Use of anti-her2 antibody drug conjugates for the treatment of breast cancer

Abstract

The application belongs to the field of biological medicine, and relates to the use of an anti-HER2 antibody drug conjugate for treating breast cancer. The application also relates to the use of an anti-HER2 antibody drug conjugate in the preparation of a medicament for treating breast cancer in a subject. The application also relates to a method for treating breast cancer in a subject, which comprises administering an anti-HER2 antibody drug conjugate to the subject. The method is beneficial to the breast cancer subject, and has good safety.

Description

Use of anti-HER2 antibody-drug conjugates in the treatment of breast cancer Technical Field

[0001] The present disclosure belongs to the field of biomedicine, and specifically relates to the use of anti-HER2 antibody-drug conjugates in the treatment of breast cancer. Background Art

[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 located on the cell surface and share a similar structure. HER2 is a ubiquitously expressed receptor protein. Abnormal gene amplification leads to protein overexpression, which in turn causes abnormal activation of signaling pathways and is a major driver of solid tumor growth. HER2 can form homodimers and heterodimers with other HER family receptors, leading to phosphorylation of receptor tyrosine residues and activation of multiple signaling pathways, including MPK, PI3K, JAK, STAT3, and PKC, ultimately contributing to cell proliferation and tumorigenesis.

[0003] Anti-HER2 targeted therapy is an important approach to treat breast cancer. Therefore, there is an urgent need to explore drugs targeting HER2 to meet the huge clinical demand for breast cancer treatment.

[0004] Summary of the Invention

[0005] Treatments for breast cancer

[0006] The present disclosure provides a method for treating breast cancer in a subject, comprising administering to the subject an anti-HER2 antibody drug conjugate of the present disclosure. The present disclosure also provides a method for second-line or later-line treatment of breast cancer in a subject, comprising administering to the subject an anti-HER2 antibody drug conjugate of the present disclosure. In some embodiments, in the method, the anti-HER2 antibody drug conjugate is administered in a therapeutically effective amount.

[0007] The present disclosure also provides the use of the anti-HER2 antibody-drug conjugate of the present disclosure in the preparation of a medicament for treating breast cancer in a subject. The present disclosure also provides the use of the anti-HER2 antibody-drug conjugate of the present disclosure in the preparation of a medicament for second-line or later-line treatment of breast cancer in a subject. In some embodiments, in the use, the medicament comprises a therapeutically effective amount of the anti-HER2 antibody-drug conjugate.

[0008] The present disclosure also provides an anti-HER2 antibody drug conjugate of the present disclosure for treating breast cancer in a subject. The present disclosure also provides an anti-HER2 antibody drug conjugate of the present disclosure for second-line treatment or later-line treatment of breast cancer in a subject. In some embodiments, the anti-HER2 antibody drug conjugate is administered to a subject in a therapeutically effective amount.

[0009] The present disclosure also provides use of the anti-HER2 antibody drug conjugate of the present disclosure for treating breast cancer in a subject.

[0010] In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered once every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). In a specific embodiment, in the method or use, the anti-HER2 antibody drug conjugate is administered once every 3 weeks. In some embodiments, in the method or use, 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. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 6 mg / kg, 7.5 mg / kg, 9 mg / kg, or a range formed by any of the above values. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered at a dose of 6 mg / kg or 7.5 mg / kg each time. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered at a dose of 7.5 mg / kg each time. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered at a dose of 6 mg / kg each time. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, or 6-7.5 mg / kg anti-HER2 antibody drug conjugate. In some embodiments, in the methods or uses, the anti-HER2 antibody drug conjugate is administered once every 3 weeks, each time at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 6 mg / kg, 7.5 mg / kg or 9 mg / kg anti-HER2 antibody drug conjugate. In some embodiments, in the methods or uses, 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, in the methods or uses, 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, in the methods or uses, 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.

[0011] In some embodiments, in the methods or uses, one treatment cycle is one week, ... In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and 6 mg / kg of anti-HER2 antibody drug conjugate is administered in each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and 6 mg / kg of anti-HER2 antibody drug conjugate is administered on day 1 of each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and 7.5 mg / kg of anti-HER2 antibody drug conjugate is administered in each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and 7.5 mg / kg of anti-HER2 antibody drug conjugate is administered on day 1 of each treatment cycle. In some embodiments, different doses of anti-HER2 antibody drug conjugate are administered to the same subject in different treatment cycles. In some embodiments, in the first treatment cycle, the anti-HER2 antibody drug conjugate is administered to the subject at a dose of 7.5 mg / kg, and in the second and subsequent treatment cycles, the anti-HER2 antibody drug conjugate is administered to the subject at a dose of 6 mg / kg. In some embodiments, the anti-HER2 antibody drug conjugate is administered to the subject at a dose of 6 mg / kg in the first treatment cycle and at a dose of 7.5 mg / kg in the second and subsequent treatment cycles.

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

[0013] In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate is administered by intravenous infusion.

[0014] In the method or use, the dosing regimen (e.g., dosing cycle, dosing time, dosage and dosage adjustment) of the anti-HER2 antibody drug conjugate can be adjusted according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient. For example, the anti-HER2 antibody drug conjugate can be delayed for 1-84 days, for example, for 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. For another example, the dosage of the anti-HER2 antibody drug conjugate can be adjusted from 6 mg / kg to 4.5 mg / kg, or from 7.5 mg / kg to 6 mg / kg.

[0015] In some embodiments, the breast cancer is unresectable, refractory, advanced, recurrent, and / or metastatic breast cancer. In some embodiments, the breast cancer is unresectable breast cancer. In some embodiments, the breast cancer is refractory breast cancer. In some embodiments, the breast cancer is advanced breast cancer. In some embodiments, the breast cancer is recurrent and / or metastatic breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is locally recurrent breast cancer. In some embodiments, the breast cancer is locally recurrent and / or metastatic breast cancer. In some embodiments, the breast cancer is unresectable recurrent breast cancer. In some embodiments, the breast cancer is unresectable metastatic breast cancer. In some embodiments, the breast cancer is locally advanced or metastatic breast cancer.

[0016] In some embodiments, the breast cancer is HER2-expressing breast cancer. In some embodiments, the breast cancer is HER2-positive breast cancer. In some embodiments, the HER2-positive breast cancer is a breast cancer whose expression of HER2 is 3+ as determined by immunohistochemistry (IHC). In some embodiments, the HER2-positive breast cancer is a breast cancer whose expression of HER2 is 2+ as determined by IHC and whose expression of HER2 is positive as determined by ISH. In some embodiments, the breast cancer is a breast cancer with low HER2 expression. In some embodiments, the breast cancer with low HER2 expression is a breast cancer whose expression of HER2 is 2+ as determined by IHC and whose expression of HER2 is negative as determined by ISH. In some embodiments, the breast cancer with low HER2 expression is a breast cancer whose expression of HER2 is 1+ as determined by IHC.

[0017] In some embodiments, the breast cancer is a recurrent and / or metastatic breast cancer expressing HER2. In some embodiments, the breast cancer is a recurrent and / or metastatic breast cancer that is HER2 positive. In some embodiments, the breast cancer is a recurrent and / or metastatic breast cancer that is determined to be 3+ by IHC, or to be positive by ISH, or to be 2+ by IHC and to be positive by ISH. In some embodiments, the breast cancer is a recurrent and / or metastatic breast cancer that is low in HER2 expression. In some embodiments, the breast cancer is a recurrent and / or metastatic breast cancer that is negative in that the expression of HER2 is 1+ by IHC, or to be 2+ by IHC and to be negative in that the expression of HER2 is negative by ISH.

[0018] In some embodiments, the subject's breast cancer is hormone receptor (HR) positive. In some embodiments, the subject's breast cancer is estrogen receptor (ER) positive. In some embodiments, the subject's breast cancer is progesterone receptor (PR) positive. In some embodiments, the breast cancer is hormone receptor (HR) negative or positive, HER2 positive, recurrent or metastatic breast cancer.

[0019] In some embodiments, the subject of the breast cancer is not suitable for surgery and / or radiation therapy. In some embodiments, the subject of the breast cancer expressed by the HER2 is not suitable for surgery and / or radiation therapy. In some embodiments, the subject of the recurrent and / or metastatic breast cancer is not suitable for surgery and / or radiation therapy. In some embodiments, the subject of the recurrent and / or metastatic breast cancer expressed by the HER2 is not suitable for surgery and / or radiation therapy. In some embodiments, the subject of the recurrent and / or metastatic breast cancer that is HER2 positive is not suitable for surgery and / or radiation therapy. In some embodiments, the subject of the recurrent and / or metastatic breast cancer that is low in HER2 is not suitable for surgery and / or radiation therapy. Not being suitable for surgery and / or radiation therapy includes not being able to benefit from surgery and / or radiation therapy, or not being able to be cured by surgery and / or radiation therapy.

[0020] In some embodiments, the subject of the breast cancer has previously received at least one first-line treatment to treat breast cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of the breast cancer has previously received at least two-line treatment to treat breast cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of the breast cancer has previously received at least three-line treatment to treat breast cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of the recurrent and / or metastatic breast cancer has previously received at least one first-line treatment to treat recurrent and / or metastatic breast cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of the recurrent and / or metastatic breast cancer has previously received at least two-line treatment to treat recurrent and / or metastatic breast cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of the recurrent and / or metastatic breast cancer has previously received at least three-line treatment to treat recurrent and / or metastatic breast cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of the HER2-expressed breast cancer has previously received at least one first-line treatment to treat HER2-expressed breast cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of the breast cancer expressed by HER2 has previously received at least two lines of treatment to treat breast cancer expressed by HER2 (e.g., treatment failure or intolerance). In some embodiments, the subject of the breast cancer expressed by HER2 has previously received at least three lines of treatment to treat breast cancer expressed by HER2 (e.g., treatment failure or intolerance). In some embodiments, the subject of the breast cancer has previously received first-line chemotherapy to treat breast cancer (e.g., treatment failure or intolerance), and the breast cancer is preferably recurrent and / or metastatic breast cancer, more preferably recurrent and / or metastatic breast cancer expressed by HER2.

[0021] In some embodiments, the subject of the breast cancer has previously received at least one first-line system chemotherapy to treat breast cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of the recurrent and / or metastatic breast cancer has previously received at least one first-line system therapy to treat breast cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of the recurrent and / or metastatic breast cancer expressed by HER2 has previously received at least one first-line system therapy to treat breast cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of the recurrent and / or metastatic breast cancer expressed by HER2 has previously received at least one first-line system therapy to treat breast cancer (e.g., treatment failure or intolerance).

