Use of her2-targeted ADC for treating gynecological tumor

Abstract

The present disclosure belongs to the field of biopharmaceutics and relates to use of an HER2-TARGETED ADC for treating a gynecological tumor. The present disclosure also relates to a method of treating a gynecological tumor in a subject, the method comprising administering to the subject an anti-HER2 antibody-drug conjugate. The present disclosure also relates to use of an anti-HER2 antibody-drug conjugate in the preparation of a drug for treating a gynecological tumor in a subject. The method or the use produces benefits to the subject and exhibits good safety.

Description

Applications of HER2-targeted ADCs in the treatment of gynecological tumors Technical Field

[0001] This disclosure pertains to the field of biomedicine and specifically relates to the use of HER2-targeting ADCs (antibody-drug conjugates) for the treatment of gynecological tumors. Background Technology

[0002] Human epidermal growth factor receptor 2 (HER2) belongs to the human epidermal growth factor receptor family, which includes EGFR (ErbB-1), HER2 / c-neu (ErbB-2), HER3 (ErbB-3), and HER4 (ErbB-4). These receptors are all located on the cell surface and have similar structures. HER2 is a widely expressed receptor protein; abnormal gene amplification leads to protein overexpression, which in turn causes abnormal activation of signaling pathways, a major pathway promoting solid tumor growth. HER2 can form homodimers and readily form heterodimers with other HER family receptors, leading to phosphorylation of receptor tyrosine residues and initiation of multiple signaling pathways, including MPK, PI3K, JAK, STAT3, and PKC, thereby causing cell proliferation and tumorigenesis.

[0003] Anti-HER2 targeted therapy is an important approach to treating gynecological tumors. Therefore, there is an urgent need to explore HER2-targeting drugs to meet the huge clinical demand for gynecological tumor treatment. Summary of the Invention

[0004] Methods for treating gynecological tumors

[0005] This disclosure provides a method for treating a subject with gynecological tumors, comprising administering the disclosed anti-HER2 antibody-drug conjugate to the subject. This disclosure also provides a method for first-line treatment of a subject with gynecological tumors, comprising administering the disclosed anti-HER2 antibody-drug conjugate to the subject. This disclosure further provides a method for second-line or later-line treatment of a subject with gynecological tumors, comprising administering the disclosed anti-HER2 antibody-drug conjugate to the subject. In some embodiments, the method involves administering the anti-HER2 antibody-drug conjugate at a therapeutically effective amount.

[0006] This disclosure also provides the use of the antiHER2 antibody-drug conjugate of this disclosure in the preparation of a medicament for treating gynecological tumors in a subject. This disclosure also provides the use of the antiHER2 antibody-drug conjugate of this disclosure in the preparation of a medicament for first-line treatment of gynecological tumors in a subject. This disclosure also provides the use of the antiHER2 antibody-drug conjugate of this disclosure in the preparation of a medicament for second-line or later-line treatment of gynecological tumors in a subject. In some embodiments, in said use, the medicament comprises a therapeutically effective amount of the antiHER2 antibody-drug conjugate.

[0007] This disclosure also provides the antiHER2 antibody-drug conjugate of this disclosure for use in treating gynecological tumors in subjects. This disclosure also provides the antiHER2 antibody-drug conjugate of this disclosure for use as first-line treatment of gynecological tumors in subjects. This disclosure also provides the antiHER2 antibody-drug conjugate of this disclosure for use as second-line or later-line treatment of gynecological tumors in subjects. In some embodiments, the antiHER2 antibody-drug conjugate is administered to the subject in a therapeutically effective amount.

[0008] This disclosure also provides the use of the antiHER2 antibody-drug conjugate of this disclosure in treating subjects with gynecological tumors.

[0009] In some embodiments, the antiHER2 antibody-drug conjugate is administered once every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w) in the method or use. In one specific embodiment, the antiHER2 antibody-drug conjugate is administered once every 3 weeks in the method or use. In some embodiments, the antiHER2 antibody-drug conjugate is administered at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, or 6-7.5 mg / kg in the method or use. In some embodiments, the antiHER2 antibody-drug conjugate is administered at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 6 mg / kg, 7.5 mg / kg, 9 mg / kg, or any range of the above values ​​in the method or use. In some embodiments, the antiHER2 antibody-drug conjugate is administered at a dose of 6 mg / kg or 7.5 mg / kg in the method or use. In some embodiments, the anti-HER2 antibody-drug conjugate is administered at a dose of 6 mg / kg per administration. In some embodiments, the anti-HER2 antibody-drug conjugate is administered at a dose of 7.5 mg / kg per administration. In some embodiments, the anti-HER2 antibody-drug conjugate is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, or 6-7.5 mg / kg of anti-HER2 antibody-drug conjugate. In some embodiments, the anti-HER2 antibody-drug conjugate is administered every 3 weeks at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 6 mg / kg, 7.5 mg / kg, or 9 mg / kg of anti-HER2 antibody-drug conjugate. In some embodiments, during the method or use, the anti-HER2 antibody-drug conjugate is administered once every 3 weeks at a dose of 6 mg / kg or 7.5 mg / kg of the anti-HER2 antibody-drug conjugate. In some embodiments, during the method or use, the anti-HER2 antibody-drug conjugate is administered once every 3 weeks at a dose of 6 mg / kg of the anti-HER2 antibody-drug conjugate. In some embodiments, during the method or use, the anti-HER2 antibody-drug conjugate is administered once every 3 weeks at a dose of 7.5 mg / kg of the anti-HER2 antibody-drug conjugate.

[0010] In some embodiments, a treatment cycle is defined as every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, a treatment cycle is defined as every 3 weeks. In some embodiments, the anti-HER2 antibody-drug conjugate is administered once per treatment cycle, with a treatment cycle of 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the anti-HER2 antibody-drug conjugate is administered once per treatment cycle, with a treatment cycle of 3 weeks.

[0011] In some embodiments, the method or use comprises a treatment cycle of 3 weeks, with the anti-HER2 antibody-drug conjugate administered in each treatment cycle. In some embodiments, the method or use comprises a treatment cycle of 3 weeks, with the anti-HER2 antibody-drug conjugate administered on day 1 of each treatment cycle. In some embodiments, the method or use comprises a treatment cycle of 3 weeks, with the anti-HER2 antibody-drug conjugate administered at 6 mg / kg or 7.5 mg / kg in each treatment cycle. In some embodiments, the method or use comprises a treatment cycle of 3 weeks, with the anti-HER2 antibody-drug conjugate administered at 6 mg / kg or 7.5 mg / kg in each treatment cycle on day 1 of each treatment cycle. In some embodiments, the method or use comprises a treatment cycle of 3 weeks, with the anti-HER2 antibody-drug conjugate administered at 6 mg / kg in each treatment cycle. In some embodiments, the method or use comprises a treatment cycle of 3 weeks, with the anti-HER2 antibody-drug conjugate administered at 6 mg / kg on day 1 of each treatment cycle. In some embodiments, the method or use is performed in a treatment cycle of 3 weeks, with 7.5 mg / kg of the anti-HER2 antibody-drug conjugate administered in each treatment cycle. In some embodiments, the method or use is performed in a treatment cycle of 3 weeks, with 7.5 mg / kg of the anti-HER2 antibody-drug conjugate administered on day 1 of each treatment cycle.

[0012] Anti-HER2 antibody-drug conjugates can be formulated with one or more pharmaceutically acceptable excipients to create a suitable pharmaceutical composition (or formulation). The pharmaceutical composition can be any suitable dosage form. In some embodiments, the anti-HER2 antibody-drug conjugate is formulated for parenteral administration. In some specific embodiments, the anti-HER2 antibody-drug conjugate is formulated for intravenous, intramuscular, or other parenteral administration. In some specific embodiments, the anti-HER2 antibody-drug conjugate can be formulated as an injectable preparation. In some specific embodiments, the anti-HER2 antibody-drug conjugate is formulated for intravenous injection or infusion.

[0013] In some embodiments, the anti-HER2 antibody drug conjugate is administered via intravenous infusion (also known as "intravenous drip") in the method or use.

[0014] In the described method or use, the dosing regimen of the anti-HER2 antibody-drug conjugate (e.g., dosing cycle, dosing time, dosing dose, and dose adjustment) can be adjusted according to the severity of the disease, the disease response, any treatment-related toxicities, the patient's age, and health status. For example, the anti-HER2 antibody-drug conjugate can be administered with a delay of 1-84 days, such as a delay of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks. As another example, the dosing dose of the anti-HER2 antibody-drug conjugate can be adjusted from 6 mg / kg to 5 mg / kg, or from 7.5 mg / kg to 6 mg / kg.

[0015] In some embodiments, the gynecological tumor is ovarian cancer (also known as epithelial ovarian cancer). In some embodiments, the gynecological tumor is a malignant germ cell tumor of the ovary and / or a sex cord-stromal tumor of the ovary. In some embodiments, the gynecological tumor is fallopian tube cancer. In some embodiments, the gynecological tumor is peritoneal cancer. In some embodiments, the peritoneal cancer is primary peritoneal cancer. In some embodiments, the peritoneal cancer is secondary peritoneal cancer.

[0016] In some embodiments, the ovarian cancer, fallopian tube cancer, and / or peritoneal cancer is serous carcinoma. In some embodiments, the ovarian cancer, fallopian tube cancer, and / or peritoneal cancer is high-grade serous carcinoma. In some embodiments, the ovarian cancer, fallopian tube cancer, and / or peritoneal cancer is low-grade serous carcinoma. In some embodiments, the ovarian cancer, fallopian tube cancer, and / or peritoneal cancer is serous adenocarcinoma. In some embodiments, the ovarian cancer, fallopian tube cancer, and / or peritoneal cancer is high-grade serous adenocarcinoma. In some embodiments, the ovarian cancer, fallopian tube cancer, and / or peritoneal cancer is low-grade serous adenocarcinoma. In some embodiments, the ovarian cancer, fallopian tube cancer, and / or peritoneal cancer is endometrioid carcinoma. In some embodiments, the ovarian cancer, fallopian tube cancer, and / or peritoneal cancer is endometrioid adenocarcinoma. In some embodiments, the ovarian cancer, fallopian tube cancer, and / or peritoneal cancer is clear cell carcinoma. In some embodiments, the ovarian cancer, fallopian tube cancer, and / or peritoneal cancer is mucinous carcinoma. In some embodiments, the ovarian cancer, fallopian tube cancer, and / or peritoneal cancer is mucinous adenocarcinoma. In some embodiments, the ovarian cancer, fallopian tube cancer, and / or peritoneal cancer is undifferentiated carcinoma. In some embodiments, the ovarian cancer, fallopian tube cancer, and / or peritoneal cancer is carcinosarcoma. In some embodiments, the ovarian cancer, fallopian tube cancer, and / or peritoneal cancer is malignant Brunner tumor.

[0017] In some embodiments, the gynecological tumor is endometrial cancer. In some embodiments, the endometrial cancer is endometrioid carcinoma, endometrioid adenocarcinoma, serous carcinoma (including high-grade serous carcinoma and low-grade serous carcinoma), serous adenocarcinoma (including high-grade serous adenocarcinoma and low-grade serous adenocarcinoma), mucinous carcinoma, mucinous adenocarcinoma, clear cell carcinoma, undifferentiated carcinoma, dedifferentiated carcinoma, mixed carcinoma, mixed cell carcinoma, carcinosarcoma, and / or other endometrial cancers (e.g., mesonephric duct carcinoma, gastric adenocarcinoma).

