), (1), (2), (4) and (5), (2), (3), (4) and (5), or (1), (2), (3), (4) and (5) described above.

[0079] In some embodiments, the triple-negative breast cancer has not received advanced treatment.

[0080] In some embodiments, the triple-negative breast cancer has a visceral metastasis.

[0081] In some embodiments, the triple-negative breast cancer has a liver metastasis.

[0082] In some embodiments, the triple-negative breast cancer has a lymph node metastasis.

[0083] In some embodiments, the triple-negative breast cancer is a primary metastatic.

[0084] In some embodiments, the triple-negative breast cancer has low HER2 expression.

[0085] In some embodiments, the triple-negative breast cancer does not express HER2.

[0086] In some embodiments, the triple-negative breast cancer has a TROP-2 expression H-score of 0, 0-10, 10-100, 100-200, or greater than 200.

[0087] In some embodiments, the patient is between 20-70 years old, for example, 25-65 years old, 30-60 years old, 35-55 years old, 40-55 years old, 40 years old, 41 years old, 42 years old, 43 years old, 44 years old, 45 years old, 46 years old, 47 years old, 48 years old, 49 years old, 50 years old, 51 years old, 52 years old, 53 years old, 54 years old, or 55 years old.

[0088] In some embodiments, the triple-negative breast cancer is a locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has received prior treatment.

[0089] In some embodiments, the triple-negative breast cancer is a locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has received more than two treatments.

[0090] In some embodiments, the triple-negative breast cancer is a locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has received more than two treatments, and wherein at least one of the treatments is performed in the case of inoperable locally advanced or metastasis of the triple-negative breast cancer.

[0091] In some embodiments, the locally advanced, locally recurrent, or metastatic triple-negative breast cancer has received first-line treatment.

[0092] In some embodiments, the locally advanced, locally recurrent, or metastatic triple-negative breast cancer has received second-line or third-line treatment.

[0093] In some embodiments, the locally advanced, locally recurrent, or metastatic triple-negative breast cancer has received more than third-line treatment.

[0094] In some embodiments, the first-line treatment, the second-line or third-line treatment, and the more than third-line treatment are each independently selected from one or more of chemotherapy, targeted therapy, immunotherapy, or combination therapy.

[0095] In some embodiments, the triple-negative breast cancer is a locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has received one or more chemotherapy treatment, or two or more chemotherapy treatments, or three or more chemotherapy treatments, or four or more chemotherapy treatments.

[0096] In some embodiments, the triple-negative breast cancer is locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has received treatment with a targeted drug.

[0097] In some embodiments, the triple-negative breast cancer is locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has received treatment with a PD-1 inhibitor or a PD-L1 inhibitor.

[0098] In some embodiments, the triple-negative breast cancer is advanced or metastatic triple-negative breast cancer and has not received treatment for advanced disease.

[0099] In some embodiments, the triple-negative breast cancer is advanced or metastatic triple-negative breast cancer and has not received treatment for advanced disease, and has visceral metastasis.

[0100] In some embodiments, the triple-negative breast cancer is advanced or metastatic triple-negative breast cancer and has not received treatment for advanced disease, and is a primary metastasis.

[0101] In some embodiments, the triple-negative breast cancer is locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has not received treatment with a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the triple-negative breast cancer is locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has visceral metastasis, e.g., bone, brain, liver, or lung metastasis.

[0102] In some embodiments, the triple-negative breast cancer is locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has liver metastasis.

[0103] In some embodiments, the triple-negative breast cancer is locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has lymph node metastasis.

[0104] In some embodiments, the locally advanced, locally recurrent, or metastatic triple-negative breast cancer has low expression of HER2.

[0105] In some embodiments, the locally advanced, locally recurrent, or metastatic triple-negative breast cancer does not express HER2.

[0106] In some embodiments, the disease is locally advanced, locally recurrent, or metastatic triple-negative breast cancer and the H-score of TROP-2 expression is 0, 0-10, 10-100, 100-200, or greater than 200.

[0107] In some embodiments, the advanced or metastatic triple-negative breast cancer has low expression of PD-L1.

[0108] In some embodiments, the late-stage or metastatic triple negative breast cancer has a PD-L1 CPS < 10.

[0109] In some embodiments, the conjugate has the following structure:

[0110] L1 is selected from and L1 is attached at position 1 to D and at position 2 to L2;

[0111] L2 is where y1 is 3, 4, 5, 6, 7, 8, 9, or 10; and L2 is attached at position 1 to L1 and at position 2 to L3;

[0112] L3 is selected from a 5-6 membered heteroaromatic ring, such as pyrazole or triazole;

[0113] L4 is where Z2 is selected from C 1-3 alkylene; R3 is H; Z3 is selected from C 1-3 alkylene; a is 0, and L4 is attached at position 2 to E and at position 1 to L3;

[0114] E is where each R4 is independently hydrogen (e.g., protium or deuterium), b is 0, 1, or 2, and E is attached at position 2 to A (e.g., to a thiol on A) and at position 1 to L4;

[0115] m1, m2, and m3 are each 1;

[0116] the biologically active molecule is selected from Preferably, the biologically active molecule is attached at position 1 of L1 via a hydroxyl of itself;

[0117] g is selected from an integer between 3-8 (e.g., 3, 4, 5, 6, 7, or 8);

[0118] A is Sacituzumab or an antigen binding fragment thereof.

[0119] In some embodiments, the conjugate has the following structure:

[0120] L1 is selected from and L1 is attached at position 1 to D and at position 2 to L2;

[0121] L2 is where y1 is 3, 4, 5, 6, 7, 8, 9, or 10; and L2 is attached at position 1 to L1 and at position 2 to L3;

[0122] L3 is selected from a 5-6 membered heteroaromatic ring, such as pyrazole or triazole;

[0123] L4 is wherein Z2 is selected from C 1-3 alkylene; R3 is H; Z3 is selected from C 1-3 alkylene; a is 1, and L4 is attached at the 2 position to E and at the 1 position to L3;

[0124] E is wherein each R4 is independently hydrogen (e.g., protium or deuterium), b is 0, 1, or 2, and E is attached at the 2 position to A (e.g., to a thiol group on A) and at the 1 position to L4;

[0125] m1, m2, and m3 are each 1;

[0126] the biologically active molecule is selected from Preferably, the biologically active molecule is attached at the 1 position of L1 via a hydroxyl group of the biologically active molecule.

[0127] g is selected from an integer between 3-8 (e.g., 3, 4, 5, 6, 7, or 8);

[0128] A is Sacituzumab or an antigen binding fragment thereof.

[0129] In some embodiments, D is selected from

[0130] In some embodiments, the conjugate is conjugate A of the following formula:

[0131] wherein g is an integer from 1-10; preferably, g is selected from an integer between 5-8, e.g., g is 5, 6, 7, or 8.

[0132] In some embodiments, the composition comprises one or more antibody drug conjugates described above.

[0133] In some embodiments, the antibody drug conjugate is conjugate A.

[0134] In some embodiments, the DAR of the composition is the average of the DARs of all antibody drug conjugate molecules present in the composition.

[0135] In some embodiments, the DAR of the composition is an integer or decimal number from 0 to 10, preferably, the DAR of the composition is an integer or decimal number from 5 to 8.

[0136] In some embodiments, the DAR of the composition is 5.1, 5.2, 5.3, 5.4, 5.5, 5.5, 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.

[0137] In some embodiments, the composition is a pharmaceutical composition.

[0138] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient.

[0139] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the antibody drug conjugate of Formula (I).

[0140] In some embodiments, the pharmaceutical composition comprises 1-1000 mg of the conjugate A, and further comprises a pharmaceutically acceptable carrier and / or excipient.

[0141] In some embodiments, the pharmaceutical composition comprises 1-100 mg, 101-200 mg, 201-300 mg, 301-400 mg, 401-500 mg, 501-600 mg, 601-700 mg, 701-800 mg, 801-900 mg, or 901-1000 mg.

[0142] In another aspect, the present application provides a method of treating locally recurrent or metastatic triple negative breast cancer in a patient, comprising the step of administering to the patient a therapeutically effective amount of the antibody drug conjugate of Formula (I) and / or a composition comprising the antibody drug conjugate of Formula (I), as described above.

[0143] In some embodiments, the patient has received more than one chemotherapy treatment, or more than two chemotherapy treatments, or more than three chemotherapy treatments, or more than four chemotherapy treatments; and / or

[0144] The patient has received more than one chemotherapy treatment, or more than two chemotherapy treatments, or more than three chemotherapy treatments, or more than four chemotherapy treatments, and wherein at least one of the chemotherapy treatments was performed in the presence of metastasis of the triple negative breast cancer.

[0145] In some specific embodiments, the patient has received two or more chemotherapy treatments, wherein at least one of the chemotherapy treatments was performed in the presence of metastasis of the triple negative breast cancer, and the triple negative breast cancer has visceral metastasis, such as liver metastasis.