[0022] In some embodiments, the subject of breast cancer has received adjuvant therapy to treat breast cancer (for example, treatment failure or intolerance) in the past. In some embodiments, the subject of breast cancer has received adjuvant therapy to treat breast cancer in the past, and treatment failed. In some embodiments, the subject of breast cancer is receiving adjuvant therapy to treat breast cancer during the period of treatment, and the disease relapses. In some embodiments, the subject of breast cancer is receiving adjuvant therapy to treat breast cancer after the subject receives adjuvant therapy to treat breast cancer, and the disease relapses within 6 months (for example 1, 2, 3, 4, 5 or 6 months) after the end of treatment. In some embodiments, the subject of recurrent and / or metastatic breast cancer has received adjuvant therapy to treat breast cancer in the past, and treatment failed. In some embodiments, the subject of recurrent and / or metastatic breast cancer is receiving adjuvant therapy to treat breast cancer during the period of treatment, and the disease relapses. In some embodiments, the subject of recurrent and / or metastatic breast cancer is receiving adjuvant therapy to treat breast cancer after the subject receives adjuvant therapy to treat breast cancer, and the disease relapses. In some embodiments, the subject of the recurrent and / or metastatic breast cancer has received adjuvant therapy for the treatment of breast cancer in the past, and the disease relapses within 6 months (e.g., 1, 2, 3, 4, 5, or 6 months) after the end of treatment. In some embodiments, the subject of the recurrent and / or metastatic breast cancer expressed by the HER2 has received adjuvant therapy for the treatment of breast cancer in the past, and treatment has failed. In some embodiments, the subject of the recurrent and / or metastatic breast cancer expressed by the HER2 has received adjuvant therapy for the treatment of breast cancer during the period of treatment. In some embodiments, the subject of the recurrent and / or metastatic breast cancer expressed by the HER2 has received adjuvant therapy for the treatment of breast cancer after the treatment. In some embodiments, the subject of the recurrent and / or metastatic breast cancer expressed by the HER2 has received adjuvant therapy for the treatment of breast cancer in the past, and the disease relapses within 6 months (e.g., 1, 2, 3, 4, 5, or 6 months) after the end of treatment. In some embodiments, the subject of the recurrent and / or metastatic breast cancer expressed by the HER2 has received adjuvant therapy for the treatment of breast cancer in the past, and treatment has failed. In some embodiments, the subject with recurrent and / or metastatic breast cancer with low HER2 expression experiences disease recurrence during adjuvant therapy for the treatment of breast cancer. In some embodiments, the subject with recurrent and / or metastatic breast cancer with low HER2 expression experiences disease recurrence after receiving adjuvant therapy for the treatment of breast cancer. In some embodiments, the subject with recurrent and / or metastatic breast cancer with low HER2 expression has previously received adjuvant therapy for the treatment of breast cancer, and the disease recurs within 6 months (e.g., 1, 2, 3, 4, 5, or 6 months) after the end of treatment.

[0023] In some embodiments, the subject of breast cancer has previously received first-line endocrine therapy to treat breast cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of breast cancer has previously received a CDK4 / 6 inhibitor in combination with endocrine therapy to treat breast cancer, and the treatment has failed. In some embodiments, the subject of breast cancer has previously received adjuvant endocrine therapy to treat breast cancer, and the disease has recurred within 12 months after the end of treatment. In some embodiments, the subject of recurrent and / or metastatic breast cancer has previously received first-line endocrine therapy to treat breast cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of recurrent and / or metastatic breast cancer has previously received a CDK4 / 6 inhibitor in combination with endocrine therapy to treat breast cancer, and the treatment has failed. In some embodiments, the subject of recurrent and / or metastatic breast cancer has previously received adjuvant endocrine therapy to treat breast cancer, and the disease has recurred. In some embodiments, the subject with recurrent and / or metastatic breast cancer has previously received adjuvant endocrine therapy for breast cancer, and the disease relapsed within 12 months after the end of treatment. In some embodiments, the subject with recurrent and / or metastatic breast cancer that expresses HER2 has previously received a CDK4 / 6 inhibitor in combination with endocrine therapy for breast cancer, and the treatment failed. In some embodiments, the subject with recurrent and / or metastatic breast cancer that expresses HER2 has experienced a disease relapse while receiving adjuvant endocrine therapy for breast cancer. In some embodiments, the subject with recurrent and / or metastatic breast cancer that expresses HER2 has previously received adjuvant endocrine therapy for breast cancer, and the disease relapsed within 12 months after the end of treatment. In some embodiments, the subject with recurrent and / or metastatic breast cancer that has low HER2 expression has previously received a CDK4 / 6 inhibitor in combination with endocrine therapy for breast cancer, and the treatment failed. In some embodiments, the subject with recurrent and / or metastatic breast cancer that has low HER2 expression has experienced a disease relapse while receiving adjuvant endocrine therapy for breast cancer. In some embodiments, the subject with recurrent and / or metastatic breast cancer and low HER2 expression has previously received adjuvant endocrine therapy for breast cancer and has had disease recurrence within 12 months after the end of treatment.

[0024] In some embodiments, the subject of breast cancer has previously received adjuvant therapy or neoadjuvant therapy to treat breast cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of breast cancer has previously received adjuvant therapy or neoadjuvant therapy to treat breast cancer, and treatment failed. In some embodiments, the subject of breast cancer is receiving adjuvant therapy or neoadjuvant therapy to treat breast cancer during the period of treatment. In some embodiments, the subject of breast cancer is receiving adjuvant therapy or neoadjuvant therapy to treat breast cancer after the disease relapses. In some embodiments, the subject of breast cancer is receiving adjuvant therapy or neoadjuvant therapy to treat breast cancer, and the disease relapses within 12 months after the end of treatment. In some embodiments, the subject of recurrent and / or metastatic breast cancer is receiving adjuvant therapy or neoadjuvant therapy to treat breast cancer, and treatment fails. In some embodiments, the subject of recurrent and / or metastatic breast cancer is receiving adjuvant therapy or neoadjuvant therapy to treat breast cancer during the period of treatment. In some embodiments, the subject of recurrent and / or metastatic breast cancer is receiving adjuvant therapy or neoadjuvant therapy to treat breast cancer after the disease relapses. In some embodiments, the subject with recurrent and / or metastatic breast cancer has previously received adjuvant therapy or neoadjuvant therapy for breast cancer, and the disease relapsed within 12 months after the end of treatment. In some embodiments, the subject with recurrent and / or metastatic breast cancer that expresses HER2 has previously received adjuvant therapy or neoadjuvant therapy for breast cancer, and the treatment failed. In some embodiments, the subject with recurrent and / or metastatic breast cancer that expresses HER2 has experienced disease relapse during adjuvant therapy or neoadjuvant therapy for breast cancer. In some embodiments, the subject with recurrent and / or metastatic breast cancer that expresses HER2 has experienced disease relapse after receiving adjuvant therapy or neoadjuvant therapy for breast cancer. In some embodiments, the subject with recurrent and / or metastatic breast cancer that expresses HER2 has previously received adjuvant therapy or neoadjuvant therapy for breast cancer, and the disease relapsed within 12 months after the end of treatment. In some embodiments, the subject with recurrent and / or metastatic breast cancer that is HER2-positive has previously received adjuvant therapy or neoadjuvant therapy for breast cancer, and the treatment failed. In some embodiments, the subject with HER2-positive recurrent and / or metastatic breast cancer has a recurrence of disease while receiving adjuvant therapy or neoadjuvant therapy for breast cancer. In some embodiments, the subject with HER2-positive recurrent and / or metastatic breast cancer has a recurrence of disease after receiving adjuvant therapy or neoadjuvant therapy for breast cancer. In some embodiments, the subject with HER2-positive recurrent and / or metastatic breast cancer has previously received adjuvant therapy or neoadjuvant therapy for breast cancer and has a recurrence of disease within 12 months after the end of treatment.

[0025] In some embodiments, the subject of the breast cancer has previously received anti-HER2 antibodies (e.g., trastuzumab) and / or taxanes for the treatment of breast cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of the recurrent and / or metastatic breast cancer has previously received anti-HER2 antibodies (e.g., trastuzumab) and / or taxanes for the treatment of breast cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of the recurrent and / or metastatic breast cancer of HER2 expression has previously received anti-HER2 antibodies (e.g., trastuzumab) and / or taxanes for the treatment of breast cancer (e.g., treatment failure or intolerance). In some embodiments, the subject of the HER2-positive recurrent and / or metastatic breast cancer has previously received anti-HER2 antibodies (e.g., trastuzumab) and / or taxanes for the treatment of breast cancer (e.g., treatment failure or intolerance).

[0026] In some embodiments, the subject with breast cancer has previously received localized radiation therapy to treat breast cancer. In some embodiments, the subject with breast cancer has previously received localized radiation therapy to treat breast cancer, and the localized radiation therapy is more than 2 weeks away from the first administration of an anti-HER2 antibody drug conjugate, and the lesion targeted by the anti-HER2 antibody drug conjugate is not within the localized radiation therapy area. In some embodiments, the subject with breast cancer has previously received localized radiation therapy to treat breast cancer, and the localized radiation therapy is more than 2 weeks away from the first administration of an anti-HER2 antibody drug conjugate, and the disease has progressed. In some embodiments, the localized radiation therapy is palliative radiation therapy or brain radiation therapy.

[0027] In some embodiments, the subject with breast cancer is a subject with HER2-expressing recurrent and / or metastatic breast cancer who has failed at least one line of systemic chemotherapy at the recurrence and / or metastasis stage. In some embodiments, the subject with breast cancer is a subject with HER2-expressing recurrent and / or metastatic breast cancer who is hormone receptor-positive and has failed at the recurrence and / or metastasis stage after receiving a CDK4 / 6 inhibitor combined with endocrine therapy. In some embodiments, the subject with breast cancer is a subject with HER2-expressing recurrent and / or metastatic breast cancer who has received trastuzumab and taxanes.

[0028] In some embodiments, the subject with breast cancer is a subject with HER2-positive recurrent and / or metastatic breast cancer who has failed after at least one line of systemic chemotherapy at the relapse and / or metastasis stage. In some embodiments, the subject with breast cancer is a subject with HER2-positive recurrent and / or metastatic breast cancer who has been treated with trastuzumab and a taxane. In some embodiments, the subject with breast cancer is a subject with HER2-positive recurrent and / or metastatic breast cancer who has failed after at least one line of systemic chemotherapy at the relapse and / or metastasis stage and has a HER2 expression of 3+ as determined by IHC, or a HER2 expression of positive as determined by ISH, or a HER2 expression of 2+ as determined by IHC and a HER2 expression of positive as determined by ISH. In some embodiments, the subject with breast cancer is a subject with HER2 expression of 3+ as determined by IHC, or a HER2 expression of positive as determined by ISH, or a HER2 expression of 2+ as determined by IHC and a HER2 expression of positive as determined by ISH, who has been treated with trastuzumab and a taxane.