[0018] In some embodiments, the gynecological tumor is cervical cancer. In some embodiments, the cervical cancer is squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, and / or neuroendocrine tumor.

[0019] In some embodiments, the gynecological tumor is an unresectable, refractory, advanced, recurrent, and / or metastatic gynecological tumor. In some embodiments, the gynecological tumor is an unresectable gynecological tumor. In some embodiments, the gynecological tumor is a refractory gynecological tumor. In some embodiments, the gynecological tumor is an advanced gynecological tumor. In some embodiments, the gynecological tumor is a recurrent gynecological tumor. In some embodiments, the gynecological tumor is a metastatic gynecological tumor. In some embodiments, the gynecological tumor is a recurrent and / or metastatic gynecological tumor. In some embodiments, the gynecological tumor is an advanced, recurrent, and / or metastatic gynecological tumor. In some embodiments, the gynecological tumor is an unresectable, advanced, recurrent, and / or metastatic gynecological tumor.

[0020] In some embodiments, the ovarian cancer is unresectable, refractory, advanced, recurrent, and / or metastatic ovarian cancer. In some embodiments, the ovarian cancer is unresectable. In some embodiments, the ovarian cancer is refractory. In some embodiments, the ovarian cancer is advanced. In some embodiments, the ovarian cancer is recurrent. In some embodiments, the ovarian cancer is metastatic. In some embodiments, the ovarian cancer is recurrent and / or metastatic. In some embodiments, the ovarian cancer is advanced, recurrent, and / or metastatic. In some embodiments, the ovarian cancer is unresectable, advanced, recurrent, and / or metastatic.

[0021] In some embodiments, the endometrial cancer is unresectable, refractory, advanced, recurrent, and / or metastatic endometrial cancer. In some embodiments, the endometrial cancer is unresectable. In some embodiments, the endometrial cancer is refractory. In some embodiments, the endometrial cancer is advanced. In some embodiments, the endometrial cancer is recurrent. In some embodiments, the endometrial cancer is metastatic. In some embodiments, the endometrial cancer is recurrent and / or metastatic. In some embodiments, the endometrial cancer is advanced, recurrent, and / or metastatic. In some embodiments, the endometrial cancer is unresectable, advanced, recurrent, and / or metastatic.

[0022] In some embodiments, the cervical cancer is unresectable, refractory, advanced, recurrent, and / or metastatic cervical cancer. In some embodiments, the cervical cancer is unresectable cervical cancer. In some embodiments, the cervical cancer is refractory cervical cancer. In some embodiments, the cervical cancer is advanced cervical cancer. In some embodiments, the cervical cancer is recurrent cervical cancer. In some embodiments, the cervical cancer is metastatic cervical cancer. In some embodiments, the cervical cancer is recurrent and / or metastatic cervical cancer. In some embodiments, the cervical cancer is advanced, recurrent, and / or metastatic cervical cancer. In some embodiments, the cervical cancer is unresectable, advanced, recurrent, and / or metastatic cervical cancer.

[0023] In some embodiments, the gynecological tumor is a gynecological tumor in which HER2 expression is determined to be 3+, 2+, 1+, or 0 by immunohistochemistry (IHC). In some embodiments, the ovarian cancer is ovarian cancer in which HER2 expression is determined to be 3+, 2+, 1+, or 0 by immunohistochemistry (IHC). In some embodiments, the endometrial cancer is endometrial cancer in which HER2 expression is determined to be 3+, 2+, 1+, or 0 by immunohistochemistry (IHC). In some embodiments, the cervical cancer is cervical cancer in which HER2 expression is determined to be 3+, 2+, 1+, or 0 by immunohistochemistry (IHC).

[0024] In some embodiments, the subject with the gynecological tumor has previously received treatment for the gynecological tumor (e.g., treatment failure or intolerance). In some embodiments, the subject with the gynecological tumor has previously received systemic therapy to treat the gynecological tumor (e.g., treatment failure or intolerance). In some embodiments, the subject with the gynecological tumor has previously received platinum-based chemotherapy to treat the gynecological tumor (e.g., treatment failure or intolerance). In some embodiments, the subject with the gynecological tumor has previously received platinum-based chemotherapy to treat the gynecological tumor and experienced disease progression or recurrence during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with the gynecological tumor has previously received platinum-based chemotherapy to treat the gynecological tumor and experienced disease progression or recurrence within 6 months (e.g., 1, 2, 3, 4, 5, or 6 months) or within 12 months (e.g., 1, 2, 3, 4, 5, or 12 months) during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with the gynecological tumor has previously received at least one first-line treatment for the gynecological tumor (e.g., treatment failure or intolerance). In some embodiments, the subject with the gynecological tumor has previously received at least one first-line systemic treatment for the gynecological tumor (e.g., treatment failure or intolerance). In some embodiments, the subject with the gynecological tumor has previously received at least one first-line platinum-based chemotherapy for the gynecological tumor (e.g., treatment failure or intolerance). In some embodiments, the subject with the gynecological tumor has previously received at least one first-line platinum-based chemotherapy for the gynecological tumor and experienced disease progression or recurrence during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with the gynecological tumor has previously received at least one first-line platinum-based chemotherapy for the gynecological tumor and experienced disease progression or recurrence within 6 months (e.g., 1, 2, 3, 4, 5, or 6 months) or within 12 months (e.g., 1, 2, 3, 4, 5, or 6 months) or within 12 months (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with the gynecological tumor has previously received no more than three lines of treatment for the gynecological tumor (e.g., treatment failure or intolerance). In some embodiments, the subject with the gynecological tumor has previously received no more than three lines of systemic treatment for the gynecological tumor (e.g., treatment failure or intolerance). In some embodiments, the subject with the gynecological tumor has previously received no more than three lines of platinum-based chemotherapy for the gynecological tumor (e.g., treatment failure or intolerance). In some embodiments, the subject with the gynecological tumor has previously received no more than three lines of platinum-based chemotherapy for the gynecological tumor and experienced disease progression or recurrence during or after treatment with the platinum-based chemotherapy regimen.In some embodiments, the subject with the gynecological tumor has previously received no more than three lines of platinum-based chemotherapy to treat the gynecological tumor, and experienced disease progression or recurrence within 6 months (e.g., 1, 2, 3, 4, 5, or 6 months) or 12 months (e.g., 1, 2, 3, 4, 5, or 6 months) or 12 months (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with the gynecological tumor has previously received neoadjuvant or adjuvant platinum-based chemotherapy to treat the gynecological tumor, and experienced disease progression or recurrence within 6 months (e.g., 1, 2, 3, 4, 5, or 6 months) or 12 months (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with the gynecological tumor is a platinum-resistant or platinum-refractory subject.

[0025] In some embodiments, the subject with the gynecological tumor has received treatment for the gynecological tumor during a recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some embodiments, the subject with the gynecological tumor has received systemic treatment for the gynecological tumor during a recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some embodiments, the subject with the gynecological tumor has received a platinum-based chemotherapy regimen for the gynecological tumor during a recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some embodiments, the subject with the gynecological tumor has received a platinum-based chemotherapy regimen for the gynecological tumor during a recurrence and / or metastasis phase, and disease progression or recurrence occurred during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with the gynecological tumor received platinum-based chemotherapy during the recurrence and / or metastasis phase to treat the gynecological tumor, and experienced disease progression or recurrence within 6 months (e.g., 1, 2, 3, 4, 5, or 6 months) or 12 months (e.g., 1, 2, 3, 4, 5, or 12 months) during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with the gynecological tumor received at least one first-line treatment for the gynecological tumor during the recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some embodiments, the subject with the gynecological tumor received at least one first-line systemic therapy for the gynecological tumor during the recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some embodiments, the subject with the gynecological tumor received at least one first-line platinum-based chemotherapy for the gynecological tumor during the recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some embodiments, the subject with the gynecological tumor has received at least one first-line platinum-based chemotherapy to treat the gynecological tumor during the recurrence and / or metastasis phase, and experienced disease progression or recurrence during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with the gynecological tumor has received at least one first-line platinum-based chemotherapy to treat the gynecological tumor during the recurrence and / or metastasis phase, and experienced disease progression or recurrence within 6 months (e.g., 1, 2, 3, 4, 5, or 6 months) or within 12 months (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with the gynecological tumor has received no more than three lines of treatment to treat the gynecological tumor during the recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some embodiments, the subject with the gynecological tumor has received no more than three lines of systemic therapy to treat the gynecological tumor during the recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some implementations, the subject with the gynecological tumor has received no more than three lines of platinum-based chemotherapy to treat the gynecological tumor during the recurrence and / or metastasis phase (e.g., treatment failure or intolerance).In some embodiments, the subject with the gynecological tumor has received no more than three lines of platinum-based chemotherapy to treat the gynecological tumor during the recurrence and / or metastasis phase, and experienced disease progression or recurrence during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with the gynecological tumor received neoadjuvant or adjuvant therapy with platinum-based chemotherapy at the recurrence and / or metastasis stage to treat the gynecological tumor, and experienced disease progression or recurrence during or within 6 months (e.g., 1, 2, 3, 4, 5, or 6 months) or 12 months (e.g., 1, 2, 3, 4, 5, or 6 months) after the completion of neoadjuvant or adjuvant therapy with platinum-based chemotherapy. In some embodiments, the subject with the gynecological tumor is a platinum-resistant or platinum-refractory subject.

[0026] In some embodiments, the subject with ovarian cancer has previously received treatment for ovarian cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with ovarian cancer has previously received systemic therapy to treat ovarian cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with ovarian cancer has previously received platinum-based chemotherapy to treat ovarian cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with ovarian cancer has previously received platinum-based chemotherapy to treat ovarian cancer and experienced disease progression or recurrence during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with ovarian cancer has previously received platinum-based chemotherapy to treat ovarian cancer and experienced disease progression or recurrence within 6 months (e.g., 1, 2, 3, 4, 5, or 6 months) during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with ovarian cancer has previously received at least one first-line treatment to treat ovarian cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with ovarian cancer has previously received at least one first-line systemic therapy to treat ovarian cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with ovarian cancer has previously received at least one first-line platinum-based chemotherapy for ovarian cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with ovarian cancer has previously received at least one first-line platinum-based chemotherapy for ovarian cancer and experienced disease progression or recurrence during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with ovarian cancer has previously received at least one first-line platinum-based chemotherapy for ovarian cancer and experienced disease progression or recurrence within 6 months (e.g., 1, 2, 3, 4, 5, or 6 months) during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject has received at least 4 treatment cycles of platinum-based chemotherapy for ovarian cancer. In some embodiments, the subject with ovarian cancer is a platinum-resistant or platinum-refractory subject. In some embodiments, the subject's previous treatment was received during the recurrence and / or metastasis phase.