[0146] In some specific embodiments, the method is further characterized by one or more of the following:

[0147] (1) the triple-negative breast cancer has visceral metastasis, for example, liver metastasis;

[0148] (2) the triple-negative breast cancer has lymph node metastasis;

[0149] (3) the triple-negative breast cancer has a TROP-2 expression H-score of 0, 0-10, 10-100, 100-200, or greater than 200; preferably, the TROP-2 expression H-score is greater than 200;

[0150] (4) the triple-negative breast cancer is HER2 non-expressing;

[0151] (5) the triple-negative breast cancer is HER2 low-expressing;

[0152] (6) the patient has received two or three prior treatments;

[0153] (7) the patient has received more than three prior treatments;

[0154] (8) the patient has received more than three prior chemotherapy treatments, or more than four prior chemotherapy treatments, and the chemotherapy treatments were administered in the setting of advanced triple-negative breast cancer;

[0155] (9) the patient has received prior targeted therapy; preferably, the targeted therapy is a PD-1 inhibitor or a PD-L1 inhibitor;

[0156] (10) the triple-negative breast cancer is a de novo triple-negative breast cancer;

[0157] (11) the triple-negative breast cancer is a non-de novo triple-negative breast cancer.

[0158] In some more particular embodiments, the method is further characterized by (1) and (3), (1) and (4), (1) and (5), (1) and (6), (1) and (7), (1) and (8), (1) and (9), (1) and (10), (1) and (11), (2) and (3), (2) and (4), (2) and (5), (2) and (6), (2) and (7), (2) and (8), (2) and (9), (2) and (10), (2) and (11), (3) and (4), (3) and (5), (3) and (6), (3) and (7), (3) and (8), (3) and (9), (3) and (10), (3) and (11), (4) and (6), (4) and (7), (4) and (8), (4) and (9), (4) and (10), (4) and (11), (5) and (6), (5) and (7), (5) and (8), (5) and (9), (5) and (10), (5) and (11), (6) and (9), (6) and (9), (6) and (11), (7) and (8), (7) and (9), (7) and (10), (7) and (11), (8) and (9), (8) and (10), (8) and (11), (1), (3) and (4), (1), (3) and (5), (1), (3) and (6), (1), (3) and (7), (1), (3) and (8), (1), (3) and (9), (1), (3) and (10), (1), (3) and (11), (1), (4) and (6), (1), (4) and (7), (1), (4) and (8), (1), (4) and (9), (1), (4) and (10), (1), (4) and (11), (1), (5) and (6), (1), (5) and (7), (1), (5) and (8), (1), (5) and (9), (1), (5) and (10), (1), (5) and (11), (1), (6) and (9), (1), (6) and (10), (1), (6) and (11), (1), (7) and (8), (1), (7) and (9), (1), (7) and (10), (1), (7) and (11), (1), (8) and (9), (1), (8) and (10), (1), (8) and (11), (2), (3) and (4), (2), (3) and (5), (2), (3) and (6), (2), (3) and (7), (2), (3) and (8), (2), (3) and (9), (2), (3) and (10), (2), (3) and (11), (2), (4) and (6), (2), (4) and (7), (2), (4) and (8), (2), (4) and (9), (2), (4) and (10), (2), (4) and (11), (2), (5) and (6), (2), (5) and (7),(2), (5) and (8), (2), (5) and (9), (2), (5) and (10), (2), (5) and (11), (2), (6) and (9), (2), (7) and (8), (2), (7) and (9), (2), (7) and (10), (2), (7) and (11), (2), (8) and (9), (2), (8) and (10), (2), (8) and (11), (3), (4) and (6), (3), (4) and (7), (3), (4) and (8), (3), (4) and (9), (3), (4) and (10), (3), (4) and (11), (3), (5) and (6), (3), (5) and (7), (3), (5) and (8), (3), (5) and (9), (3), (5) and (10), (3), (5) and (11), (3), (6) and (9), (3), (6) and (10), (3), (6) and (11), (3), (7) and (8), (3), (7) and (9), (3), (7) and (10), (3), (7) and (11), (3), (8) and (9), (3), (8) and (10), (3), (8) and (11), (4), (6) and (9), (4), (6) and (10), (4), (6) and (11), (4), (7) and (8), (4), (7) and (9), (4), (7) and (10), (4), (7) and (11), (4), (8) and (9), (4), (8) and (10), (4), (8) and (11), (5), (6) and (9), (5), (6) and (10), (5), (6) and (11), (5), (7) and (8), (5), (7) and (9), (5), (7) and (10), (5), (7) and (11), (5), (8) and (9), (5), (8) and (10), (5), (8) and (11), (7), (8) and (9), (1), (3), (4) and (6), (1), (3), (4) and (7), (1), (3), (4) and (8), (1), (3), (4) and (9), (1), (3), (4) and (10), (1), (3), (4) and (11), (1), (3), (5) and (6), (1), (3), (5) and (7), (1), (3), (5) and (8), (1), (3), (5) and (9), (1), (3), (5) and (10), (1), (3), (5) and (11), (1), (3), (6) and (9), (1), (3), (6) and (10), (1), (3), (6) and (11), (1), (3), (7) and (8), (1), (3), (7) and (9), (1), (3), (8) and (9), (1), (4), (6) and (9),(1), (5), (6), and (9), (1), (7), (8), and (9), (2), (3), (4), and (6), (2), (3), (4), and (7), (2), (3), (4), and (8), (2), (3), (4), and (9), (2), (3), (5), and (6), (2), (3), (5), and (7), (2), (3), (5), and (8), (2), (3), (5), and (9), (2), (3), (6), and (9), (2), (3), (7), and (8), (2), (3), (7), and (9), (2), (3), (8), and (9), (2), (4), (6), and (9), (2), (5), (6), and (9), (2), (7), (8), and (9), (3), (4), (6), and (9), (3), (5), (6), and (9), (3), (7), (8), and (9), (4), (7), (8), and (9), (5), (7), (8), and (9), (1), (3), (4), (6), and (9), (1), (3), (4), (7), and (8), (1), (3), (4), (7), and (9), (1), (3), (5), (6), and (9), (1), (3), (5), (7), and (8), (1), (3), (5), (7), and (9), (1), (4), (7), (8), and (9), (1), (5), (7), (8), and (9), (2), (3), (4), (6), and (9), (2), (3), (4), (7), and (8), (2), (3), (4), (7), and (9), (2), (3), (5), (6), and (9), (2), (3), (5), (7), and (8), (2), (3), (5), (7), and (9), (2), (4), (7), (8), and (9), (2), (5), (7), (8), and (9), (3), (4), (7), (8), and (9), (3), (5), (7), (8), and (9), (1), (3), (4), (7), (8), and (9), (1), (3), (5), (7), (8), and (9), (2), (3), (4), (7), (8), and (9), (2), (3), (5), (7), (8), and (9), (1), (3), (4), (6), (9), and (10), (1), (3), (4), (7), (8), and (10), (1), (3), (4), (7), (9), and (10), (1), (3), (5), (6), (9), and (10), (1), (3), (5), (7), (8), and (10), (1), (3), (5), (7), (9), and (10), (1), (4), (7), (8), (9), and (10),(1), (5), (7), (8), (9), and (10), (2), (3), (4), (6), (9), and (10), (2), (3), (4), (7), (8), and (10), (2), (3), (4), (7), (9), and (10), (2), (3), (5), (6), (9), and (10), (2), (3), (5), (7), (8), and (10), (2), (3), (5), (7), (9), and (10), (2), (4), (7), (8), (9), and (10), (2), (5), (7), (8), (9), and (10), (3), (4), (7), (8), (9), and (10), (3), (5), (7), (8), (9), and (10), (1), (3), (4), (7), (8), (9), and (10), (1), (3), (5), (7), (8), (9), and (10), (2), (3), (4), (7), (8), (9), and (10), (2), (3), (5), (7), (8), (9), and (10), (1), (3), (4), (6), (9), and (11), (1), (3), (4), (7), (8), and (11), (1), (3), (4), (7), (9), and (11), (1), (3), (5), (6), (9), and (11), (1), (3), (5), (7), (8), and (11), (1), (3), (5), (7), (9), and (11), (1), (4), (7), (8), (9), and (11), (1), (5), (7), (8), (9), and (11), (2), (3), (4), (6), (9), and (11), (2), (3), (4), (7), (8), and (11), (2), (3), (4), (7), (9), and (11), (2), (3), (5), (6), (9), and (11), (2), (3), (5), (7), (8), and (11), (2), (3), (5), (7), (9), and (11), (2), (4), (7), (8), (9), and (11), (2), (5), (7), (8), (9), and (11), (3), (4), (7), (8), (9), and (11), (3), (5), (7), (8), (9), and (11), (1), (3), (4), (7), (8), (9), and (11), (1), (3), (5), (7), (8), (9), and (11), (2), (3), (4), (7), (8), (9), and (11), (2), (3), (5), (7), (8), (9), and (11).

