Application of HER2 (human epidermal growth factor receptor 2) targeting antigen binding construct and small molecule medicine in combined treatment of breast cancer

Abstract

The invention belongs to the field of biological medicine, and provides application of a HER2-targeting antigen binding construct and a small molecule drug in combined treatment of breast cancer. Also provided is a pharmaceutical combination comprising an antigen binding construct targeting HER2, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant, comprising an antigen binding construct targeting HER2. Also provided is a pharmaceutical combination comprising an antigen binding construct targeting HER2, comprising an antigen binding construct targeting HER2 and a chemotherapeutic drug. The invention further provides a kit for treating tumors. The kit comprises the medicine composition. In addition, the invention also provides application of the medicine composition in preparation of medicines for treating tumors and a method for treating tumors by using the medicine composition.

Description

Technical Field

[0001] The present disclosure belongs to the field of biomedicine, and specifically relates to the use of a HER2-targeting antigen-binding construct in combination with a small molecule drug for the treatment of breast cancer. Background Art

[0002] In recent years, the incidence of tumors has been on the rise, and malignant tumors have poor treatment efficacy and high late-stage metastasis rates. Although conventional treatments currently used in clinical practice, such as radiotherapy, chemotherapy, and surgery, can relieve pain and prolong survival, they all have limitations.

[0003] 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 triggers abnormal activation of signaling pathways and is a major driver of solid tumor growth. HER2 expression is low in normal cells, but it is overexpressed or amplified in various tumors, including breast cancer. It readily forms heterodimers with other HER family receptors, leading to receptor tyrosine phosphorylation and activation of multiple signaling pathways, including MPK, PI3K, JAK, STAT3, and PKC, ultimately contributing to cell proliferation and tumorigenesis.

[0004] For tumors with abnormal HER2 expression, more effective treatments are needed for clinical use. SUMMARY OF THE INVENTION

[0005] In one aspect, the present disclosure provides a pharmaceutical combination comprising an antigen-binding construct targeting HER2, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant.

[0006]

[0007] In one aspect, the present disclosure provides a drug combination comprising an antigen-binding construct targeting HER2 and a taxane drug.

[0008] In one aspect, the present disclosure provides a drug combination comprising an antigen-binding construct targeting HER2 and a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is a taxane anti-tumor drug, an antimetabolite anti-tumor drug (e.g., a fluorouracil anti-tumor drug or a cytosine anti-tumor drug), a vinca alkaloid anti-tumor drug, or a tubulin inhibitor anti-tumor drug. In some embodiments, the chemotherapeutic agent is nab-paclitaxel, capecitabine, gemcitabine, vinorelbine, or eribulin.

[0009] In some embodiments, the drug combination is used to treat a tumor.

[0010] In another aspect, the present disclosure further provides a method for treating a tumor in a subject, comprising administering a drug combination of the present disclosure to the subject. Additionally, the present disclosure further provides the use of the drug combination of the present disclosure in the preparation of a medicament for treating a tumor in a subject. Additionally, the present disclosure further provides the use of the drug combination of the present disclosure in treating a tumor in a subject. In some embodiments, in the methods or uses, the drug combination of the present disclosure is administered in a therapeutically effective amount.

[0011] On the other hand, the present disclosure also provides a method for treating a tumor in a subject, comprising administering to the subject an antigen-binding construct targeting HER2 of the present disclosure, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant. Additionally, the present disclosure further provides the use of an antigen-binding construct targeting HER2 of the present disclosure, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant in the preparation of a medicament for treating a tumor in a subject. Alternatively, the present disclosure further provides the use of an antigen-binding construct targeting HER2, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant in the preparation of a medicament for combining the treatment of a tumor in a subject. Alternatively, the present disclosure further provides the use of an antigen-binding construct targeting HER2 in the preparation of a medicament for combining the treatment of a tumor in a subject with a compound of formula (I) or a pharmaceutically acceptable salt thereof and fulvestrant. Additionally, the present disclosure further provides the use of an antigen-binding construct targeting HER2 of the present disclosure, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant in the treatment of a tumor in a subject. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant are administered in therapeutically effective amounts.

[0012] On the other hand, the present disclosure also provides a method for treating a tumor in a subject, comprising administering to the subject an antigen-binding construct targeting HER2 of the present disclosure and a chemotherapeutic drug. In addition, the present disclosure also provides the use of the antigen-binding construct targeting HER2 of the present disclosure and a chemotherapeutic drug in the preparation of a medicament for treating a tumor in a subject. In addition, the present disclosure also provides the use of the antigen-binding construct targeting HER2 of the present disclosure and a chemotherapeutic drug in the treatment of a tumor in a subject. Alternatively, the present disclosure also provides the use of the antigen-binding construct targeting HER2 and a chemotherapeutic drug in the preparation of a medicament for the combined treatment of a tumor in a subject. Alternatively, the present disclosure also provides the use of the antigen-binding construct targeting HER2 in the preparation of a medicament for the combined treatment of a tumor in a subject with a chemotherapeutic drug. In some embodiments, in the method or use, the antigen-binding construct targeting HER2 of the present disclosure and a chemotherapeutic drug are administered in a therapeutically effective amount. In some embodiments, in the above methods or uses, the chemotherapy drug is a taxane anti-tumor drug, an antimetabolite anti-tumor drug (e.g., a fluorouracil anti-tumor drug or a cytosine anti-tumor drug), a vinca alkaloid anti-tumor drug, or a tubulin inhibitor anti-tumor drug. In some embodiments, the chemotherapy drug is albumin-paclitaxel, capecitabine, gemcitabine, vinorelbine, or eribulin.

[0013] On the other hand, the present disclosure provides a kit for treating tumors, which includes a drug combination of the present disclosure. In some embodiments, the kit includes an antigen binding construct targeting HER2, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant. In other embodiments, the kit includes an antigen binding construct targeting HER2 and a chemotherapy drug. In some embodiments, in the above-mentioned methods or uses, the chemotherapy drug is a taxane anti-tumor drug, an antimetabolite anti-tumor drug (for example, a fluorouracil anti-tumor drug or a cytosine anti-tumor drug), a vinblastine anti-tumor drug, or a microtubule inhibitor anti-tumor drug. In some embodiments, the chemotherapy drug is albumin paclitaxel, capecitabine, gemcitabine, vinorelbine or eribulin. In some embodiments, the kit is one or more detachable independent packages.

[0014] In addition, the present disclosure also provides an antigen-binding construct targeting HER2 for treating tumors. The present disclosure also provides a method for treating a tumor in a subject, comprising administering the antigen-binding construct targeting HER2 of the present disclosure to the subject. The present disclosure also provides the use of the antigen-binding construct targeting HER2 in the preparation of a medicament for treating a tumor in a subject. The present disclosure also provides the use of the antigen-binding construct targeting HER2 for treating tumors. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 is administered in a therapeutically effective amount.

[0015] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 is administered once every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). In some embodiments, the antigen-binding construct targeting HER2 is administered once every 2 weeks. In some embodiments, the antigen-binding construct targeting HER2 is administered once every 3 weeks. In some embodiments, the antigen-binding construct targeting HER2 is administered at a dosage of 2.5-50 mg / kg, 2.5-30 mg / kg, 2.5-10 mg / kg, 5-10 mg / kg, 10-30 mg / kg, or 20-30 mg / kg. In some embodiments, the antigen-binding construct for targeting HER2 is administered at a dosage of 2.5mg / kg, 5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg or 50mg / kg or the range formed by any two of the above values. In some embodiments, the antigen-binding construct for targeting HER2 is administered at a dosage of 2.5mg / kg, 5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg or 30mg / kg or the range formed by any two of the above values. In some embodiments, the antigen-binding construct for targeting HER2 is administered at a dosage of 20mg / kg. In some embodiments, the antigen-binding construct for targeting HER2 is administered at a dosage of 30mg / kg. In some embodiments, the antigen-binding construct for targeting HER2 is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time with a dosage of 2.5-50mg / kg or 2.5-30mg / kg of the antigen-binding construct for targeting HER2. In some embodiments, the antigen-binding construct for targeting HER2 is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time with a dosage of 2.5mg / kg, 5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg, or 50mg / kg or the scope of any two values ​​formed by the antigen-binding construct for targeting HER2. In some embodiments, the antigen-binding construct for targeting HER2 is administered every 1 week, each time with a dosage of 2.5-10mg / kg or 5-10mg / kg of the antigen-binding construct for targeting HER2. In some embodiments, the antigen-binding construct targeting HER2 is administered once every week, each time at a dose of 2.5 mg / kg, 5 mg / kg, or 10 mg / kg of the antigen-binding construct targeting HER2.In some embodiments, the antigen-binding construct targeting HER2 is administered once every 2 weeks at a dose of 20 mg / kg of the antigen-binding construct targeting HER2. In some embodiments, the antigen-binding construct targeting HER2 is administered once every 3 weeks at a dose of 30 mg / kg of the antigen-binding construct targeting HER2.

[0016] In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and the antigen-binding construct targeting HER2 is administered once or three times in each treatment cycle. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and the antigen-binding construct targeting HER2 is administered once on the 1st day of each treatment cycle. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and the antigen-binding construct targeting HER2 is administered once on the 1st day, 8th day, and 15th day of each treatment cycle. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and 30 mg / kg of the antigen-binding construct targeting HER2 is administered on the 1st day of each treatment cycle. In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and 2.5 mg / kg of the antigen-binding construct targeting HER2 is administered once on the 1st day, 8th day, and 15th day of each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and 5 mg / kg of the antigen-binding construct targeting HER2 is administered once on day 1, day 8, and day 15 of each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and 10 mg / kg of the antigen-binding construct targeting HER2 is administered once on day 1, day 8, and day 15 of each treatment cycle.

[0017] In some embodiments, in the methods or uses, one treatment cycle is four weeks, and the antigen-binding construct targeting HER2 is administered twice in each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is four weeks, and the antigen-binding construct targeting HER2 is administered once on day 1 and day 15 of each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is four weeks, and the antigen-binding construct targeting HER2 is administered once on day 1 and day 15 of each treatment cycle.

[0018] In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is breast cancer. Detailed Description of the Invention

[0019] I. Antigen-binding constructs targeting HER2, compounds of formula (I) or pharmaceutically acceptable salts thereof, and fulvestrant

[0020] Drug combinations

[0021] In one aspect, the present disclosure provides a pharmaceutical combination comprising an antigen-binding construct targeting HER2, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant.

[0022] In some embodiments, in the drug combination, the unit dose of the antigen-binding construct targeting HER2 is 100-600 mg, 200-600 mg, or 200-400 mg. In some embodiments, in the drug combination, the unit dose of the antigen-binding construct targeting HER2 is 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, and / or 600 mg, or the range formed by any two of the above values. In some embodiments, in the drug combination, the unit dose of the antigen-binding construct targeting HER2 is 200 mg, 400 mg, and / or 600 mg. In some embodiments, in the drug combination, the unit dose of the antigen-binding construct targeting HER2 is 200 mg.

[0023] In some embodiments, the unit dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is 50 mg, 60 mg, 100 mg, 120 mg, 150 mg and / or 180 mg. In some embodiments, the unit dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is 50 mg and / or 60 mg.

[0024] In some embodiments, in the pharmaceutical combination, the unit dosage of fulvestrant is 250 mg and / or 500 mg.

[0025] In some embodiments, the drug combination comprises a unit dose of 100-600 mg, 200-600 mg, or 200-400 mg of an antigen-binding construct targeting HER2, a unit dose of 50 mg, 60 mg, 100 mg, 120 mg, 150 mg and / or 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a unit dose of 250 mg of fulvestrant. In some embodiments, the drug combination includes an antigen-binding construct targeting HER2 at a unit dose of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, and / or 600 mg, or a range formed by any two of the above values, a compound of formula (I) or a pharmaceutically acceptable salt thereof at a unit dose of 50 mg, 60 mg, 100 mg, 120 mg, 150 mg and / or 180 mg, and fulvestrant at a unit dose of 250 mg. In some embodiments, the drug combination includes an antigen-binding construct targeting HER2 at a unit dose of 200 mg, 400 mg and / or 600 mg, a compound of formula (I) or a pharmaceutically acceptable salt thereof at a unit dose of 50 mg and / or 60 mg, and fulvestrant at a unit dose of 250 mg. In some embodiments, the pharmaceutical combination comprises a unit dose of 200 mg of an antigen-binding construct targeting HER2, a unit dose of 50 mg and / or 60 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a unit dose of 250 mg of fulvestrant.

[0026] In some embodiments, the drug combination includes 2.5-50mg / kg, 2.5-30mg / kg, 2.5-10mg / kg, 5-10mg / kg, 10-30mg / kg or 20-30mg / kg of the antigen-binding construct for targeting HER2. In some embodiments, the drug combination includes 2.5mg / kg, 5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg or 50mg / kg or the antigen-binding construct for targeting HER2 of the range formed by any two values ​​above. In some embodiments, the drug combination includes 2.5mg / kg, 5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg or 30mg / kg of the antigen-binding construct for targeting HER2. In some embodiments, the drug combination includes 20mg / kg of the antigen-binding construct for targeting HER2.

[0027] In some embodiments, the drug combination includes 30-240mg, 60-180mg, 90-180mg, 120-180mg, 150-180mg or 150-240mg of formula (I) compound or its pharmaceutically acceptable salt. In some embodiments, the drug combination includes 30mg, 60mg, 90mg, 120mg, 150mg, 180mg or 240mg or the range formed by any two of the above values ​​of formula (I) compound or its pharmaceutically acceptable salt. In some embodiments, the drug combination includes 120mg, 150mg or 180mg or the range formed by any two of the above values ​​of formula (I) compound or its pharmaceutically acceptable salt. In some embodiments, the drug combination includes 120mg, 150mg or 180mg of formula (I) compound or its pharmaceutically acceptable salt.

[0028] In some embodiments, the pharmaceutical combination comprises 250-500 mg of fulvestrant. In some embodiments, the pharmaceutical combination comprises 250 mg or 500 mg of fulvestrant. In some embodiments, the pharmaceutical combination comprises 500 mg of fulvestrant.