[0027] In some embodiments, the platinum-resistant or platinum-refractory subject with ovarian cancer has previously received treatment for ovarian cancer (e.g., treatment failure or intolerance). In some embodiments, the platinum-resistant or platinum-refractory subject with ovarian cancer has previously received systemic therapy for ovarian cancer (e.g., treatment failure or intolerance). In some embodiments, the platinum-resistant or platinum-refractory subject with ovarian cancer has previously received platinum-based chemotherapy for ovarian cancer (e.g., treatment failure or intolerance). In some embodiments, the platinum-resistant or platinum-refractory subject with ovarian cancer has previously received platinum-based chemotherapy for ovarian cancer and experienced disease progression or recurrence during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the platinum-resistant or platinum-refractory subject with ovarian cancer has previously received platinum-based chemotherapy for ovarian cancer and experienced disease progression or recurrence within 6 months (e.g., 1, 2, 3, 4, 5, or 6 months) during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the platinum-resistant or platinum-refractory subject with ovarian cancer has previously received at least one first-line treatment for ovarian cancer (e.g., treatment failure or intolerance). In some embodiments, the platinum-resistant or platinum-refractory subject with ovarian cancer has previously received at least one first-line systemic therapy for ovarian cancer (e.g., treatment failure or intolerance). In some embodiments, the platinum-resistant or platinum-refractory subject with ovarian cancer has previously received at least one first-line platinum-based chemotherapy for ovarian cancer (e.g., treatment failure or intolerance). In some embodiments, the platinum-resistant or platinum-refractory subject with ovarian cancer has previously received at least one first-line platinum-based chemotherapy for ovarian cancer and experienced disease progression or recurrence during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the platinum-resistant or platinum-refractory ovarian cancer patient has previously received at least one first-line platinum-based chemotherapy for ovarian cancer and experienced disease progression or recurrence during or within 6 months (e.g., 1, 2, 3, 4, 5, or 6 months) after treatment with the platinum-based chemotherapy regimen. In some embodiments, the patient has received at least four cycles of platinum-based chemotherapy for ovarian cancer. In some embodiments, the patient's previous treatment was received during the recurrence and / or metastasis phase.

[0028] In some embodiments, the subject with endometrial cancer has previously received treatment for endometrial cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with endometrial cancer has previously received systemic therapy to treat endometrial cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with endometrial cancer has previously received platinum-based chemotherapy to treat endometrial cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with endometrial cancer has previously received platinum-based chemotherapy to treat endometrial cancer and experienced disease progression or recurrence during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with endometrial cancer has previously received platinum-based chemotherapy to treat endometrial cancer and experienced disease progression or recurrence within 12 months (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with endometrial cancer has previously received at least one first-line treatment for endometrial cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with endometrial cancer has previously received at least one first-line systemic treatment for endometrial cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with endometrial cancer has previously received at least one first-line platinum-based chemotherapy for endometrial cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with endometrial cancer has previously received at least one first-line platinum-based chemotherapy for endometrial cancer and experienced disease progression or recurrence during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with endometrial cancer has previously received at least one first-line platinum-based chemotherapy for endometrial cancer and experienced disease progression or recurrence within 12 months (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with endometrial cancer has previously received no more than three lines of treatment for endometrial cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with endometrial cancer has previously received no more than three lines of systemic therapy for endometrial cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with endometrial cancer has previously received no more than three lines of platinum-based chemotherapy for endometrial cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with endometrial cancer has previously received no more than three lines of platinum-based chemotherapy for endometrial cancer and experienced disease progression or recurrence during or after treatment with the platinum-based chemotherapy regimen.In some embodiments, the subject with endometrial cancer has previously received no more than three lines of platinum-based chemotherapy to treat endometrial cancer, and experienced disease progression or recurrence during or within 12 months of completing platinum-based chemotherapy (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months). In some embodiments, the subject with endometrial cancer has previously received neoadjuvant or adjuvant platinum-based chemotherapy to treat endometrial cancer, and experienced disease progression or recurrence during or within 12 months of completing neoadjuvant or adjuvant platinum-based chemotherapy (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months). In some embodiments, the subject with endometrial cancer is platinum-resistant or platinum-refractory.

[0029] In some embodiments, the subject with endometrial cancer has received treatment for endometrial cancer during a recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some embodiments, the subject with endometrial cancer has received systemic therapy for endometrial cancer during a recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some embodiments, the subject with endometrial cancer has received a platinum-based chemotherapy regimen for endometrial cancer during a recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some embodiments, the subject with endometrial cancer has received a platinum-based chemotherapy regimen for endometrial cancer during a recurrence and / or metastasis phase, and disease progression or recurrence occurred during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with endometrial cancer has received a platinum-based chemotherapy regimen for endometrial cancer during a recurrence and / or metastasis phase, and disease progression or recurrence occurred during or within 12 months after treatment with the platinum-based chemotherapy regimen (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months). In some embodiments, the subject with endometrial cancer has received at least one first-line treatment for endometrial cancer during the recurrence and / or metastasis stage (e.g., treatment failure or intolerance). In some embodiments, the subject with endometrial cancer has received at least one first-line systemic treatment for endometrial cancer during the recurrence and / or metastasis stage (e.g., treatment failure or intolerance). In some embodiments, the subject with endometrial cancer has received at least one first-line platinum-based chemotherapy for endometrial cancer during the recurrence and / or metastasis stage (e.g., treatment failure or intolerance). In some embodiments, the subject with endometrial cancer has received at least one first-line platinum-based chemotherapy for endometrial cancer during the recurrence and / or metastasis stage, and experienced disease progression or recurrence during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with endometrial cancer has received at least one first-line platinum-based chemotherapy to treat endometrial cancer during the recurrence and / or metastasis stage, and experienced disease progression or recurrence during or within 12 months after the completion of platinum-based chemotherapy (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months). In some embodiments, the subject with endometrial cancer has received no more than three lines of treatment to treat endometrial cancer during the recurrence and / or metastasis stage (e.g., treatment failure or intolerance). In some embodiments, the subject with endometrial cancer has received no more than three lines of systemic therapy to treat endometrial cancer during the recurrence and / or metastasis stage (e.g., treatment failure or intolerance). In some embodiments, the subject with endometrial cancer has received no more than three lines of platinum-based chemotherapy to treat endometrial cancer during the recurrence and / or metastasis stage (e.g., treatment failure or intolerance).In some embodiments, the subject with endometrial cancer has received no more than three lines of platinum-based chemotherapy to treat endometrial cancer during the recurrence and / or metastasis stage, and experienced disease progression or recurrence during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with endometrial cancer has received no more than three lines of platinum-based chemotherapy to treat endometrial cancer during the recurrence and / or metastasis stage, and experienced disease progression or recurrence within 12 months (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with endometrial cancer has received neoadjuvant or adjuvant platinum-based chemotherapy to treat endometrial cancer during the recurrence and / or metastasis stage, and experienced disease progression or recurrence within 6 months (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) during or after neoadjuvant or adjuvant platinum-based chemotherapy. In some implementations, the subjects with endometrial cancer are platinum-resistant or platinum-refractory subjects.

[0030] In some embodiments, the subject with cervical cancer has previously received treatment for cervical cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with cervical cancer has previously received systemic therapy for cervical cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with cervical cancer has previously received platinum-based chemotherapy for cervical cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with cervical cancer has previously received platinum-based chemotherapy for cervical cancer and experienced disease progression or recurrence during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with cervical cancer has previously received platinum-based chemotherapy for cervical cancer and experienced disease progression or recurrence within 12 months (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with cervical cancer has previously received at least one first-line treatment for cervical cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with cervical cancer has previously received at least one line of systemic therapy to treat cervical cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with cervical cancer has previously received at least one line of platinum-based chemotherapy to treat cervical cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with cervical cancer has previously received at least one line of platinum-based chemotherapy to treat cervical cancer and experienced disease progression or recurrence during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with cervical cancer has previously received at least one line of platinum-based chemotherapy to treat cervical cancer and experienced disease progression or recurrence within 12 months (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with cervical cancer has previously received no more than three lines of treatment to treat cervical cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with cervical cancer has previously received no more than three lines of systemic therapy for cervical cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with cervical cancer has previously received no more than three lines of platinum-based chemotherapy for cervical cancer (e.g., treatment failure or intolerance). In some embodiments, the subject with cervical cancer has previously received no more than three lines of platinum-based chemotherapy for cervical cancer and experienced disease progression or recurrence during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with cervical cancer has previously received no more than three lines of platinum-based chemotherapy for cervical cancer and experienced disease progression or recurrence within 12 months (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) during or after treatment with the platinum-based chemotherapy regimen.In some embodiments, the subject with cervical cancer has previously received neoadjuvant or adjuvant therapy with platinum-based chemotherapy to treat cervical cancer, and experienced disease progression or recurrence during or within 12 months after the completion of neoadjuvant or adjuvant therapy with platinum-based chemotherapy (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months). In some embodiments, the subject with cervical cancer is a platinum-resistant or platinum-refractory subject.

[0031] In some embodiments, the subject with cervical cancer has received treatment for cervical cancer during a recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some embodiments, the subject with cervical cancer has received systemic therapy for cervical cancer during a recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some embodiments, the subject with cervical cancer has received a platinum-based chemotherapy regimen for cervical cancer during a recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some embodiments, the subject with cervical cancer has received a platinum-based chemotherapy regimen for cervical cancer during a recurrence and / or metastasis phase, and disease progression or recurrence occurred during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with cervical cancer has received a platinum-based chemotherapy regimen for cervical cancer during a recurrence and / or metastasis phase, and disease progression or recurrence occurred during or within 12 months after treatment with the platinum-based chemotherapy regimen (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months). In some embodiments, the subject with cervical cancer has received at least one first-line treatment for cervical cancer during the recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some embodiments, the subject with cervical cancer has received at least one first-line systemic treatment for cervical cancer during the recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some embodiments, the subject with cervical cancer has received at least one first-line platinum-based chemotherapy for cervical cancer during the recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some embodiments, the subject with cervical cancer has received at least one first-line platinum-based chemotherapy for cervical cancer during the recurrence and / or metastasis phase, and disease progression or recurrence occurred during or after treatment with the platinum-based chemotherapy regimen. In some embodiments, the subject with cervical cancer has received at least one first-line platinum-based chemotherapy for cervical cancer during the recurrence and / or metastasis phase, and disease progression or recurrence occurred during or within 12 months after treatment with the platinum-based chemotherapy regimen (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months). In some embodiments, the subject with cervical cancer has received no more than three lines of treatment for cervical cancer during the recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some embodiments, the subject with cervical cancer has received no more than three lines of systemic therapy for cervical cancer during the recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some embodiments, the subject with cervical cancer has received no more than three lines of platinum-based chemotherapy for cervical cancer during the recurrence and / or metastasis phase (e.g., treatment failure or intolerance). In some embodiments, the subject with cervical cancer has received no more than three lines of platinum-based chemotherapy for cervical cancer during the recurrence and / or metastasis phase, and disease progression or recurrence occurred during or after treatment with the platinum-based chemotherapy regimen.In some embodiments, the subject with cervical cancer has received no more than three lines of platinum-based chemotherapy to treat cervical cancer during the recurrence and / or metastasis phase, and experienced disease progression or recurrence during or within 12 months after the completion of platinum-based chemotherapy (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months). In some embodiments, the subject with cervical cancer has received neoadjuvant or adjuvant platinum-based chemotherapy to treat cervical cancer during the recurrence and / or metastasis phase, and experienced disease progression or recurrence during or within 12 months after the completion of platinum-based chemotherapy (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months). In some embodiments, the subject with cervical cancer is a platinum-resistant or platinum-refractory subject.

[0032] In some embodiments, the subject with the gynecological tumor has previously received localized radiation therapy to treat the gynecological tumor. In other embodiments, the localized radiation therapy was administered more than 4 weeks after the first administration of the anti-HER2 antibody-drug conjugate, and the disease has progressed.

[0033] Anti-HER2 antibody-drug conjugates

[0034] The anti-HER2 antibody-drug conjugates used in this disclosure are formed by linking a drug-linker of the structure shown in Formula Ia to an antigen-binding construct targeting HER2.