[0159] In some embodiments, the triple-negative breast cancer is a locally advanced or metastatic triple-negative breast cancer that is inoperable, or for which standard treatment is not available, or for which standard treatment has failed.

[0160] In some embodiments, the triple-negative breast cancer is a triple-negative breast cancer that has failed and / or relapsed after treatment with a first-line chemotherapeutic drug. In some embodiments, the first-line chemotherapeutic drug refers to a first-line chemotherapeutic drug recommended by the NCCN guidelines and CSCO diagnosis and treatment guidelines for the triple-negative breast cancer.

[0161] In some embodiments, the triple-negative breast cancer is a triple-negative breast cancer that has failed and / or relapsed after radiotherapy. In some embodiments, the chemotherapy, radiotherapy, targeted therapy, endocrine therapy, or immunotherapy refers to a chemotherapy, radiotherapy, targeted therapy, endocrine therapy, or immunotherapy recommended by the NCCN guidelines and CSCO diagnosis and treatment guidelines for the triple-negative breast cancer.

[0162] In some embodiments, the triple-negative breast cancer is a tumor that has failed and / or relapsed after treatment with a targeted drug or immunotherapy. In some embodiments, the targeted drug or immunotherapy refers to a targeted drug or immunotherapy recommended by the NCCN guidelines and CSCO diagnosis and treatment guidelines for the triple-negative breast cancer.

[0163] In some embodiments, the triple-negative breast cancer is a locally advanced, locally recurrent, or metastatic triple-negative breast cancer.

[0164] In some embodiments, the triple-negative breast cancer is a locally recurrent triple-negative breast cancer.

[0165] In some embodiments, the triple-negative breast cancer is a metastatic triple-negative breast cancer.

[0166] In some embodiments, the triple-negative breast cancer is a locally advanced recurrent triple-negative breast cancer.

[0167] In some embodiments, the triple-negative breast cancer is a locally recurrent and metastatic triple-negative breast cancer.

[0168] In some embodiments, the triple-negative breast cancer is a locally advanced and metastatic triple-negative breast cancer.

[0169] In some embodiments, the triple-negative breast cancer has received prior treatment.

[0170] In some embodiments, the triple-negative breast cancer has received more than two treatments.

[0171] In some embodiments, the triple-negative breast cancer has received more than two systemic treatments.

[0172] In some embodiments, the triple-negative breast cancer has received more than two treatments, and wherein at least one of the treatments was performed in the case of inoperable locally advanced or in the case of metastasis of the triple-negative breast cancer.

[0173] In some embodiments, the triple-negative breast cancer has received first-line treatment.

[0174] In some embodiments, the triple-negative breast cancer has received second- or third-line treatment.

[0175] In some embodiments, the triple-negative breast cancer has received more than third-line treatment.

[0176] In some embodiments, the first-line treatment, the second- or third-line treatment, and the more than third-line treatment are each independently selected from one or more of surgery, chemotherapy, radiotherapy, targeted therapy, endocrine therapy, and immunotherapy.

[0177] In some embodiments, the triple-negative breast cancer has received more than one chemotherapy treatment, or more than two chemotherapy treatments, or more than three chemotherapy treatments, or more than four chemotherapy treatments. In some embodiments, the triple-negative breast cancer has received more than one chemotherapy treatment, or more than two chemotherapy treatments, or more than three chemotherapy treatments, or more than four chemotherapy treatments, and at least one of the chemotherapies was performed in the case of metastasis of the disease. In some embodiments, the triple-negative breast cancer has received more than three chemotherapy treatments, or more than four chemotherapy treatments, and the chemotherapy treatments were performed in the case of advanced triple-negative breast cancer.

[0178] In some embodiments, the triple-negative breast cancer has received targeted drug treatment.

[0179] In some embodiments, the triple-negative breast cancer has received treatment with a PD-1 inhibitor or a PD-L1 inhibitor.

[0180] In some embodiments, the triple-negative breast cancer has not received treatment with a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor or the PD-L1 inhibitor is selected from nivolumab, cemiplimab, dostarlimab, pidilizumab, tislelizumab, and pembrolizumab.

[0181] In some embodiments, the triple-negative breast cancer is locally advanced triple-negative breast cancer.

[0182] In some embodiments, the triple-negative breast cancer is metastatic triple-negative breast cancer.

[0183] In some embodiments, the triple-negative breast cancer has not received late-line therapy.

[0184] In some embodiments, the triple-negative breast cancer has liver metastasis.

[0185] In some embodiments, the triple-negative breast cancer has lymph node metastasis.

[0186] In some embodiments, the triple-negative breast cancer has low HER2 expression.

[0187] In some embodiments, the triple-negative breast cancer does not express HER2.

[0188] In some embodiments, the triple-negative breast cancer has a H-score of TROP-2 expression of 0, 0-10, 10-100, 100-200, or greater than 200.

[0189] In some embodiments, the triple-negative breast cancer has a H-score of TROP-2 expression of greater than 200.

[0190] In some embodiments, the patient is an adult. In some specific embodiments, the patient is between 20-70 years of age, e.g., 25-65 years of age, 30-60 years of age, 35-55 years of age, 40-55 years of age, 40 years of age, 41 years of age, 42 years of age, 43 years of age, 44 years of age, 45 years of age, 46 years of age, 47 years of age, 48 years of age, 49 years of age, 50 years of age, 51 years of age, 52 years of age, 53 years of age, 54 years of age, or 55 years of age.

[0191] In some embodiments, the triple-negative breast cancer is advanced triple-negative breast cancer.

[0192] In some specific embodiments, the method is further characterized by one or more of the following:

[0193] (1) the patient has an ECOG score of 0-2, e.g., 0, 1, or 2; preferably, the patient has an ECOG score of 1;

[0194] (2) the triple-negative breast cancer has a PD-L1 CPS of <10;

[0195] (3) the triple-negative breast cancer has a visceral metastasis;

[0196] (4) the triple-negative breast cancer is primary metastatic triple-negative breast cancer;

[0197] (5) the patient has a disease free interval (DFI) of 6 months or more, for example, 6-12 months, and further for example, > 12 months.

[0198] In some embodiments, the triple-negative breast cancer is advanced triple-negative breast cancer, and the PD-L1 CPS is < 10.

[0199] In some embodiments, the triple-negative breast cancer patient is a locally advanced stage TNBC patient who is not amenable to curative surgery for advanced disease, or a metastatic TNBC patient who has not received treatment for advanced disease.

[0200] In some more specific embodiments, the advanced triple-negative breast cancer is characterized by (1) and (2), (1) and (3), (1) and (4), (1) and (5), (2) and (3), (2) and (4), (2) and (5), (3) and (4), (3) and (5), (4) and (5), (1), (3) and (4), (1), (3) and (5), (1), (4) and (5), (2), (3) and (4), (2), (3) and (5), (2), (4) and (5), (3), (4) and (5), (1), (2), (3) and (4), (1), (2), (3) and (5), (1), (2), (4) and (5), (2), (3), (4) and (5), or (1), (2), (3), (4) and (5) described above.

[0201] In some embodiments, the patient is an adult. In some specific embodiments, the patient is between 20 and 70 years of age, for example, between 25 and 65 years of age, between 30 and 60 years of age, between 35 and 55 years of age, between 40 and 55 years of age, 40 years of age, 41 years of age, 42 years of age, 43 years of age, 44 years of age, 45 years of age, 46 years of age, 47 years of age, 48 years of age, 49 years of age, 50 years of age, 51 years of age, 52 years of age, 53 years of age, 54 years of age, or 55 years of age.

[0202] In some embodiments, the patient has received prior therapy.

[0203] In some embodiments, the patient has received more than two therapies.

[0204] In some embodiments, the patient has received more than two therapies, and wherein at least one of the therapies was for inoperable locally advanced or in the event of metastasis of the disease.

[0205] In some embodiments, the patient has received first line therapy.

[0206] In some embodiments, the patient has received two or three lines of treatment.

[0207] In some embodiments, the patient has received more than three lines of treatment.

[0208] In some embodiments, the one, two or three lines of treatment, and the more than three lines of treatment are each independently selected from one or more of chemotherapy, targeted therapy, immunotherapy, or combination therapy.

[0209] In some embodiments, the patient has received more than one line of chemotherapy, or more than two lines of chemotherapy, or more than three lines of chemotherapy, or more than four lines of chemotherapy. In some embodiments, the patient has received more than one line of chemotherapy, or more than two lines of chemotherapy, or more than three lines of chemotherapy, or more than four lines of chemotherapy, and at least one of the chemotherapies was administered in the context of metastatic disease.

[0210] In some embodiments, the patient has received more than one line of chemotherapy, or more than two lines of chemotherapy, or more than three lines of chemotherapy, or more than four lines of chemotherapy, due to advanced disease.

[0211] In some embodiments, the patient has received targeted therapy.

[0212] In some embodiments, the patient has received treatment with a PD-1 inhibitor or a PD-L1 inhibitor.

[0213] In some embodiments, the patient has not received treatment with a PD-1 inhibitor or a PD-L1 inhibitor.