[0029] In some embodiments, the drug combination comprises 2.5-50 mg / kg, 2.5-30 mg / kg, 2.5-10 mg / kg, 5-10 mg / kg, 10-30 mg / kg, or 20-30 mg / kg of an antigen-binding construct targeting HER2, 30-240 mg, 60-180 mg, 90-180 mg, 120-180 mg, 150-180 mg, or 150-240 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 250-500 mg of fulvestrant. In some embodiments, the drug combination comprises 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, or 50 mg / kg, or a range formed by any two of the above values, an antigen-binding construct targeting HER2, 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 180 mg, or 240 mg, or a range formed by any two of the above values, of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 250 mg or 500 mg of fulvestrant. In some embodiments, the drug combination comprises 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg or 30 mg / kg of an antigen-binding construct targeting HER2, 120 mg, 150 mg, or 180 mg, or a range formed by any two of the above values ​​of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 500 mg of fulvestrant. In some embodiments, the drug combination comprises 20 mg / kg of an antigen-binding construct targeting HER2, 120 mg, 150 mg or 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 500 mg of fulvestrant.

[0030] In some embodiments, the drug combination is suitable for the preparation used in a single treatment cycle (such as a treatment cycle of 4 weeks), and it includes the antigen-binding constructs for the targeting HER2 of 7.5-50mg / kg, 7.5-40mg / kg, 15-40mg / kg, 15-30mg / kg or 30-40mg / kg. In some embodiments, the drug combination is suitable for the preparation used in a single treatment cycle, and it includes the antigen-binding constructs for the targeting HER2 of 7.5mg / kg, 15mg / kg, 20mg / kg, 30mg / kg, 40mg / kg or 50mg / kg or the scope formed by any two values. In some embodiments, the drug combination is suitable for the preparation used in a single treatment cycle, and it includes the antigen-binding constructs for the targeting HER2 of 7.5mg / kg, 15mg / kg, 30mg / kg or 40mg / kg. In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, which includes 40 mg / kg of an antigen-binding construct targeting HER2.

[0031] In some embodiments, the drug combination is a preparation suitable for use in a single treatment cycle (e.g., a 4-week treatment cycle), comprising 840-6720 mg, 1680-5040 mg, 2520-5040 mg, 3360-5040 mg, 4200-5040 mg, or 4200-6720 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination is a preparation suitable for use in a single treatment cycle, comprising 840 mg, 1680 mg, 2520 mg, 3360 mg, 4200 mg, 5040 mg, or 6720 mg, or a range formed by any two of the above values, of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination is a preparation suitable for administration within a single treatment cycle, comprising 1680 mg, 3360 mg, 4200 mg, or 5040 mg, or a range formed by any two of the above values, of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination is a preparation suitable for administration within a single treatment cycle, comprising 3360 mg, 4200 mg, or 5040 mg, or a range formed by any two of the above values, of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the drug combination is a preparation suitable for administration within a single treatment cycle, comprising 3360 mg, 4200 mg, or 5040 mg, or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the drug combination is a preparation suitable for administration within a single treatment cycle (e.g., a treatment cycle of 4 weeks), which includes 500-1000 mg of fulvestrant. In some embodiments, the drug combination is a preparation suitable for administration within a single treatment cycle, which includes 500 mg or 1000 mg of fulvestrant. In some embodiments, the drug combination is a preparation suitable for administration within the first treatment cycle, which includes 1000 mg of fulvestrant. In some embodiments, the drug combination is a preparation suitable for administration within the second treatment cycle and subsequent single treatment cycles, which includes 500 mg of fulvestrant.

[0033] In some embodiments, the drug combination is a formulation suitable for administration within a single treatment cycle (e.g., a 4-week treatment cycle), comprising 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of an antigen-binding construct targeting HER2, 840-6720 mg, 1680-5040 mg, 2520-5040 mg, 3360-5040 mg, 4200-5040 mg, or 4200-6720 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 500-1000 mg of fulvestrant. In some embodiments, the drug combination is a formulation suitable for administration within a single treatment cycle, comprising 7.5 mg / kg, 15 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, or 50 mg / kg, or a range formed by any two of the above values, an antigen-binding construct targeting HER2, 840 mg, 1680 mg, 2520 mg, 3360 mg, 4200 mg, 5040 mg, or 6720 mg, or a range formed by any two of the above values, of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 500 mg or 1000 mg of fulvestrant. In some embodiments, the drug combination is a formulation suitable for administration within a single treatment cycle, comprising 7.5 mg / kg, 15 mg / kg, 30 mg / kg or 40 mg / kg of an antigen-binding construct targeting HER2, 1680 mg, 3360 mg, 4200 mg or 5040 mg, or a range formed by any two of the above values ​​of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 500 mg or 1000 mg of fulvestrant. In some embodiments, the drug combination is a formulation suitable for administration within a single treatment cycle, comprising 40 mg / kg of an antigen-binding construct targeting HER2, 3360 mg, 4200 mg or 5040 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 500 mg or 1000 mg of fulvestrant. In some embodiments, the drug combination is a preparation suitable for administration in the first treatment cycle, comprising 40 mg / kg of an antigen-binding construct targeting HER2, 3360 mg, 4200 mg, or 5040 mg, or a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 1000 mg of fulvestrant. In some embodiments, the drug combination is a preparation suitable for administration in a single treatment cycle in the second treatment cycle and thereafter, comprising 40 mg / kg of an antigen-binding construct targeting HER2, 3360 mg, 4200 mg, 5040 mg, or a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 500 mg of fulvestrant.In some embodiments, the drug combination is a preparation suitable for administration in the first treatment cycle, comprising 40 mg / kg of an antigen-binding construct targeting HER2, 3360 mg, 4200 mg or 5040 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 1000 mg of fulvestrant. In some embodiments, the drug combination is a preparation suitable for administration in a single treatment cycle in the second treatment cycle and thereafter, comprising 40 mg / kg of an antigen-binding construct targeting HER2, 3360 mg, 4200 mg or 5040 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 500 mg of fulvestrant.

[0034] In some embodiments, the amount of the antigen-binding construct targeting HER2 in the pharmaceutical combination is a daily dose. In some embodiments, the amount of the antigen-binding construct targeting HER2 in the pharmaceutical combination is a single dose. In some embodiments, the amount of the antigen-binding construct targeting HER2 in the pharmaceutical combination is a once-daily dose. In some embodiments, the amount of the antigen-binding construct targeting HER2 in the pharmaceutical combination is a dose for half a treatment cycle, where one treatment cycle is four weeks.

[0035] In some embodiments, in the pharmaceutical combination, the content of the compound of formula (I) or its pharmaceutically acceptable salt is a daily dose. In some embodiments, in the pharmaceutical combination, the content of the compound of formula (I) or its pharmaceutically acceptable salt is a single dose. In some embodiments, in the pharmaceutical combination, the content of the compound of formula (I) or its pharmaceutically acceptable salt is a once-a-day dose. In some embodiments, in the pharmaceutical combination, the content of the compound of formula (I) or its pharmaceutically acceptable salt is a dose for one treatment cycle, and one treatment cycle is 4 weeks.

[0036] In some embodiments, the amount of fulvestrant in the pharmaceutical combination is a daily dose. In some embodiments, the amount of fulvestrant in the pharmaceutical combination is a single dose. In some embodiments, the amount of fulvestrant in the pharmaceutical combination is a once-daily dose. In some embodiments, the amount of fulvestrant in the pharmaceutical combination is a dose for one treatment cycle, where one treatment cycle is four weeks.

[0037] In some embodiments, the antigen-binding construct targeting HER2 can be a pharmaceutical composition of an antigen-binding construct targeting HER2. Wherein, the pharmaceutical composition of the antigen-binding construct targeting HER2 is a single dose or multiple doses, preferably a multiple dose; in some embodiments, the multiple doses can be composed of a single dose of 100-600 mg, 200-600 mg, or 200-400 mg of the pharmaceutical composition of the antigen-binding construct targeting HER2 (for example, composed of more than two single doses of the pharmaceutical composition); in some embodiments, the multiple doses can be composed of a single dose of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg and / or 600 mg of the pharmaceutical composition of the antigen-binding construct targeting HER2; in some embodiments, the multiple doses can be composed of a single dose of 200 mg, 400 mg and / or 600 mg of the pharmaceutical composition of the antigen-binding construct targeting HER2; in some embodiments, the multiple doses can be composed of a single dose of 200 mg of the pharmaceutical composition of the antigen-binding construct targeting HER2.

[0038] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Wherein, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses, preferably multiple doses; in some embodiments, the multiple doses can be composed of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof in a single dose of 50 mg, 60 mg, 100 mg, 120 mg, 150 mg and / or 180 mg (e.g., composed of two or more single doses of the pharmaceutical composition). In some embodiments, the multiple doses can be composed of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof in a single dose of 50 mg and / or 60 mg.

[0039] In some embodiments, the fulvestrant can be a pharmaceutical composition of fulvestrant. The pharmaceutical composition of fulvestrant is a single dose or multiple doses, preferably multiple doses; in some embodiments, the multiple doses can consist of a single dose of 250 mg of the pharmaceutical composition of fulvestrant (e.g., consisting of two or more single doses of the pharmaceutical composition); or, in some embodiments, the multiple doses can consist of a single dose of 500 mg of the pharmaceutical composition of fulvestrant.

[0040] In some embodiments, the drug combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2, a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition of fulvestrant. In some embodiments, the drug combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2, a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition of fulvestrant, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared to be suitable for administering 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of the antigen-binding construct targeting HER2 to the patient per treatment cycle. The pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a single dose or multiple doses suitable for continuous daily administration of 30-240 mg, 60-180 mg, 90-180 mg, 120-180 mg, 150-180 mg, or 150-240 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the patient, and the pharmaceutical composition of fulvestrant is prepared as a single dose or multiple doses suitable for administering 500-1000 mg of fulvestrant to the patient per treatment cycle. In some embodiments, the drug combination includes a pharmaceutical composition of an antigen-binding construct targeting HER2, a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition of fulvestrant, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering 7.5 mg / kg, 15 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg or 50 mg / kg of the antigen-binding construct targeting HER2 to the patient per treatment cycle, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a single dose or multiple doses suitable for administering 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 180 mg or 240 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the patient continuously every day, and the pharmaceutical composition of fulvestrant is prepared as a single dose or multiple doses suitable for administering 500 mg or 1000 mg of fulvestrant to the patient per treatment cycle.In some embodiments, the drug combination includes a pharmaceutical composition of an antigen-binding construct targeting HER2, a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition of fulvestrant, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering 7.5 mg / kg, 15 mg / kg, 30 mg / kg or 40 mg / kg of the antigen-binding construct targeting HER2 to the patient per treatment cycle, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a single dose or multiple doses suitable for administering 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the patient continuously every day, and the pharmaceutical composition of fulvestrant is prepared as a single dose or multiple doses suitable for administering 500 mg or 1000 mg of fulvestrant to the patient per treatment cycle. In some embodiments, the drug combination includes a pharmaceutical composition of an antigen-binding construct targeting HER2, a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition of fulvestrant, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering 40 mg / kg of the antigen-binding construct targeting HER2 to the patient per treatment cycle, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a single dose or multiple doses suitable for administering 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the patient continuously every day, and the pharmaceutical composition of fulvestrant is prepared as a single dose or multiple doses suitable for administering 500 mg or 1000 mg of fulvestrant to the patient per treatment cycle. In some embodiments, the drug combination includes a pharmaceutical composition of an antigen-binding construct targeting HER2, a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition of fulvestrant, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering 40 mg / kg of the antigen-binding construct targeting HER2 to the patient per treatment cycle, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a single dose or multiple doses suitable for administering 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the patient continuously every day, and the pharmaceutical composition of fulvestrant is prepared as a single dose or multiple doses suitable for administering 1000 mg of fulvestrant to the patient in the first treatment cycle, and administering 500 mg of fulvestrant to the patient in the second treatment cycle and subsequent single treatment cycles. In some embodiments, one treatment cycle is 4 weeks.

[0041] In some embodiments, in the drug combination, the antigen-binding construct targeting HER2, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant can be packaged separately or packaged together. Wherein, the antigen-binding construct targeting HER2 can be packaged in a single portion or multiple portions, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be packaged in a single portion or multiple portions, and fulvestrant can be packaged in a single portion or multiple portions. In some embodiments, the antigen-binding construct targeting HER2 can be packaged in a single portion or multiple equal portions (e.g., 2 equal portions, 3 equal portions, 4 equal portions, 5 equal portions, 6 equal portions, 7 equal portions, 8 equal portions or more equal portions), the compound of formula (I) or a pharmaceutically acceptable salt thereof can be packaged in a single portion or multiple equal portions (e.g., 2 equal portions, 3 equal portions, 4 equal portions or other equal portions), and fulvestrant can be packaged in a single portion or multiple equal portions (e.g., 2 equal portions, 3 equal portions, 4 equal portions or other equal portions).

[0042] In some embodiments, the drug combination is packaged in the same kit, and optionally, the kit further includes instructions for the combined use of an antigen-binding construct targeting HER2, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and Fulvestrant to treat tumors. In other embodiments, the antigen-binding construct targeting HER2, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and Fulvestrant in the drug combination are separately packaged in respective medicine boxes, and optionally, the medicine box further includes instructions for the combined use of an antigen-binding construct targeting HER2, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and Fulvestrant to treat tumors. In some embodiments, the instructions may be instructions in the instructions of a commercially available Fulvestrant injection kit. In some embodiments, the instructions are instructions for Fulvestrant injection (e.g., In other embodiments, the pharmaceutical composition of the antigen-binding construct targeting HER2, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition of fulvestrant in the pharmaceutical combination are separately packaged in respective medicine boxes.

[0043] In some embodiments, the pharmaceutical combination is a fixed combination.In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition or in the form of a liquid pharmaceutical composition.

[0044] In some embodiments, the pharmaceutical combination is a non-fixed combination. In some embodiments, in the non-fixed combination, the antigen-binding construct targeting HER2, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant are each in the form of a pharmaceutical composition.

[0045] In some embodiments, the pharmaceutical composition of the antigen-binding construct targeting HER2 in the non-fixed combination is a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition of the antigen-binding construct targeting HER2 in the non-fixed combination is a lyophilized formulation. In some embodiments, the pharmaceutical composition of the antigen-binding construct targeting HER2 in the non-fixed combination is a powder for injection.

[0046] In some specific embodiments, in the non-fixed combination, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition. In some specific embodiments, in the non-fixed combination, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule.