[0029] In some embodiments, the subject of breast cancer is a subject with low HER2 expression recurrent and / or metastatic breast cancer who has failed after at least one line of systemic chemotherapy at the recurrence and / or metastasis stage. In some embodiments, the subject of breast cancer is a subject with low HER2 expression recurrent and / or metastatic breast cancer who has failed after receiving at least one line of systemic chemotherapy at the recurrence and / or metastasis stage. In some embodiments, the subject of breast cancer is a subject with low HER2 expression recurrent and / or metastatic breast cancer who has failed after receiving at least one line of systemic chemotherapy at the recurrence and / or metastasis stage. In some embodiments, the subject of breast cancer is a subject with 1+ HER2 expression by IHC or 2+ HER2 expression by IHC and negative HER2 expression by ISH. In some embodiments, the subject of breast cancer is a subject with 1+ HER2 expression by IHC or 2+ HER2 expression by IHC and negative HER2 expression by ISH, who has failed after receiving at least one line of systemic chemotherapy at the recurrence and / or metastasis stage.

[0030] In some embodiments, the subject of breast cancer is a locally advanced or metastatic breast cancer subject with low expression of HER2 who has not received chemotherapy at the recurrence and / or metastasis stage. In some embodiments, the subject of breast cancer is an unresectable locally advanced or metastatic breast cancer subject with low expression of HER2 who has not received chemotherapy at the recurrence and / or metastasis stage. In some embodiments, the subject of breast cancer is a locally advanced or metastatic breast cancer subject with negative expression of HER2 determined by IHC as 1+ or 2+ by IHC and negative expression of HER2 determined by ISH at the recurrence and / or metastasis stage. In some embodiments, the subject of breast cancer is an unresectable locally advanced or metastatic breast cancer subject with negative expression of HER2 determined by IHC as 1+ or 2+ by IHC and negative expression of HER2 determined by ISH at the recurrence and / or metastasis stage.

[0031] In some embodiments, the subject of breast cancer is a subject with HR-positive, HER2-low expression of locally advanced or metastatic breast cancer who has not received chemotherapy at the recurrence and / or metastasis stage. In some embodiments, the subject of breast cancer is a subject with HR-positive and HER2-low expression of locally advanced or metastatic breast cancer who has received at least one line of endocrine therapy at the recurrence and / or metastasis stage and has disease progression or adjuvant endocrine therapy within 24 months of disease progression. In some embodiments, the subject of breast cancer is a subject with HR-positive and HER2-low expression of unresectable locally advanced or metastatic breast cancer who has not received chemotherapy at the recurrence and / or metastasis stage, or has received at least one line of endocrine therapy at the recurrence and / or metastasis stage and has disease progression or adjuvant endocrine therapy within 24 months of disease progression.

[0032] In some embodiments, the subject with breast cancer is a subject with hormone receptor negative or positive, HER2 positive recurrent or metastatic breast cancer. In some embodiments, the subject with breast cancer is a subject with (1) hormone receptor negative or positive, and (2) HER2 expression is 3+ as determined by IHC, or HER2 expression is positive as determined by ISH, or HER2 expression is 2+ as determined by IHC and HER2 expression is positive as determined by ISH.

[0033] Anti-HER2 Antibody Drug Conjugates

[0034] The anti-HER2 antibody drug conjugate used in the present disclosure is formed by connecting a drug-linker having a structure represented by the following formula Ia to an antigen-binding construct targeting HER2:

[0035] Wherein, R1 and R2 in Formula Ia are independently selected from hydrogen (H) or deuterium (D), and the 3-position of -(succinimide-3-yl-N)- in Formula Ia (i.e., The position of the connection) is connected 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,

[0037] The first antigen-binding fragment comprises: a heavy chain CDR1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a light chain CDR1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6,

[0038] The second antigen-binding fragment comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO: 9, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 10, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 11, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 13, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 14.

[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. In some embodiments, R1 and R2 are hydrogen.

[0040] In some embodiments, the anti-HER2 antibody drug conjugate has an average number of drug-linker connections per antigen-binding construct targeting HER2 of 2 to 8. In some embodiments, the anti-HER2 antibody drug conjugate has an average number of drug-linker connections per antigen-binding construct targeting HER2 of 4 to 7. In some embodiments, the anti-HER2 antibody drug conjugate has an average number of drug-linker connections per antigen-binding construct targeting HER2 of 5 to 6. In some embodiments, the anti-HER2 antibody drug conjugate has an average number of drug-linker connections per antigen-binding construct targeting HER2 of 5.5 to 6. In some embodiments, the anti-HER2 antibody drug conjugate has an average number of drug-linker connections per antigen-binding construct targeting HER2 of 5.8 to 6.

[0041] The anti-HER2 antibody drug conjugate used in the present disclosure can also be represented by the structure shown in the following formula II:

[0042] Wherein, R1 and R2 in Formula II are independently selected from hydrogen or deuterium. In some embodiments, the drug-linker (specifically, position 3 of -(succinimidyl-3-yl-N)-) is connected to the antigen-binding construct targeting HER2 through a thioether bond. In some embodiments, R1 and R2 are hydrogen. n has the same meaning as DAR and represents the average number of cytotoxic drugs attached to each antigen-binding construct targeting HER2. 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.

[0043] Table 1. CDR sequences of exemplary antigen-binding constructs targeting HER2

[0044] It will be understood by those skilled in the art that, unless otherwise specified, the term "CDR" or "complementarity determining region" of a given antigen-binding fragment or region thereof (e.g., variable region) should be understood to encompass complementarity determining regions defined by any known scheme. Although the CDRs claimed in the present disclosure are based on the sequences shown in Table 1 (one definition), amino acid sequences corresponding to other CDR definition rules (e.g., one or more combinations of the AbM, CCG, Kabat, Chothia, IMGT, or Contact definitions known in the art) should also fall within the scope of protection of the present disclosure.

[0045] In some embodiments, 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 of 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 of SEQ ID NO:8. In some embodiments, the first antigen-binding fragment comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7, and a light chain variable region having the amino acid sequence of 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.

[0046] 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 a HCDR1 having the amino acid sequence of SEQ ID NO: 1, a HCDR2 having the amino acid sequence of SEQ ID NO: 2, and a HCDR3 having the amino acid sequence of SEQ ID NO: 3, the light chain variable region comprises a LCDR1 having the amino acid sequence of SEQ ID NO: 4, a LCDR2 having the amino acid sequence of SEQ ID NO: 5, and a LCDR3 having the amino acid sequence of SEQ ID NO: 6, and the heavy chain variable region comprises 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 SEQ ID NO: 7, and the light chain variable region comprises 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 SEQ ID NO: 8, 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.

[0047] 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 to the amino acid sequence set forth in SEQ ID NO:7 or SEQ ID NO:8 are located in the FR regions.

[0048] In some embodiments, the second 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 of SEQ ID NO:15, 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 of SEQ ID NO:16. In some embodiments, the second antigen-binding fragment comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 15, and a light chain variable region having the amino acid sequence of 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 a HCDR1 having the amino acid sequence of SEQ ID NO:9, a HCDR2 having the amino acid sequence of SEQ ID NO:10, and a HCDR3 having the amino acid sequence of SEQ ID NO:11, the light chain variable region comprises a LCDR1 having the amino acid sequence of SEQ ID NO:12, a LCDR2 having the amino acid sequence of SEQ ID NO:13, and a LCDR3 having the amino acid sequence of SEQ ID NO:14, and the heavy chain variable region comprises 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 SEQ ID NO:15, and the light chain variable region comprises 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 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 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 set forth in SEQ ID NO: 15 or SEQ ID NO: 16 are located in the FR regions.

[0051] In some embodiments, the antigen-binding construct targeting HER2 may further comprise an immunoglobulin constant region, or a fragment, analog, variant, or derivative of the 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 a human immunoglobulin heavy chain, such as IgG1, IgG2, IgG3, and IgG4 or other classes of immunoglobulin heavy chains, preferably IgG4 heavy chains. In some embodiments, the light chain constant region is derived from a human immunoglobulin light chain, such as a kappa light chain or a lambda light chain of a human immunoglobulin. In some embodiments, the constant region may comprise any modification described herein, such as 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, and deletion of the C-terminal lysine of the heavy chain constant region typically occurs during recombinant expression. In some embodiments, the constant region comprises a mutation that alters effector function. In some embodiments, any amino acid residue in the constant region may be substituted with an amino acid residue of any allotype.

[0052] In some embodiments, the antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence 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 of SEQ ID NO: 17, a second polypeptide chain having an amino acid sequence 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 of SEQ ID NO: 18, and a second polypeptide chain having an amino acid sequence 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 of SEQ ID NO: NO: 19 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 to a third polypeptide chain. In some embodiments, the antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence as set forth in SEQ ID NO: 17, a second polypeptide chain having an amino acid sequence as set forth in SEQ ID NO: 18, and a third polypeptide chain having an amino acid sequence as set forth 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 as set forth in SEQ ID NO: 17, the amino acid sequence of the second polypeptide chain is as set forth in SEQ ID NO: 18, and the amino acid sequence of the third polypeptide chain is as set forth in SEQ ID NO: 19.

[0053] In some embodiments, the antigen-binding construct targeting HER2 comprises a first polypeptide chain, a second polypeptide chain, and a third polypeptide chain, wherein the first polypeptide chain comprises a HCDR1 having an amino acid sequence as shown in SEQ ID NO: 1, a HCDR2 having an amino acid sequence as shown in SEQ ID NO: 2, a HCDR3 having an amino acid sequence as shown in SEQ ID NO: 3, a LCDR1 having an amino acid sequence as shown in SEQ ID NO: 4, a LCDR2 having an amino acid sequence as shown in SEQ ID NO: 5, and a LCDR3 having an amino acid sequence as shown in SEQ ID NO: 6; the second polypeptide chain comprises a HCDR1 having an amino acid sequence as shown in SEQ ID NO: 9, a HCDR2 having an amino acid sequence as shown in SEQ ID NO: 10, and a HCDR3 having an amino acid sequence as shown in SEQ ID NO: 11; the third polypeptide chain comprises a LCDR1 having an amino acid sequence as shown in SEQ ID NO: 12, a LCDR2 having an amino acid sequence as shown in SEQ ID NO: 13, and a LCDR3 having an amino acid sequence as shown in SEQ ID NO: 14, and the first polypeptide chain comprises a HCDR1 having an amino acid sequence as shown in SEQ ID NO: 15, a LCDR2 having an amino acid sequence as shown in SEQ ID NO: 16, and a LCDR3 having an amino acid sequence as shown in SEQ ID NO: 17. NO:17, the first polypeptide chain comprises 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 of SEQ ID NO:18, the second polypeptide chain comprises 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 of SEQ ID NO:19, the third polypeptide chain comprises 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 of SEQ ID NO:20 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.

[0054] In some embodiments, the C-terminal lysine of the amino acid sequence set forth in SEQ ID NO: 17 is deleted, as shown in SEQ ID NO: 20. In some embodiments, the C-terminal lysine of the amino acid sequence set forth in SEQ ID NO: 18 is deleted, as shown in SEQ ID NO: 21. In some embodiments, the C-terminal lysine of the first and second polypeptide chains is 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.