[0214] In some embodiments, the PD-1 inhibitor or the PD-L1 inhibitor is selected from nivolumab, cemiplimab, dostarlimab, pidilizumab, tislelizumab, and pembrolizumab. In some embodiments, the patient has visceral metastasis, such as bone, brain, liver, or lung metastasis.

[0215] In some embodiments, the patient has liver metastasis.

[0216] In some embodiments, the patient has lymph node metastasis.

[0217] In some embodiments, the patient has low HER2 expression.

[0218] In some embodiments, the patient does not express HER2.

[0219] In some embodiments, the disease has a TROP-2 expression H-score (H-score) of 0, 0-10, 10-100, 100-200, or greater than 200.

[0220] In some embodiments, the triple-negative breast cancer has a TROP-2 expression H-score (H-score) of greater than 200.

[0221] In some embodiments, the patient is between 20-70 years of age, e.g., 25-65 years of age, 30-60 years of age, 35-55 years of age, 40-55 years of age, 40 years of age, 41 years of age, 42 years of age, 43 years of age, 44 years of age, 45 years of age, 46 years of age, 47 years of age, 48 years of age, 49 years of age, 50 years of age, 51 years of age, 52 years of age, 53 years of age, 54 years of age, or 55 years of age.

[0222] In some embodiments, the patient has locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has received more than two treatments.

[0223] In some embodiments, the patient has locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has received more than two systemic treatments.

[0224] In some embodiments, the patient has locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has received more than two treatments, and wherein at least one of the treatments was performed in the context of inoperable locally advanced or metastatic triple-negative breast cancer.

[0225] In some embodiments, the patient has locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has received first line treatment.

[0226] In some embodiments, the patient has locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has received second or third line treatment.

[0227] In some embodiments, the patient has locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has received greater than third line treatment.

[0228] In some embodiments, the first line treatment, second or third line treatment, and greater than third line treatment are each independently selected from one or more of chemotherapy, targeted therapy, immunotherapy, or combination therapy.

[0229] In some embodiments, the patient has locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has received more than one chemotherapy treatment, or more than two chemotherapy treatments, or more than three chemotherapy treatments, or more than four chemotherapy treatments.

[0230] In some embodiments, the patient has locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has received a targeted drug treatment.

[0231] In some embodiments, the patient has locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has received treatment with a PD-1 inhibitor or a PD-L1 inhibitor.

[0232] In some embodiments, the triple-negative breast cancer is advanced or metastatic triple-negative breast cancer and has not received an advanced treatment.

[0233] In some embodiments, the triple-negative breast cancer is advanced or metastatic triple-negative breast cancer and has not received an advanced treatment, and has a visceral metastasis.

[0234] In some embodiments, the triple-negative breast cancer is advanced or metastatic triple-negative breast cancer and has not received an advanced treatment, and is a primary metastasis.

[0235] In some embodiments, the patient has locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has not received treatment with a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the patient has locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has a visceral metastasis, such as a bone, brain, liver, or lung metastasis.

[0236] In some embodiments, the patient has locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has a liver metastasis.

[0237] In some embodiments, the patient has locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has a lymph node metastasis.

[0238] In some embodiments, the patient having locally advanced, locally recurrent, or metastatic triple-negative breast cancer has low expression of HER2.

[0239] In some embodiments, the patient having locally advanced, locally recurrent, or metastatic triple-negative breast cancer does not express HER2.

[0240] In some embodiments, the patient has locally advanced, locally recurrent, or metastatic triple-negative breast cancer and has a H-score of TROP-2 expression of 0, 0-10, 10-100, 100-200, or greater than 200.

[0241] In some embodiments, the PD-L1 of the late-stage or metastatic triple-negative breast cancer is low expression.

[0242] In some embodiments, the PD-L1 of the late-stage or metastatic triple-negative breast cancer is PD-L1 CPS < 10.

[0243] In some embodiments, the pharmaceutical composition comprises the antibody drug conjugate and a pharmaceutically acceptable carrier and / or excipient.

[0244] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the antibody drug conjugate of Formula (I).

[0245] In some embodiments, the antibody drug conjugate or the pharmaceutical composition is administered once every 7-35 days, preferably once every 7-28 days, for example, once every 7 days, 14 days, 21 days, 28 days, or 35 days.

[0246] In some embodiments, the antibody drug conjugate or the pharmaceutical composition is administered once every 14 days.

[0247] In some embodiments, the route of administration of the conjugate or pharmaceutical composition includes, but is not limited to, oral, transdermal injection, rectal administration, transmucosal administration, intramuscular injection, intramedullary injection, intravenous injection, or intraperitoneal injection, preferably intravenous injection.

[0248] In some embodiments, the dose of the antibody drug conjugate per administration is 1 mg / kg to 30 mg / kg based on the body weight of the patient; 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. In some embodiments, the dose of the antibody drug conjugate per administration is 4 mg / kg based on the body weight of the patient.

[0249] In some embodiments, the dose of the antibody drug conjugate per administration is 5 mg / kg based on the body weight of the patient.

[0250] In some embodiments, the dosage of the antibody drug conjugate is 4 mg / kg based on the body weight of the patient, once every 14 days.

[0251] In some embodiments, the dosage of the antibody drug conjugate is 5 mg / kg based on the body weight of the patient, once every 14 days.

[0252] In some embodiments, the dosage regimen of the antibody drug conjugate is divided into one or more dosing phases (e.g., one phase, two phases, three phases, or four phases), and each of the dosing cycle and the dosage of each phase is independently selected from the dosing cycle or the dosage described above.

[0253] In some embodiments, the use or method of the present application causes tumor elimination or volume reduction.

[0254] In some embodiments, the use or method of the present application causes tumor volume reduction of at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, or at least 40%.

[0255] In some embodiments, for the dosage regimen of 4 mg / kg or 5 mg / kg of conjugate A once every 14 days, the patients with locally recurrent or metastatic triple-negative breast cancer can achieve a median PFS of more than 4 months, or more than 4.5 months, or more than 5 months; the proportion of 6-month PFS is greater than 30%, greater than 35%, or greater than 40%.

[0256] In some embodiments, for the dosage regimen of 4 mg / kg or 5 mg / kg of conjugate A once every 14 days, the patients with locally recurrent or metastatic triple-negative breast cancer can achieve a median PFS of 5.7 months, and the proportion of 6-month PFS is 43.4%.

[0257] In some embodiments, for the dosage regimen of 4 mg / kg or 5 mg / kg of conjugate A once every 14 days, the objective response rate (ORR) of the patients with locally recurrent or metastatic triple-negative breast cancer is greater than 30%, greater than 35%, or greater than 40%.

[0258] In some embodiments, for the dosage regimen of 4 mg / kg or 5 mg / kg of conjugate A once every 14 days, the objective response rate (ORR) of the patients with locally recurrent or metastatic triple-negative breast cancer is 43.8%.

[0259] In some embodiments, the median PFS for locally recurrent or metastatic triple- negative breast cancer patients with a TROP2 H-score > 200 is more than 4 months, more than 4.5 months, or more than 5 months for conjugate A at 4 mg / kg or 5 mg / kg with a dosing regimen of once every 14 days.

[0260] In some embodiments, the median PFS for locally recurrent or metastatic triple- negative breast cancer patients with a TROP2 H-score > 200 is 5.8 months for conjugate A at 4 mg / kg or 5 mg / kg with a dosing regimen of once every 14 days. In yet another embodiment, the objective response rate (ORR) for locally recurrent or metastatic triple-negative breast cancer patients with a TROP2 H-score > 200 is 52.1% for conjugate A at 4 mg / kg or 5 mg / kg with a dosing regimen of once every 14 days.

[0261] In some embodiments, the objective response rate (ORR) for locally recurrent or metastatic triple-negative breast cancer patients with a TROP2 H-score < 200 is more than 20%, more than 25%, more than 30%, or more than 35% for conjugate A at 4 mg / kg or 5 mg / kg with a dosing regimen of once every 14 days.

[0262] In some embodiments, the objective response rate (ORR) for locally recurrent or metastatic triple-negative breast cancer patients with a TROP2 H-score < 200 is 39.6%.

[0263] In some embodiments, the median PFS for locally recurrent or metastatic triple- negative breast cancer patients who have received prior treatment with a PD-1 or PD-L1 inhibitor is more than 4 months, more than 4.5 months, or more than 5 months, and the ORR is more than 30%, more than 35%, more than 40%, more than 45%, or more than 50% for conjugate A at 4 mg / kg or 5 mg / kg with a dosing regimen of once every 14 days.

[0264] In some embodiments, the median PFS for locally recurrent or metastatic triple- negative breast cancer patients who have received prior treatment with a PD-1 or PD-L1 inhibitor is 5.6 months, and the ORR is 56.3% for conjugate A at 4 mg / kg or 5 mg / kg with a dosing regimen of once every 14 days.