[0047] In some specific embodiments, in the non-fixed combination, the pharmaceutical composition of fulvestrant is a liquid pharmaceutical composition. In some specific embodiments, in the non-fixed combination, the pharmaceutical composition of fulvestrant is an injection.

[0048] On the other hand, the present disclosure provides a kit comprising a pharmaceutical composition of an antigen-binding construct targeting HER2, a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition of fulvestrant, optionally further comprising instructions for combining the pharmaceutical composition of the antigen-binding construct targeting HER2, the pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition of fulvestrant to treat tumors. In some embodiments, the kit is used to treat tumors. In some embodiments, the instructions may be instructions in the instructions of a commercially available fulvestrant injection kit. In some embodiments, the instructions are instructions for fulvestrant injection (e.g., ) instructions in the manual.

[0049] In another aspect, the present disclosure further provides a pharmaceutical pack comprising individually packaged pharmaceutical compositions in separate containers, wherein a first container comprises a pharmaceutical composition comprising an antigen-binding construct targeting HER2, a second container comprises a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a third container comprises a pharmaceutical composition comprising fulvestrant. In some embodiments, the pharmaceutical pack is used to treat tumors.

[0050] In some embodiments, the pharmaceutical composition of the antigen-binding construct targeting HER2 in the kit or pharmaceutical pack is a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition of the antigen-binding construct targeting HER2 in the kit or pharmaceutical pack is a lyophilized formulation. In some embodiments, the pharmaceutical composition of the antigen-binding construct targeting HER2 in the kit or pharmaceutical pack is a powder for injection.

[0051] In some specific embodiments, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the kit or pharmaceutical package is a solid pharmaceutical composition. In some specific embodiments, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the kit or pharmaceutical package is a capsule.

[0052] In some specific embodiments, the pharmaceutical composition of fulvestrant in the kit or pharmaceutical package is a liquid pharmaceutical composition. In some specific embodiments, the pharmaceutical composition of fulvestrant in the kit or pharmaceutical package is an injection.

[0053] In some embodiments, the tumor is a solid tumor. In some embodiments, the solid tumor is breast cancer.

[0054] Uses and methods

[0055] The present disclosure also provides a method for treating a tumor in a subject, comprising administering a drug combination of the present disclosure to the subject. In another aspect, the present disclosure also provides the use of the drug combination of the present disclosure in the preparation of a medicament for treating a tumor in a subject. In some embodiments, in the methods or uses, the drug combination of the present disclosure is administered in a therapeutically effective amount. In some embodiments, in the uses, the medicament comprises a therapeutically effective amount of the drug combination of the present disclosure.

[0056] The present disclosure also provides a method for treating a tumor in a subject, comprising administering to the subject an antigen-binding construct targeting HER2 of the present disclosure, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant. In some embodiments, in the method, the antigen-binding construct targeting HER2, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant are administered in a therapeutically effective amount.

[0057] The present disclosure also provides the use of the antigen-binding construct targeting HER2 of the present disclosure, the compound of formula (I) or its pharmaceutically acceptable salt and fulvestrant in the preparation of a medicament for treating a tumor in a subject. The present disclosure also provides the use of the antigen-binding construct targeting HER2 of the present disclosure in the preparation of a medicament for treating a tumor in a subject in combination with the compound of formula (I) or its pharmaceutically acceptable salt and fulvestrant. In some embodiments, in the use, the medicament comprises a therapeutically effective amount of the antigen-binding construct targeting HER2, the compound of formula (I) or its pharmaceutically acceptable salt and fulvestrant.

[0058] In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is a HER2-positive tumor. In some embodiments, the tumor is breast cancer. In some embodiments, the tumor is HER2-positive breast cancer. In some embodiments, the tumor is HR-positive and HER2-positive breast cancer. In some embodiments, the tumor is HR-negative and HER2-positive breast cancer. In some embodiments, the tumor is recurrent and / or metastatic breast cancer. In some embodiments, the tumor is locally advanced breast cancer. In some embodiments, the tumor is locally advanced, recurrent, and / or metastatic breast cancer that is HR-positive and HER2-positive. In some embodiments, the tumor is advanced breast cancer. In some embodiments, the tumor is advanced, recurrent, and / or metastatic breast cancer that is HR-positive and HER2-positive. In some embodiments, the tumor is advanced breast cancer. In some embodiments, the tumor is advanced, recurrent, and / or metastatic breast cancer that is HR-positive and HER2-positive. In some embodiments, the tumor is advanced breast cancer. In some embodiments, the tumor is advanced, recurrent, and / or metastatic breast cancer that is HR-negative and HER2-positive.

[0059] In some embodiments, in the method or use, the pharmaceutical combination comprises an antigen-binding construct targeting HER2, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant.

[0060] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2, the compound of formula (I) or its pharmaceutically acceptable salt and fulvestrant can be administered simultaneously, successively and / or alternately. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2, the compound of formula (I) or its pharmaceutically acceptable salt and fulvestrant are administered successively. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2, the compound of formula (I) or its pharmaceutically acceptable salt and fulvestrant are each in the form of a pharmaceutical composition and can be administered simultaneously, successively and / or alternately. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2, the compound of formula (I) or its pharmaceutically acceptable salt and fulvestrant are each in the form of a pharmaceutical composition and can be administered successively. In some embodiments, in the methods or uses, the compound of formula (I) or its pharmaceutically acceptable salt is administered first, then the antigen-binding construct targeting HER2 is administered, and finally fulvestrant is administered. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant are each in the form of a pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered first, the antigen-binding construct targeting HER2 is administered secondarily, and fulvestrant is administered last. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant are each in the form of a pharmaceutical composition and are packaged in different medicine boxes.

[0061] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant are administered in the same or different dosing regimens. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant are administered in different dosing regimens.

[0062] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 is administered once every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). In some embodiments, the antigen-binding construct targeting HER2 is administered once every 2 weeks. In some embodiments, the antigen-binding construct targeting HER2 is administered once every 3 weeks. In some embodiments, the antigen-binding construct targeting HER2 is administered at a dosage of 2.5-50 mg / kg, 2.5-30 mg / kg, 2.5-10 mg / kg, 5-10 mg / kg, 10-30 mg / kg, or 20-30 mg / kg. In some embodiments, the antigen-binding construct for targeting HER2 is administered at a dosage of 2.5mg / kg, 5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg or 50mg / kg or the range formed by any two of the above values. In some embodiments, the antigen-binding construct for targeting HER2 is administered at a dosage of 2.5mg / kg, 5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg or 30mg / kg or the range formed by any two of the above values. In some embodiments, the antigen-binding construct for targeting HER2 is administered at a dosage of 20mg / kg. In some embodiments, the antigen-binding construct for targeting HER2 is administered at a dosage of 30mg / kg. In some embodiments, the antigen-binding construct for targeting HER2 is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time with a dosage of 2.5-50mg / kg or 2.5-30mg / kg of the antigen-binding construct for targeting HER2. In some embodiments, the antigen-binding construct for targeting HER2 is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time with a dosage of 2.5mg / kg, 5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg, or 50mg / kg or the scope of any two values ​​formed by the antigen-binding construct for targeting HER2. In some embodiments, the antigen-binding construct for targeting HER2 is administered every 1 week, each time with a dosage of 2.5-10mg / kg or 5-10mg / kg of the antigen-binding construct for targeting HER2. In some embodiments, the antigen-binding construct targeting HER2 is administered once every week, each time at a dose of 2.5 mg / kg, 5 mg / kg, or 10 mg / kg of the antigen-binding construct targeting HER2.In some embodiments, the antigen-binding construct targeting HER2 is administered once every 2 weeks at a dose of 20 mg / kg of the antigen-binding construct targeting HER2. In some embodiments, the antigen-binding construct targeting HER2 is administered once every 3 weeks at a dose of 30 mg / kg of the antigen-binding construct targeting HER2.

[0063] In some embodiments, in the method or use, the compound of formula (I) or its pharmaceutically acceptable salt is applied once a day. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is applied at a dosage of 30-240mg, 60-180mg, 90-180mg, 120-180mg, 150-180mg or 150-240mg. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is applied at a dosage of 30mg, 60mg, 90mg, 120mg, 150mg, 180mg or 240mg or the range formed by any two of the above values. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is applied at a dosage of 120mg, 150mg or 180mg. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is administered once daily, each time at a dosage of 30-240 mg, 60-180 mg, 90-180 mg, 120-180 mg, 150-180 mg, or 150-240 mg of the compound of formula (I) or its pharmaceutically acceptable salt. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is administered once daily, each time at a dosage of 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 180 mg, or 240 mg, or a range of any two values ​​of the compound of formula (I) or its pharmaceutically acceptable salt. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is administered once every 3 weeks, each time at a dosage of 120 mg, 150 mg, or 180 mg of the compound of formula (I) or its pharmaceutically acceptable salt.

[0064] In some embodiments, in the methods or uses, the antigen binding construct targeting HER2, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant have the same or different treatment cycles. In some specific embodiments, the antigen binding construct targeting HER2, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant have different treatment cycles, for example, for the antigen binding construct targeting HER2, every 1 week, every 2 weeks, or every 3 weeks is a treatment cycle, for the compound of formula (I) or a pharmaceutically acceptable salt thereof and fulvestrant, every 4 weeks is a treatment cycle. In some specific embodiments, the antigen binding construct targeting HER2, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant have the same treatment cycle, for example, every 4 weeks is a treatment cycle.

[0065] In some embodiments, in the methods or uses, every 4 weeks is a treatment cycle, and an antigen-binding construct targeting HER2, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant are administered in each treatment cycle. In some embodiments, in the methods or uses, every 4 weeks is a treatment cycle, an antigen-binding construct targeting HER2 is administered twice in each treatment cycle, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered 28 times in each treatment cycle, fulvestrant is administered twice in the first treatment cycle, and fulvestrant is administered once in each treatment cycle thereafter. In some embodiments, in the methods or uses, every 4 weeks is a treatment cycle, an antigen-binding construct targeting HER2 is administered once on day 1 and day 15 of each treatment cycle, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily on days 1-28 of each treatment cycle, fulvestrant is administered once on day 1 and day 15 of the first treatment cycle, and fulvestrant is administered once on day 1 of the second treatment cycle and each treatment cycle thereafter.

[0066] In some specific embodiments, in the methods or uses, every 4 weeks is a treatment cycle, 40 mg / kg of the antigen-binding construct targeting HER2 is administered in each treatment cycle, 1680-5040 mg, or 3360-5040 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in each treatment cycle, and 500-1000 mg of fulvestrant is administered in each treatment cycle. In some specific embodiments, in the methods or uses, every 4 weeks is a treatment cycle, 40 mg / kg of the antigen-binding construct targeting HER2 is administered in each treatment cycle, 3360 mg, 4200 mg, or 5040 mg, or a range formed by any two of the above values, of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in each treatment cycle, and 500 mg or 1000 mg of fulvestrant is administered in each treatment cycle. In some specific embodiments, in the methods or uses, one treatment cycle is four weeks, 20 mg / kg of the antigen-binding construct targeting HER2 is administered on the 1st day and the 15th day of each treatment cycle, 80-180 mg, or 120-180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily on days 1-28 of each treatment cycle, 500 mg of fulvestrant is administered on the 1st day and the 15th day of the first treatment cycle, and 500 mg of fulvestrant is administered on the 1st day of the second treatment cycle and each subsequent treatment cycle. In some specific embodiments, in the methods or uses, one treatment cycle is four weeks, 20 mg / kg of the antigen-binding construct targeting HER2 is administered on the 1st day and the 15th day of each treatment cycle, 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily on days 1 to 28 of each treatment cycle, 500 mg of fulvestrant is administered on the 1st day and the 15th day of the first treatment cycle, and 500 mg of fulvestrant is administered on the 1st day of the second treatment cycle and each subsequent treatment cycle.

[0067] In some embodiments, in each treatment cycle, the antigen-binding construct targeting HER2, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant are administered in multiple doses or a single dose. In some embodiments, in each treatment cycle, the antigen-binding construct targeting HER2, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant are administered in multiple doses.

[0068] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 can be administered to the subject at a dose selected from 0.01 to 50 mg / kg, 0.1 to 50 mg / kg, 1 to 50 mg / kg, 2.5 to 40 mg / kg, 5 to 40 mg / kg, 7.5 to 40 mg / kg, 10 to 40 mg / kg, 15 to 40 mg / kg, 20 to 40 mg / kg, 30 to 40 mg / kg, 2.5 to 30 mg / kg, 5 to 30 mg / kg, 7.5 to 30 mg / kg, 10 to 30 mg / kg, 15 to 30 mg / kg, and 20 to 30 mg / kg.

[0069] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2, the compound of formula (I) or a pharmaceutically acceptable salt thereof and / or the dosing regimen of fulvestrant (e.g., treatment cycle, dosage, route of administration, intravenous infusion rate, etc.) 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, a treatment cycle of the antigen-binding construct targeting HER2 can be adjusted to 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks or 12 weeks. For another example, in some embodiments, the single dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof can be adjusted from 150 mg to 120 mg, or from 150 mg to 180 mg.

[0070] II. Antigen-binding constructs and chemotherapeutic drugs targeting HER2

[0071] Drug combinations

[0072] In one aspect, the present disclosure provides a drug combination comprising an antigen-binding construct targeting HER2 and a chemotherapy drug. In some embodiments, the chemotherapy drug is selected from one or more of platinum-based antitumor drugs, camptothecin-based antitumor drugs, taxane-based antitumor drugs, nitrogen mustard-based antitumor drugs, antimetabolite-based antitumor drugs, anthracycline-based antitumor drugs, vinca-based antitumor drugs, podophylloalkaloid-based antitumor drugs, hormone-based antitumor drugs, antibiotic-based antitumor drugs, and tubulin inhibitor-based antitumor drugs. In some embodiments, the chemotherapy drug is a taxane-based antitumor drug, antimetabolite-based antitumor drug, vinca-based antitumor drug, or tubulin inhibitor-based antitumor drug. In some embodiments, the chemotherapy drug is a taxane-based antitumor drug, a fluorouracil-based antitumor drug, a cytosine-based antitumor drug, a vinca-based antitumor drug, or a tubulin inhibitor-based antitumor drug. In some specific embodiments, the chemotherapy drug is albumin-based paclitaxel, capecitabine, gemcitabine, vinorelbine, or eribulin.