[0055] 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 set forth in SEQ ID NO: 17, 18 or 19 are located in the FR region or the constant region.

[0056] In other embodiments, the antigen-binding construct targeting HER2 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 other embodiments, the antigen-binding construct targeting HER2 is selected from Zanidatamab (ZW25), KN026, MBS301, KM257 or BCD-147.

[0057] The antibody drug conjugate preferably used in the present disclosure is formed by connecting a drug-linker having a structure represented by the following formula Ia to an antigen-binding construct targeting HER2:

[0058] Wherein, the 3-position of -(succinimide-3-yl-N)- in Formula Ia is linked to an antigen-binding construct targeting HER2,

[0059] The HER2-targeting antigen-binding construct consists of three polypeptide chains, 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, and

[0060] For one HER2-targeting antigen-binding construct, the average number of drug-linker connections was 5 to 6.

[0061] In some embodiments, the 3-position of -(succinimidyl-3-yl-N)- in Formula Ia is linked to the antigen-binding construct targeting HER2 through a thioether bond.

[0062] The antibody drug conjugates preferably used in the present disclosure can also be represented by the structure shown in the following formula II:

[0063] Where n is 5 to 6,

[0064] The HER2-targeting antigen-binding construct is composed of three polypeptide chains, 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. In some embodiments, the drug-linker is connected to the HER2-targeting antigen-binding construct via a thioether bond.

[0065] In other specific embodiments, the anti-HER2 antibody drug conjugates disclosed herein are selected from MRG002, ARX788, A166, SHR-A1811, BB-1701, SYD985, FS-1502, or BAT8001.

[0066] The anti-HER2 antibody-drug conjugates disclosed herein also include isomers, pharmaceutically acceptable salts, or solvates of the anti-HER2 antibody-drug conjugates, their isomers, or their pharmaceutically acceptable salts.

[0067] Technical Effects

[0068] Administration of the anti-HER2 antibody drug conjugates disclosed herein has one or more of the following effects:

[0069] (1) Producing benefits to subjects with breast cancer, preferably metastatic and / or recurrent breast cancer;

[0070] (2) Good safety;

[0071] (3) It is well tolerated in the subjects.

[0072] Definition and Description

[0073] Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this disclosure, it is intended to refer to the corresponding commercial product or its active ingredient.

[0074] As used herein, the structure of "-(succinimidyl-3-yl-N)-" is as follows:

[0075] Unless otherwise specified, use a solid wedge key. and dotted wedge key Indicates the absolute configuration of a stereocenter.

[0076] Unless otherwise specified, when a group has a linkable site, the link between that site and other groups can be represented by a wavy line. express.

[0077] The term "antigen binding construct" refers to any agent 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. An antigen binding construct can be a monomer, dimer, multimer, protein, peptide, protein or peptide complex, antibody, or antigen binding fragment thereof, etc. An antigen binding construct can be a monospecific, bispecific, or multispecific polypeptide construct. In some aspects, an antigen binding construct can include, for example, one or more antigen binding fragments (e.g., Fab or scFv) connected to one or more Fc.

[0078] The "antigen-binding fragment" of an antibody refers to one or more fragments of an antibody that retain the function of specifically binding to an antigen (e.g., HER2 protein). It has been demonstrated that the antigen-binding function of an antibody can be implemented by a fragment of a full-length antibody. Examples encompassed within the term "antigen-binding fragment" of an antibody include: (i) a Fab fragment: a monovalent fragment consisting of a VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments connected by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of a VH and CH1 domain; (iv) an Fv fragment consisting of the VL and VH domains of a single-arm antibody; (v) a dAb fragment consisting of a VH domain (see Ward et al., Nature. 341: 544-546 (1989)); and (vi) a nanobody, an antibody comprising a single variable domain and two constant domains. In addition, although the two domains VL and VH of the Fv fragment are encoded by different genes, VH and VL can be connected into a single protein chain by a recombinant method through a linker, wherein VL and VH are paired to form a monovalent molecule called single-chain Fv (scFv) (see Bird et al., Science. 242: 423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. 85: 5879-5883 (1988)), and these single-chain antibodies are also encompassed by the term antigen-binding fragment. These antibody fragments can be obtained by conventional techniques known to those skilled in the art, and the fragments can be functionally screened by the same method as full-length antibodies.

[0079] The term "identity" is also known as consistency. The "percentage (%) identity" of an amino acid sequence refers to the percentage of amino acid residues in the sequence to be aligned that are identical to the amino acid residues in the specific amino acid sequence shown in this article, after comparing the sequence to be aligned and, if necessary, introducing gaps to achieve maximum sequence identity, and not considering any conservative substitutions as part of sequence identity. The alignment of amino acid sequences for identity can be performed in a variety of ways within the scope of the art, such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine the appropriate parameters for aligning sequences, including any algorithm needed to obtain maximum alignment over the full length of the comparison sequence.

[0080] The term "treating" means administering a compound of the present disclosure to prevent, ameliorate, or eliminate a disease or one or more symptoms associated with the disease, and includes but is not limited to:

[0081] (i) preventing a disease or disease state from occurring in a mammal, particularly where such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state;

[0082] (ii) inhibiting the disease or disease state, i.e., curbing its development;

[0083] (iii) alleviate the disease or condition, even if the disease or condition regresses;

[0084] (iv) reducing any direct or indirect pathological consequences of the disease or disease state.

[0085] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" may vary depending on factors such as the compound and its ability to elicit a desired response in a subject, the disease state and its severity, the route of administration, and the age, sex, and weight of the mammal to be treated.

[0086] The terms "administering" or "administering" refer to 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.

[0087] The route of administration of antibody drug conjugates (such as anti-HER2 antibody drug conjugates) includes intravenous, intramuscular, intraperitoneal, spinal column or other parenteral administration routes.Term used herein " parenteral administration " refers to, the mode of administration of the non-enteral administration carried out by injection usually, and includes but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, spinal column, epidural and intrasternal injection and infusion and in vivo electroporation.Administration can also be performed, for example, once, repeatedly, and / or in one or more extended time periods.

[0088] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0089] The term "pharmaceutically acceptable salt" refers to a salt of a compound (e.g., the antibody-drug conjugates of the present disclosure) that is safe and effective when used in mammals and has the desired biological activity. For example, the salt may 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.

[0090] The term "excipient" refers to any ingredient other than the active ingredient (e.g., the antibody drug conjugate of the present disclosure). The choice of excipient will largely depend on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0091] The term "solvate" refers to an association of a compound with solvent molecules.

[0092] In the present disclosure, "HER2-positive" breast cancer is not particularly limited as long as it is a breast cancer recognized by those skilled in the art as overexpressing HER2. Preferably, it includes, for example, a breast cancer whose HER2 expression is 3+ as determined by immunohistochemistry (IHC) (i.e., HER2 detection by IHC is determined to be IHC 3+), or / and a breast cancer whose HER2 expression is 2+ as determined by IHC and whose HER2 expression is positive as determined by in situ hybridization (ISH) (i.e., HER2 detection by IHC is determined to be IHC 2+ and HER2 detection by ISH is determined to be ISH+). It should be noted that the in situ hybridization methods disclosed herein include, but are not limited to, fluorescence in situ hybridization (FISH) and dual-color in situ hybridization (DISH).

[0093] In the present disclosure, "HER2-low-expressing" breast cancer is not particularly limited as long as it is recognized by those skilled in the art as HER2-low-expressing breast cancer. Preferably, it includes, for example, breast cancer in which HER2 expression is 2+ as determined by IHC and HER2 expression is negative as determined by ISH (i.e., HER2 detection by IHC is determined as IHC 2+ and HER2 detection by ISH is determined as ISH-), or / and breast cancer in which HER2 expression is 1+ as determined by IHC (i.e., HER2 detection by IHC is determined as IHC 1+).

[0094] As used herein, 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.

[0095] As used herein, "combination" or "combined use" means that two or more active ingredients can be administered to a subject simultaneously as a single formulation, or sequentially in any order as a single formulation. Alternatively, all of the active ingredients are formulated in a single formulation and administered to a subject simultaneously. Alternatively, some of the active ingredients are formulated in a single formulation, and the other parts of the active ingredients are each administered to a subject simultaneously as a single formulation, or sequentially in any order.

[0096] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients (e.g., the anti-HER2 antibody drug conjugates of the present disclosure) and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredients to a subject. As used herein, the terms "pharmaceutical composition" and "preparation" have the same meaning and are used interchangeably.

[0097] As used herein, "treatment failure" is defined as disease progression or recurrence during or after the last treatment.

[0098] As used herein, a "line of treatment" refers to a position in the order in which a patient receives different drugs or other treatments. The term "first-line treatment" refers to a drug that can be selected first or selected by standard according to the patient's condition for treatment. "Second-line treatment" and "third-line treatment" are administered after first-line treatment and second-line treatment, respectively. If the patient does not show a positive clinical outcome for first-line treatment or second-line treatment, or shows a positive clinical response but later develops disease progression or recurrence, or the condition at this time is resistant to the previous treatment that has caused a positive clinical response, the patient will receive a subsequent treatment regimen (e.g., second-line treatment or third-line treatment). Non-limiting examples of clinical outcomes include tumor response, overall survival, progression-free survival, disease-free survival, time to tumor recurrence, time to tumor progression, relative risk, toxicity, or side effects.

[0099] The words “comprise,” “comprise,” or “comprises,” and variations thereof such as comprises or comprising, should be construed in an open, non-exclusive sense, ie, “including but not limited to.”

[0100] Herein, singular terms encompass plural referents and vice versa unless the context clearly dictates otherwise.

[0101] As used herein, "about" means within the acceptable error range 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" can mean within 1 or more than 1 standard deviation as practiced in the art. Alternatively, "about" can mean a range of up to ±5%, such as fluctuations within ±2%, within ±1%, or within ±0.5% of the specific numerical range given. When a specific value is given in the present disclosure or claims, unless otherwise indicated, the meaning of "about" should be considered to be within the acceptable error range for that specific value. In this document, unless otherwise indicated, all values ​​for drug doses, times, step parameters, or conditions are modified by "about" by default.

[0102] For the 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 disclosure predates the filing date of the present disclosure. All statements regarding the dates of these documents or representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation of these publications herein does not constitute an admission that such publications are part of the common general knowledge in the art in any country.

[0103] The present disclosure also provides the following specific implementation schemes, but the protection scope of the present disclosure is not limited thereto:

[0104] Embodiment 1. A method for treating breast cancer in a subject, comprising administering to the subject an anti-HER2 antibody drug conjugate, wherein the anti-HER2 antibody drug conjugate is represented by the following formula Ia

[0105] The drug-linker of the structure shown is connected to the antigen-binding construct targeting HER2.