[0265] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg with a dosing regimen of once every 14 days, the median PFS for patients who have not received prior treatment with a PD-1 or PD-L1 inhibitor is more than 4 months, more than 4.5 months, more than 5 months, more than 5.5 months, more than 6 months, more than 6.5 months, or more than 7 months and the ORR is greater than 30%, greater than 35%, or greater than 40%.

[0266] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg with a dosing regimen of once every 14 days, the median PFS for patients who have not received prior treatment with a PD-1 or PD-L1 inhibitor is 7.2 months and the ORR is 41.8%.

[0267] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg with a dosing regimen of once every 14 days, the median PFS for patients with locally recurrent or metastatic triple-negative breast cancer who have received prior 2ndor 3rdline therapy is more than 4 months, more than 4.5 months, more than 5 months, more than 5.5 months, more than 6 months, or more than 6.5 months.

[0268] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg with a dosing regimen of once every 14 days, the median PFS for patients with locally recurrent or metastatic triple-negative breast cancer who have received prior 2ndor 3rdline therapy is 6.9 months.

[0269] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg with a dosing regimen of once every 14 days, the median PFS for patients with locally recurrent or metastatic triple-negative breast cancer who have received prior greater than 3rdline therapy is more than 4 months, more than 4.5 months, more than 5 months, or more than 5.5 months.

[0270] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg with a dosing regimen of once every 14 days, the median PFS for patients with locally recurrent or metastatic triple-negative breast cancer who have received prior greater than 3rdline therapy is 5.7 months.

[0271] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg with a dosing regimen of once every 14 days, the median PFS for patients with locally recurrent or metastatic triple-negative breast cancer who have developed liver metastases is more than 2 months, more than 2.5 months, more than 3 months, more than 3.5 months, or more than 4 months.

[0272] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, a dosing regimen of once every 14 days, the median PFS for locally recurrent or metastatic triple-negative breast cancer patients with liver metastasis is 4.3 months.

[0273] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, a dosing regimen of once every 14 days, the median PFS for locally recurrent or metastatic triple-negative breast cancer patients without liver metastasis is more than 5 months, more than 5.5 months, more than 6 months, more than 6.5 months, more than 7 months, more than 7.5 months, or more than 8 months.

[0274] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, a dosing regimen of once every 14 days, the median PFS for locally recurrent or metastatic triple-negative breast cancer patients without liver metastasis is 8.4 months.

[0275] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, a dosing regimen of once every 14 days, the median PFS for locally recurrent or metastatic primary triple-negative breast cancer patients is more than 3 months, more than 3.5 months, more than 4 months, more than 4.5 months, more than 5 months, or more than 5.5 months.

[0276] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, a dosing regimen of once every 14 days, the median PFS for locally recurrent or metastatic primary triple-negative breast cancer patients is 5.8 months.

[0277] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, a dosing regimen of once every 14 days, the median PFS for locally recurrent or metastatic non-primary triple-negative breast cancer patients is more than 5 months, more than 5.5 months, more than 6 months, more than 6.5 months, or more than 7 months.

[0278] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, a dosing regimen of once every 14 days, the median PFS for locally recurrent or metastatic non-primary triple-negative breast cancer patients is 7.2 months.

[0279] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, a dosing regimen of once every 14 days, the median PFS for locally recurrent or metastatic triple-negative breast cancer patients with lymph node metastasis is more than 4 months, more than 4.5 months, more than 5 months, more than 5.5 months, more than 6 months, or more than 6.5 months.

[0280] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, a dosing regimen of once every 14 days, the median PFS for locally recurrent or metastatic triple-negative breast cancer patients with lymph node metastasis is 6.7 months.

[0281] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, a dosing regimen of once every 14 days, the median PFS for locally recurrent or metastatic triple-negative breast cancer patients without lymph node metastasis is more than 4 months, more than 4.5 months, more than 5 months, more than 5.5 months, more than 6 months, more than 6.5 months, or more than 7 months.

[0282] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, a dosing regimen of once every 14 days, the median PFS for locally recurrent or metastatic triple-negative breast cancer patients without lymph node metastasis is 7.2 months.

[0283] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, a dosing regimen of once every 14 days, the median PFS for locally recurrent or metastatic triple-negative breast cancer patients with visceral metastasis is more than 4 months, more than 4.5 months, more than 5 months, or more than 5.5 months.

[0284] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, a dosing regimen of once every 14 days, the median PFS for locally recurrent or metastatic triple-negative breast cancer patients with visceral metastasis is 5.8 months.

[0285] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, a dosing regimen of once every 14 days, the median PFS for locally recurrent or metastatic triple-negative breast cancer patients without visceral metastasis is more than 5 months, more than 5.5 months, more than 6 months, more than 6.5 months, more than 7 months, more than 7.5 months, or more than 8 months.

[0286] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, a dosing regimen of once every 14 days, the median PFS for locally recurrent or metastatic triple-negative breast cancer patients without visceral metastasis is 8.3 months.

[0287] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, a dosing regimen of once every 14 days, the median PFS for locally recurrent or metastatic triple-negative breast cancer patients with low HER2 expression is more than 4 months, more than 4.5 months, more than 5 months, or more than 5.5 months.

[0288] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, dosing regimen of once every 14 days, the median PFS for patients with locally recurrent or metastatic triple-negative breast cancer with low HER2 expression is 5.6 months.

[0289] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, dosing regimen of once every 14 days, the median PFS for patients with locally recurrent or metastatic triple-negative breast cancer with no HER2 expression is more than 5 months, more than 5.5 months, more than 6 months, more than 6.5 months, or more than 7 months.

[0290] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, dosing regimen of once every 14 days, the median PFS for patients with locally recurrent or metastatic triple-negative breast cancer with no HER2 expression is 7.2 months.

[0291] In some embodiments, for conjugate A at 5 mg / kg, dosing regimen of once every 14 days, the objective response rate (ORR) for patients with advanced / metastatic triple-negative breast cancer who have not received prior treatment for advanced disease is 70.7% (29 / 41) and the disease control rate (DCR) is 92.7%. The median duration of response (mDoR) is 12.2 months, the median progression-free survival (mPFS) is 13.4 months, and the 12-month PFS rate is 64.6% (95% CI: 45.0%, 78.7%). In specific embodiments, the patients are patients with locally advanced stage TNBC who are inoperable or patients with metastatic TNBC.

[0292] In some embodiments, for conjugate A at 5 mg / kg, dosing regimen of once every 14 days, the ORR for patients with advanced / metastatic triple-negative breast cancer who have not received prior treatment for advanced disease and have PD-L1 CPS <10 is 71.9% (23 / 32), the DCR is 93.8%, the mPFS is 13.1 months, and the 12-month PFS rate is 59.1% (95% CI: 37.1%, 75.7%). In specific embodiments, the patients are patients with locally advanced stage TNBC who are inoperable or patients with metastatic TNBC.

[0293] In some embodiments, for conjugate A at 4 mg / kg or 5 mg / kg, dosing regimen of once every 14 days, the incidence of the most common grade 3 treatment-related adverse event of neutropenia is 50% or less, 45% or less, 40% or less, 35% or less, or 33% or less.

[0294] In some embodiments, the incidence of the most common grade 3 treatment-related adverse event of neutropenia was 32.3% for conjugate A at 4 mg / kg or 5 mg / kg, administered once every 14 days.

[0295] In some embodiments, the incidence of the most common grade 3 treatment-related adverse event of leukopenia was 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, or 26% or less for conjugate A at 4 mg / kg or 5 mg / kg, administered once every 14 days.

[0296] In some embodiments, the incidence of the most common grade 3 treatment-related adverse event of leukopenia was 25.4% for conjugate A at 4 mg / kg or 5 mg / kg, administered once every 14 days.

[0297] Definitions

[0298] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Reference herein to technical terms used herein is intended to refer to the technical terms as commonly understood by those skilled in the art, including variations or substitutions of the techniques that are obvious to those skilled in the art or equivalent techniques. Although the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the present application.

[0299] Drug antibody ratio (DAR) represents the number of drug linkers bound to an antibody. In a composition comprising one or more antibody drug conjugates, the DAR value of the composition represents the average number of drug linkers bound to an antibody for each antibody drug conjugate.

[0300] “HER2 low expression” means an IHC score of 1+ or 2+, but an ISH result of negative.

[0301] “HER2 non-expression” means an IHC score of 0 or an IHC score of 1+ and an ISH result of negative.

[0302] NCCN guidelines refer to the clinical practice guidelines for various malignant tumors published by the National Comprehensive Cancer Network (NCCN) of the United States.

[0303] CSCO diagnosis and treatment guidelines refer to the clinical diagnosis and treatment guidelines for various malignant tumors published by the Chinese Society of Clinical Oncology (CSCO).

[0304] Objective response rate (ORR) refers to the proportion of patients whose tumors shrink to a certain extent and remain for a certain period of time, including CR and PR cases. The response evaluation criteria in solid tumors version 1.1 (RECIST 1.1 criteria) is used to evaluate the objective response of tumors. Subjects must have measurable tumor lesions at baseline, and the efficacy evaluation criteria are divided into complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD) according to the RECIST 1.1 criteria.