[0073] In some embodiments, the drug combination comprises an antigen-binding construct targeting HER2 and nab-paclitaxel. In some embodiments, the drug combination comprises an antigen-binding construct targeting HER2 and capecitabine. In some embodiments, the drug combination comprises an antigen-binding construct targeting HER2 and gemcitabine. In some embodiments, the drug combination comprises an antigen-binding construct targeting HER2 and vinorelbine. In some embodiments, the drug combination comprises an antigen-binding construct targeting HER2 and eribulin.

[0074] In some embodiments, in the drug combination, the unit dose of the antigen-binding construct targeting HER2 is 100-600 mg, 200-600 mg, or 200-400 mg. In some embodiments, in the drug combination, the unit dose of the antigen-binding construct targeting HER2 is 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, and / or 600 mg, or the range formed by any two of the above values. In some embodiments, in the drug combination, the unit dose of the antigen-binding construct targeting HER2 is 200 mg, 400 mg, and / or 600 mg. In some embodiments, in the drug combination, the unit dose of the antigen-binding construct targeting HER2 is 200 mg.

[0075] In some embodiments, in the pharmaceutical combination, the unit dose of nab-paclitaxel is 100 mg.

[0076] In some embodiments, in the pharmaceutical combination, the unit dose of capecitabine is 150 mg and / or 500 mg.

[0077] In some embodiments, in the pharmaceutical combination, the unit dose of gemcitabine is 0.2 g and / or 1 g.

[0078] In some embodiments, in the pharmaceutical combination, the unit dose of vinorelbine is 10 mg.

[0079] In some embodiments, in the pharmaceutical combination, the unit dose of eribulin is 1 mg.

[0080] In some embodiments, the drug combination comprises a unit dose of 100-600 mg, 200-600 mg, or 200-400 mg of an antigen-binding construct targeting HER2, and a unit dose of 100 mg of nab-paclitaxel. In some embodiments, the drug combination comprises a unit dose of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, and / or 600 mg, or a range formed by any two of the above values, and a unit dose of 100 mg of nab-paclitaxel. In some embodiments, the drug combination comprises a unit dose of 200 mg, 400 mg, and / or 600 mg of an antigen-binding construct targeting HER2, and a unit dose of 100 mg of nab-paclitaxel. In some embodiments, the pharmaceutical combination comprises a unit dose of 200 mg of an antigen-binding construct targeting HER2 and a unit dose of 100 mg of nab-paclitaxel.

[0081] In some embodiments, the drug combination comprises an antigen-binding construct targeting HER2 at a unit dose of 100-600 mg, 200-600 mg, or 200-400 mg, and a capecitabine at a unit dose of 150 mg and / or 500 mg. In some embodiments, the drug combination comprises an antigen-binding construct targeting HER2 at a unit dose of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, and / or 600 mg, or a range formed by any two of the above values, and a capecitabine at a unit dose of 150 mg and / or 500 mg. In some embodiments, the drug combination comprises an antigen-binding construct targeting HER2 at a unit dose of 200 mg, 400 mg, and / or 600 mg, and a capecitabine at a unit dose of 150 mg and / or 500 mg. In some embodiments, the pharmaceutical combination comprises a unit dose of 200 mg of an antigen-binding construct targeting HER2 and a unit dose of 150 mg and / or 500 mg of capecitabine.

[0082] In some embodiments, the drug combination includes the antigen-binding construct for targeting HER2 of 100-600mg, 200-600mg or 200-400mg, and the gemcitabine of 0.2g and / or 1g in a unit dose. In some embodiments, the drug combination includes the antigen-binding construct for targeting HER2 of 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg and / or 600mg or the scope formed by any two values ​​in a unit dose, and the gemcitabine of 0.2g and / or 1g in a unit dose. In some embodiments, the drug combination includes the antigen-binding construct for targeting HER2 of 200mg, 400mg and / or 600mg in a unit dose, and the gemcitabine of 0.2g and / or 1g in a unit dose. In some embodiments, the pharmaceutical combination comprises a unit dose of 200 mg of an antigen-binding construct targeting HER2 and a unit dose of 0.2 g and / or 1 g of gemcitabine.

[0083] In some embodiments, the drug combination includes an antigen-binding construct for targeting HER2 in a unit dose of 100-600 mg, 200-600 mg, or 200-400 mg, and a vinorelbine unit dose of 10 mg. In some embodiments, the drug combination includes an antigen-binding construct for targeting HER2 in a unit dose of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, and / or 600 mg, or a range formed by any two of the above values, and a vinorelbine unit dose of 10 mg. In some embodiments, the drug combination includes an antigen-binding construct for targeting HER2 in a unit dose of 200 mg, 400 mg, and / or 600 mg, and a vinorelbine unit dose of 10 mg. In some embodiments, the pharmaceutical combination comprises a unit dose of 200 mg of an antigen-binding construct targeting HER2 and a unit dose of 10 mg of vinorelbine.

[0084] In some embodiments, the pharmaceutical combination comprises a unit dose of 100-600 mg, 200-600 mg, or 200-400 mg of an antigen-binding construct targeting HER2, and a unit dose of 1 mg of eribulin. In some embodiments, the pharmaceutical combination comprises a unit dose of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, and / or 600 mg, or a range formed by any two of the above values, and a unit dose of 1 mg of eribulin. In some embodiments, the pharmaceutical combination comprises a unit dose of 200 mg, 400 mg, and / or 600 mg of an antigen-binding construct targeting HER2, and a unit dose of 1 mg of eribulin. In some embodiments, the pharmaceutical combination comprises a unit dose of 200 mg of an antigen-binding construct targeting HER2, and a unit dose of 1 mg of eribulin.

[0085] In some embodiments, the drug combination includes 2.5-50mg / kg, 2.5-30mg / kg, 2.5-10mg / kg, 5-10mg / kg, 10-30mg / kg or 20-30mg / kg of the antigen-binding construct for targeting HER2. In some embodiments, the drug combination includes 2.5mg / kg, 5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg or 50mg / kg or the antigen-binding construct for targeting HER2 of the range formed by any two values ​​above. In some embodiments, the drug combination includes 2.5mg / kg, 5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg or 30mg / kg of the antigen-binding construct for targeting HER2. In some embodiments, the drug combination includes 30mg / kg of the antigen-binding construct for targeting HER2.

[0086] In some embodiments, the drug combination comprises 130-260 mg, or 180-260 mg of nab-paclitaxel. In some embodiments, the drug combination comprises 130 mg, 180 mg, 200 mg, 220 mg, or 260 mg of nab-paclitaxel. In some embodiments, the drug combination comprises 260 mg of nab-paclitaxel.

[0087] In some embodiments, the drug combination comprises 500-1000 mg / m 2 In some embodiments, the drug combination includes 500 mg / m 2, 750mg / m 2 or 1000 mg / m 2 In some embodiments, the drug combination includes 1000 mg / m 2 In some embodiments, the pharmaceutical combination comprises 600-2300 mg, or 1150-2300 mg of capecitabine. In some embodiments, the pharmaceutical combination comprises 600 mg, 750 mg, 800 mg, 900 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1300 mg, 1400 mg, 1450 mg, 1500 mg, 1600 mg, 1750 mg, 1800 mg, 2000 mg, 2150 mg, or 2300 mg of capecitabine. In some embodiments, the pharmaceutical combination comprises 1150 mg, 1300 mg, 1450 mg, 1600 mg, 1750 mg, 1800 mg, 2000 mg, 2150 mg, or 2300 mg of capecitabine.

[0088] In some embodiments, the drug combination comprises 750-1000 mg / m 2 In some embodiments, the drug combination includes 750 mg / m 2 or 1000 mg / m 2 In some embodiments, the drug combination includes 1000 mg / m 2 of gemcitabine.

[0089] In some embodiments, the drug combination comprises 25 mg / m 2 Changchunruibin.

[0090] In some embodiments, the drug combination comprises 0.7-1.4 mg / m 2 In some embodiments, the drug combination includes 0.7 mg / m 2 , 1.1mg / m 2 or 1.4 mg / m 2 In some embodiments, the drug combination includes 1.4 mg / m 2 of Eriblin.

[0091] In some embodiments, the drug combination comprises 2.5-50 mg / kg, 2.5-30 mg / kg, 2.5-10 mg / kg, 5-10 mg / kg, 10-30 mg / kg, or 20-30 mg / kg of an antigen-binding construct targeting HER2, and 130-260 mg, or 180-260 mg of nab-paclitaxel. In some embodiments, the drug combination comprises 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, or 50 mg / kg, or a range formed by any two of the foregoing values, and 130 mg, 180 mg, 200 mg, 220 mg, or 260 mg of nab-paclitaxel. In some embodiments, the drug combination comprises 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, or 30 mg / kg of an antigen-binding construct targeting HER2 and 130 mg, 180 mg, 200 mg, 220 mg, or 260 mg of nab-paclitaxel. In some embodiments, the drug combination comprises 30 mg / kg of an antigen-binding construct targeting HER2 and 260 mg of nab-paclitaxel.

[0092] In some embodiments, the drug combination comprises 2.5-50 mg / kg, 2.5-30 mg / kg, 2.5-10 mg / kg, 5-10 mg / kg, 10-30 mg / kg, or 20-30 mg / kg of an antigen-binding construct targeting HER2 and 500-1000 mg / kg of 2 In some embodiments, the drug combination comprises 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, or 50 mg / kg, or a range formed by any two of the above values, of an antigen-binding construct targeting HER2, and 500 mg / kg of capecitabine. 2 , 750mg / m 2 or 1000 mg / m 2 In some embodiments, the drug combination includes 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg or 30 mg / kg of an antigen-binding construct targeting HER2, and 750 mg / kg 2 or 1000 mg / m 2In some embodiments, the drug combination includes 30 mg / kg of an antigen-binding construct targeting HER2 and 1000 mg / m 2 In some embodiments, the drug combination comprises 2.5-50 mg / kg, 2.5-30 mg / kg, 2.5-10 mg / kg, 5-10 mg / kg, 10-30 mg / kg, or 20-30 mg / kg of an antigen-binding construct targeting HER2 and 600-2300 mg, or 1150-2300 mg of capecitabine. In some embodiments, the drug combination comprises 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, or 50 mg / kg, or a range formed by any two of the foregoing values, of an antigen-binding construct targeting HER2, and 600 mg, 750 mg, 800 mg, 900 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1300 mg, 1400 mg, 1450 mg, 1500 mg, 1600 mg, 1750 mg, 1800 mg, 2000 mg, 2150 mg, or 2300 mg of capecitabine. In some embodiments, the drug combination comprises 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg or 30 mg / kg of an antigen-binding construct targeting HER2, and 1150 mg, 1300 mg, 1450 mg, 1600 mg, 1750 mg, 1800 mg, 2000 mg, 2150 mg or 2300 mg of capecitabine. In some embodiments, the drug combination comprises 30 mg / kg of an antigen-binding construct targeting HER2, and 1150 mg, 1300 mg, 1450 mg, 1600 mg, 1750 mg, 1800 mg, 2000 mg, 2150 mg or 2300 mg of capecitabine.

[0093] In some embodiments, the drug combination comprises 2.5-50 mg / kg, 2.5-30 mg / kg, 2.5-10 mg / kg, 5-10 mg / kg, 10-30 mg / kg, or 20-30 mg / kg of an antigen-binding construct targeting HER2 and 750-1000 mg / kg of 2In some embodiments, the drug combination comprises 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, or 50 mg / kg, or a range formed by any two of the above values, of an antigen-binding construct targeting HER2, and 750 mg / kg 2 or 1000 mg / m 2 In some embodiments, the drug combination includes 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg or 30 mg / kg of an antigen-binding construct targeting HER2, and 750 mg / kg 2 or 1000 mg / m 2 In some embodiments, the drug combination includes 30 mg / kg of an antigen-binding construct targeting HER2 and 1000 mg / m 2 of gemcitabine.

[0094] In some embodiments, the drug combination comprises 2.5-50 mg / kg, 2.5-30 mg / kg, 2.5-10 mg / kg, 5-10 mg / kg, 10-30 mg / kg, or 20-30 mg / kg of an antigen-binding construct targeting HER2, and 25 mg / kg 2 In some embodiments, the drug combination comprises 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, or 50 mg / kg, or a range formed by any two of the above values, of an antigen-binding construct targeting HER2, and 25 mg / kg 2 In some embodiments, the drug combination includes 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg or 30 mg / kg of an antigen-binding construct targeting HER2, and 25 mg / kg 2 In some embodiments, the drug combination includes 30 mg / kg of an antigen-binding construct targeting HER2 and 25 mg / m 2 Changchunruibin.

[0095] In some embodiments, the drug combination comprises 2.5-50 mg / kg, 2.5-30 mg / kg, 2.5-10 mg / kg, 5-10 mg / kg, 10-30 mg / kg, or 20-30 mg / kg of an antigen-binding construct targeting HER2 and 0.7-1.4 mg / kg of 2 In some embodiments, the drug combination comprises 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, or 50 mg / kg, or a range formed by any two of the above values, of an antigen-binding construct targeting HER2, and 0.7 mg / m 2 , 1.1mg / m 2 or 1.4 mg / m 2 In some embodiments, the drug combination includes 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg or 30 mg / kg of an antigen-binding construct targeting HER2, and 0.7 mg / m 2 , 1.1mg / m 2 or 1.4 mg / m 2 In some embodiments, the drug combination includes 30 mg / kg of an antigen-binding construct targeting HER2 and 1.4 mg / m 2 of Eriblin.

[0096] In some embodiments, the drug combination is suitable for the preparation used in a single treatment cycle (such as a treatment cycle of 3 weeks), and it includes the antigen-binding constructs for the targeting HER2 of 7.5-50mg / kg, 7.5-40mg / kg, 15-40mg / kg, 15-30mg / kg or 30-40mg / kg. In some embodiments, the drug combination is suitable for the preparation used in a single treatment cycle, and it includes the antigen-binding constructs for the targeting HER2 of 7.5mg / kg, 15mg / kg, 20mg / kg, 30mg / kg, 40mg / kg or 50mg / kg or the scope formed by any two values. In some embodiments, the drug combination is suitable for the preparation used in a single treatment cycle, and it includes the antigen-binding constructs for the targeting HER2 of 7.5mg / kg, 15mg / kg, 30mg / kg or 40mg / kg. In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, which includes 40 mg / kg of an antigen-binding construct targeting HER2.