[0106] R1 and R2 in Formula Ia are independently selected from hydrogen (H) or deuterium (D), the 3-position of -(succinimide-3-yl-N)- is connected to the antigen-binding construct targeting HER2,

[0107] The HER2-targeting antigen-binding construct comprises a first antigen-binding fragment and a second antigen-binding fragment, wherein the first antigen-binding fragment comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding fragment comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO: 9, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 10, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 11, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 13, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 14.

[0108] Embodiment 2. The method according to embodiment 1, wherein the average number of drug-linker connections per HER2-targeting antigen-binding construct is 4 to 7.

[0109] Embodiment 3. The method according to embodiment 2, wherein the average number of drug-linker connections per HER2-targeting antigen-binding construct is 5 to 6.

[0110] Embodiment 4. The method according to embodiment 3, wherein the average number of drug-linker connections per HER2-targeting antigen-binding construct is 5.5 to 6.

[0111] Embodiment 5. The method according to any one of embodiments 1-4, wherein

[0112] (i) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence 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 of SEQ ID NO:7;

[0113] (ii) the first antigen-binding fragment comprises a light chain variable region whose amino acid sequence 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 of SEQ ID NO:8;

[0114] (iii) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence 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 of SEQ ID NO:7, and a light chain variable region whose amino acid sequence 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 of SEQ ID NO:8;

[0115] (iv) the second antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence 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 of SEQ ID NO: 15;

[0116] (v) the second antigen-binding fragment comprises a light chain variable region whose amino acid sequence 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 of SEQ ID NO: 16;

[0117] (vi) the second antigen-binding fragment comprises a heavy chain variable region that 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 to the amino acid sequence of SEQ ID NO: 15, and a light chain variable region that 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 to the amino acid sequence of SEQ ID NO: 16; or

[0118] (vii) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence 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 of SEQ ID NO:7, and a light chain variable region whose amino acid sequence 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 of SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identical to SEQ ID NO: 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 of SEQ ID NO:15, 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 of SEQ ID NO:16.

[0119] Embodiment 6. The method according to any one of embodiments 1-5, wherein

[0120] (i) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence 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 of SEQ ID NO: 17 or 20;

[0121] (ii) the antigen-binding construct targeting HER2 comprises a second polypeptide chain whose amino acid sequence 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 of SEQ ID NO: 18 or 21;

[0122] (iii) the antigen-binding construct targeting HER2 comprises a third polypeptide chain whose amino acid sequence 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 of SEQ ID NO: 19; or

[0123] (iv) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence 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 of SEQ ID NO: 17, a second polypeptide chain whose amino acid sequence 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 of SEQ ID NO: 18, and a second polypeptide chain whose amino acid sequence 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 of SEQ ID NO: a 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%, 99% or 100% identity to the amino acid sequence of NO:19;

[0124] 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 of SEQ ID NO: 20, 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 of SEQ ID NO: 21, and 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 of SEQ ID NO: a 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%, 99% or 100% identity to the amino acid sequence of NO:19;

[0125] 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 of SEQ ID NO: 17, 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 of SEQ ID NO: 21, and 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 of SEQ ID NO: a third polypeptide chain 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 of NO:19; or

[0126] 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 of SEQ ID NO: 20, 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 of SEQ ID NO: 18, and 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 of SEQ ID NO: The invention also provides a method for preparing a polypeptide chain 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 NO:19.

[0127] Embodiment 7. The method of any one of Embodiments 1-6, wherein the anti-HER2 antibody drug conjugate is administered in a therapeutically effective amount.

[0128] Embodiment 8. The method according to any one of embodiments 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.

[0129] Embodiment 9. The method according to embodiment 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, 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.

[0130] Embodiment 10. The method according to any one of embodiments 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.

[0131] Embodiment 11. The method according to any one of embodiments 1-10, wherein the anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous injection or infusion.

[0132] Embodiment 12. The method of any one of Embodiments 1-11, wherein the anti-HER2 antibody drug conjugate is administered by intravenous infusion.

[0133] Embodiment 13. The method of any one of Embodiments 1-12, wherein the breast cancer is recurrent and / or metastatic breast cancer, or locally advanced or metastatic breast cancer.

[0134] Embodiment 14. The method of any one of Embodiments 1-13, wherein the breast cancer is unresectable breast cancer.

[0135] Embodiment 15. The method of any one of Embodiments 1-14, wherein the breast cancer is HER2-expressing breast cancer.

[0136] Embodiment 16. The method of any one of Embodiments 1-15, wherein the breast cancer is HER2-positive breast cancer.

[0137] Embodiment 17. The method according to embodiment 16, wherein the HER2-positive breast cancer is a breast cancer whose HER2 expression is determined to be 3+ by IHC.

[0138] Embodiment 18. The method according to embodiment 16, wherein the HER2-positive breast cancer is a breast cancer in which the expression of HER2 is determined to be 2+ by IHC and the expression of HER2 is determined to be positive by ISH.

[0139] Embodiment 19. The method of any one of Embodiments 1-15, wherein the breast cancer is HER2-low expressing breast cancer.

[0140] Embodiment 20. The method according to embodiment 19, wherein the breast cancer with low HER2 expression is a breast cancer in which the expression of HER2 is 2+ as determined by IHC and the expression of HER2 is negative as determined by ISH.

[0141] Embodiment 21. The method according to embodiment 19, wherein the breast cancer with low HER2 expression is a breast cancer whose HER2 expression is determined to be 1+ by IHC.

[0142] Embodiment 22. The method of any one of Embodiments 1-21, wherein the breast cancer is hormone receptor-positive or hormone receptor-negative breast cancer.

[0143] Embodiment 23. The method of any one of Embodiments 1-22, wherein the breast cancer is hormone receptor-positive breast cancer.

[0144] Embodiment 24. The method according to embodiment 23, wherein the breast cancer is estrogen receptor or / and progesterone receptor positive breast cancer.

[0145] Embodiment 25. The use according to any one of embodiments 1-18, wherein the breast cancer is hormone receptor negative or positive, HER2-positive recurrent or metastatic breast cancer.

[0146] Embodiment 26. The method of any one of Embodiments 1-25, wherein the subject with breast cancer is not suitable for surgery and / or radiation therapy.

[0147] Embodiment 27. The method of any one of Embodiments 1-26, wherein the subject with breast cancer has previously received at least one line of treatment for breast cancer.

[0148] Embodiment 28. The method according to any one of Embodiments 1 to 27, wherein the subject with breast cancer is a subject with HER2-expressing recurrent and / or metastatic breast cancer who has failed at least one line of systemic chemotherapy at the recurrent and / or metastatic stage;

[0149] The breast cancer subject is a subject with hormone receptor-positive, recurrent and / or metastatic breast cancer that expresses HER2 and has failed CDK4 / 6 inhibitor combined with endocrine therapy at the recurrent and / or metastatic stage;

[0150] The breast cancer subject is a subject with HER2-expressing recurrent and / or metastatic breast cancer who has received treatment with trastuzumab and taxanes;

[0151] The breast cancer subject is a subject with locally advanced or metastatic breast cancer with low HER2 expression who has not received chemotherapy at the recurrence and / or metastasis stage; or

[0152] The breast cancer subjects are HR-positive and HER2-low expressing locally advanced or metastatic breast cancer subjects who have received at least one line of endocrine therapy at the recurrence and / or metastasis stage and whose disease has progressed or whose disease has progressed within 24 months after the start of adjuvant endocrine therapy.

[0153] Embodiment 29. The method according to any one of claims 1 to 28, wherein the subject with breast cancer is a subject with HER2-positive recurrent and / or metastatic breast cancer who has failed at least one line of systemic chemotherapy at the recurrent and / or metastatic stage;

[0154] The breast cancer subject is a subject with HER2-positive recurrent and / or metastatic breast cancer who has received treatment with trastuzumab and taxanes;

[0155] The breast cancer subject is a subject with recurrent and / or metastatic breast cancer with low HER2 expression who has failed at least one line of systemic chemotherapy at the recurrent and / or metastatic stage;

[0156] The breast cancer subject is a subject with hormone receptor-positive, recurrent and / or metastatic breast cancer with low HER2 expression who has failed CDK4 / 6 inhibitor combined with endocrine therapy at the recurrent and / or metastatic stage;

[0157] The breast cancer subject is a subject with unresectable locally advanced or metastatic breast cancer with low HER2 expression who has not received chemotherapy at the recurrence and / or metastasis stage; or

[0158] The breast cancer subjects are HR-positive and HER2-low expressing unresectable locally advanced or metastatic breast cancer subjects who have received at least one line of endocrine therapy at the recurrence and / or metastasis stage and whose disease has progressed or whose disease has progressed within 24 months after the start of adjuvant endocrine therapy.

[0159] Embodiment 30. The method of any one of Embodiments 1-29, wherein the anti-HER2 antibody drug conjugate is used for second-line treatment or later-line treatment of breast cancer in a subject.

[0160] Embodiment 31. The method of any one of Embodiments 1-30, wherein the subject with breast cancer has previously received adjuvant therapy or neoadjuvant therapy for breast cancer.

[0161] Embodiment 32. The method of any one of Embodiments 1-31, wherein the subject with breast cancer has previously received localized radiation therapy to treat breast cancer.

[0162] Embodiment 33. The method of any one of Embodiments 1-32, wherein the subject with breast cancer has previously received anti-HER2 antibody therapy, taxanes, CDK4 / 6 inhibitors, endocrine therapy, and / or adjuvant endocrine therapy.

[0163] Embodiment 34. The method of any one of Embodiments 1-33, wherein the subject with breast cancer has not received chemotherapy at the recurrence and / or metastasis stage.

[0164] Embodiment 35. Use of an anti-HER2 antibody drug conjugate in the preparation of a medicament for treating breast cancer in a subject, comprising administering the anti-HER2 antibody drug conjugate to the subject, wherein the anti-HER2 antibody drug conjugate is represented by the following formula Ia

[0165] The drug-linker of the structure shown is connected to the antigen-binding construct targeting HER2.

[0166] R1 and R2 in Formula Ia are independently selected from hydrogen (H) or deuterium (D), the 3-position of -(succinimide-3-yl-N)- is connected to the antigen-binding construct targeting HER2,

[0167] The HER2-targeting antigen-binding construct comprises a first antigen-binding fragment and a second antigen-binding fragment, wherein the first antigen-binding fragment comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding fragment comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO: 9, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 10, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 11, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 13, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 14.

[0168] Embodiment 36. The use according to embodiment 35, wherein the average number of drug-linker connections per HER2-targeting antigen-binding construct is 4 to 7.

[0169] Embodiment 37. The use according to embodiment 36, wherein the average number of drug-linker connections per HER2-targeting antigen-binding construct is 5 to 6.

[0170] Embodiment 38. The use according to embodiment 37, wherein the average number of drug-linker connections per HER2-targeting antigen-binding construct is 5.5 to 6.