[0035] In formula Ia, the 3-position of -(succinimide-3-yl-N)- (i.e., with The connection point is linked to the antigen-binding construct targeting HER2.

[0036] The HER2-targeting antigen-binding construct comprises a first antigen-binding fragment and a second antigen-binding fragment. The first antigen-binding fragment comprises: a heavy chain CDR1 (HCDR1) containing the amino acid sequence shown in SEQ ID NO:1, an HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, an HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, a light chain CDR1 (LCDR1) containing the amino acid sequence shown in SEQ ID NO:4, an LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and an LCDR3 containing the amino acid sequence shown in SEQ ID NO:6.

[0037] The second antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:9, HCDR2 containing the amino acid sequence shown in SEQ ID NO:10, HCDR3 containing the amino acid sequence shown in SEQ ID NO:11, LCDR1 containing the amino acid sequence shown in SEQ ID NO:12, LCDR2 containing the amino acid sequence shown in SEQ ID NO:13, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:14.

[0038] In some embodiments, the first antigen-binding fragment binds monovalently and specifically to the ECD4 antigen of HER2 on HER2-expressing cells. In some embodiments, the first antigen-binding fragment is scFv. In some embodiments, the second antigen-binding fragment binds monovalently and specifically to the ECD2 antigen of HER2 on HER2-expressing cells. In some embodiments, the second antigen-binding fragment is Fab.

[0039] In some embodiments, the 3-position of the -(succinimide-3-yl-N)- is linked to the antigen-binding construct targeting HER2 via a thioether bond.

[0040] In some embodiments, the average number of drug-connectors for each HER2-targeting antigen-binding construct in the anti-HER2 antibody drug conjugate is 2 to 8. In some embodiments, the average number of drug-connectors for each HER2-targeting antigen-binding construct in the anti-HER2 antibody drug conjugate is 4 to 7. In some embodiments, the average number of drug-connectors for each HER2-targeting antigen-binding construct in the anti-HER2 antibody drug conjugate is 5 to 6. In some embodiments, the average number of drug-connectors for each HER2-targeting antigen-binding construct in the anti-HER2 antibody drug conjugate is 5.5 to 6. In some embodiments, the average number of drug-connectors for each HER2-targeting antigen-binding construct in the anti-HER2 antibody drug conjugate is 5.8 to 6.

[0041] Table 1. Exemplary CDR sequences of antigen-binding constructs targeting HER2

[0042] Those skilled in the art will understand that, unless otherwise specified, the term "CDR" or "complementarity-determining region" for a given antibody or its antigen-binding fragment or its region (e.g., variable region) should be understood to encompass complementarity-determining regions defined by any known scheme. While the CDRs claimed in this disclosure are based on the sequences shown in Table 1 (one definition), the amino acid sequences corresponding to other CDR definition rules (e.g., combinations of one or more of the definitions of AbM, CCG, Kabat, Chothia, IMGT, or Contact, as well as those known in the art) should also fall within the scope of this disclosure.

[0043] In some embodiments, the first antigen-binding fragment comprises: HCDR1, HCDR2, and HCDR3 in a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:7 or an amino acid sequence having at least 80% identity with it, and LCDR1, LCDR2, and LCDR3 in a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:8 or an amino acid sequence having at least 80% identity with it.

[0044] In some embodiments, the first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 7. In some embodiments, the first antigen-binding fragment comprises a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 8. In some embodiments, the first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 7, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 8. In some embodiments, the first antigen-binding fragment comprises a heavy chain variable region having the amino acid sequence shown in SEQ ID NO:7 and a light chain variable region having the amino acid sequence shown in SEQ ID NO:8. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the first antigen-binding fragment is as shown in SEQ ID NO:7, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO:8.

[0045] In some embodiments, the first antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1 having the amino acid sequence shown in SEQ ID NO:1, HCDR2 having the amino acid sequence shown in SEQ ID NO:2, and HCDR3 having the amino acid sequence shown in SEQ ID NO:3; the light chain variable region comprises LCDR1 having the amino acid sequence shown in SEQ ID NO:4, LCDR2 having the amino acid sequence shown in SEQ ID NO:5, and LCDR3 having the amino acid sequence shown in SEQ ID NO:6; and the heavy chain variable region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO:7; and the light chain variable region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 87%, 88%, 89%, 99%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO:7; and the light chain variable region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO:7; NO:8 has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical.

[0046] In some embodiments, the different amino acids in the amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:7 or SEQ ID NO:8 are located in the frame region (FR).

[0047] In some embodiments, the second antigen-binding fragment comprises: HCDR1, HCDR2, and HCDR3 in a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:15 or an amino acid sequence having at least 80% identity with it, and LCDR1, LCDR2, and LCDR3 in a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:16 or an amino acid sequence having at least 80% identity with it.

[0048] In some embodiments, the second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 15. In some embodiments, the second antigen-binding fragment comprises a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 16. In some embodiments, the second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:15, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:16. In some embodiments, the second antigen-binding fragment comprises a heavy chain variable region having the amino acid sequence shown in SEQ ID NO:15 and a light chain variable region having the amino acid sequence shown in SEQ ID NO:16. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the second antigen-binding fragment is as shown in SEQ ID NO:15, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO:16.

[0049] In some embodiments, the second antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1 having the amino acid sequence shown in SEQ ID NO:9, HCDR2 having the amino acid sequence shown in SEQ ID NO:10, and HCDR3 having the amino acid sequence shown in SEQ ID NO:11; the light chain variable region comprises LCDR1 having the amino acid sequence shown in SEQ ID NO:12, LCDR2 having the amino acid sequence shown in SEQ ID NO:13, and LCDR3 having the amino acid sequence shown in SEQ ID NO:14; and the heavy chain variable region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO:15; and the light chain variable region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 87%, 88%, 89%, 99%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO:15; and the light chain variable region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO:15. NO:16 has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical.

[0050] In some embodiments, the differing amino acids in the amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:15 or SEQ ID NO:16 are located in FR.

[0051] In some embodiments, the HER2-targeting antigen-binding construct may further comprise a constant region of an immunoglobulin, or a fragment, analog, variant, or derivative of said constant region. In some embodiments, the constant region comprises a heavy chain constant region and a light chain constant region. In some embodiments, the heavy chain constant region is derived from the heavy chain of human immunoglobulins, such as IgG1, IgG2, IgG3, and IgG4, or the heavy chain of other classes of immunoglobulins, preferably the heavy chain of IgG1. In some embodiments, the light chain constant region is derived from the light chain of human immunoglobulins, such as the κ or λ light chain of human immunoglobulins. In some embodiments, the constant region may contain any modifications described herein, such as the insertion, deletion, substitution, or chemical modification of amino acids. In some embodiments, the C-terminal lysine of the heavy chain constant region may be present or absent; the deletion of the C-terminal lysine of the heavy chain constant region typically occurs during recombinant expression. In some embodiments, the constant region contains mutations that alter effector function. In some embodiments, any amino acid residue of the constant region may be substituted with any allotype amino acid residue.

[0052] In some embodiments, the HER2-targeting antigen-binding construct comprises a first polypeptide chain, a second polypeptide chain, and a third polypeptide chain, wherein: the first polypeptide chain comprises HCDR1 of the amino acid sequence shown in SEQ ID NO:1, HCDR2 of the amino acid sequence shown in SEQ ID NO:2, HCDR3 of the amino acid sequence shown in SEQ ID NO:3, LCDR1 of the amino acid sequence shown in SEQ ID NO:4, LCDR2 of the amino acid sequence shown in SEQ ID NO:5, and LCDR3 of the amino acid sequence shown in SEQ ID NO:6.

[0053] The second polypeptide chain comprises HCDR1 of the amino acid sequence shown in SEQ ID NO:9, HCDR2 of the amino acid sequence shown in SEQ ID NO:10, and HCDR3 of the amino acid sequence shown in SEQ ID NO:11.

[0054] The third polypeptide chain comprises LCDR1 with the amino acid sequence shown in SEQ ID NO:12, LCDR2 with the amino acid sequence shown in SEQ ID NO:13, and LCDR3 with the amino acid sequence shown in SEQ ID NO:14.

[0055] In some embodiments, the HER2-targeting antigen-binding construct comprises a first polypeptide chain, a second polypeptide chain, and a third polypeptide chain, wherein:

[0056] The first polypeptide chain includes a heavy chain variable region of the amino acid sequence shown in SEQ ID NO:7 and a light chain variable region of the amino acid sequence shown in SEQ ID NO:8;

[0057] The second polypeptide chain contains the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:15;

[0058] The third polypeptide chain contains the light chain variable region of the amino acid sequence shown in SEQ ID NO:16.

[0059] In some embodiments, the HER2-targeting antigen-binding construct comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:17. In some embodiments, the HER2-targeting antigen-binding construct comprises a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:18. In some embodiments, the HER2-targeting antigen-binding construct comprises a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:19. In some embodiments, the HER2-targeting antigen-binding construct comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:17; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:17. The amino acid sequence shown in SEQ ID NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity. In some embodiments, the HER2-targeting antigen-binding construct comprises a first polypeptide chain having the amino acid sequence shown in SEQ ID NO:17, a second polypeptide chain having the amino acid sequence shown in SEQ ID NO:18, and a third polypeptide chain having the amino acid sequence shown in SEQ ID NO:19.In some specific embodiments, the antigen-binding construct targeting HER2 consists of three polypeptide chains, wherein the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:17, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:18, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19.

[0060] In some embodiments, the HER2-targeting antigen-binding construct comprises a first polypeptide chain, a second polypeptide chain, and a third polypeptide chain. The first polypeptide chain comprises HCDR1 having the amino acid sequence shown in SEQ ID NO:1, HCDR2 having the amino acid sequence shown in SEQ ID NO:2, HCDR3 having the amino acid sequence shown in SEQ ID NO:3, LCDR1 having the amino acid sequence shown in SEQ ID NO:4, LCDR2 having the amino acid sequence shown in SEQ ID NO:5, and LCDR3 having the amino acid sequence shown in SEQ ID NO:6. The second polypeptide chain comprises HCDR1 having the amino acid sequence shown in SEQ ID NO:9, HCDR2 having the amino acid sequence shown in SEQ ID NO:10, and HCDR3 having the amino acid sequence shown in SEQ ID NO:11. The third polypeptide chain comprises LCDR1 having the amino acid sequence shown in SEQ ID NO:12, LCDR2 having the amino acid sequence shown in SEQ ID NO:13, and LCDR3 having the amino acid sequence shown in SEQ ID NO:14. Furthermore, the first polypeptide chain comprises amino acids with the amino acid sequence shown in SEQ ID NO:1. The amino acid sequence shown in NO:17 has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:18. The second polypeptide chain comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:18. The third polypeptide chain comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 100% identity with the amino acid sequence shown in SEQ ID NO:18. The amino acid sequence shown in NO:19 has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical.

[0061] In some embodiments, the C-terminal lysine residue of the amino acid sequence shown in SEQ ID NO:17 is deleted, as shown in SEQ ID NO:20. In some embodiments, the C-terminal lysine residue of the amino acid sequence shown in SEQ ID NO:18 is deleted, as shown in SEQ ID NO:21. In some embodiments, the C-terminal lysine residues of the first and second polypeptide chains are deleted, the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:20, and the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:21.