[0097] In some embodiments, the drug combination is a formulation suitable for administration within a single treatment cycle (e.g., a 3-week treatment cycle) comprising 130-260 mg, or 180-260 mg of nab-paclitaxel. In some embodiments, the drug combination is a formulation suitable for administration within a single treatment cycle comprising 130 mg, 180 mg, 200 mg, 220 mg, or 260 mg of nab-paclitaxel. In some embodiments, the drug combination is a formulation suitable for administration within a single treatment cycle comprising 260 mg of nab-paclitaxel.

[0098] In some embodiments, the drug combination is a formulation suitable for administration within a single treatment cycle (e.g., a 3-week treatment cycle) comprising 14-28 g / m 2 In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 14 g / m 2 , 21g / m 2 or 28g / m 2 In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 28 g / m 2 In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 16.8-64.4 g, or 32.2-64.4 g of capecitabine. In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 16.8 g, 21 g, 22.4 g, 25.2 g, 28 g, 29.4 g, 30.8 g, 32.2 g, 33.6 g, 36.4 g, 39.2 g, 40.6 g, 42 g, 44.8 g, 49 g, 50.4 g, 56 g, 60.2 g, or 64.4 g of capecitabine. In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle that includes 32.2 g, 36.4 g, 40.6 g, 44.8 g, 49 g, 50.4 g, 56 g, 60.2 g, or 64.4 g of capecitabine.

[0099] In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle (e.g., a 3-week treatment cycle) comprising 1500-2000 mg / m 2 In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 1500 mg / m 2 or 2000 mg / m 2 In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 2000 mg / m2 of gemcitabine.

[0100] In some embodiments, the drug combination is a formulation suitable for administration within a single treatment cycle (e.g., a 3-week treatment cycle) comprising 50 mg / m 2 Changchunruibin.

[0101] In some embodiments, the drug combination is a formulation suitable for administration within a single treatment cycle (e.g., a 3-week treatment cycle) comprising 1.4-2.8 mg / m 2 In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 1.4 mg / m 2 , 2.2mg / m 2 or 2.8 mg / m 2 In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 2.8 mg / m 2 of Eriblin.

[0102] In some embodiments, the drug combination is a preparation suitable for use in a single treatment cycle (e.g., a 3-week treatment cycle), comprising an antigen-binding construct targeting HER2 of 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg, and 130-260 mg or 180-260 mg of nab-paclitaxel. In some embodiments, the drug combination is a preparation suitable for use in a single treatment cycle, comprising an antigen-binding construct targeting HER2 of 7.5 mg / kg, 15 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, or 50 mg / kg, or a range formed by any two of the above values, and 130 mg, 180 mg, 200 mg, 220 mg, or 260 mg of nab-paclitaxel. In some embodiments, the drug combination is a formulation suitable for administration within a single treatment cycle, comprising 7.5 mg / kg, 15 mg / kg, 30 mg / kg, or 40 mg / kg of an antigen-binding construct targeting HER2, and 130 mg, 180 mg, 200 mg, 220 mg, or 260 mg of nab-paclitaxel. In some embodiments, the drug combination is a formulation suitable for administration within a single treatment cycle, comprising 30 mg / kg of an antigen-binding construct targeting HER2, and 260 mg of nab-paclitaxel.

[0103] In some embodiments, the drug combination is a formulation suitable for administration within a single treatment cycle (e.g., a 3-week treatment cycle), comprising 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of an antigen-binding construct targeting HER2, and 14-28 g / m 2 In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 7.5 mg / kg, 15 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, or 50 mg / kg, or a range formed by any two of the above values, of an antigen-binding construct targeting HER2, and 14 g / m 2 , 21g / m 2 or 28g / m 2 In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 7.5 mg / kg, 15 mg / kg, 30 mg / kg or 40 mg / kg of an antigen-binding construct targeting HER2, and 14 g / m 2 , 21g / m 2 or 28g / m 2 In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 30 mg / kg of an antigen-binding construct targeting HER2 and 28 g / m 2In some embodiments, the drug combination is a formulation suitable for administration within a single treatment cycle (e.g., a 3-week treatment cycle), comprising 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of an antigen-binding construct targeting HER2, and 16.8-64.4 g, or 32.2-64.4 g of capecitabine. In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 7.5 mg / kg, 15 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, or 50 mg / kg, or a range formed by any two of the foregoing values, of an antigen-binding construct targeting HER2, and 16.8 g, 21 g, 22.4 g, 25.2 g, 28 g, 29.4 g, 30.8 g, 32.2 g, 33.6 g, 36.4 g, 39.2 g, 40.6 g, 42 g, 44.8 g, 49 g, 50.4 g, 56 g, 60.2 g, or 64.4 g of capecitabine. In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 7.5 mg / kg, 15 mg / kg, 30 mg / kg, or 40 mg / kg of an antigen-binding construct targeting HER2, and 16.8 g, 21 g, 22.4 g, 25.2 g, 28 g, 29.4 g, 30.8 g, 32.2 g, 33.6 g, 36.4 g, 39.2 g, 40.6 g, 42 g, 44.8 g, 49 g, 50.4 g, 56 g, 60.2 g, or 64.4 g of capecitabine. In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 30 mg / kg of an antigen-binding construct targeting HER2 and 32.2 g, 36.4 g, 40.6 g, 44.8 g, 49 g, 50.4 g, 56 g, 60.2 g, or 64.4 g of capecitabine.

[0104] In some embodiments, the drug combination is a formulation suitable for administration within a single treatment cycle (e.g., a 3-week treatment cycle), comprising 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of an antigen-binding construct targeting HER2, and 1500-2000 mg / kg of 2 In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 7.5 mg / kg, 15 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, or 50 mg / kg, or a range formed by any two of the above values, of an antigen-binding construct targeting HER2, and 1500 mg / m2 or 2000 mg / m 2 In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 7.5 mg / kg, 15 mg / kg, 30 mg / kg or 40 mg / kg of an antigen-binding construct targeting HER2, and 1500 mg / m 2 or 2000 mg / m 2 In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 30 mg / kg of an antigen-binding construct targeting HER2 and 2000 mg / m 2 of gemcitabine.

[0105] In some embodiments, the drug combination is a formulation suitable for administration within a single treatment cycle (e.g., a 3-week treatment cycle), comprising 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of an antigen-binding construct targeting HER2, and 50 mg / kg 2 In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 7.5 mg / kg, 15 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, or 50 mg / kg, or a range formed by any two of the above values, of an antigen-binding construct targeting HER2, and 50 mg / kg of vinorelbine. 2 In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 7.5 mg / kg, 15 mg / kg, 30 mg / kg or 40 mg / kg of an antigen-binding construct targeting HER2, and 50 mg / m 2 In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 30 mg / kg of an antigen-binding construct targeting HER2 and 50 mg / m 2 Changchunruibin.

[0106] In some embodiments, the drug combination is a formulation suitable for administration within a single treatment cycle (e.g., a 3-week treatment cycle), comprising 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of an antigen-binding construct targeting HER2, and 1.4-2.8 mg / kg of 2In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 7.5 mg / kg, 15 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, or 50 mg / kg, or a range formed by any two of the above values, of an antigen-binding construct targeting HER2, and 1.4 mg / m 2 , 2.2mg / m 2 or 2.8 mg / m 2 In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 7.5 mg / kg, 15 mg / kg, 30 mg / kg, or 40 mg / kg of an antigen-binding construct targeting HER2, and 1.4 mg / m 2 , 2.2mg / m 2 or 2.8 mg / m 2 In some embodiments, the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 30 mg / kg of an antigen-binding construct targeting HER2 and 2.8 mg / m 2 of Eriblin.

[0107] In some embodiments, the amount of the antigen-binding construct targeting HER2 in the pharmaceutical combination is a daily dose. In some embodiments, the amount of the antigen-binding construct targeting HER2 in the pharmaceutical combination is a single dose. In some embodiments, the amount of the antigen-binding construct targeting HER2 in the pharmaceutical combination is a once-daily dose. In some embodiments, the amount of the antigen-binding construct targeting HER2 in the pharmaceutical combination is a dose for half a treatment cycle, where one treatment cycle is 3 weeks.

[0108] In some embodiments, the amount of nab-paclitaxel in the pharmaceutical combination is a daily dose. In some embodiments, the amount of nab-paclitaxel in the pharmaceutical combination is a single dose. In some embodiments, the amount of nab-paclitaxel in the pharmaceutical combination is a once-daily dose.

[0109] In some embodiments, the amount of capecitabine in the pharmaceutical combination is a single dose. In some embodiments, capecitabine is administered twice daily. In some embodiments, the amount of capecitabine in the pharmaceutical combination is a dose for one treatment cycle, where one treatment cycle is three weeks.

[0110] In some embodiments, the amount of gemcitabine in the pharmaceutical combination is a daily dose. In some embodiments, the amount of gemcitabine in the pharmaceutical combination is a single dose. In some embodiments, the amount of gemcitabine in the pharmaceutical combination is a single daily dose.

[0111] In some embodiments, the amount of gemcitabine in the drug combination is a dosage for one treatment cycle, and one treatment cycle is 3 weeks.

[0112] In some embodiments, the amount of vinorelbine in the pharmaceutical combination is a daily dose. In some embodiments, the amount of vinorelbine in the pharmaceutical combination is a single dose. In some embodiments, the amount of vinorelbine in the pharmaceutical combination is a once-a-day dose.

[0113] In some embodiments, the content of vinorelbine in the drug combination is a dose for one treatment cycle, and one treatment cycle is 3 weeks.

[0114] In some embodiments, the amount of eribulin in the pharmaceutical combination is a daily dose. In some embodiments, the amount of eribulin in the pharmaceutical combination is a single dose. In some embodiments, the amount of eribulin in the pharmaceutical combination is a once-daily dose.

[0115] In some embodiments, the content of eribulin in the pharmaceutical combination is a dosage for one treatment cycle, and one treatment cycle is 3 weeks.

[0116] In some embodiments, the antigen-binding construct targeting HER2 can be a pharmaceutical composition of an antigen-binding construct targeting HER2. Wherein, the pharmaceutical composition of the antigen-binding construct targeting HER2 is a single dose or multiple doses, preferably a multiple dose; in some embodiments, the multiple doses may consist of a single dose of 100-600 mg, 200-600 mg, or 200-400 mg of the pharmaceutical composition of the antigen-binding construct targeting HER2; in some embodiments, the multiple doses may consist of a single dose of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg and / or 600 mg of the pharmaceutical composition of the antigen-binding construct targeting HER2; in some embodiments, the multiple doses may consist of a single dose of 200 mg, 400 mg and / or 600 mg of the pharmaceutical composition of the antigen-binding construct targeting HER2; in some embodiments, the multiple doses may consist of a single dose of 200 mg of the pharmaceutical composition of the antigen-binding construct targeting HER2.

[0117] In some embodiments, the albumin-paclitaxel can be a pharmaceutical composition of albumin-paclitaxel, wherein the pharmaceutical composition of albumin-paclitaxel is a single dose or multiple doses, preferably multiple doses; in some embodiments, the multiple doses can consist of a single dose of 100 mg of the pharmaceutical composition of albumin-paclitaxel.

[0118] In some embodiments, the capecitabine may be a pharmaceutical composition of capecitabine, wherein the pharmaceutical composition of capecitabine is a single dose or multiple doses, preferably multiple doses; in some embodiments, the multiple doses may consist of a single dose of 150 mg and / or 500 mg of the pharmaceutical composition of capecitabine.

[0119] In some embodiments, the gemcitabine may be a pharmaceutical composition of gemcitabine, wherein the pharmaceutical composition of gemcitabine is a single dose or multiple doses, preferably multiple doses; in some embodiments, the multiple doses may consist of a single dose of 0.2 g and / or 1 g of the pharmaceutical composition of gemcitabine.

[0120] In some embodiments, the vinorelbine may be a pharmaceutical composition of vinorelbine, wherein the pharmaceutical composition of vinorelbine is a single dose or multiple doses, preferably multiple doses; in some embodiments, the multiple doses may consist of a single dose of 10 mg of the pharmaceutical composition of vinorelbine.

[0121] In some embodiments, the eribulin may be a pharmaceutical composition of eribulin, wherein the pharmaceutical composition of eribulin is a single dose or multiple doses, preferably multiple doses; in some embodiments, the multiple doses may consist of a single dose of 1 mg of the pharmaceutical composition of eribulin.

[0122] In some embodiments, the drug combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of nab-paclitaxel, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering to the patient 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of the antigen-binding construct targeting HER2 per treatment cycle, and the pharmaceutical composition of nab-paclitaxel is prepared as a single dose or multiple doses suitable for administering to the patient 130-260 mg, or 180-260 mg of nab-paclitaxel per treatment cycle. In some embodiments, the drug combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of nab-paclitaxel, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering to the patient 7.5 mg / kg, 15 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg or 50 mg / kg of the antigen-binding construct targeting HER2 per treatment cycle, and the pharmaceutical composition of nab-paclitaxel is prepared as a single dose or multiple doses suitable for administering to the patient 130 mg, 180 mg, 200 mg, 220 mg or 260 mg of nab-paclitaxel per treatment cycle. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of albumin-paclitaxel, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering 7.5 mg / kg, 15 mg / kg, 30 mg / kg or 40 mg / kg of the antigen-binding construct targeting HER2 to the patient per treatment cycle, and the pharmaceutical composition of albumin-paclitaxel is prepared as a single dose or multiple doses suitable for administering 130 mg, 180 mg, 200 mg, 220 mg or 260 mg of albumin-paclitaxel to the patient per treatment cycle. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of albumin-paclitaxel, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering 30 mg / kg of the antigen-binding construct targeting HER2 to the patient per treatment cycle, and the pharmaceutical composition of albumin-paclitaxel is prepared as a single dose or multiple doses suitable for administering 260 mg of albumin-paclitaxel to the patient per treatment cycle. In some embodiments, one treatment cycle is 3 weeks.