[0305] Progressive disease (PD): the minimum value of the sum of the diameters of all measured target lesions throughout the study is taken as the reference, and the diameter sum is increased by at least 20% (if the baseline measurement is the minimum, the baseline value is taken as the reference); in addition, the absolute value of the diameter sum must be increased by at least 5 mm (the appearance of one or more new lesions is also considered as disease progression).

[0306] Stable disease (SD): the degree of reduction of target lesions is not as high as PR, and the degree of increase is also not as high as PD level, which is between the two, and the minimum value of the sum of the diameters can be used as a reference during the study.

[0307] Partial remission (PR): the sum of target lesions is reduced by at least 30% compared with baseline.

[0308] Complete remission (CR): all target lesions disappear, and the short diameter of all pathological lymph nodes (including target nodes and non-target nodes) must be reduced to <10 mm.

[0309] Dose limiting toxicity (DLT): drug toxicity that becomes the main reason for limiting the continued increase of drug dose.

[0310] Adverse event (AE): any adverse medical event that occurs in a patient or clinical research subject after receiving a drug, but it is not necessarily causally related to treatment.

[0311] Treatment emergent adverse event (TEAE): any AE that occurs or worsens after the first administration or after the first administration.

[0312] Treatment-related adverse event (TRAE): an adverse event that occurs after the start of treatment and is related to the treatment received by the patient.

[0313] Progression free survival (PFS): refers to the time from the time a patient begins treatment until the first recorded disease progression or death from any cause, whichever occurs first.

[0314] Overall survival (OS): refers to the time from the time a patient begins treatment until the patient dies.

[0315] “Patient” refers to a mammal that has been made a subject of treatment, observation, or experiment. The mammal can be male or female. The mammal can be one or more selected from the group consisting of a human, a bovine (e.g., a cow), a porcine (e.g., a pig), an ovine (e.g., a sheep), a caprine (e.g., a goat), an equine (e.g., a horse), a canine (e.g., a domestic dog), a feline (e.g., a domestic cat), a leporine (a rabbit), a rodent (e.g., a rat or a mouse), a procyonid (Procyon lotor) (e.g., a raccoon). In particular embodiments, the patient is a human. DETAILED DESCRIPTION

[0316] The technical solutions in the embodiments of the present application will be described clearly and completely below in combination with the drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. The following description of at least one exemplary embodiment is merely illustrative in nature and not intended to further limit the present application or its application or uses. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the scope of protection of the present application.

[0317] Example 1.4-((S)-2-(4-aminobutyl)-3-(4-((6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-ynoylamido)methyl)-1H-1,2,3-triazol-1-yl)-4,8-dioxo-6,12,15,18,21,24,27,30,33-nonaoxa-3,9-diazatetracontanoylamido)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 IM-1)

[0318] Step one: synthesis of 6-(2-(methylsulfonyl)pyrimidin-5-yl)-N-(prop-2-yn-1-yl)hex-5-ynoyl amide (Compound 3-5)

[0319] 25 °C, 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), N, N-diisopropylethylamine (738 mg, 5.67 mmol) was added, followed by O-(7-azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (1.63 g, 4.25 mmol), and the reaction was stirred for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash silica gel column (ethyl acetate / petroleum ether = 3 / 1) to give the title compound, 700 mg. ESI-MS (m / z): 306.1 [M+H]+.

[0320] Step two: 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-diazapentatriacontanoyl)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)

[0321] T-030 (250 mg, 0.49 mmol) was dissolved in dichloromethane (10 mL) at 25 °C under nitrogen protection, and a solution of 4-dimethylaminopyridine (478 mg, 3.91 mmol) in dichloromethane (3 mL) was added at 0 °C, followed by a solution of triphosgene (72 mg, 0.24 mmol) in dichloromethane (10 mL) dropwise. After the addition was completed, the reaction was stirred at 0 °C for 20 min and blown with nitrogen for 20 min. A solution of (S)-2-(32-azido-5-oxo-3,9,12,15,18,21,24,27,30-nonaoxa-6-azatetracosanoyl)-N-(4- (hydroxymethyl)phenyl)-6(((4-methoxyphenyl)diphenylmethyl)amino)hexanamide (518 mg, 0.49 mmol) in dichloromethane (7 mL) was added, and the reaction was stirred at 0 °C for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to give the title compound, 500 mg. ESI-MS (m / z): 1597.5 [M+H]+.

[0322] Step three: Synthesis of (S)-4-ethyl-11-(2-(N-isopropylmethanesulfonamido)ethyl)- 3,14-dioxo-3,4,12,14-tetrahydro-lH-pyrano[3',4':6,7]indolizino[l,2-b]quinolin-4-yl (4- ((S)-2-(4-(((4-methoxyphenyl)diphenylmethyl)amino)butyl)-35-(4-((6-(2- (methylsulf onyl)pyrimidin-5-yl)hex-5-ynoylamido)methyl)-lH-l,2,3-triazol-l-yl)-4,8- dioxo-6,12,15,18,21,24,27,30,33-nonaoxatricosa-3,9-diazonanoylamido)benzyl) carbamate (Compound 33-2)

[0323] 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 reaction was stirred for 1 h. Purification by preparative high performance liquid chromatography gave the title compound, 30 mg. ESI-MS (m / z): 815.9 [(M-273) / 2 + H]+.

[0324] Step four: Synthesis of 4-((S)-2-(4-aminobutyl)-35-(4-((6-(2- (methylsulf onyl)pyrimidin-5-yl)hex-5-ynoylamido)methyl)-lH-l,2,3-triazol-l-yl)-4,8-dioxo- 6,12,15,18,21,24,27,30,33-nonaoxatricosa-3,9-diazonanoylamido)benzyl ((S)-4-ethyl- 11-(2-(N-isopropylmethanesulfonamido)ethyl)-3,14-dioxo-3,4,12,14-tetrahydro-lH- pyrano[3',4':6,7]indolizino[l,2-b]quinolin-4-yl) carbonate (Compound IM-1)

[0325] Compound 33-2 (30 mg, 0.02 mmol) was dissolved in dichloromethane (1.0 mL) and trifluoroacetic acid (0.2 mL) was added. The reaction was stirred at room temperature for 30 min. Purification by preparative high performance liquid chromatography gave the trifluoroacetate salt of the title compound, 20.0 mg. Its structure was characterized as follows:

[0326] 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 = 19.28 Hz, 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] + 。[ɑ] D 20 = -19.55° (c = 1.000 g / 100 mL, CH3CN).

[0327] Example 2. Preparation of conjugate A

[0328] Take 0.3 mL of Sacituzumab antibody (anti-Trop-2, 33.5 mg / mL), dilute with 0.25 mL of a solution containing 20 mM PB, 150 mM NaCl and 20 mM sodium edetate (pH 7.6), then add 0.45 mL of a solution containing 20 mM PB and 150 mM NaCl (pH 7.6) and mix, adjust the pH to 7.4 with a 1 M Na2HPO4 solution, add 10 mM TCEP (tris (2-carboxyethyl) phosphine) solution and mix, and let stand at room temperature for 30 min. Add 10 times the amount of IM-1 trifluoroacetate dissolved in dimethyl sulfoxide to the above solution system, mix, let stand at room temperature for 2 h, and after completion, add 6.1 μl of 100 mM cysteine to terminate the reaction. Finally, replace the buffer with a PBS buffer solution at pH 6.5 using a G-25 gel column to obtain the product of IM-1 conjugated with Sacituzumab antibody, designated as Conjugate A.

[0329] The molecular weight of Conjugate A was analyzed by LCMS method, and the actual molecular weight of the light chain and heavy chain of Conjugate A was correlated with the theoretical molecular weight of the light chain and heavy chain of the conjugated toxin, and it was determined that 1-8 toxins (i.e., γ is 1-8) were conjugated to each antibody molecule in Conjugate A. Further, the average conjugation ratio (DAR) was calculated to be about 6.9 according to the percentage of each conjugate with different number of toxins.

[0330] Referring to Example 2, prepare batch by batch to obtain Conjugate A samples with DAR values ranging from 6 to 8 (such as 7.3 or 7.4), and perform the following clinical studies.

[0331] Experimental Example 1.