[0062] In some embodiments, the HER2-targeting antigen-binding construct comprises:

[0063] (1) A first polypeptide chain comprising the amino acid sequence shown in SEQ ID NO:17 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it; a second polypeptide chain comprising the amino acid sequence shown in SEQ ID NO:18 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it; and a second polypeptide chain comprising SEQ ID NO:17. The amino acid sequence shown in NO:19 or the third polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it;

[0064] (2) A first polypeptide chain comprising the amino acid sequence shown in SEQ ID NO:20 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it; a second polypeptide chain comprising the amino acid sequence shown in SEQ ID NO:18 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it; and a second polypeptide chain comprising SEQ ID NO:20. The amino acid sequence shown in NO:19 or the third polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it;

[0065] (3) A first polypeptide chain comprising the amino acid sequence shown in SEQ ID NO:17 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it; a second polypeptide chain comprising the amino acid sequence shown in SEQ ID NO:21 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it; and a second polypeptide chain comprising SEQ ID NO:21. The amino acid sequence shown in NO:19 or the third polypeptide chain having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it;

[0066] (4) A first polypeptide chain comprising the amino acid sequence shown in SEQ ID NO:20 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it; a second polypeptide chain comprising the amino acid sequence shown in SEQ ID NO:21 or an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with it; and a second polypeptide chain comprising SEQ ID NO:20. NO:19, or a third polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to it.

[0067] In some embodiments, the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:20, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:21, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19. In some embodiments, the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:17, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:21, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19. In some embodiments, the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:20, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:18, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19.

[0068] In some embodiments, the different amino acids in the amino acid sequences that have at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequences shown in SEQ ID NO: 17, 18, 19, 20, or 21 are located in the FR and / or constant regions.

[0069] In some embodiments, the HER2-targeting antigen-binding construct is selected from Expi Her2-1, Expi Her2-3, Expi Her2-4, Expi Her2-5, 23C2 Her2-1, 23C2 Her2-3, 23C2 Her2-4, or 23C2 Her2-5 (see WO2021219046 or CN115279791A). In some other embodiments, the HER2-targeting antigen-binding construct is selected from Zanidatamab (ZW25), KN026, MBS301, KM257, or BCD-147.

[0070] The anti-HER2 antibody-drug conjugate used in this disclosure can also be represented by the structure shown in Formula II:

[0071] The HER2-targeting antigen-binding construct is as described above. In some embodiments, the drug-linker is linked to the HER2-targeting antigen-binding construct via a thioether bond (at position 3 of -(succinimide-3-yl-N)-). n has the same meaning as DAR, representing the average number of cytotoxic drug links per HER2-targeting antigen-binding construct. In some embodiments, n is 2 to 8. In some embodiments, n is 4 to 7. In some embodiments, n is 5 to 6. In some embodiments, n is 5.5 to 6. In some embodiments, n is 5.8 to 6.

[0072] The antibody-drug conjugates preferred in this disclosure are formed by linking a drug-linker of the structure shown in Formula Ia to an antigen-binding construct targeting HER2.

[0073] in,

[0074] In formula Ia, the 3-position of -(succinimide-3-yl-N)- is linked to the antigen-binding construct targeting HER2.

[0075] The HER2-targeting antigen-binding construct comprises three polypeptide chains: the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:17 or a variant with a C-terminal lysine deletion; the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:18 or a variant with a C-terminal lysine deletion; and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19 (for example, the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:17, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:18, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19; or the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:20, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:21, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19; or the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:20, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:18, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19; or the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:17, and the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:19). As shown in NO:21, the amino acid sequence of the third polypeptide chain is as shown in SEQ ID NO:19, and

[0076] For a single antigen-binding construct targeting HER2, the average number of drug-connector linkages is 5 to 6.

[0077] In some embodiments, the 3-position of -(succinimide-3-yl-N)- in Formula Ia is linked to an antigen-binding construct targeting HER2 via a thioether bond.

[0078] The antibody-drug conjugates preferred in this disclosure can also be represented by the structure shown in Formula II:

[0079] Where n is between 5 and 6,

[0080] The antigen-binding construct targeting HER2 consists of three polypeptide chains. The amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:17 or is a variant with a C-terminal lysine deletion. The amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:18 or is a variant with a C-terminal lysine deletion. The amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19. (For example, the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:17, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:18, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19; or, the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:20, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:21, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19; or, the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:20, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:18, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19; or, the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:17, and the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:19.) As shown in NO:21, the amino acid sequence of the third polypeptide chain is as shown in SEQ ID NO:19. In some embodiments, the drug-connector is linked to the antigen-binding construct targeting HER2 via a thioether bond.

[0081] The anti-HER2 antibody drug conjugates described in this disclosure also include pharmaceutically acceptable salts of the anti-HER2 antibody drug conjugate, or stereoisomers or tautomers thereof, or solvates of the anti-HER2 antibody drug conjugate, its isomers, or its pharmaceutically acceptable salts.

[0082] In some embodiments, the anti-HER2 antibody drug conjugate of this disclosure is in the form of a pharmaceutical composition. In some embodiments, the pharmaceutical composition may comprise one or more pharmaceutically acceptable excipients.

[0083] In some embodiments, the pharmaceutical composition may be any suitable dosage form. In some embodiments, the anti-HER2 antibody drug conjugate is in the form of a formulation for parenteral administration. In some specific embodiments, the anti-HER2 antibody drug conjugate is in the form of a formulation for intravenous, intramuscular, or other parenteral administration routes. In some specific embodiments, the anti-HER2 antibody drug conjugate is in the form of an injectable preparation. In some specific embodiments, the anti-HER2 antibody drug conjugate is in the form of a formulation for intravenous injection or infusion.

[0084] Technical effect

[0085] Applying the anti-HER2 antibody-drug conjugate or pharmaceutical composition comprising the present disclosure may achieve one or more of the following effects, but is not limited thereto:

[0086] (1) It provides benefit to subjects with gynecologic tumors (especially those with advanced, recurrent and / or metastatic gynecologic tumors), preferably demonstrating good efficacy in second-line or later-line treatment of gynecologic tumors, including but not limited to ovarian cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer and cervical cancer;

[0087] (2) Demonstrates good safety; and

[0088] (3) It was well tolerated by the subjects.

[0089] In some embodiments, when the anti-HER2 antibody-drug conjugate of this disclosure is used to treat subjects with gynecologic tumors, the objective response rate (ORR) is 30% or higher, 35% or higher, 40% or higher, 45% or higher, 50% or higher, 55% or higher, 60% or higher, 65% or higher, 70% or higher, 75% or higher, or 80% or higher. In some embodiments, the gynecologic tumor is as described above in this disclosure. In some embodiments, efficacy is evaluated according to RECIST 1.1 criteria.

[0090] Definitions and Explanations

[0091] Unless otherwise stated, the following terms as used in this disclosure have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When trade names appear in this disclosure, they are intended to refer to the corresponding product or its active ingredient.

[0092] As used in this article, the structure of "-(succinimide-3-yl-N)-" is as follows:

[0093] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration representing the center of a solid.

[0094] Unless otherwise specified, when a group has a connectable site, the connection between that site and other groups can be indicated by a wavy line. express.

[0095] The term "antigen-binding construct" refers to any reagent capable of binding to an antigen, such as a polypeptide or polypeptide complex. In some aspects, an antigen-binding construct is a polypeptide that specifically binds to a target antigen. Antigen-binding constructs can be monomers, dimers, polymers, proteins, peptides, protein or peptide complexes, antibodies, or antigen-binding fragments thereof. Antigen-binding constructs can be single-specific, bispecific, or multispecific polypeptide constructs. In some aspects, antigen-binding constructs may include, for example, one or more antigen-binding fragments (e.g., Fab or scFv) linked to one or more Fc cells.

[0096] An antibody's "antigen-binding fragment" refers to one or more fragments of an antibody that retain the function of specifically binding to an antigen (e.g., the HER2 protein). It has been demonstrated that the antigen-binding function of an antibody can be exercised through fragments of a full-length antibody. Examples encompassed in the term "antigen-binding fragment" of an antibody include: (i) Fab fragments: monovalent fragments consisting of VL, VH, CL, and CH1 domains; (ii) F(ab')2 fragments, bivalent fragments comprising two Fab fragments connected by a disulfide bridge in the hinge region; (iii) Fd fragments consisting of VH and CH1 domains; (iv) Fv fragments consisting of the VL and VH domains of a single arm of the antibody; (v) dAb fragments consisting of the VH domain (see Ward et al., Nature. 341:544-546 (1989)); and (vi) nanobodies, an antibody comprising a single variable domain and two constant domains. Furthermore, although the two domains VL and VH of the Fv fragment are encoded by different genes, VH and VL can be linked into a single protein chain via a linker using recombination methods. VL and VH pair to form a monovalent molecule called a single-chain Fv (scFv) (see Bird et al., Science. 242:423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. 85:5879-5883 (1988)). These single-chain antibodies are also covered under the term antigen-binding fragment. These antibody fragments can be obtained by those skilled in the art using known conventional techniques, and the fragments can be functionally screened using the same methods as full-length antibodies.

[0097] The term "identity," also known as consistency, refers to the percentage of amino acid residues in the sequence to be aligned that are identical to those in the specific amino acid sequence shown herein, after aligning the sequence to be aligned with it and, if necessary, introducing vacancies to achieve the maximum percentage of sequence identity, and without considering any conservative substitutions as part of the sequence identity. Amino acid sequence alignment for identity can be performed in various ways within the scope of the art. Those skilled in the art can determine the appropriate parameters for the aligned sequences, including any algorithm required to achieve the maximum alignment across the full length of the compared sequences.

[0098] The term "treatment" means administering the compounds described in this disclosure to improve or eliminate a disease or one or more symptoms associated with said disease, and includes, but is not limited to:

[0099] (i) Suppress the disease or disease state, that is, curb its development;

[0100] (ii) Relieve the disease or disease state, even if the disease or disease state subsides;

[0101] (iii) To reduce any direct or indirect pathological consequences of disease or disease state.

[0102] The term "therapeutic effective amount" means (i) the amount of the disclosed compound used to treat a particular disease, condition, or disorder, or (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder. The amount of the disclosed compound constituting a "therapeutic effective amount" can vary depending on factors such as the compound and its ability to elicit the desired response in an individual, the disease state and its severity, the route of administration, and the age, sex, and weight of the mammal to be treated.

[0103] The terms “administration,” “application,” or “giving” indicate the physical introduction of a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.

[0104] Antibody-drug conjugates (e.g., anti-HER2 antibody-drug conjugates) can be administered via intravenous, intramuscular, intraperitoneal, spinal, or other parenteral routes. As used herein, the term "parenteral administration" refers to non-enteral administration methods typically performed by injection, including but not limited to intravenous, intramuscular, intra-arterial, intrathecal, intralymphatic, intralesional, intracystic, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, intra-articular, subcapsular, subarachnoid, spinal, epidural, and intrasternal injections and infusions, as well as intracorporeal electroporation. Administration can also be performed, for example, once, multiple times, and / or over one or more extended time periods.

[0105] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0106] The term "pharmaceutically acceptable salt" refers to a salt of a compound (such as the antibody-drug conjugate of this disclosure) that is safe and effective when used in mammals and has the intended biological activity. For example, it can be a metal salt, an ammonium salt, a salt formed with an organic base, a salt formed with an inorganic acid, a salt formed with an organic acid, a salt formed with a basic or acidic amino acid, etc.

[0107] The term "excipient" refers to any component other than the active ingredient (e.g., the antibody-drug conjugate of this disclosure). The selection of excipients will largely depend on factors such as the specific route of administration, the excipient's efficacy in solubility and stability, and the nature of the dosage form.