[0123] In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of capecitabine, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering to the patient 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of the antigen-binding construct targeting HER2 per treatment cycle, and the pharmaceutical composition of capecitabine is prepared as a single dose or multiple doses suitable for administering to the patient 500-1000 mg / kg twice a day for 14 consecutive days. 2 In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of capecitabine, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses of 7.5 mg / kg, 15 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg or 50 mg / kg of the antigen-binding construct targeting HER2 is administered to the patient per treatment cycle, and the pharmaceutical composition of capecitabine is prepared as a single dose or multiple doses of 500 mg / kg twice a day for 14 consecutive days. 2 , 750mg / m 2 or 1000 mg / m 2 In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of capecitabine, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses of 7.5 mg / kg, 15 mg / kg, 30 mg / kg or 40 mg / kg of the antigen-binding construct targeting HER2 is administered to the patient per treatment cycle, and the pharmaceutical composition of capecitabine is prepared as a single dose or multiple doses of 500 mg / kg twice a day for 14 consecutive days. 2 , 750mg / m 2 or 1000 mg / m 2 In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of capecitabine, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering 30 mg / kg of the antigen-binding construct targeting HER2 to the patient per treatment cycle, and the pharmaceutical composition of capecitabine is prepared as a single dose or multiple doses suitable for administering 1000 mg / m2 of the antigen-binding construct targeting HER2 to the patient twice a day for 14 consecutive days. 2Single or multiple doses of capecitabine. In some embodiments, the pharmaceutical combination includes a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of capecitabine, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of the antigen-binding construct targeting HER2 to the patient per treatment cycle, and the pharmaceutical composition of capecitabine is prepared as a single dose or multiple doses suitable for administering 600-2300 mg or 1150-2300 mg of capecitabine to the patient twice a day for 14 consecutive days. In some embodiments, the drug combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of capecitabine, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering to the patient 7.5 mg / kg, 15 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg or 50 mg / kg of the antigen-binding construct targeting HER2 per treatment cycle, and the pharmaceutical composition of capecitabine is prepared as a single dose or multiple doses suitable for administering to the patient 600 mg, 750 mg, 800 mg, 900 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1300 mg, 1400 mg, 1450 mg, 1500 mg, 1600 mg, 1750 mg, 1800 mg, 2000 mg, 2150 mg or 2300 mg of capecitabine twice a day for 14 consecutive days. In some embodiments, the drug combination includes a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of capecitabine, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering 7.5 mg / kg, 15 mg / kg, 30 mg / kg or 40 mg / kg of the antigen-binding construct targeting HER2 to the patient per treatment cycle, and the pharmaceutical composition of capecitabine is prepared as a single dose or multiple doses suitable for administering 600 mg, 750 mg, 800 mg, 900 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1300 mg, 1400 mg, 1450 mg, 1500 mg, 1600 mg, 1750 mg, 1800 mg, 2000 mg, 2150 mg or 2300 mg of capecitabine to the patient twice a day for 14 consecutive days.In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of capecitabine, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering 30 mg / kg of the antigen-binding construct targeting HER2 to the patient per treatment cycle, and the pharmaceutical composition of capecitabine is prepared as a single dose or multiple doses suitable for administering 1150 mg, 1300 mg, 1450 mg, 1600 mg, 1750 mg, 1800 mg, 2000 mg, 2150 mg, or 2300 mg of capecitabine to the patient twice a day for 14 consecutive days. In some embodiments, one treatment cycle is 3 weeks.

[0124] In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of gemcitabine, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering to the patient 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of the antigen-binding construct targeting HER2 per treatment cycle, and the pharmaceutical composition of gemcitabine is prepared as a single dose or multiple doses suitable for administering to the patient 1500-2000 mg / kg per treatment cycle. 2 In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of gemcitabine, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses of 7.5 mg / kg, 15 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg or 50 mg / kg of the antigen-binding construct targeting HER2 is administered to the patient per treatment cycle, and the pharmaceutical composition of gemcitabine is prepared as a single dose or multiple doses of 1500 mg / kg of the antigen-binding construct targeting HER2 is administered to the patient per treatment cycle. 2 or 2000 mg / m 2 In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of gemcitabine, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses of 7.5 mg / kg, 15 mg / kg, 30 mg / kg or 40 mg / kg of the antigen-binding construct targeting HER2 is administered to the patient per treatment cycle, and the pharmaceutical composition of gemcitabine is prepared as a single dose or multiple doses of 1500 mg / kg of the antigen-binding construct targeting HER2 is administered to the patient per treatment cycle. 2 or 2000 mg / m 2In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of gemcitabine, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering 30 mg / kg of the antigen-binding construct targeting HER2 to the patient per treatment cycle, and the pharmaceutical composition of gemcitabine is prepared as a single dose or multiple doses suitable for administering 2000 mg / m2 of the antigen-binding construct targeting HER2 to the patient per treatment cycle. 2 Single or multiple doses of gemcitabine. In some embodiments, one treatment cycle is 3 weeks.

[0125] In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of vinorelbine, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering to the patient 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of the antigen-binding construct targeting HER2 per treatment cycle, and the pharmaceutical composition of vinorelbine is prepared as a single dose or multiple doses suitable for administering to the patient 50 mg / kg per treatment cycle. 2 In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of vinorelbine, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses of 7.5 mg / kg, 15 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg or 50 mg / kg of the antigen-binding construct targeting HER2 is administered to the patient per treatment cycle, and the pharmaceutical composition of vinorelbine is prepared as a single dose or multiple doses of 50 mg / kg of the antigen-binding construct targeting HER2 is administered to the patient per treatment cycle. 2 In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of vinorelbine, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses of 7.5 mg / kg, 15 mg / kg, 30 mg / kg or 40 mg / kg of the antigen-binding construct targeting HER2 is administered to the patient per treatment cycle, and the pharmaceutical composition of vinorelbine is prepared as a single dose or multiple doses of 50 mg / kg of the antigen-binding construct targeting HER2 is administered to the patient per treatment cycle. 2In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of vinorelbine, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering 30 mg / kg of the antigen-binding construct targeting HER2 to the patient per treatment cycle, and the pharmaceutical composition of vinorelbine is prepared as a single dose or multiple doses suitable for administering 50 mg / m2 of the antigen-binding construct targeting HER2 to the patient per treatment cycle. 2 Single or multiple doses of vinorelbine. In some embodiments, one treatment cycle is 3 weeks.

[0126] In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of eribulin, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering to the patient 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of the antigen-binding construct targeting HER2 per treatment cycle, and the pharmaceutical composition of eribulin is prepared as a single dose or multiple doses suitable for administering to the patient 1.4-2.8 mg / kg per treatment cycle. 2 In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of eribulin, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering to the patient 7.5 mg / kg, 15 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, or 50 mg / kg of the antigen-binding construct targeting HER2 per treatment cycle, and the pharmaceutical composition of eribulin is prepared as a single dose or multiple doses suitable for administering to the patient 1.4 mg / kg per treatment cycle. 2 , 2.2mg / m 2 or 2.8 mg / m 2 In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of eribulin, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses of 7.5 mg / kg, 15 mg / kg, 30 mg / kg, or 40 mg / kg of the antigen-binding construct targeting HER2 is administered to the patient per treatment cycle, and the pharmaceutical composition of eribulin is prepared as a single dose or multiple doses of 1.4 mg / kg of the antigen-binding construct targeting HER2 is administered to the patient per treatment cycle. 2 , 2.2mg / m 2 or 2.8 mg / m 2In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of eribulin, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 is prepared as a single dose or multiple doses suitable for administering 30 mg / kg of the antigen-binding construct targeting HER2 to the patient per treatment cycle, and the pharmaceutical composition of eribulin is prepared as a single dose or multiple doses suitable for administering 2.8 mg / m2 to the patient per treatment cycle. 2 Single or multiple doses of eribulin. In some embodiments, one treatment cycle is 3 weeks.

[0127] In some embodiments, in the drug combination, the antigen-binding construct targeting HER2 and the chemotherapeutic agent can be packaged separately or together. Wherein, the antigen-binding construct targeting HER2 can be packaged in a single portion or multiple portions, and the chemotherapeutic agent can be packaged in a single portion or multiple portions. In some embodiments, the antigen-binding construct targeting HER2 can be packaged in a single portion or multiple portions (e.g., 2 equal portions, 3 equal portions, 4 equal portions, 5 equal portions, 6 equal portions, 7 equal portions, 8 equal portions or more equal portions), and the chemotherapeutic agent can be packaged in a single portion or multiple portions.

[0128] In some embodiments, in the pharmaceutical combination, the antigen-binding construct targeting HER2 and nab-paclitaxel can be packaged separately or together. The antigen-binding construct targeting HER2 can be packaged in a single portion or multiple portions, and nab-paclitaxel can be packaged in a single portion or multiple portions. In some embodiments, the antigen-binding construct targeting HER2 can be packaged in a single portion or multiple portions (e.g., 2 equal portions, 3 equal portions, 4 equal portions, 5 equal portions, 6 equal portions, 7 equal portions, 8 equal portions, or more equal portions), and nab-paclitaxel can be packaged in a single portion or multiple portions.

[0129] In some embodiments, in the pharmaceutical combination, the antigen-binding construct targeting HER2 and capecitabine can be packaged separately or together. Wherein, the antigen-binding construct targeting HER2 can be packaged in a single portion or multiple portions, and capecitabine can be packaged in a single portion or multiple portions. In some embodiments, the antigen-binding construct targeting HER2 can be packaged in a single portion or multiple equal portions (e.g., 2 equal portions, 3 equal portions, 4 equal portions, 5 equal portions, 6 equal portions, 7 equal portions, 8 equal portions or more equal portions), and capecitabine can be packaged in a single portion or multiple equal portions.

[0130] In some embodiments, in the drug combination, the antigen-binding construct targeting HER2 and gemcitabine can be packaged separately or packaged together. Wherein, the antigen-binding construct targeting HER2 can be packaged in a single portion or multiple portions, and gemcitabine can be packaged in a single portion or multiple portions. In some embodiments, the antigen-binding construct targeting HER2 can be packaged in a single portion or multiple portions (e.g., 2 equal portions, 3 equal portions, 4 equal portions, 5 equal portions, 6 equal portions, 7 equal portions, 8 equal portions or more equal portions), and gemcitabine can be packaged in a single portion or multiple portions.

[0131] In some embodiments, in the drug combination, the antigen-binding construct targeting HER2 and vinorelbine can be packaged separately or together. Wherein, the antigen-binding construct targeting HER2 can be packaged in a single portion or multiple portions, and vinorelbine can be packaged in a single portion or multiple portions. In some embodiments, the antigen-binding construct targeting HER2 can be packaged in a single portion or multiple portions (e.g., 2 equal portions, 3 equal portions, 4 equal portions, 5 equal portions, 6 equal portions, 7 equal portions, 8 equal portions or more equal portions), and vinorelbine can be packaged in a single portion or multiple portions.

[0132] In some embodiments, in the pharmaceutical combination, the antigen-binding construct targeting HER2 and eribulin can be packaged separately or together. The antigen-binding construct targeting HER2 can be packaged in a single portion or multiple portions, and eribulin can be packaged in a single portion or multiple portions. In some embodiments, the antigen-binding construct targeting HER2 can be packaged in a single portion or multiple portions (e.g., 2 equal portions, 3 equal portions, 4 equal portions, 5 equal portions, 6 equal portions, 7 equal portions, 8 equal portions, or more equal portions), and eribulin can be packaged in a single portion or multiple portions.

[0133] In some embodiments, the drug combination is packaged in the same kit, and optionally, the kit further comprises instructions for using the antigen-binding construct targeting HER2 and the chemotherapeutic drug in combination to treat tumors. In other embodiments, the antigen-binding construct targeting HER2 and the chemotherapeutic drug in the drug combination are separately packaged in their own kits, and optionally, the kit further comprises instructions for using the antigen-binding construct targeting HER2 and the chemotherapeutic drug in combination to treat tumors.

[0134] In some embodiments, the drug combination is packaged in the same kit, and optionally, the kit further comprises instructions for using the antigen-binding construct targeting HER2 and nab-paclitaxel in combination to treat tumors. In other embodiments, the antigen-binding construct targeting HER2 and nab-paclitaxel in the drug combination are separately packaged in separate kits, and optionally, the kit further comprises instructions for using the antigen-binding construct targeting HER2 and nab-paclitaxel in combination to treat tumors.

[0135] In some embodiments, the drug combination is packaged in the same kit, and optionally, the kit further comprises instructions for using the antigen-binding construct targeting HER2 and capecitabine in combination to treat tumors. In other embodiments, the antigen-binding construct targeting HER2 and capecitabine in the drug combination are separately packaged in their own kits, and optionally, the kit further comprises instructions for using the antigen-binding construct targeting HER2 and capecitabine in combination to treat tumors.

[0136] In some embodiments, the drug combination is packaged in the same kit, and optionally, the kit further comprises instructions for using the antigen-binding construct targeting HER2 and gemcitabine in combination to treat tumors. In other embodiments, the antigen-binding construct targeting HER2 and gemcitabine in the drug combination are separately packaged in their own medicine boxes, and optionally, the medicine box further comprises instructions for using the antigen-binding construct targeting HER2 and gemcitabine in combination to treat tumors.

[0137] In some embodiments, the drug combination is packaged in the same kit, and optionally, the kit further comprises instructions for using the antigen-binding construct targeting HER2 and vinorelbine in combination to treat tumors. In other embodiments, the antigen-binding construct targeting HER2 and vinorelbine in the drug combination are separately packaged in their own medicine boxes, and optionally, the medicine box further comprises instructions for using the antigen-binding construct targeting HER2 and vinorelbine in combination to treat tumors.

[0138] In some embodiments, the pharmaceutical combination is packaged in the same kit, and optionally, the kit further comprises instructions for using the antigen-binding construct targeting HER2 and eribulin in combination to treat tumors. In other embodiments, the antigen-binding construct targeting HER2 and eribulin in the pharmaceutical combination are separately packaged in separate kits, and optionally, the kit further comprises instructions for using the antigen-binding construct targeting HER2 and eribulin in combination to treat tumors.

[0139] In some embodiments, the pharmaceutical combination is a fixed combination.In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition or in the form of a liquid pharmaceutical composition.