[0332] In a randomized phase III trial, Conjugate A was compared with physician's choice of chemotherapy (eribulin, vinorelbine, capecitabine or gemcitabine) in patients with locally recurrent or metastatic triple-negative breast cancer (TNBC) who had previously received two or more chemotherapy, at least one of which was given in the setting of metastatic disease. The primary endpoint was blinded independent central review (BICR) progression-free survival (PFS). Patients were randomized to receive Conjugate A (i.e., Conjugate A group, including 130 patients) or physician's choice of chemotherapy (i.e., chemotherapy group, including 133 patients). The dose of Conjugate A was 5 mg / kg, administered every 14 days. Of the patients in the chemotherapy group, 88 (66.2%) received eribulin, administered as a 1.4 mg / m 2 intravenously on days 1 and 8 of a 21-day cycle; 4 (3.0%) received capecitabine, administered as tablets at a dose of 1000-1250 mg / m 2twice daily on days 1-14 of a 21-day cycle; 20 (15.0%) received gemcitabine, intravenous infusion at a dose of 1000 mg / m 2 twice daily on days 1-14 of a 21-day cycle; 20 (15.0%) received gemcitabine, intravenous infusion at a dose of 1000 mg / m 2 twice daily on days 1-14 of a 21-day cycle; 20 (15.0%) received gemcitabine, intravenous infusion at a dose of 1000 mg / m The median age of patients was 51 years; 87% of patients had visceral metastases; 26% of patients had prior treatment with a PD-1 inhibitor or a PD-L1 inhibitor; 48% of patients received three or more lines of chemotherapy for advanced disease. In the ADC A arm, 24.6% (32 / 130) of patients had prior treatment with a PD-1 or PD-L1 inhibitor, and in the chemotherapy arm, 27.1% (36 / 133) of patients had prior treatment with a PD-1 or PD-L1 inhibitor.

[0333] According to the interim analysis, the primary endpoint of PFS was met, with ADC A arm reducing the risk of disease progression or death by 69% compared to the chemotherapy arm. The median PFS assessed by BICR was 5.7 months in the ADC A arm and 2.3 months in the chemotherapy arm; the proportion of patients with 6-month PFS was 43.4% in the ADC A arm and 11.1% in the chemotherapy arm. In the patient population with H-score >200 for TROP2, the median PFS was 5.8 months in the ADC A arm and 1.9 months in the chemotherapy arm, with a hazard ratio (HR) of 0.28, indicating a 72% chance of extending the median PFS in the ADC A arm compared to the chemotherapy arm. In the first planned interim analysis of overall survival (OS), with a median follow-up of 10.4 months, the OS data for the ADC A arm were statistically superior to the OS data for the chemotherapy arm, with an HR of 0.53, indicating a 47% chance of extending OS for patients in the ADC A arm compared to the chemotherapy arm. The median OS had not been reached in the ADC A arm, i.e., the median OS for the ADC A arm had not been reached at the data cutoff date; the median OS for the chemotherapy arm was 9.4 months, with a minimum of 8.5 months and a maximum of 11.7 months. The objective response rate (ORR) assessed by BICR was 43.8% in the ADC A arm and 12.8% in the chemotherapy arm.

[0334] Clinical benefit of conjugate A compared to physician’s choice of chemotherapy was observed in patients who had received prior treatment with a PD-1 or PD-L1 inhibitor: the median PFS by BICR for patients in the conjugate A arm who had received prior treatment with a PD-1 or PD-L1 inhibitor was 5.6 months, the median PFS by BICR for patients in the chemotherapy arm who had received prior treatment with a PD-1 or PD-L1 inhibitor was 2.7 months, with a hazard ratio (HR) of 0.31; the objective response rate (ORR) by BICR for patients in the conjugate A arm who had received prior treatment with a PD-1 or PD-L1 inhibitor was 56.3%, the objective response rate (ORR) by BICR for patients in the chemotherapy arm who had received prior treatment with a PD-1 or PD-L1 inhibitor was 5.6%. Similar improvements in efficacy outcomes for conjugate A compared to physician’s choice of chemotherapy were also observed for those patients who had not received prior treatment with a PD-1 or PD-L1 inhibitor: the median PFS by BICR for patients in the conjugate A arm who had not received prior treatment with a PD-1 or PD-L1 inhibitor was 7.2 months, the median PFS by BICR for patients in the chemotherapy arm who had not received prior treatment with a PD-1 or PD-L1 inhibitor was 2.3 months, with a hazard ratio (HR) of 0.34; the ORR for patients in the conjugate A arm who had not received prior treatment with a PD-1 or PD-L1 inhibitor was 41.8%, the ORR for patients in the chemotherapy arm who had not received prior treatment with a PD-1 or PD-L1 inhibitor was 14.4%.

[0335] According to the BICR evaluation results: for patients who had received 2 or 3 lines of treatment, the median PFS of the conjugate A group was 6.9 months, and the median PFS of the chemotherapy group was 2.6 months; for patients who had received more than 3 lines of treatment, the median PFS of the conjugate A group was 5.7 months, and the median PFS of the chemotherapy group was 1.5 months; for patients with liver metastasis, the median PFS of the conjugate A group was 4.3 months, and the median PFS of the chemotherapy group was 1.8 months; for patients without liver metastasis, the median PFS of the conjugate A group was 8.4 months, and the median PFS of the chemotherapy group was 2.7 months; for patients who were first diagnosed with triple-negative breast cancer, the median PFS of the conjugate A group was 5.8 months, and the median PFS of the chemotherapy group was 2.0 months; for patients who were not first diagnosed with triple-negative breast cancer, the median PFS of the conjugate A group was 7.2 months, and the median PFS of the chemotherapy group was 2.6 months; for patients with lymph node metastasis, the median PFS of the conjugate A group was 6.7 months, and the median PFS of the chemotherapy group was 2.5 months; for patients without lymph node metastasis, the median PFS of the conjugate A group was 7.2 months, and the median PFS of the chemotherapy group was 2.6 months; for patients with internal organ metastasis, the median PFS of the conjugate A group was 5.8 months, and the median PFS of the chemotherapy group was 2.5 months; for patients without internal organ metastasis, the median PFS of the conjugate A group was 8.3 months, and the median PFS of the chemotherapy group was 4.2 months; for patients with low HER2 expression, the median PFS of the conjugate A group was 5.6 months, and the median PFS of the chemotherapy group was 2.3 months; for patients without HER2 expression, the median PFS of the conjugate A group was 7.2 months, and the median PFS of the chemotherapy group was 2.6 months.

[0336] According to the BICR evaluation results: for patients with high Trop-2 expression (i.e., H score greater than 200), the ORR of the conjugate A group was 52.1%, and the ORR of the chemotherapy group was 10.8%; for patients with low Trop-2 expression (i.e., H score less than or equal to 200), the ORR of the conjugate A group was 39.6%, and the ORR of the chemotherapy group was 14.6%.

[0337] The above results show that in various patient subgroups, conjugate A has shown a significantly better treatment effect than the chemotherapy group.

[0338] The most common grade ≥3 treatment-related adverse events (TRAEs) included neutropenia (32.3% in the conjugate A group and 47.0% in the chemotherapy group) and leukopenia (25.4% in the conjugate A group and 36.4% in the chemotherapy group). Furthermore, patients in the conjugate A group who had received PD-1 or PD-L1 inhibitor therapy had similar safety data to those who had not. The median exposure time for conjugate A was 24.9 weeks, compared to 8.6 weeks for chemotherapy. Although the median duration of exposure to conjugate A was nearly three times longer than that for chemotherapy, the incidence of grade ≥3 TRAEs was similar in both the conjugate A and chemotherapy groups. This suggests that conjugate A was less likely to cause adverse events than chemotherapy.

[0339] The above research results demonstrate that, regardless of whether patients have previously received PD-1 or PD-L1 inhibitor therapy, monotherapy with conjugate A shows statistically significant and clinically meaningful advantages in PFS and OS compared to chemotherapy, and has a manageable safety profile for patients with advanced TNBC who have received multiple prior therapies and have limited treatment options.

[0340] Experimental Example 2.

[0341] A phase II clinical trial enrolled patients with treatment-naïve advanced / metastatic triple-negative breast cancer (a / mTNBC) at an advanced / metastatic stage, specifically those with TNBC in two categories: 1. locally advanced TNBC that is not surgically curable; 2. metastatic TNBC. Patient PD-L1 or TROP2 status was not restricted. Enrolled patients received conjugate A at a dose of 5 mg / kg every two weeks (Q2W) until disease progression or intolerable toxicity. For patients with recurrent TNBC, a disease-free interval (DFI) of at least 6 months was required for enrollment. Tumors were assessed by investigators every 6 weeks according to RECIST v1.1 criteria.

[0342] A total of 41 patients were enrolled, with a median age of 55 years; 43.9% had an ECOG score of 1; 78.0% had a PD-L1 CPS <10. 61.0% of patients had visceral metastases at baseline, 29.3% had primary metastases, 19.5% had a DFI of 6-12 months, and 51.2% had a DFI >12 months. The median follow-up time was 18.6 months. The objective response rate (ORR) was 70.7% (29 / 41), and the disease control rate (DCR) was 92.7%. The median duration of response (mDoR) was 12.2 months, the median progression-free survival (mPFS) was 13.4 months, and the 12-month PFS rate was 64.6% (95% CI: 45.0%, 78.7%). In the 32 patients with a PD-L1 CPS <10, the ORR was 71.9% (23 / 32), and the DCR was 93.8%. The mPFS for this subgroup was 13.1 months, and the 12-month PFS rate was 59.1% (95% CI: 37.1%, 75.7%). No treatment-related deaths occurred, and no cases of neuropathy or interstitial lung disease / pneumonitis were reported.