[0108] In this document, the terms “subject,” “patient,” or “subject” are used interchangeably. “Subject,” “patient,” or “subject” includes any human or non-human animal. The term “non-human animal” includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the subject, patient, or subject is a mammal. In some embodiments, the subject, patient, or subject is a mouse. In some embodiments, the subject, patient, or subject is a human.

[0109] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients (such as the anti-HER2 antibody drug conjugate of this disclosure) and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the active ingredient to a subject. In this document, the terms "pharmaceutical composition" and "formulation" have the same meaning and are used interchangeably.

[0110] The words “comprise,” “comprise,” or “comprise,” and their English variations such as comprises or comprising, should be understood in an open, non-exclusive sense, meaning “including but not limited to.”

[0111] In this document, unless the context clearly indicates otherwise, singular terms encompass plural referents, and vice versa.

[0112] As used herein, “about” means within an acceptable range of error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” may, in accordance with art practice, mean within one or more standard deviations. Alternatively, “about” may mean a range of up to ±5%, such as fluctuations within ±2%, ±1%, or ±0.5% of a given specific numerical range. When a particular value is given in this disclosure or claims, unless otherwise stated, “about” shall be understood to mean within an acceptable range of error for that particular value. In this document, unless otherwise stated, all values ​​for dosage, time, procedure parameters, or conditions of the medicine are implicitly modified by “about”.

[0113] For purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their publications predate the filing date of this disclosure. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publications are part of the general knowledge in the art.

[0114] This disclosure also provides the following specific implementation schemes, but the scope of protection of this disclosure is not limited thereto:

[0115] Implementation Scheme 1. A method for treating a subject with a gynecological tumor, comprising administering an anti-HER2 antibody-drug conjugate to the subject, wherein the anti-HER2 antibody-drug conjugate is composed of a drug-linker of the structure shown in Formula Ia linked to an antigen-binding construct targeting HER2.

[0116] In formula Ia, the 3-position of -(succinimide-3-yl-N)- is linked to the antigen-binding construct targeting HER2.

[0117] The HER2-targeting antigen-binding construct comprises a first antigen-binding fragment and a second antigen-binding fragment. The first antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:1, HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, LCDR1 containing the amino acid sequence shown in SEQ ID NO:4, LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:6. The second antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:9, HCDR2 containing the amino acid sequence shown in SEQ ID NO:10, HCDR3 containing the amino acid sequence shown in SEQ ID NO:11, LCDR1 containing the amino acid sequence shown in SEQ ID NO:12, LCDR2 containing the amino acid sequence shown in SEQ ID NO:13, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:14.

[0118] Implementation Scheme 2. The method according to Implementation Scheme 1, wherein the average number of drug-connectors in each HER2-targeting antigen-binding construct is 4 to 7.

[0119] Implementation Scheme 3. The method according to Implementation Scheme 2, wherein the average number of drug-connectors for each HER2-targeting antigen-binding construct is 5 to 6.

[0120] Implementation Scheme 4. The method according to Implementation Scheme 3, wherein the average number of drug-connectors for each HER2-targeting antigen-binding construct is 5.5 to 6.

[0121] Implementation Scheme 5. The method according to any one of Implementation Schemes 1-4, wherein,

[0122] (i) The first antigen-binding fragment comprises a heavy chain variable region having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:7;

[0123] (ii) The first antigen-binding fragment comprises a light chain variable region having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:8;

[0124] (iii) The first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:8;

[0125] (iv) The second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:15;

[0126] (v) The second antigen-binding fragment comprises a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:16;

[0127] (vi) The second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 15, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 16; or

[0128] (vii) The first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8. The amino acid sequence shown in NO:15 has a heavy chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:16, and a light chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:16.

[0129] Implementation Scheme 6. The method according to any one of Implementation Schemes 1-5, wherein,

[0130] (i) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:17 or 20;

[0131] (ii) The antigen-binding construct targeting HER2 comprises a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO: 18 or 21;

[0132] (iii) The antigen-binding construct targeting HER2 comprises a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:19; or

[0133] (iv) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:17; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity.

[0134] The HER2-targeting antigen-binding construct comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:20; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:21; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:20; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 87%, 88%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:20. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity.

[0135] The HER2-targeting antigen-binding construct comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:17; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:21; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:21; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:17. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity; or

[0136] The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:20; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:18; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:20; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:20. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity.

[0137] Implementation Scheme 7. The method according to any one of Implementation Schemes 1-6, wherein the anti-HER2 antibody drug conjugate is administered in a therapeutically effective amount.

[0138] Implementation Scheme 8. The method according to any one of Implementation Schemes 1-7, wherein the anti-HER2 antibody drug conjugate is administered at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, or 6-7.5 mg / kg each time; preferably, the anti-HER2 antibody drug conjugate is administered at a dose of 6-7.5 mg / kg each time.

[0139] Implementation Scheme 9. The method according to Implementation Scheme 8, wherein the anti-HER2 antibody drug conjugate is administered at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 6 mg / kg, 7.5 mg / kg or 9 mg / kg each time; preferably, the anti-HER2 antibody drug conjugate is administered at a dose of 6 mg / kg or 7.5 mg / kg each time.

[0140] Implementation Scheme 10. The method according to any one of Implementation Schemes 1-9, wherein the anti-HER2 antibody drug conjugate is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; preferably, the anti-HER2 antibody drug conjugate is administered once every 3 weeks.

[0141] Implementation Scheme 11. The method according to any one of Implementation Schemes 1-10, wherein the anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous injection or infusion.

[0142] Implementation Scheme 12. The method according to any one of Implementation Schemes 1-11, wherein the administration of the anti-HER2 antibody drug conjugate is performed by intravenous infusion.

[0143] Implementation Scheme 13. The method according to any one of Implementation Schemes 1-12, wherein the gynecological tumor is an advanced, recurrent, and / or metastatic gynecological tumor.

[0144] Implementation Scheme 14. The method according to any one of Implementation Schemes 1-13, wherein the gynecological tumor is an unresectable gynecological tumor.

[0145] Implementation Scheme 15. The method according to any one of Implementation Schemes 1-14, wherein the gynecological tumor is ovarian cancer, malignant ovarian germ cell tumor and / or ovarian sex cord-stromal tumor.

[0146] Implementation Scheme 16. The method according to any one of Implementation Schemes 1-14, wherein the gynecological tumor is fallopian tube cancer.

[0147] Implementation Scheme 17. The method according to any one of Implementation Schemes 1-14, wherein the gynecological tumor is peritoneal cancer; preferably, the peritoneal cancer is primary peritoneal cancer.

[0148] Implementation Scheme 18. The method according to any one of Implementation Schemes 15-17, wherein the ovarian cancer, fallopian tube cancer and / or peritoneal cancer is serous carcinoma, serous adenocarcinoma, high-grade serous carcinoma, high-grade serous adenocarcinoma, low-grade serous carcinoma, low-grade serous adenocarcinoma, endometrioid carcinoma, endometrioid adenocarcinoma, clear cell carcinoma, mucinous carcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, carcinosarcoma or malignant Brenner tumour.

[0149] Implementation Scheme 19. The method according to any one of Implementation Schemes 1-14, wherein the gynecological tumor is endometrial cancer; preferably, the endometrial cancer is endometrioid carcinoma, endometrioid adenocarcinoma, serous carcinoma, high-grade serous carcinoma, low-grade serous carcinoma, serous adenocarcinoma, high-grade serous adenocarcinoma, low-grade serous adenocarcinoma, mucinous carcinoma, mucinous adenocarcinoma, clear cell carcinoma, undifferentiated carcinoma, dedifferentiated carcinoma, mixed carcinoma, carcinosarcoma or other endometrial cancers.

[0150] Implementation Scheme 20. The method according to any one of Implementation Schemes 1-14, wherein the gynecological tumor is cervical cancer; preferably, the cervical cancer is squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma or neuroendocrine tumor.

[0151] Implementation Scheme 21. The method according to any one of Implementation Schemes 1-20, wherein the gynecological tumor is a gynecological tumor in which HER2 expression is determined to be 3+, 2+, 1+ or 0 by IHC.

[0152] Implementation Scheme 22. The method according to any one of Implementation Schemes 1-21, wherein the subject of the gynecological tumor has previously received treatment for the gynecological tumor; preferably, the subject of the gynecological tumor has previously received at least one first-line treatment for the gynecological tumor; optionally, the subject of the gynecological tumor has previously received no more than three lines of treatment for the gynecological tumor.

[0153] Implementation Scheme 23. The method according to any one of Implementation Schemes 1-22, wherein the subject of the gynecological tumor has previously received systemic therapy to treat the gynecological tumor; preferably, the subject of the gynecological tumor has previously received at least one line of systemic therapy to treat the gynecological tumor; optionally, the subject of the gynecological tumor has previously received no more than three lines of systemic therapy to treat the gynecological tumor.

[0154] Implementation Scheme 24. The method according to any one of Implementation Schemes 1-23, wherein the subject of the gynecological tumor has previously received a platinum-based chemotherapy regimen to treat the gynecological tumor; preferably, the subject of the gynecological tumor has previously received at least one first-line platinum-based chemotherapy regimen to treat the gynecological tumor; optionally, the subject of the gynecological tumor has previously received no more than three lines of platinum-based chemotherapy regimen to treat the gynecological tumor.

[0155] Implementation Scheme 25. The method according to any one of Implementation Schemes 1-24, wherein the subject of the gynecological tumor experiences disease progression or recurrence during or after treatment with a platinum-based chemotherapy regimen; preferably, the subject of the gynecological tumor experiences disease progression or recurrence within 6 months or 12 months after treatment with a platinum-based chemotherapy regimen.

[0156] Implementation Scheme 26. The method according to any one of Implementation Schemes 1-25, wherein the subject of the gynecological tumor has previously received neoadjuvant or adjuvant therapy with a platinum-based chemotherapy regimen to treat the gynecological tumor, and has experienced disease progression or recurrence during or within 12 months after receiving neoadjuvant or adjuvant therapy with a platinum-based chemotherapy regimen.

[0157] Implementation Scheme 27. The method according to any one of Implementation Schemes 1-26, wherein the subject of the gynecological tumor is a platinum-resistant subject or a platinum-refractory subject.

[0158] Implementation Scheme 28. The method according to any one of Implementation Schemes 1-27, wherein the subject of the gynecological tumor previously received treatment during the recurrence and / or metastasis stage.

[0159] Implementation Scheme 29. The method according to any one of Implementation Schemes 1-28, wherein the subject of the gynecological tumor has previously received local radiotherapy to treat the gynecological tumor; preferably, the local radiotherapy was administered more than 4 weeks after the first administration of the anti-HER2 antibody drug conjugate and the disease progressed.

[0160] Implementation Scheme 30. The method according to any one of Implementation Schemes 1-29, wherein the anti-HER2 antibody drug conjugate is used for second-line or later-line treatment of a subject with gynecological tumors.

[0161] Implementation Scheme 31. Use of an anti-HER2 antibody drug conjugate in the preparation of a medicament for treating gynecological tumors in a subject, wherein the anti-HER2 antibody drug conjugate is formed by linking a drug-linker of the structure shown in Formula Ia to an antigen-binding construct targeting HER2.

[0162] In formula Ia, the 3-position of -(succinimide-3-yl-N)- is linked to the antigen-binding construct targeting HER2.