[0140] In some embodiments, the drug combination is a non-fixed combination. In some embodiments, in the non-fixed combination, the antigen-binding construct targeting HER2 and the chemotherapy drug are each in the form of a pharmaceutical composition. In some embodiments, the antigen-binding construct targeting HER2 and the chemotherapy drug are each in the form of a pharmaceutical composition and are separately packaged in their own medicine boxes. In some embodiments, in the non-fixed combination, the antigen-binding construct targeting HER2 and nab-paclitaxel are each in the form of a pharmaceutical composition. In some embodiments, in the non-fixed combination, the antigen-binding construct targeting HER2 and capecitabine are each in the form of a pharmaceutical composition. In some embodiments, in the non-fixed combination, the antigen-binding construct targeting HER2 and gemcitabine are each in the form of a pharmaceutical composition. In some embodiments, in the non-fixed combination, the antigen-binding construct targeting HER2 and vinorelbine are each in the form of a pharmaceutical composition. In some embodiments, in the non-fixed combination, the antigen-binding construct targeting HER2 and eribulin are each in the form of a pharmaceutical composition.

[0141] In some embodiments, the pharmaceutical composition of the antigen-binding construct targeting HER2 in the non-fixed combination is a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition of the antigen-binding construct targeting HER2 in the non-fixed combination is a lyophilized formulation. In some embodiments, the pharmaceutical composition of the antigen-binding construct targeting HER2 in the non-fixed combination is a powder for injection.

[0142] In some embodiments, the pharmaceutical composition of nab-paclitaxel in the non-fixed combination is a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition of nab-paclitaxel in the non-fixed combination is a lyophilized formulation. In some embodiments, the pharmaceutical composition of nab-paclitaxel in the non-fixed combination is a powder for injection.

[0143] In some specific embodiments, in the non-fixed combination, the pharmaceutical composition of capecitabine is a solid pharmaceutical composition. In some specific embodiments, in the non-fixed combination, the pharmaceutical composition of capecitabine is a tablet.

[0144] In some specific embodiments, in the non-fixed combination, the pharmaceutical composition of gemcitabine is a solid pharmaceutical composition. In some specific embodiments, in the non-fixed combination, the pharmaceutical composition of gemcitabine is a lyophilized formulation. In some specific embodiments, in the non-fixed combination, the pharmaceutical composition of gemcitabine is a powder for injection.

[0145] In some specific embodiments, in the non-fixed combination, the pharmaceutical composition of vinorelbine is a liquid pharmaceutical composition. In some specific embodiments, in the non-fixed combination, the pharmaceutical composition of vinorelbine is an injection.

[0146] In some embodiments, the pharmaceutical composition of eribulin in the non-fixed combination is a liquid pharmaceutical composition. In some embodiments, the pharmaceutical composition of eribulin in the non-fixed combination is an injection.

[0147] In another aspect, the present disclosure provides a kit comprising a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of a chemotherapeutic agent, and optionally further comprising instructions for combining the pharmaceutical composition of the antigen-binding construct targeting HER2 and the pharmaceutical composition of the chemotherapeutic agent to treat a tumor. In some embodiments, the kit is used to treat a tumor.

[0148] In another aspect, the present disclosure provides a kit comprising a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of nab-paclitaxel, and optionally further comprising instructions for using the pharmaceutical composition of the antigen-binding construct targeting HER2 and the pharmaceutical composition of nab-paclitaxel in combination to treat a tumor. In some embodiments, the kit is used to treat a tumor.

[0149] In another aspect, the present disclosure provides a kit comprising a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of capecitabine, and optionally further comprising instructions for using the pharmaceutical composition of the antigen-binding construct targeting HER2 and the pharmaceutical composition of capecitabine in combination to treat a tumor. In some embodiments, the kit is used to treat a tumor.

[0150] In another aspect, the present disclosure provides a kit comprising a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of gemcitabine, and optionally further comprising instructions for using the pharmaceutical composition of the antigen-binding construct targeting HER2 and the pharmaceutical composition of gemcitabine in combination to treat a tumor. In some embodiments, the kit is used to treat a tumor.

[0151] In another aspect, the present disclosure provides a kit comprising a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of vinorelbine, and optionally further comprising instructions for using the pharmaceutical composition of the antigen-binding construct targeting HER2 and the pharmaceutical composition of vinorelbine in combination to treat a tumor. In some embodiments, the kit is used to treat a tumor.

[0152] In another aspect, the present disclosure provides a kit comprising a pharmaceutical composition of an antigen-binding construct targeting HER2 and a pharmaceutical composition of eribulin, and optionally further comprising instructions for using the pharmaceutical composition of the antigen-binding construct targeting HER2 and the pharmaceutical composition of eribulin in combination to treat a tumor. In some embodiments, the kit is used to treat a tumor.

[0153] On the other hand, the present disclosure also provides a drug package, which contains single-packaged pharmaceutical compositions in separate containers, wherein the first container includes a pharmaceutical composition of an antigen-binding construct targeting HER2, and the second container includes a pharmaceutical composition of a chemotherapeutic drug. In some embodiments, the drug package contains single-packaged pharmaceutical compositions in separate containers, wherein the first container includes a pharmaceutical composition of an antigen-binding construct targeting HER2, and the second container includes a pharmaceutical composition of albumin-paclitaxel. In some embodiments, the drug package contains single-packaged pharmaceutical compositions in separate containers, wherein the first container includes a pharmaceutical composition of an antigen-binding construct targeting HER2, and the second container includes a pharmaceutical composition of capecitabine. In some embodiments, the drug package contains single-packaged pharmaceutical compositions in separate containers, wherein the first container includes a pharmaceutical composition of an antigen-binding construct targeting HER2, and the second container includes a pharmaceutical composition of gemcitabine. In some embodiments, the pharmaceutical package comprises individually packaged pharmaceutical compositions in separate containers, wherein the first container comprises a pharmaceutical composition comprising an antigen-binding construct targeting HER2, and the second container comprises a pharmaceutical composition comprising white vinorelbine. In some embodiments, the pharmaceutical package comprises individually packaged pharmaceutical compositions in separate containers, wherein the first container comprises a pharmaceutical composition comprising an antigen-binding construct targeting HER2, and the second container comprises a pharmaceutical composition comprising white eribulin. In some embodiments, the pharmaceutical package is used to treat tumors.

[0154] In some embodiments, the pharmaceutical composition of the antigen-binding construct targeting HER2 in the kit or pharmaceutical pack is a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition of the antigen-binding construct targeting HER2 in the kit or pharmaceutical pack is a lyophilized formulation. In some embodiments, the pharmaceutical composition of the antigen-binding construct targeting HER2 in the kit or pharmaceutical pack is a powder for injection.

[0155] In some embodiments, the pharmaceutical composition of nab-paclitaxel in the kit or pharmaceutical package is a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition of nab-paclitaxel in the kit or pharmaceutical package is a lyophilized formulation. In some embodiments, the pharmaceutical composition of nab-paclitaxel in the kit or pharmaceutical package is a powder for injection.

[0156] In some specific embodiments, the pharmaceutical composition of capecitabine in the kit or pharmaceutical pack is a solid pharmaceutical composition. In some specific embodiments, the pharmaceutical composition of capecitabine in the kit or pharmaceutical pack is a tablet.

[0157] In some specific embodiments, the pharmaceutical composition of gemcitabine in the kit or drug package is a solid pharmaceutical composition. In some specific embodiments, the pharmaceutical composition of gemcitabine in the kit or drug package is a lyophilized preparation. In some specific embodiments, the pharmaceutical composition of gemcitabine in the kit or drug package is a powder injection.

[0158] In some specific embodiments, the pharmaceutical composition of vinorelbine in the kit or pharmaceutical package is a liquid pharmaceutical composition. In some specific embodiments, the pharmaceutical composition of vinorelbine in the kit or pharmaceutical package is an injection.

[0159] In some specific embodiments, the pharmaceutical composition of eribulin in the kit or pharmaceutical package is a liquid pharmaceutical composition. In some specific embodiments, the pharmaceutical composition of eribulin in the kit or pharmaceutical package is an injection.

[0160] In some embodiments, the tumor is a solid tumor. In some embodiments, the solid tumor is breast cancer.

[0161] Uses and methods

[0162] The present disclosure also provides a method for treating a tumor in a subject, comprising administering a drug combination of the present disclosure to the subject. In another aspect, the present disclosure also provides the use of the drug combination of the present disclosure in the preparation of a medicament for treating a tumor in a subject. In some embodiments, in the methods or uses, the drug combination of the present disclosure is administered in a therapeutically effective amount. In some embodiments, in the uses, the medicament comprises a therapeutically effective amount of the drug combination of the present disclosure.

[0163] The present disclosure also provides a method for treating a tumor in a subject, comprising administering to the subject an antigen-binding construct targeting HER2 of the present disclosure and a chemotherapeutic drug. In some embodiments, in the method, the antigen-binding construct targeting HER2 and the chemotherapeutic drug are administered in a therapeutically effective amount.

[0164] The present disclosure also provides a method for treating a tumor in a subject, comprising administering to the subject an antigen-binding construct targeting HER2 of the present disclosure and nab-paclitaxel. In some embodiments, in the method, the antigen-binding construct targeting HER2 and nab-paclitaxel are administered in a therapeutically effective amount.

[0165] The present disclosure also provides a method for treating a tumor in a subject, comprising administering to the subject an antigen-binding construct targeting HER2 of the present disclosure and capecitabine. In some embodiments, in the method, the antigen-binding construct targeting HER2 and capecitabine are administered in a therapeutically effective amount.

[0166] The present disclosure also provides a method for treating a tumor in a subject, comprising administering to the subject an antigen-binding construct targeting HER2 of the present disclosure and gemcitabine. In some embodiments, in the method, the antigen-binding construct targeting HER2 and gemcitabine are administered in a therapeutically effective amount.

[0167] The present disclosure also provides a method for treating a tumor in a subject, comprising administering to the subject an antigen-binding construct targeting HER2 of the present disclosure and vinorelbine. In some embodiments, in the method, the antigen-binding construct targeting HER2 and vinorelbine are administered in a therapeutically effective amount.

[0168] The present disclosure also provides a method for treating a tumor in a subject, comprising administering to the subject an antigen-binding construct targeting HER2 of the present disclosure and eribulin. In some embodiments, in the method, the antigen-binding construct targeting HER2 and eribulin are administered in a therapeutically effective amount.

[0169] The present disclosure also provides the use of the antigen-binding construct targeting HER2 of the present disclosure and a chemotherapeutic agent in the preparation of a medicament for treating a tumor in a subject. The present disclosure also provides the use of the antigen-binding construct targeting HER2 of the present disclosure in the preparation of a medicament for combining with a chemotherapeutic agent to treat a tumor in a subject. In some embodiments, in the use, the medicament comprises a therapeutically effective amount of the antigen-binding construct targeting HER2 and the chemotherapeutic agent.

[0170] The present disclosure also provides uses of the HER2-targeting antigen-binding construct and nab-paclitaxel in the preparation of a medicament for treating a tumor in a subject. The present disclosure also provides uses of the HER2-targeting antigen-binding construct in the preparation of a medicament for combining with nab-paclitaxel to treat a tumor in a subject. In some embodiments, in the uses, the medicament comprises a therapeutically effective amount of the HER2-targeting antigen-binding construct and nab-paclitaxel.

[0171] The present disclosure also provides uses of the HER2-targeting antigen-binding construct and capecitabine of the present disclosure in the preparation of a medicament for treating a tumor in a subject. The present disclosure also provides uses of the HER2-targeting antigen-binding construct of the present disclosure in the preparation of a medicament for combining with capecitabine to treat a tumor in a subject. In some embodiments, in the uses, the medicament comprises a therapeutically effective amount of the HER2-targeting antigen-binding construct and capecitabine.

[0172] The present disclosure also provides the use of the antigen-binding construct targeting HER2 of the present disclosure and gemcitabine in the preparation of a medicament for treating a tumor in a subject. The present disclosure also provides the use of the antigen-binding construct targeting HER2 of the present disclosure in the preparation of a medicament for treating a tumor in a subject in combination with gemcitabine. In some embodiments, in the use, the medicament comprises a therapeutically effective amount of the antigen-binding construct targeting HER2 and gemcitabine.

[0173] The present disclosure also provides the use of the antigen-binding construct targeting HER2 of the present disclosure and vinorelbine in the preparation of a medicament for treating a tumor in a subject. The present disclosure also provides the use of the antigen-binding construct targeting HER2 of the present disclosure in the preparation of a medicament for treating a tumor in a subject in combination with vinorelbine. In some embodiments, in the use, the medicament comprises a therapeutically effective amount of the antigen-binding construct targeting HER2 and vinorelbine.

[0174] The present disclosure also provides uses of the HER2-targeting antigen-binding construct of the present disclosure and eribulin in the preparation of a medicament for treating a tumor in a subject. The present disclosure also provides uses of the HER2-targeting antigen-binding construct of the present disclosure in the preparation of a medicament for treating a tumor in a subject in combination with eribulin. In some embodiments, in such uses, the medicament comprises a therapeutically effective amount of the HER2-targeting antigen-binding construct and eribulin.

[0175] In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is breast cancer. In some embodiments, the tumor is HER2-positive breast cancer. In some embodiments, the tumor is recurrent and / or metastatic breast cancer. In some embodiments, the tumor is locally advanced breast cancer. In some embodiments, the tumor is HER2-positive recurrent and / or metastatic breast cancer. In some embodiments, the tumor is HER2-positive locally advanced breast cancer. In some embodiments, the tumor is HER2-positive locally advanced, recurrent and / or metastatic breast cancer. In some embodiments, the tumor is advanced breast cancer. In some embodiments, the tumor is HR-positive and HER2-positive advanced, recurrent and / or metastatic breast cancer. In some embodiments, the tumor is HR-positive and HER2-negative advanced, recurrent and / or metastatic breast cancer.

[0176] In some embodiments, in the methods or uses, the drug combination comprises an antigen-binding construct targeting HER2 and a chemotherapy drug. In some embodiments, the chemotherapy drug is selected from one or more of platinum-based antitumor drugs, camptothecin-based antitumor drugs, taxane-based antitumor drugs, nitrogen mustard-based antitumor drugs, antimetabolites, anthracyclines, vinblastine-based antitumor drugs, podophylloalkaloid-based antitumor drugs, hormone-based antitumor drugs, antibiotic-based antitumor drugs, and tubulin inhibitor-based antitumor drugs. In some embodiments, the chemotherapy drug is a taxane-based antitumor drug, antimetabolites, vinblastine-based antitumor drug, or tubulin inhibitor-based antitumor drug. In some embodiments, the chemotherapy drug is a taxane-based antitumor drug, a fluorouracil-based antitumor drug, a cytosine-based antitumor drug, a vinblastine-based antitumor drug, or a tubulin inhibitor-based antitumor drug. In some specific embodiments, the chemotherapy drug is nab-paclitaxel, capecitabine, gemcitabine, vinorelbine, or eribulin.