[0343] The above results demonstrate that conjugate A exhibits good antitumor activity and manageable safety as a first-line treatment for a / mTNBC patients, regardless of PD-L1 status.

[0344] Various modifications to the present application will be apparent to those skilled in the art from the foregoing description, which serves only as illustration of the principles of the application. Such modifications are intended to fall within the scope of the following claims. Each of the references cited in the present application, including all patents, patent applications, journal articles, books and any other publications, are incorporated herein by reference in their entireties.

Claims

Use of an antibody drug conjugate of formula (I) or a composition containing the antibody drug conjugate in the manufacture of a medicament for treating locally advanced, locally recurrent or metastatic triple negative breast cancer in a patient; {D-[L1-(L2) m1 -(L3) m2 -(L4) m3 -E]} γ -A Formula (I) wherein, L1 is wherein each R1and R2is independently hydrogen (e.g., protium or deuterium), halogen, carboxylic acid group, sulfonic acid group, cyano, C 1-6 alkyl, haloC 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; Z1is an amino acid or a peptide consisting of 2-10 amino acids; x1and x2are each independently 0, 1, 2, 3, 4, 5, or 6; and L1is attached at position 1 to D and at position 2 to L2; L2 is wherein, y1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and L2 is connected to L1 at position 1 of L2 and L3 at position 2 of L2; L3 is selected from a 5-12 membered heteroaromatic ring; L4 is wherein Z2is selected from C 1-6 alkylene, C 2-10 alkenylene, C 2-10 alkynylene, and C 3- 8 cycloalkylene; R3is selected from H and C 1-6 alkyl; Z3is absent or selected from C 1-6 alkylene; or, R3together with Z3and the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclyl group; a is 0, 1, 2, 3, 4, 5, or 6, and L4is attached at the 2 position to E and at the 1 position to L3; E is wherein, each R4 is independently hydrogen (e.g., protium or deuterium), b is 0, 1 or 2, and E is connected to A at position 2 of E (e.g., to a thiol on A) and L4 at position 1 of E; m1, m2 and m3 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; D is a fragment of a biologically active molecule; g is selected from an integer between 1 and 10; preferably, g is selected from an integer between 3 and 8 (e.g., 3, 4, 5, 6, 7 or 8); A is an anti-Trop-2 antibody or antigen binding fragment thereof. Use according to claim 1, wherein, The patient has previously received one or more chemotherapy treatments, or two or more chemotherapy treatments, or three or more chemotherapy treatments, or four or more chemotherapy treatments; and / or The patient has previously received one or more chemotherapy treatments, or two or more chemotherapy treatments, or three or more chemotherapy treatments, or four or more chemotherapy treatments, and wherein at least one of the chemotherapy treatments was performed in the event of metastasis of the triple negative breast cancer. Use according to claim 1 or 2, characterized in that One or more of the following: (1) the triple negative breast cancer has a visceral metastasis, e.g., a liver metastasis; (2) the triple negative breast cancer has a lymph node metastasis; (3) the triple negative breast cancer has a H-score of TROP-2 expression of 0, 0-10, 10-100, 100-200, or greater than 200; preferably, the H-score of TROP-2 expression is greater than 200; (4) the triple negative breast cancer is HER2 non-expressing; (5) the triple negative breast cancer is HER2 low-expressing; (6) the patient has previously received two or three treatments; (7) the patient has previously received three or more treatments; (8) the patient has previously received three or more chemotherapy treatments, or four or more chemotherapy treatments, and the chemotherapy treatments were performed in the event of advanced stage of the triple negative breast cancer; (9) the patient has previously received a targeted drug treatment; preferably, the targeted drug is a PD-1 inhibitor or a PD-L1 inhibitor drug; (10) the triple negative breast cancer is a primary triple negative breast cancer; (11) the triple negative breast cancer is a non-primary triple negative breast cancer. The use according to claim 3, wherein the treatment is selected from one or more of surgery, chemotherapy, radiotherapy, targeted therapy, endocrine therapy and immunotherapy. The use of claim 3, wherein the PD-1 inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, cemiplimab, dostarlimab, pidilizumab, tislelizumab, and pembrolizumab. The use of any one of claims 1-5, wherein the triple-negative breast cancer is locally advanced triple-negative breast cancer. The use of any one of claims 1-6, wherein the triple-negative breast cancer is locally advanced or metastatic triple-negative breast cancer. The use of claim 7, wherein the patient has not been treated at the stage of disease progression / metastasis. Use according to claim 7 or 8, characterized in that One or more of the following: (1) the patient has an ECOG score of 0-2, for example, 0, 1, or 2; preferably, the patient has an ECOG score of 1; (2) the triple-negative breast cancer has a PD-L1 CPS < 10; (3) the triple-negative breast cancer has a visceral metastasis; (4) the triple-negative breast cancer is a primary metastatic triple-negative breast cancer; (5) the patient has a disease-free interval (DFI) of more than 6 months, for example, 6-12 months, and for example, > 12 months. The use of any one of claims 1-9, wherein the patient is aged 20-70 years, for example, 25-65 years, 30-60 years, 35-55 years, 40-55 years, 40 years, 41 years, 42 years, 43 years, 44 years, 45 years, 46 years, 47 years, 48 years, 49 years, 50 years, 51 years, 52 years, 53 years, 54 years, or 55 years. The use of any one of claims 1-10, wherein the conjugate has the following structure: L1is selected from and L1 is connected to D at position 1 of L1 and L2 at position 2 of L1; L2 is wherein, y1 is 3, 4, 5, 6, 7, 8, 9, or 10; and L2 is connected to L1 at position 1 of L2 and L3 at position 2 of L2; L3 is selected from a 5-6 membered heteroaromatic ring, for example, pyrazole or triazole; L4 is wherein Z2is selected from C 1-3 alkylene; R3is H; Z3is selected from C 1-3 alkylene; a is 1, and L4is attached at the 2-position to E and at the 1 -position to L3; E is wherein each R4 is independently hydrogen (e.g., protium or deuterium), b is 0, 1, or 2, and E is connected to A at position 2 of E (e.g., to a thiol group on A) and L4 at position 1 of E; m1, m2, and m3 are each 1; The biologically active molecule is selected from Preferably, the biologically active molecule is connected to position 1 of L1 via a hydroxyl group of itself. y is selected from an integer between 3-8 (e.g., 3, 4, 5, 6, 7, or 8); A is Sacituzumab or an antigen-binding fragment thereof. Use according to any one of claims 1 to 11, said conjugate structure being as follows: wherein y is an integer between 1-10; preferably, y is selected from an integer between 5-8. y is an integer between 1-10; preferably, y is selected from an integer between 5-8. The use according to any one of claims 1-12, wherein the DAR value of the composition is 1-10; preferably, the DAR value is 5-8; for example, the DAR value of the composition is 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. The use according to any one of claims 1-13, wherein the composition is a pharmaceutical composition; preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient; preferably, the pharmaceutical composition comprises a therapeutically effective amount of the antibody drug conjugate of Formula (I). A method of treating locally advanced, locally recurrent or metastatic triple-negative breast cancer in a patient, the method comprising the step of administering to the patient a therapeutically effective amount of an antibody drug conjugate or a composition comprising the antibody drug conjugate, wherein the antibody drug conjugate or the composition is as defined in any one of claims 1, 11-14; and the locally advanced, locally recurrent or metastatic triple-negative breast cancer in the patient is as defined in any one of claims 1-10. The method according to claim 15, wherein the antibody drug conjugate or the composition is administered once every 7-35 days, preferably once every 7-21 days, for example once every 7 days, 14 days, 21 days. The method according to claim 15 or 16, wherein the route of administration of the antibody drug conjugate or the composition comprises, but is not limited to, oral, transdermal injection, rectal administration, transmucosal administration, intramuscular injection, intramedullary injection, intravenous injection, intraperitoneal injection, preferably intravenous injection. The method according to any one of claims 15-17, wherein the dose of the antibody drug conjugate per administration is 1 mg / kg to 30 mg / kg based on the body weight of the patient; preferably 1 mg / kg to 20 mg / kg; more preferably 2 mg / kg to 12 mg / kg; further preferably 3-7 mg / kg; further preferably 3-5 mg / kg; further preferably 3 mg / kg, 4 mg / kg or 5 mg / kg. The method according to any one of claims 15-18, which is divided into one or more administration phases (for example one, two, three or four phases), each phase having an administration cycle as defined in claim 16 and / or each phase having a dose as defined in claim 18. An antibody drug conjugate or a composition comprising the antibody drug conjugate for use in the treatment of locally advanced, locally recurrent or metastatic triple-negative breast cancer in a patient, wherein the antibody drug conjugate or the composition is as defined in any one of claims 1, 11-14; and the locally advanced, locally recurrent or metastatic triple-negative breast cancer in the patient is as defined in any one of claims 1-10.

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