[0171] Embodiment 39. The use according to any one of embodiments 35-38, wherein

[0172] (i) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence 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 of SEQ ID NO:7;

[0173] (ii) the first antigen-binding fragment comprises a light chain variable region whose amino acid sequence 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 of SEQ ID NO:8;

[0174] (iii) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence 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 of SEQ ID NO:7, and a light chain variable region whose amino acid sequence 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 of SEQ ID NO:8;

[0175] (iv) the second antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence 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 of SEQ ID NO: 15;

[0176] (v) the second antigen-binding fragment comprises a light chain variable region whose amino acid sequence 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 of SEQ ID NO: 16;

[0177] (vi) the second antigen-binding fragment comprises a heavy chain variable region that 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 to the amino acid sequence of SEQ ID NO:15, and a light chain variable region that 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 to the amino acid sequence of SEQ ID NO:16; or

[0178] (vii) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence 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 of SEQ ID NO:7, and a light chain variable region whose amino acid sequence 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 of SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identical to SEQ ID NO: 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 of SEQ ID NO:15, 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 of SEQ ID NO:16.

[0179] Embodiment 40. The use according to any one of embodiments 35-39, wherein

[0180] (i) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence 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 of SEQ ID NO: 17 or 20;

[0181] (ii) the antigen-binding construct targeting HER2 comprises a second polypeptide chain whose amino acid sequence 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 of SEQ ID NO: 18 or 21;

[0182] (iii) the antigen-binding construct targeting HER2 comprises a third polypeptide chain whose amino acid sequence 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 of SEQ ID NO: 19; or

[0183] (iv) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence 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 of SEQ ID NO: 17, a second polypeptide chain whose amino acid sequence 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 of SEQ ID NO: 18, and a second polypeptide chain whose amino acid sequence 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 of SEQ ID NO: a 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%, 99% or 100% identity to the amino acid sequence of NO:19;

[0184] 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 of SEQ ID NO: 20, 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 of SEQ ID NO: 21, and 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 of SEQ ID NO: a 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%, 99% or 100% identity to the amino acid sequence of NO:19;

[0185] 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 of SEQ ID NO: 17, 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 of SEQ ID NO: 21, and 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 of SEQ ID NO: a third polypeptide chain 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 of NO:19; or

[0186] 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 of SEQ ID NO: 20, 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 of SEQ ID NO: 18, and 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 of SEQ ID NO: The invention also provides a method for preparing a polypeptide chain 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 NO:19.

[0187] Embodiment 41. The use according to any one of Embodiments 35-40, wherein the anti-HER2 antibody drug conjugate is administered in a therapeutically effective amount.

[0188] Embodiment 42. The use according to any one of Embodiments 35-41, 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.

[0189] Embodiment 43. The use according to embodiment 42, wherein the anti-HER2 antibody drug conjugate is administered at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 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.

[0190] Embodiment 44. The use according to any one of embodiments 35-43, 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.

[0191] Embodiment 45. The use according to any one of Embodiments 35-44, wherein the anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous injection or infusion.

[0192] Embodiment 46. The use according to any one of Embodiments 35-45, wherein the anti-HER2 antibody drug conjugate is administered by intravenous infusion.

[0193] Embodiment 47. The use according to any one of Embodiments 35-46, wherein the breast cancer is recurrent and / or metastatic breast cancer, or locally advanced or metastatic breast cancer.

[0194] Embodiment 48. The use according to any one of Embodiments 35-47, wherein the breast cancer is unresectable breast cancer.

[0195] Embodiment 49. The use according to any one of Embodiments 35-48, wherein the breast cancer is HER2-expressing breast cancer.

[0196] Embodiment 50. The use according to any one of embodiments 35-49, wherein the breast cancer is HER2-positive breast cancer.

[0197] Embodiment 51. The use according to embodiment 50, wherein the HER2-positive breast cancer is a breast cancer whose HER2 expression is determined to be 3+ by IHC.

[0198] Embodiment 52. The use according to embodiment 50, wherein the HER2-positive breast cancer is a breast cancer in which the expression of HER2 is determined to be 2+ by IHC and the expression of HER2 is determined to be positive by ISH.

[0199] Embodiment 53. The use according to any one of Embodiments 35-49, wherein the breast cancer is HER2-low expressing breast cancer.

[0200] Embodiment 54. The use according to embodiment 53, wherein the breast cancer with low HER2 expression is a breast cancer in which the expression of HER2 is determined to be 2+ by IHC and the expression of HER2 is negative by ISH.

[0201] Embodiment 55. The use according to embodiment 53, wherein the breast cancer with low HER2 expression is a breast cancer whose HER2 expression is determined to be 1+ by IHC.

[0202] Embodiment 56. The use according to any one of Embodiments 35-55, wherein the breast cancer is hormone receptor-positive or hormone receptor-negative breast cancer.

[0203] Embodiment 57. The use according to any one of Embodiments 35-56, wherein the breast cancer is hormone receptor-positive breast cancer.

[0204] Embodiment 58. The use according to embodiment 57, wherein the breast cancer is estrogen receptor or / and progesterone receptor positive breast cancer.

[0205] Embodiment 59. The use according to any one of embodiments 35-52, wherein the breast cancer is hormone receptor negative or positive, HER2-positive recurrent or metastatic breast cancer.

[0206] Embodiment 60. The use according to any one of embodiments 35-59, wherein the subject with breast cancer is not suitable for surgery and / or radiation therapy.

[0207] Embodiment 61. The use according to any one of embodiments 35-60, wherein the subject with breast cancer has previously received at least one line of treatment for breast cancer.

[0208] Embodiment 62. The use according to any one of Embodiments 35-61, wherein the subject with breast cancer is a subject with HER2-expressing recurrent and / or metastatic breast cancer who has failed at least one line of systemic chemotherapy at the recurrent and / or metastatic stage;

[0209] The breast cancer subject is a subject with hormone receptor-positive, recurrent and / or metastatic breast cancer that expresses HER2 and has failed CDK4 / 6 inhibitor combined with endocrine therapy at the recurrent and / or metastatic stage;

[0210] The breast cancer subject is a subject with HER2-expressing recurrent and / or metastatic breast cancer who has received treatment with trastuzumab and taxanes;

[0211] The breast cancer subject is a subject with locally advanced or metastatic breast cancer with low HER2 expression who has not received chemotherapy at the recurrence and / or metastasis stage; or

[0212] The breast cancer subjects are HR-positive and HER2-low expressing locally advanced or metastatic breast cancer subjects who have received at least one line of endocrine therapy at the recurrence and / or metastasis stage and whose disease has progressed or whose disease has progressed within 24 months after the start of adjuvant endocrine therapy.

[0213] Embodiment 63. The use according to any one of claims 35 to 62, wherein the subject with breast cancer is a subject with HER2-positive recurrent and / or metastatic breast cancer who has failed at least one line of systemic chemotherapy at the recurrent and / or metastatic stage;

[0214] The breast cancer subject is a subject with HER2-positive recurrent and / or metastatic breast cancer who has received treatment with trastuzumab and taxanes;

[0215] The breast cancer subject is a subject with recurrent and / or metastatic breast cancer with low HER2 expression who has failed at least one line of systemic chemotherapy at the recurrent and / or metastatic stage;

[0216] The breast cancer subject is a subject with hormone receptor-positive, recurrent and / or metastatic breast cancer with low HER2 expression who has failed CDK4 / 6 inhibitor combined with endocrine therapy at the recurrent and / or metastatic stage;

[0217] The breast cancer subject is a subject with unresectable locally advanced or metastatic breast cancer with low HER2 expression who has not received chemotherapy at the recurrence and / or metastasis stage; or

[0218] The breast cancer subjects are HR-positive and HER2-low expressing unresectable locally advanced or metastatic breast cancer subjects who have received at least one line of endocrine therapy at the recurrence and / or metastasis stage and whose disease has progressed or whose disease has progressed within 24 months after the start of adjuvant endocrine therapy.

[0219] Embodiment 64. The use according to any one of Embodiments 35-63, wherein the anti-HER2 antibody drug conjugate is used for second-line treatment or later-line treatment of breast cancer in a subject.

[0220] Embodiment 65. The use according to any one of embodiments 35-64, wherein the subject with breast cancer has previously received adjuvant therapy or neoadjuvant therapy for breast cancer.

[0221] Embodiment 66. The use according to any one of Embodiments 35-65, wherein the subject with breast cancer has previously received localized radiation therapy to treat breast cancer.

[0222] Embodiment 67. The use according to any one of Embodiments 35-66, wherein the subject with breast cancer has previously received anti-HER2 antibody therapy, taxanes, CDK4 / 6 inhibitors, endocrine therapy, and / or adjuvant endocrine therapy.

[0223] Embodiment 68. The use according to any one of embodiments 35-67, wherein the subject with breast cancer has not received chemotherapy at the recurrence and / or metastasis stage. Example

[0224] For the purpose of clarity, the present disclosure is further illustrated with examples, but the examples do not limit the scope of the present disclosure.

[0225] The entire contents of the patent application documents WO2022033578 or CN115702008A are incorporated into the present disclosure. In the following examples, the anti-HER2 antibody drug conjugates were prepared by referring to the preparation method described in WO2022033578 to prepare the anti-HER2 antibody drug conjugate (hereinafter referred to as ADC1) represented by the following formula:

[0226] The drug-linker is connected to the HER2-targeting antigen-binding construct via a thioether bond, and n is 5 to 6. Briefly, the nucleic acid sequences encoding the three polypeptide chains of the HER2-targeting antigen-binding construct (amino acid sequences are shown in SEQ ID NOs: 17, 18, and 19, respectively) 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)phosphine hydrochloride and then reacted with a linker-payload selected from the structure shown in the following formula to ultimately obtain ADC1:

[0227] Example 1: Phase Ib clinical trial for HER2-expressing breast cancer

[0228] 1. Research objectives:

[0229] 1.1 Main Purpose:

[0230] To evaluate the efficacy of ADC1 in subjects with HER2-expressing recurrent and / or metastatic breast cancer.

[0231] 1.2 Secondary Purpose:

[0232] (1) To evaluate the safety of ADC1 in subjects with HER2-expressing recurrent and / or metastatic breast cancer;

[0233] (2) Evaluate the pharmacokinetic (PK) characteristics and immunogenicity of ADC1 in subjects with HER2-expressing recurrent and / or metastatic breast cancer.