[0163] The HER2-targeting antigen-binding construct comprises a first antigen-binding fragment and a second antigen-binding fragment. The first antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:1, HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, LCDR1 containing the amino acid sequence shown in SEQ ID NO:4, LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:6. The second antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:9, HCDR2 containing the amino acid sequence shown in SEQ ID NO:10, HCDR3 containing the amino acid sequence shown in SEQ ID NO:11, LCDR1 containing the amino acid sequence shown in SEQ ID NO:12, LCDR2 containing the amino acid sequence shown in SEQ ID NO:13, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:14.

[0164] Implementation Scheme 32. The use according to Implementation Scheme 31, wherein the average number of drug-connectors in each HER2-targeting antigen-binding construct is 4 to 7.

[0165] Implementation Scheme 33. The use according to Implementation Scheme 32, wherein the average number of drug-connectors in each HER2-targeting antigen-binding construct is 5 to 6.

[0166] Implementation Scheme 34. The use according to Implementation Scheme 33, wherein the average number of drug-connectors in each HER2-targeting antigen-binding construct is 5.5 to 6.

[0167] Implementation Scheme 35. The use according to any one of Implementation Schemes 31-34, wherein,

[0168] (i) The first antigen-binding fragment comprises a heavy chain variable region having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:7;

[0169] (ii) The first antigen-binding fragment comprises a light chain variable region having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:8;

[0170] (iii) The first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:8;

[0171] (iv) The second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:15;

[0172] (v) The second antigen-binding fragment comprises a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:16;

[0173] (vi) The second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 15, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 16; or

[0174] (vii) The first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8. The amino acid sequence shown in NO:15 has a heavy chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:16, and a light chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:16.

[0175] Implementation Scheme 36. The use according to any one of Implementation Schemes 31-35, wherein,

[0176] (i) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:17 or 20;

[0177] (ii) The antigen-binding construct targeting HER2 comprises a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO: 18 or 21;

[0178] (iii) The antigen-binding construct targeting HER2 comprises a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:19; or

[0179] (iv) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:17; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity.

[0180] The HER2-targeting antigen-binding construct comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:20; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:21; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:20; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 87%, 88%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:20. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity.

[0181] The HER2-targeting antigen-binding construct comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:17; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:21; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:21; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:17. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity; or

[0182] The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:20; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:18; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:20; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:20. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity.

[0183] Implementation Scheme 37. The use according to any one of Implementation Schemes 31-36, wherein the antiHER2 antibody drug conjugate is administered in a therapeutically effective amount.

[0184] Implementation Scheme 38. The use according to any one of Implementation Schemes 31-37, wherein the drug is formulated to be administered at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, or 6-7.5 mg / kg per administration; preferably, the drug is formulated to be administered at a dose of 6-7.5 mg / kg per administration.

[0185] Implementation Scheme 39. The use according to Implementation Scheme 38, wherein the drug is formulated to be administered at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 6 mg / kg, 7.5 mg / kg or 9 mg / kg per administration; preferably, the drug is formulated to be administered at a dose of 6 mg / kg or 7.5 mg / kg per administration.

[0186] Implementation Scheme 40. The use according to any one of Implementation Schemes 31-39, wherein the anti-HER2 antibody drug conjugate is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; preferably, the anti-HER2 antibody drug conjugate is administered once every 3 weeks.

[0187] Implementation Scheme 41. The use according to any one of Implementation Schemes 31-40, wherein the anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous injection or infusion.

[0188] Implementation Scheme 42. The use according to any one of Implementation Schemes 31-41, wherein the administration of the anti-HER2 antibody drug conjugate is by intravenous infusion.

[0189] Implementation Scheme 43. The use according to any one of Implementation Schemes 31-42, wherein the gynecological tumor is an advanced, recurrent and / or metastatic gynecological tumor.

[0190] Implementation Scheme 44. The use according to any one of Implementation Schemes 31-43, wherein the gynecological tumor is an unresectable gynecological tumor.

[0191] Implementation Scheme 45. The use according to any one of Implementation Schemes 31-44, wherein the gynecological tumor is ovarian cancer, malignant ovarian germ cell tumor and / or ovarian sex cord-stromal tumor.

[0192] Implementation Scheme 46. The use according to any one of Implementation Schemes 31-44, wherein the gynecological tumor is fallopian tube cancer.

[0193] Implementation Scheme 47. The use according to any one of Implementation Schemes 31-44, wherein the gynecological tumor is peritoneal cancer; preferably, the peritoneal cancer is primary peritoneal cancer.

[0194] Implementation Scheme 48. The use according to any one of Implementation Schemes 45-47, wherein the ovarian cancer, fallopian tube cancer and / or peritoneal cancer is serous carcinoma, serous adenocarcinoma, high-grade serous carcinoma, high-grade serous adenocarcinoma, low-grade serous carcinoma, low-grade serous adenocarcinoma, endometrioid carcinoma, endometrioid adenocarcinoma, clear cell carcinoma, mucinous carcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, carcinosarcoma or malignant Brunner tumor.

[0195] Implementation Scheme 49. The use according to any one of Implementation Schemes 31-44, wherein the gynecological tumor is endometrial cancer; preferably, the endometrial cancer is endometrioid carcinoma, endometrioid adenocarcinoma, serous carcinoma, high-grade serous carcinoma, low-grade serous carcinoma, serous adenocarcinoma, high-grade serous adenocarcinoma, low-grade serous adenocarcinoma, mucinous carcinoma, mucinous adenocarcinoma, clear cell carcinoma, undifferentiated carcinoma, dedifferentiated carcinoma, mixed carcinoma, carcinosarcoma or other endometrial cancers.

[0196] Implementation Scheme 50. The use according to any one of Implementation Schemes 31-44, wherein the gynecological tumor is cervical cancer; preferably, the cervical cancer is squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma or neuroendocrine tumor.

[0197] Implementation Scheme 51. The use according to any one of Implementation Schemes 31-50, wherein the gynecological tumor is a gynecological tumor in which HER2 expression is determined to be 3+, 2+, 1+ or 0 by IHC.

[0198] Implementation Scheme 52. The use according to any one of Implementation Schemes 31-51, wherein the subject of the gynecological tumor has previously received treatment for the gynecological tumor; preferably, the subject of the gynecological tumor has previously received at least one first-line treatment for the gynecological tumor; optionally, the subject of the gynecological tumor has previously received no more than three lines of treatment for the gynecological tumor.

[0199] Implementation Scheme 53. The use according to any one of Implementation Schemes 31-52, wherein the subject of the gynecological tumor has previously received systemic therapy to treat the gynecological tumor; preferably, the subject of the gynecological tumor has previously received at least one line of systemic therapy to treat the gynecological tumor; optionally, the subject of the gynecological tumor has previously received no more than three lines of systemic therapy to treat the gynecological tumor.

[0200] Implementation Scheme 54. The use according to any one of Implementation Schemes 31-53, wherein the subject of the gynecological tumor has previously received a platinum-based chemotherapy regimen to treat the gynecological tumor; preferably, the subject of the gynecological tumor has previously received at least one first-line platinum-based chemotherapy regimen to treat the gynecological tumor; optionally, the subject of the gynecological tumor has previously received no more than three lines of platinum-based chemotherapy regimen to treat the gynecological tumor.

[0201] Implementation Scheme 55. The use according to any one of Implementation Schemes 31-54, wherein the subject of the gynecological tumor experiences disease progression or recurrence during or after treatment with a platinum-based chemotherapy regimen; preferably, the subject of the gynecological tumor experiences disease progression or recurrence within 6 months or 12 months after treatment with a platinum-based chemotherapy regimen.

[0202] Implementation Scheme 56. The use according to any one of Implementation Schemes 31-55, wherein the subject of the gynecological tumor has previously received neoadjuvant or adjuvant therapy with a platinum-based chemotherapy regimen to treat the gynecological tumor, and has experienced disease progression or recurrence during or within 12 months after receiving neoadjuvant or adjuvant therapy with a platinum-based chemotherapy regimen.

[0203] Implementation Scheme 57. The use according to any one of Implementation Schemes 31-56, wherein the subject of the gynecological tumor is a platinum-resistant subject or a platinum-refractory subject.

[0204] Implementation Scheme 58. The use according to any one of Implementation Schemes 31-57, wherein the subject of the gynecological tumor has previously received treatment during a recurrence and / or metastasis phase.

[0205] Implementation Scheme 59. The use according to any one of Implementation Schemes 31-58, wherein the subject of the gynecological tumor has previously received local radiotherapy to treat the gynecological tumor; preferably, the local radiotherapy was administered more than 4 weeks after the first administration of the anti-HER2 antibody drug conjugate and the disease progressed.

[0206] Implementation Scheme 60. The use according to any one of Implementation Schemes 31-59, wherein the anti-HER2 antibody drug conjugate is used for second-line or later-line treatment of a subject with gynecological tumors. Example

[0207] For clarity, this disclosure is further illustrated by examples, but the examples are not intended to limit the scope of this disclosure.

[0208] The entire contents of patent application documents WO2022033578 or CN115702008A are incorporated herein by reference. In the following examples, the anti-HER2 antibody drug conjugate was prepared according to the method described in WO2022033578, resulting in the anti-HER2 antibody drug conjugate represented by the following formula (hereinafter referred to as ADC1):

[0209] In this process, the drug-linker is linked to the HER2-targeting antigen-binding construct via a thioether bond, where n is 5 to 6. In short, the nucleic acid sequences of the three polypeptide chains (amino acid sequences shown in SEQ ID NO: 17, 18, and 19, respectively) encoding the HER2-targeting antigen-binding construct are cloned into the pcDNA3.1 expression vector, co-transfected into FUT8-knockout CHO-S cells for expression, and purified by protein A to prepare the HER2-targeting antigen-binding construct. The HER2-targeting antigen-binding construct is treated with tris(2-carboxyethyl)phosphonic acid hydrochloride, and then reacted with a linker-payload selected from the structure shown below to finally obtain ADC1:

[0210] Example 1: Clinical trial of HER2-expressing gynecological tumors

[0211] 1. Research Objective:

[0212] 1.1 Main Purpose:

[0213] To evaluate the efficacy of ADC1 therapy in treating recurrent and / or metastatic advanced gynecological tumors.

[0214] 1.2 Secondary Objectives:

[0215] To evaluate the safety of ADC1 therapy for recurrent and / or metastatic advanced gynecological tumors.

[0216] 2. Test subjects:

[0217] Patients with recurrent and / or metastatic advanced gynecological tumors (including ovarian cancer, endometrial cancer, cervical cancer, with HER2 expression levels of IHC 3+, IHC 2+, IHC 1+, or IHC 0) who have previously received ≥1 line of platinum-based chemotherapy.

[0218] 3. Selection Criteria

[0219] Only those who meet all of the following inclusion criteria can be enrolled in this trial:

[0220] (1) Participants voluntarily joined this study and signed an informed consent form;

[0221] (2) Age ≥ 18 years (at the time of signing informed consent); female; ECOG score: 0-1; expected survival period of more than 3 months;

[0222] (3) Histologically confirmed, unresectable recurrent and / or metastatic advanced gynecological tumors, including:

[0223] 1) Cohort 1: Epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer;

[0224] 2) Cohort 2 Endometrial cancer: Histopathologically confirmed endometrial cancer, including endometrioid adenocarcinoma, mucinous adenocarcinoma, serous adenocarcinoma, clear cell carcinoma, undifferentiated carcinoma, and carcinosarcoma;

[0225] 3) Cohort 3 Cervical cancer: Cervical cancer confirmed by histopathology, including squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma;

[0226] 4) Cohort 4: Epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer meeting the criteria of Cohort 1, endometrial cancer meeting the criteria of Cohort 2, and cervical cancer meeting the criteria of Cohort 3;

[0227] (4) Confirm HER2 expression status (IHC 3+, 2+, 1+ or 0) in tumor tissue;

[0228] Note: HER2 expression results can be obtained from historical results of local laboratories with testing qualifications (within 2 years prior to signing informed consent), while fresh or archived tumor tissue that meets the requirements can be collected for the central laboratory to verify HER2 expression levels.