[0234] 2. Selection Criteria

[0235] Only those who meet all of the following inclusion criteria can be enrolled in this trial:

[0236] (1) The subjects voluntarily participated in this study and signed the informed consent form;

[0237] (2) Age: 18-75 years old (at the time of signing the informed consent); ECOG score: ≤1; expected survival time: more than 3 months;

[0238] (3) Patients with breast cancer confirmed to express HER2 by pathological examination, with evidence of local recurrence or distant metastasis, who are not suitable for surgery or radiotherapy with curative intent;

[0239] a) HER2 expression was defined as 1+, 2+, or 3+ by standard immunohistochemistry (IHC) assay;

[0240] b) HER2 low expression (cohort 1 subjects) was defined as 1+ or 2+ on standard immunohistochemistry (IHC); if the test showed 2+, in situ hybridization (ISH) was required to confirm the negative result;

[0241] c) HER2 positivity (Cohort 2 subjects) was defined as: 3+ or 2+ on standard immunohistochemistry (IHC); if the test showed 2+, in situ hybridization (ISH) was required to confirm the positive result, or ISH alone was positive;

[0242] (4) Cohort 1 subjects (HER2 low expression) must meet the following previous treatment requirements:

[0243] a) Failure of at least one line of systemic chemotherapy in the relapse and / or metastasis stage; relapse during adjuvant chemotherapy or within 6 months after the end of adjuvant chemotherapy is considered as failure of first-line chemotherapy;

[0244] b) Hormone receptor-positive (HR-positive) subjects who have failed CDK4 / 6 inhibitor combined endocrine therapy at the relapse and / or metastasis stage; those who relapse during or within 12 months after adjuvant endocrine therapy are considered to have failed first-line endocrine therapy (HR-positive includes ER-positive and / or PR-positive, defined as: the proportion of positively stained tumor cells in all tumor cells ≥ 1%);

[0245] (5) Cohort 2 subjects (HER2 positive) must meet the following previous treatment requirements:

[0246] a) Failure of at least one line of systemic therapy in the recurrent and / or metastatic stage; recurrence during or within 12 months after (neo)adjuvant therapy is considered a failure of first-line therapy;

[0247] b) Patients who have received trastuzumab and taxanes in any previous stage of the disease;

[0248] (6) disease progression or intolerance during or after the most recent treatment before enrollment;

[0249] (7) at least one measurable lesion according to RECIST 1.1 criteria;

[0250] (8) The major organs function well and meet the standards of routine blood tests, biochemical tests, coagulation function tests, and cardiac ultrasound assessment;

[0251] (9) Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study and within 6 months after the end of the study; the serum pregnancy test should be negative within 7 days before enrollment in the study, and the subjects must be non-breastfeeding; male subjects should agree to use contraceptive measures during the study and within 6 months after the end of the study.

[0252] 3. Trial Drugs

[0253] ADC1 for injection (specification: 100 mg / bottle) is developed and provided by Shunxin Pharmaceutical Co., Ltd. of Zhengda Tianqing Pharmaceutical Group.

[0254] 4. Treatment options

[0255] Cohort 1 subjects were randomly assigned to two dose groups (with planned doses of 6.0 mg / kg and 7.5 mg / kg, respectively) in the order of enrollment. Cohort 2 subjects were also divided into two dose groups (with planned doses of 6.0 mg / kg and 7.5 mg / kg, respectively). The planned dose for approximately the first 50 subjects in Cohort 2 was 6.0 mg / kg, and the dose for subsequent subjects was 7.5 mg / kg. The dosing regimens of the two cohorts can be adjusted based on the severity of the disease, the response to the disease, any treatment-related toxicity, and the age and health status of the patient.

[0256] ADC1 is administered by intravenous infusion once every 3 weeks, with 21 days as a treatment cycle, until the disease progresses or the researcher determines that it is not suitable for continued medication.

[0257] 5. Evaluation Criteria

[0258] Effectiveness evaluation: RECIST 1.1 criteria were used to determine the disease status.

[0259] Safety evaluation: The NCI-CTC AE 5.0 standard was used to judge the severity of adverse events.

[0260] 6. Endpoint indicators

[0261] Objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR), etc.

[0262] The incidence and severity of adverse events (AEs) and serious adverse events (SAEs);

[0263] Pharmacokinetic parameters and immunogenicity parameters (such as the incidence of anti-drug antibodies), etc.

[0264] 7. Results

[0265] 7.1 Queue 1

[0266] From November 21, 2023, to March 28, 2024, a total of 73 subjects in Cohort 1 received at least one dose of 6.0 mg / kg ADC1 (n=37) or 7.5 mg / kg ADC1 (n=36). All subjects were female with a median age of 53 years. 48 subjects were identified as IHC 1+ by IHC for HER2 testing, while the remaining subjects were identified as IHC 2+ by IHC for HER2 testing and ISH- by ISH for HER2 testing. 73 subjects received chemotherapy in the metastatic stage, and all HR-positive subjects (n=50) had previously received CDK4 / 6 inhibitors. In Cohort 1, the median number of previous lines of therapy received by subjects in the metastatic stage was 4 (range 1-10), and the median number of previous lines of chemotherapy received was 2 (range 1-5). 12.3% (n=9) of the subjects had previously received ADC treatment, including 5 subjects who had previously received anti-HER2 ADC treatment and 5 subjects who had previously received ADC treatment targeting TROP2.

[0267] As of August 1, 2024, the ORR for subjects in Cohort 1 was 50.7% (37 / 73), with the 7.5 mg / kg dose group (58.3%, 21 / 36) achieving a significantly better ORR than the 6.0 mg / kg dose group (43.2%, 16 / 37). The ORRs for HR-positive and HR-negative patients were 50.0% (25 / 50) and 52.2% (12 / 23), respectively. For subjects in Cohort 1 who had previously received ADC treatment, the ORR was 44.4% (4 / 9).

[0268] Surprisingly, no subjects in cohort 1 reported interstitial lung disease (ILD), demonstrating a favorable safety profile.

[0269] Example results are as follows:

[0270] 7.2 Queue 2

[0271] Example results are as follows:

[0272] Example 2: Phase III clinical trial of HER2-expressing breast cancer

[0273] 1. Research objectives:

[0274] 1.3 Main Purpose:

[0275] The aim is to demonstrate that ADC1 can significantly prolong progression-free survival (PFS) compared with investigator-selected chemotherapy in subjects with HR-positive, HER2-low-expressing recurrent and / or metastatic breast cancer.

[0276] 1.4 Secondary objectives:

[0277] (1) To evaluate the progression-free survival (PFS) of ADC1 compared with investigator's choice of chemotherapy in subjects with recurrent and / or metastatic breast cancer with low HER2 expression;

[0278] (2) Evaluate overall survival (OS), objective response rate (ORR), duration of response (DOR), and clinical benefit rate (CBR) of ADC1 compared with investigator's choice of chemotherapy in subjects with HR-positive, HER2-low-expressing recurrent and / or metastatic breast cancer;

[0279] (3) Evaluate overall survival (OS), objective response rate (ORR), duration of response (DOR), and clinical benefit rate (CBR) of ADC1 compared with investigator's choice of chemotherapy in subjects with recurrent and / or metastatic breast cancer with low HER2 expression;

[0280] (4) Evaluate the safety of ADC1 versus investigator-selected chemotherapy in subjects with HER2-low expressing recurrent and / or metastatic breast cancer, including the incidence and severity of adverse events (AEs), abnormal laboratory values, and serious adverse events (SAEs);

[0281] (5) Evaluate the pharmacokinetic (PK) characteristics and immunogenicity of ADC1 in subjects with low HER2-expressing recurrent and / or metastatic breast cancer.

[0282] 2. Selection Criteria

[0283] Only those who meet all of the following inclusion criteria can be enrolled in this trial:

[0284] (1) The subjects voluntarily participated in this study, signed the informed consent form, and had good compliance;

[0285] (2) Age: 18-75 years old (at the time of signing the informed consent); ECOG score: 0-1; expected survival time more than 3 months;

[0286] (3) Pathologically confirmed HER2 low expression, unresectable locally advanced or metastatic breast cancer

[0287] a) HER2 low expression (IHC 2+ and ISH-, or IHC 1+) confirmed by central laboratory pathology test results;

[0288] b) If there are multiple previous HER2 pathology results, the specimen sent to the central laboratory must be from the most recent tumor tissue pathology specimen during the recurrence and / or metastasis stage of breast cancer, and the specimen must meet the pathological diagnosis of HER2 low expression;

[0289] c) Previous pathology reports have not diagnosed HER2-positive (IHC 3+ or ISH+) breast cancer;

[0290] (4) Hormone receptor (HR) status has been confirmed; if the subject has multiple ER / PR results at the relapse and / or metastasis stage, the most recent test result will be used to confirm eligibility;

[0291] (5) The subject's previous treatment must meet the following requirements:

[0292] a) Those who have not received systemic chemotherapy for breast cancer at the recurrence and / or metastasis stage; those whose disease progressed during or within 12 months after (neo)adjuvant chemotherapy are considered to have received first-line chemotherapy;

[0293] b) Subjects with HR-positive breast cancer who have received at least one line of endocrine therapy and have had disease progression at the recurrence and / or metastasis stage, or whose disease has progressed within 24 months of starting adjuvant endocrine therapy, and the investigator determines that the subject can no longer benefit from endocrine therapy (Note: If disease progression occurs more than 24 months after starting adjuvant endocrine therapy, it is not considered as first-line endocrine therapy at the recurrence and / or metastasis stage);

[0294] c) Subjects with HR-positive breast cancer who received targeted therapy including CDK4 / 6 inhibitors, HDAC inhibitors, PARP inhibitors, and PI3K / mTOR / AKT inhibitors. Monotherapy is not included in the number of lines of endocrine therapy.

[0295] d) Subjects with HR-negative breast cancer who are known to have positive PD-L1 expression (CPS ≥ 1) are not eligible for inclusion;

[0296] e) The number of previous lines of systemic anti-cancer treatment is defined by disease progression. If disease progression does not occur, changing drug therapy or adding a new anti-cancer drug to the original drug will still be considered the same line of treatment;

[0297] (6) disease progression confirmed by imaging examination (during the most recent treatment or after completion of treatment);

[0298] (7) at least one measurable lesion according to RECIST 1.1 (except for patients with only skin and / or brain lesions as measurable lesions);

[0299] (8) The major organs function well and meet the standards of routine blood tests, biochemical tests, coagulation function tests, and cardiac ultrasound assessment;

[0300] (9) Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study and within 6 months after the end of the study; the serum pregnancy test should be negative within 7 days before study enrollment, and the subjects must be non-breastfeeding; male subjects should agree to use contraceptive measures during the study and within 6 months after the end of the study.

[0301] 3. Trial Drugs

[0302] Experimental group: ADC1 for injection (specification: 100 mg / bottle), developed and provided by Shunxin Pharmaceutical Co., Ltd. of Zhengda Tianqing Pharmaceutical Group.

[0303] Control group: The chemotherapy regimen was selected by the researchers. The optional chemotherapy drugs included capecitabine, paclitaxel, and albumin-paclitaxel, all of which were developed and provided by Shunxin Pharmaceutical Co., Ltd. of Zhengda Tianqing Pharmaceutical Group.

[0304] 4. Treatment options

[0305] Experimental group: ADC1 was administered by intravenous infusion once every 3 weeks, 7.5 mg / kg each time, and 21 days was a treatment cycle.