[0229] (5) The subject meets any of the following criteria:

[0230] 1) Epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer: Platinum-resistant or refractory patients who have received ≥1 line of platinum-based chemotherapy, including patients whose disease progressed or relapsed ≤6 months after the completion of previous platinum-based chemotherapy.

[0231] 2) Endometrial cancer: Patients who have received ≥1 line of platinum-based chemotherapy during the recurrence or metastasis stage and whose disease progressed during or after treatment, or who have received no more than 3 lines of systemic therapy during the recurrence or metastasis stage, or whose disease progressed or recurred ≤12 months after receiving neoadjuvant or adjuvant platinum-based therapy, are also considered as first-line systemic therapy for recurrent and / or metastatic advanced disease.

[0232] 3) Cervical cancer: Patients who have received ≥1 line of platinum-based chemotherapy during the recurrence or metastasis stage and whose disease progressed during or after treatment, or who have received no more than 3 lines of systemic therapy during the recurrence or metastasis stage, or whose disease progressed or recurred ≤12 months after receiving neoadjuvant or adjuvant platinum-based therapy, are also considered as first-line systemic therapy for recurrent and / or metastatic advanced disease.

[0233] Note: Disease progression requires evidence of objective imaging or clinical disease progression (e.g., cytological reports of new ascites or pleural effusion), or a persistently elevated tumor marker CA125 (confirmed after 1 week) accompanied by clinical symptoms or physical examination suggesting disease progression.

[0234] (6) Confirmed to have at least one measurable lesion according to RECIST 1.1 criteria;

[0235] (7) The major organs are in good function and meet the standards for routine blood tests, biochemical tests, and coagulation function tests;

[0236] (8) Women of fertility must meet the following criteria: negative serum / urine pregnancy test results before the first use of medication; consent to use highly effective contraceptive methods (annual failure rate less than 1%) throughout the study period; women of fertility are defined as premenopausal women who have not been recorded to tubal ligation or hysterectomy, or women who have been menopausal for no more than 1 year.

[0237] 4. Test drug

[0238] ADC1 for injection (specification: 100mg / vial) was developed and supplied by Nanjing Shunxin Pharmaceutical Co., Ltd., a subsidiary of Chia Tai Tianqing Pharmaceutical Group.

[0239] 5. Treatment Plan

[0240] Cohorts 1-3: ADC1 was administered intravenously every 3 weeks at a dose of 7.5 mg / kg, and intravenously dripped on day 1, with each 3-week (21-day) treatment cycle constituting one treatment cycle;

[0241] Cohort 4: ADC1 was administered intravenously every 3 weeks at a dose of 6 mg / kg, and intravenous drip was given on day 1. Each treatment cycle consisted of 3 weeks (21 days).

[0242] The dosing regimen may be adjusted based on disease severity, disease response, any treatment-related toxicities, patient age, and health status. Efficacy assessments will be conducted every 6 weeks (42±7 days), and every 12 weeks (84±7 days) thereafter. Patients with disease control (CR+PR+SD) and tolerable adverse reactions may continue treatment until disease progression or intolerable toxicity, at which point the study will end if the investigator deems continued treatment inappropriate.

[0243] 6. Evaluation Criteria

[0244] Effectiveness evaluation: The disease status was determined using the RECIST 1.1 criteria.

[0245] Safety assessment: The severity of adverse events was determined using the NCI-CTC AE 5.0 standard.

[0246] 7. Endpoint Indicators

[0247] Primary endpoint:

[0248] Objective response rate (ORR)

[0249] Secondary endpoint:

[0250] Progression-free survival (PFS), disease control rate (DCR), duration of remission (DOR), and overall survival (OS), etc.

[0251] The occurrence of all adverse events (AEs), serious adverse events (SAEs), and treatment-related adverse events (TEAEs), as well as abnormal laboratory test indicators;

[0252] Exploratory endpoint:

[0253] Incidence of ADC1 immunogenicity (ADA);

[0254] Biomarker analysis, such as the correlation between genes related to the ERBB2 gene signaling pathway and therapeutic efficacy.

[0255] 8. Results

[0256] The results showed that ADC1 had good efficacy (including but not limited to, higher ORR, longer PFS, higher DCR, longer DOR, and longer OS) in advanced, recurrent and / or metastatic gynecological tumors (including epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, and cervical cancer), exhibited low immunogenicity, and demonstrated good safety in clinical trials.

[0257] The specific results of a representative subset of the participants are shown in the table below:

Claims

1. A method for treating a gynecological tumor in a subject, comprising administering an anti-HER2 antibody-drug conjugate to the subject, wherein, The anti-HER2 antibody-drug conjugate is formed by linking a drug-linker of the structure shown in Formula Ia with an antigen-binding construct targeting HER2. In formula Ia, the 3-position of -(succinimide-3-yl-N)- is linked to the antigen-binding construct targeting HER2. The HER2-targeting antigen-binding construct comprises a first antigen-binding fragment and a second antigen-binding fragment. The first antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:1, HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, LCDR1 containing the amino acid sequence shown in SEQ ID NO:4, LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:

6. The second antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:9, HCDR2 containing the amino acid sequence shown in SEQ ID NO:10, HCDR3 containing the amino acid sequence shown in SEQ ID NO:11, LCDR1 containing the amino acid sequence shown in SEQ ID NO:12, LCDR2 containing the amino acid sequence shown in SEQ ID NO:13, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:

14.

2. The method according to claim 1, wherein, The average number of drug-linkers for each HER2-targeting antigen-binding construct is 4 to 7, 5 to 6, or 5.5 to 6.

3. The method according to claim 1 or 2, wherein, (i) The first antigen-binding fragment comprises a heavy chain variable region having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:7; (ii) The first antigen-binding fragment comprises a light chain variable region having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:8; (iii) The first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:8; (iv) The second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:15; (v) The second antigen-binding fragment comprises a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:16; (vi) The second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 15, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 16; or (vii) The first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:

8. The amino acid sequence shown in NO:15 has a heavy chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:16, and a light chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:

16.

4. The method according to any one of claims 1-3, wherein, (i) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:17 or 20; (ii) The antigen-binding construct targeting HER2 comprises a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO: 18 or 21; (iii) The antigen-binding construct targeting HER2 comprises a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:19; or (iv) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:17; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:

18. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity. The HER2-targeting antigen-binding construct comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:20; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:21; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:20; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 87%, 88%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:

20. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity. The HER2-targeting antigen-binding construct comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:17; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:21; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:21; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:

17. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity; or The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:20; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:18; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:20; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:

20. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity.

5. The method according to any one of claims 1-4, wherein, The anti-HER2 antibody drug conjugate is administered at doses of 1.5-9 mg / kg, 4.5-7.5 mg / kg, 6-7.5 mg / kg, 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 6 mg / kg, 7.5 mg / kg, or 9 mg / kg each time; preferably, the anti-HER2 antibody drug conjugate is administered at doses of 6-7.5 mg / kg, 6 mg / kg, or 7.5 mg / kg each time.

6. The method according to any one of claims 1-5, wherein, The anti-HER2 antibody drug conjugate is administered once every 1 week, 2 weeks, 3 weeks, or 4 weeks; preferably, the anti-HER2 antibody drug conjugate is administered once every 3 weeks.

7. The method according to any one of claims 1-6, wherein, The anti-HER2 antibody drug conjugate is formulated for intravenous injection or infusion; optionally, the anti-HER2 antibody drug conjugate is administered via intravenous infusion.

8. The method according to any one of claims 1-7, wherein, The gynecological tumor is an advanced, recurrent, and / or metastatic gynecological tumor; optionally, the gynecological tumor is an unresectable gynecological tumor.

9. The method according to any one of claims 1-8, wherein, The gynecological tumors are ovarian cancer, malignant ovarian germ cell tumors, ovarian sex cord-stromal tumors, fallopian tube cancer, and / or peritoneal cancer; preferably, the peritoneal cancer is primary peritoneal cancer. Optionally, the ovarian cancer, fallopian tube cancer, and / or peritoneal cancer are serous carcinoma, serous adenocarcinoma, high-grade serous carcinoma, high-grade serous adenocarcinoma, low-grade serous carcinoma, low-grade serous adenocarcinoma, endometrioid carcinoma, endometrioid adenocarcinoma, clear cell carcinoma, mucinous carcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, carcinosarcoma, or malignant Brenner tumor.

10. The method according to any one of claims 1-8, wherein, The gynecological tumor is endometrial cancer; preferably, the endometrial cancer is endometrioid carcinoma, endometrioid adenocarcinoma, serous carcinoma, high-grade serous carcinoma, low-grade serous carcinoma, serous adenocarcinoma, high-grade serous adenocarcinoma, low-grade serous adenocarcinoma, mucinous carcinoma, mucinous adenocarcinoma, clear cell carcinoma, undifferentiated carcinoma, dedifferentiated carcinoma, mixed carcinoma, carcinosarcoma, or other endometrial cancers.

11. The method according to any one of claims 1-8, wherein, The gynecological tumor is cervical cancer; preferably, the cervical cancer is squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, or a neuroendocrine tumor.

12. The method according to any one of claims 1-11, wherein, The gynecological tumors referred to are those in which HER2 expression is determined to be 3+, 2+, 1+ or 0 by IHC.

13. The method according to any one of claims 1-12, wherein, The subject with the gynecological tumor has previously received treatment for the gynecological tumor; preferably, the subject with the gynecological tumor has previously received at least one first-line treatment for the gynecological tumor. Preferably, The subject with the gynecological tumor has previously received systemic therapy to treat the gynecological tumor; preferably, the subject with the gynecological tumor has previously received at least one first-line systemic therapy to treat the gynecological tumor. Preferably, The subject with the gynecological tumor has previously received platinum-based chemotherapy to treat the gynecological tumor; preferably, the subject with the gynecological tumor has previously received at least one first-line platinum-based chemotherapy to treat the gynecological tumor. Optionally, the subject of the gynecological tumor has previously received treatment during the recurrence and / or metastasis stage; Optionally, the subjects with the gynecological tumors are platinum-resistant or platinum-refractory subjects.

14. The method according to any one of claims 1-13, wherein, The subject with the gynecological tumor experienced disease progression or recurrence during or after treatment with a platinum-based chemotherapy regimen; preferably, the subject experienced disease progression or recurrence within 6 or 12 months after treatment with a platinum-based chemotherapy regimen; and / or The subjects with gynecological tumors had previously received neoadjuvant or adjuvant therapy with platinum-based chemotherapy regimens to treat gynecological tumors, and experienced disease progression or recurrence during or within 12 months after receiving neoadjuvant or adjuvant therapy with platinum-based chemotherapy regimens.

15. The method according to any one of claims 1-14, wherein, The anti-HER2 antibody-drug conjugate is used for second-line or later-line treatment of gynecological tumors in subjects.

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