[0306] Control group: (1) Capecitabine: Oral administration, 2 times a day, 1000-1250 mg / m 2 , administered continuously from day 1 to day 14, with 21 days as one treatment cycle; (2) Paclitaxel: intravenous infusion, administered once every 3 weeks, 175 mg / m 2 21 days is one treatment cycle; (3) Albumin-paclitaxel: intravenous infusion, once every 3 weeks, 260 mg / m 2 , 21 days as a treatment cycle; or intravenous infusion, once on the 1st day and once on the 8th day, each time 100 mg / m 2 or 125 mg / m 2 , 21 days as a treatment cycle; or intravenous infusion, once on the 1st day, 8th day, and 15th day, each time 100 mg / m 2 or 125 mg / m 2 , 21 days is one treatment cycle.

[0307] 5. Evaluation Criteria

[0308] Effectiveness evaluation: RECIST 1.1 criteria were used to determine the disease status.

[0309] Safety evaluation: The NCI-CTC AE 5.0 standard was used to judge the severity of adverse events.

[0310] 6. Endpoint indicators

[0311] 6.1 Primary Endpoint

[0312] Progression-free survival (PFS) in subjects with HR-positive, HER2-low-expressing recurrent and / or metastatic breast cancer as assessed by an independent radiological review committee (IRC).

[0313] 6.2 Key Secondary End Points

[0314] IRC-assessed progression-free survival (PFS) in subjects with recurrent and / or metastatic breast cancer who have low HER2 expression.

[0315] 6.3 Secondary End Points

[0316] Investigator-assessed progression-free survival (PFS), overall survival (OS), duration of response (DOR), objective response rate (ORR), and clinical benefit rate (CBR) in the HR-positive, HER2-low expression population;

[0317] Investigator-assessed progression-free survival (PFS), overall survival (OS), duration of response (DOR), objective response rate (ORR), and clinical benefit rate (CBR) in the HER2-low expression population;

[0318] The incidence and severity of adverse events (AEs) and serious adverse events (SAEs), as well as abnormal laboratory test indicators.

[0319] Blood concentrations of ADC drug, total antibody, and cytotoxic drug for ADC1;

[0320] Immunogenicity of ADC1: such as ADA incidence. 6.4 Exploratory Endpoints

[0321] Progression-free survival (PFS), overall survival (OS), duration of response (DOR), objective response rate (ORR), and clinical benefit rate (CBR) in the HR-negative, HER2-low expression population.

[0322] In this study, the use of ADC1 can achieve expected clinical benefits.

Claims

1. An anti-HER2 antibody drug conjugate for treating breast cancer in a subject, wherein: The anti-HER2 antibody drug conjugate is represented by the following formula Ia The drug-linker of the structure shown is connected to an antigen-binding construct targeting HER2, R1 and R2 in Formula Ia are independently selected from hydrogen or deuterium, preferably, R1 and R2 are hydrogen, The 3-position of -(succinimidyl-3-yl-N)- is linked to an 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 comprising the amino acid sequence of SEQ ID NO: 1, HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, LCDR1 comprising the amino acid sequence of SEQ ID NO: 4, LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, The second antigen-binding fragment comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:9, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:10, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:11, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:12, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:

14.

2. The anti-HER2 antibody drug conjugate for treating breast cancer in a subject according to claim 1, wherein: The average number of drug-linker connections per HER2-targeting antigen-binding construct is 4 to 7, 5 to 6, or 5.5 to 6.

3. The anti-HER2 antibody-drug conjugate for treating breast cancer in a subject according to claim 1 or 2, wherein: (i) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence 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 of SEQ ID NO:7; (ii) the first antigen-binding fragment comprises a light chain variable region whose amino acid sequence 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 of SEQ ID NO:8; (iii) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence 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 of SEQ ID NO:7, and a light chain variable region whose amino acid sequence 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 of SEQ ID NO:8; (iv) the second antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence 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 of SEQ ID NO:15; (v) the second antigen-binding fragment comprises a light chain variable region whose amino acid sequence 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 of SEQ ID NO:16; (vi) the second antigen-binding fragment comprises an amino acid sequence that is at least 80%, 81%, : a heavy chain variable region that is at least 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 of 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 of SEQ ID NO:16; or (vii) the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence 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 of SEQ ID NO:7, and a light chain variable region whose amino acid sequence 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 of SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence of SEQ ID NO:

9. 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 of SEQ ID NO:15, and a light chain variable region that 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 to the amino acid sequence of SEQ ID NO:

16.

4. The anti-HER2 antibody drug conjugate for treating breast cancer in a subject according to any one of claims 1 to 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 of SEQ ID NO: 18 or 21; (iii) the antigen-binding construct targeting HER2 comprises a third polypeptide chain whose amino acid sequence 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 of SEQ ID NO: 19; or (iv) the antigen-binding construct targeting HER2 comprises a first polypeptide chain whose amino acid sequence 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 of SEQ ID NO: 17 or 20, a second polypeptide chain whose amino acid sequence 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 of SEQ ID NO: 18 or 21, and a second polypeptide chain whose amino acid sequence 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 of SEQ ID NO: The amino acid sequence shown in NO:19 has a third polypeptide chain 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.

5. The anti-HER2 antibody drug conjugate for treating breast cancer in a subject according to any one of claims 1 to 4, wherein: The anti-HER2 antibody drug conjugate is administered to the subject at a dose of 1.5-9 mg / kg, 4.5-7.5 mg / kg, or 6-7.5 mg / kg each time; alternatively, the anti-HER2 antibody drug conjugate is administered to the subject at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 6 mg / kg, 7.5 mg / kg or 9 mg / kg each time.

6. The anti-HER2 antibody drug conjugate for treating breast cancer in a subject according to any one of claims 1 to 5, wherein: The anti-HER2 antibody drug conjugate is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks.

7. The anti-HER2 antibody drug conjugate for treating breast cancer in a subject according to any one of claims 1 to 6, wherein: The anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous injection or infusion.

8. The anti-HER2 antibody drug conjugate for treating breast cancer in a subject according to any one of claims 1 to 7, wherein: The breast cancer is recurrent and / or metastatic breast cancer, or locally advanced or metastatic breast cancer.

9. The anti-HER2 antibody drug conjugate for treating breast cancer in a subject according to any one of claims 1 to 8, wherein: The breast cancer is unresectable breast cancer; The breast cancer is HER2-expressing breast cancer; and / or The breast cancer is hormone receptor positive breast cancer.

10. The anti-HER2 antibody drug conjugate for treating breast cancer in a subject according to any one of claims 1 to 9, wherein: The breast cancer is HER2-positive breast cancer or HER2-low-expressing breast cancer; The breast cancer is estrogen receptor and / or progesterone receptor positive breast cancer; or The breast cancer is hormone receptor negative or positive, HER2-positive recurrent or metastatic breast cancer; Wherein, the HER2-positive breast cancer is a breast cancer in which the expression of HER2 is 3+ as determined by IHC, or the HER2-positive breast cancer is a breast cancer in which the expression of HER2 is 2+ as determined by IHC and the expression of HER2 is positive as determined by ISH; And wherein, the breast cancer with low HER2 expression is a breast cancer in which the expression of HER2 is 2+ as determined by IHC and the expression of HER2 is negative as determined by ISH, or the breast cancer with low HER2 expression is a breast cancer in which the expression of HER2 is 1+ as determined by IHC.

11. The anti-HER2 antibody drug conjugate for treating breast cancer in a subject according to any one of claims 1 to 10, wherein: The subject with breast cancer is not suitable for surgery and / or radiotherapy; The subject with breast cancer has previously received at least one line of treatment for breast cancer; The subject with breast cancer has previously received adjuvant therapy or neoadjuvant therapy for breast cancer; The subject with breast cancer has previously received local radiation therapy to treat breast cancer; The subject with breast cancer has previously received anti-HER2 antibody therapy, taxanes, CDK4 / 6 inhibitors, endocrine therapy and / or adjuvant endocrine therapy; and / or The breast cancer subject has not received chemotherapy at the recurrence and / or metastasis stage.

12. The anti-HER2 antibody drug conjugate for treating breast cancer in a subject according to any one of claims 1 to 11, wherein: The breast cancer subject is a subject with HER2-expressing recurrent and / or metastatic breast cancer who has failed at least one line of systemic chemotherapy at the recurrent and / or metastatic stage; The breast cancer subject is a subject with hormone receptor-positive, recurrent and / or metastatic breast cancer with HER2 expression who has failed CDK4 / 6 inhibitor combined with endocrine therapy at the recurrent and / or metastatic stage; The breast cancer subject is a subject with HER2-expressing recurrent and / or metastatic breast cancer who has been treated with trastuzumab and taxanes; The breast cancer subject is a subject with locally advanced or metastatic breast cancer with low HER2 expression who has not received chemotherapy at the recurrence and / or metastasis stage; or The breast cancer subjects are HR-positive and HER2-low expressing locally advanced or metastatic breast cancer subjects who have received at least one line of endocrine therapy at the recurrence and / or metastasis stage and whose disease has progressed or whose disease has progressed within 24 months from the start of adjuvant endocrine therapy.

13. The anti-HER2 antibody drug conjugate for treating breast cancer in a subject according to any one of claims 1 to 12, wherein: The breast cancer subject is a subject with HER2-positive recurrent and / or metastatic breast cancer who has failed at least one line of systemic chemotherapy at the recurrent and / or metastatic stage; The breast cancer subject is a subject with HER2-positive recurrent and / or metastatic breast cancer who has been treated with trastuzumab and taxanes; The breast cancer subject is a subject with recurrent and / or metastatic breast cancer with low HER2 expression who has failed at least one line of systemic chemotherapy at the recurrent and / or metastatic stage; The breast cancer subject is a subject with hormone receptor-positive, recurrent and / or metastatic breast cancer with low HER2 expression who has failed CDK4 / 6 inhibitor combined with endocrine therapy at the recurrent and / or metastatic stage; The breast cancer subject is a subject with unresectable locally advanced or metastatic breast cancer with low HER2 expression who has not received chemotherapy at the recurrence and / or metastasis stage; or The breast cancer subjects are HR-positive and HER2-low expressing unresectable locally advanced or metastatic breast cancer subjects who have received at least one line of endocrine therapy at the recurrent and / or metastatic stage and whose disease has progressed or whose disease has progressed within 24 months from the start of adjuvant endocrine therapy.

14. The anti-HER2 antibody drug conjugate for treating breast cancer in a subject according to any one of claims 1 to 13, wherein: The anti-HER2 antibody drug conjugate is used for second-line treatment or later-line treatment of breast cancer in a subject.

15. The anti-HER2 antibody drug conjugate for treating breast cancer in a subject according to any one of claims 1 to 14, wherein: The anti-HER2 antibody-drug conjugate is formulated into a pharmaceutical composition together with one or more pharmaceutically acceptable excipients, and the pharmaceutical composition contains a therapeutically effective amount of the anti-HER2 antibody-drug conjugate.