[0177] In some embodiments, in the methods or uses, the drug combination comprises an antigen-binding construct targeting HER2 and nab-paclitaxel. In some embodiments, in the methods or uses, the drug combination comprises an antigen-binding construct targeting HER2 and capecitabine. In some embodiments, in the methods or uses, the drug combination comprises an antigen-binding construct targeting HER2 and gemcitabine. In some embodiments, in the methods or uses, the drug combination comprises an antigen-binding construct targeting HER2 and vinorelbine. In some embodiments, in the methods or uses, the drug combination comprises an antigen-binding construct targeting HER2 and eribulin.

[0178] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and the chemotherapeutic agent may be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and the chemotherapeutic agent are administered sequentially. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and the chemotherapeutic agent are each in the form of a pharmaceutical composition and may be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and the chemotherapeutic agent are each in the form of a pharmaceutical composition and are administered sequentially. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and the chemotherapeutic agent are administered first, followed by the chemotherapeutic agent. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and the chemotherapeutic agent are each in the form of a pharmaceutical composition, and the antigen-binding construct targeting HER2 is administered first, followed by the chemotherapeutic agent. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and the chemotherapeutic agent are each in the form of a pharmaceutical composition and are packaged in different medicine boxes. In some embodiments, the chemotherapy drug is nab-paclitaxel, capecitabine, gemcitabine, vinorelbine, or eribulin.

[0179] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and nab-paclitaxel can be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and nab-paclitaxel are administered sequentially. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and nab-paclitaxel are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and nab-paclitaxel are each in the form of a pharmaceutical composition and can be administered sequentially. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 is administered first, followed by nab-paclitaxel. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and nab-paclitaxel are each in the form of a pharmaceutical composition and can be administered first, followed by nab-paclitaxel.

[0180] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and capecitabine can be administered simultaneously, sequentially and / or alternately. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and capecitabine are administered sequentially. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and capecitabine are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially and / or alternately. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and capecitabine are each in the form of a pharmaceutical composition and are administered sequentially. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 is administered first, followed by capecitabine. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and capecitabine are each in the form of a pharmaceutical composition, and the antigen-binding construct targeting HER2 is administered first, followed by capecitabine.

[0181] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and gemcitabine can be administered simultaneously, successively and / or alternately. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and gemcitabine are administered successively. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and gemcitabine are each in the form of a pharmaceutical composition and can be administered simultaneously, successively and / or alternately. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and gemcitabine are each in the form of a pharmaceutical composition and are administered successively. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 is administered first, and then gemcitabine is administered. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and gemcitabine are each in the form of a pharmaceutical composition, and the antigen-binding construct targeting HER2 is administered first, and then gemcitabine is administered.

[0182] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and vinorelbine can be administered simultaneously, sequentially and / or alternately. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and vinorelbine are administered sequentially. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and vinorelbine are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially and / or alternately. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and vinorelbine are each in the form of a pharmaceutical composition and are administered sequentially. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 is administered first, and then vinorelbine is administered. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and vinorelbine are each in the form of a pharmaceutical composition, and the antigen-binding construct targeting HER2 is administered first, and then vinorelbine is administered.

[0183] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and eribulin can be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and eribulin are administered sequentially. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and eribulin are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and eribulin are each in the form of a pharmaceutical composition and are administered sequentially. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 is administered first, followed by eribulin. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and eribulin are each in the form of a pharmaceutical composition, and the antigen-binding construct targeting HER2 is administered first, followed by eribulin.

[0184] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and the chemotherapeutic agent are administered in the same or different dosing regimens. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and the chemotherapeutic agent are administered in different dosing regimens.

[0185] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and nab-paclitaxel are administered in the same or different dosing regimens. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and nab-paclitaxel are administered in different dosing regimens.

[0186] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and capecitabine are administered in the same or different dosing regimens. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and capecitabine are administered in different dosing regimens.

[0187] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and gemcitabine are administered with the same or different dosing regimens, respectively. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and gemcitabine are administered with different dosing regimens, respectively.

[0188] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and vinorelbine are administered in the same or different dosing regimens. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and vinorelbine are administered in different dosing regimens.

[0189] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and eribulin are administered at the same or different dosing schedules. In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and eribulin are administered at different dosing schedules.

[0190] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 is administered once every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). In some embodiments, the antigen-binding construct targeting HER2 is administered once every 2 weeks. In some embodiments, the antigen-binding construct targeting HER2 is administered once every 3 weeks. In some embodiments, the antigen-binding construct targeting HER2 is administered at a dosage of 2.5-50 mg / kg, 2.5-30 mg / kg, 2.5-10 mg / kg, 5-10 mg / kg, 10-30 mg / kg, or 20-30 mg / kg. In some embodiments, the antigen-binding construct for targeting HER2 is administered at a dosage of 2.5mg / kg, 5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg or 50mg / kg or the range formed by any two of the above values. In some embodiments, the antigen-binding construct for targeting HER2 is administered at a dosage of 2.5mg / kg, 5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg or 30mg / kg or the range formed by any two of the above values. In some embodiments, the antigen-binding construct for targeting HER2 is administered at a dosage of 20mg / kg. In some embodiments, the antigen-binding construct for targeting HER2 is administered at a dosage of 30mg / kg. In some embodiments, the antigen-binding construct for targeting HER2 is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time with a dosage of 2.5-50mg / kg or 2.5-30mg / kg of the antigen-binding construct for targeting HER2. In some embodiments, the antigen-binding construct for targeting HER2 is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time with a dosage of 2.5mg / kg, 5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg, or 50mg / kg or the scope of any two values ​​formed by the antigen-binding construct for targeting HER2. In some embodiments, the antigen-binding construct for targeting HER2 is administered every 1 week, each time with a dosage of 2.5-10mg / kg or 5-10mg / kg of the antigen-binding construct for targeting HER2. In some embodiments, the antigen-binding construct targeting HER2 is administered once every week, each time at a dose of 2.5 mg / kg, 5 mg / kg, or 10 mg / kg of the antigen-binding construct targeting HER2.In some embodiments, the antigen-binding construct targeting HER2 is administered once every 2 weeks at a dose of 20 mg / kg of the antigen-binding construct targeting HER2. In some embodiments, the antigen-binding construct targeting HER2 is administered once every 3 weeks at a dose of 30 mg / kg of the antigen-binding construct targeting HER2.

[0191] In some embodiments, in the methods or uses, the nab-paclitaxel is administered once every 3 weeks. In some embodiments, the nab-paclitaxel is administered at a dose of 130-260 mg, or 180-260 mg each time. In some embodiments, the nab-paclitaxel is administered at a dose of 130 mg, 180 mg, 200 mg, 220 mg, or 260 mg each time. In some embodiments, the nab-paclitaxel is administered at a dose of 260 mg each time. In some embodiments, the nab-paclitaxel is administered once every 3 weeks at a dose of 130-260 mg, or 180-260 mg of nab-paclitaxel each time. In some embodiments, the nab-paclitaxel is administered once every 3 weeks at a dose of 130 mg, 180 mg, 200 mg, 220 mg, or 260 mg of nab-paclitaxel each time. In some embodiments, the nab-paclitaxel is administered once every 3 weeks at a dose of 260 mg of nab-paclitaxel each time.

[0192] In some embodiments, in the method or use, the capecitabine is administered twice a day. In some embodiments, the capecitabine is administered at a dose of 500-1000 mg / m 2 In some embodiments, the capecitabine is administered at a dose of 500 mg / m 2 , 750mg / m 2 or 1000 mg / m 2 In some embodiments, the capecitabine is administered at a dose of 1000 mg / m 2In some embodiments, the capecitabine is administered at a dose of 600-2300 mg or 1150-2300 mg each time. In some embodiments, the capecitabine is administered at a dose of 600 mg, 750 mg, 800 mg, 900 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1300 mg, 1400 mg, 1450 mg, 1500 mg, 1600 mg, 1750 mg, 1800 mg, 2000 mg, 2150 mg or 2300 mg each time. In some embodiments, the capecitabine is administered at a dose of 1150 mg, 1300 mg, 1450 mg, 1600 mg, 1750 mg, 1800 mg, 2000 mg, 2150 mg or 2300 mg each time. In some embodiments, the capecitabine is administered twice daily at a dose of 500-1000 mg / m 2 In some embodiments, the capecitabine is administered twice daily at a dose of 500 mg / m 2 , 750mg / m 2 or 1000 mg / m 2 In some embodiments, the capecitabine is administered twice daily at a dose of 1000 mg / m 2 In some embodiments, the capecitabine is administered twice daily at a dose of 600-2300 mg, or 1150-2300 mg capecitabine. In some embodiments, the capecitabine is administered twice daily at a dose of 600 mg, 750 mg, 800 mg, 900 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1300 mg, 1400 mg, 1450 mg, 1500 mg, 1600 mg, 1750 mg, 1800 mg, 2000 mg, 2150 mg, or 2300 mg capecitabine. In some embodiments, the capecitabine is administered twice daily at a dose of 1150 mg, 1300 mg, 1450 mg, 1600 mg, 1750 mg, 1800 mg, 2000 mg, 2150 mg, or 2300 mg capecitabine. In some embodiments, the capecitabine is administered for 14 consecutive days. In some embodiments, the capecitabine is administered for 14 consecutive days, twice daily.

[0193] In some embodiments, in the method or use, the gemcitabine is administered once a week for two consecutive weeks followed by a one-week rest period. In some embodiments, the gemcitabine is administered at a dose of 750-1000 mg / m 2In some embodiments, the gemcitabine is administered at a dose of 750 mg / m 2 or 1000 mg / m 2 In some embodiments, the gemcitabine is administered at a dose of 1000 mg / m 2 In some embodiments, the gemcitabine is administered once a week at a dose of 750-1000 mg / m 2 In some embodiments, the gemcitabine is administered once a week at a dose of 750 mg / m 2 or 1000 mg / m 2 In some embodiments, the gemcitabine is administered once a week at a dose of 1000 mg / m 2 The dose of gemcitabine was administered for two weeks followed by one week of rest.

[0194] In some embodiments, in the method or use, the vinorelbine is administered once a week for two consecutive weeks followed by a one-week rest period. In some embodiments, the vinorelbine is administered at a dose of 25 mg / m 2 In some embodiments, the vinorelbine is administered once a week at a dose of 25 mg / m 2 Vinorelbine was administered at a dose of 1 week after two weeks of continuous administration.

[0195] In some embodiments, in the method or use, the eribulin is administered once a week for two consecutive weeks followed by a one-week rest period. In some embodiments, the eribulin is administered at a dose of 0.7-1.4 mg / m 2 In some embodiments, the eribulin is administered at a dose of 0.7 mg / m 2 , 1.1mg / m 2 or 1.4 mg / m 2 In some embodiments, the eribulin is administered at a dose of 1.4 mg / m 2 In some embodiments, the eribulin is administered once a week at a dose of 0.7-1.4 mg / m 2 In some embodiments, the eribulin is administered once a week at a dose of 0.7 mg / m 2 , 1.1mg / m 2 or 1.4 mg / m 2 In some embodiments, the eribulin is administered once a week at a dose of 1.4 mg / m 2Eribulin was administered at a dose of 1 week, followed by two weeks of continuous administration.

[0196] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and the chemotherapy drug have the same or different treatment cycles. In some specific embodiments, the antigen-binding construct targeting HER2 and the chemotherapy drug have different treatment cycles, for example, for the antigen-binding construct targeting HER2, every 1 week, every 2 weeks, or every 4 weeks is a treatment cycle, and for the chemotherapy drug, every 3 weeks is a treatment cycle. In some specific embodiments, the antigen-binding construct targeting HER2 and the chemotherapy drug have the same treatment cycle, for example, every 3 weeks is a treatment cycle.

[0197] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and nab-paclitaxel have the same or different treatment cycles. In some specific embodiments, the antigen-binding construct targeting HER2 and nab-paclitaxel have different treatment cycles, for example, for the antigen-binding construct targeting HER2, one treatment cycle is every 1 week, every 2 weeks, or every 4 weeks, and for nab-paclitaxel, one treatment cycle is every 3 weeks. In some specific embodiments, the antigen-binding construct targeting HER2 and nab-paclitaxel have the same treatment cycle, for example, one treatment cycle is every 3 weeks.

[0198] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and capecitabine have the same or different treatment cycles. In some specific embodiments, the antigen-binding construct targeting HER2 and capecitabine have different treatment cycles, for example, for the antigen-binding construct targeting HER2, every 1 week, every 2 weeks, or every 4 weeks is a treatment cycle, and for capecitabine, every 3 weeks is a treatment cycle. In some specific embodiments, the antigen-binding construct targeting HER2 and capecitabine have the same treatment cycle, for example, every 3 weeks is a treatment cycle.

[0199] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and gemcitabine have the same or different treatment cycles. In some specific embodiments, the antigen-binding construct targeting HER2 and gemcitabine have different treatment cycles, for example, for the antigen-binding construct targeting HER2, every 1 week, every 2 weeks or every 4 weeks is a treatment cycle, and for gemcitabine, every 3 weeks is a treatment cycle. In some specific embodiments, the antigen-binding construct targeting HER2 and gemcitabine have the same treatment cycle, for example, every 3 weeks is a treatment cycle.

[0200] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and vinorelbine have the same or different treatment cycles. In some specific embodiments, the antigen-binding construct targeting HER2 and vinorelbine have different treatment cycles, for example, for the antigen-binding construct targeting HER2, every 1 week, every 2 weeks or every 4 weeks is a treatment cycle, and for vinorelbine, every 3 weeks is a treatment cycle. In some specific embodiments, the antigen-binding construct targeting HER2 and vinorelbine have the same treatment cycle, for example, every 3 weeks is a treatment cycle.

[0201] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 and eribulin have the same or different treatment cycles. In some specific embodiments, the antigen-binding construct targeting HER2 and eribulin have different treatment cycles, for example, for the antigen-binding construct targeting HER2, every 1 week, every 2 weeks, or every 4 weeks is a treatment cycle, and for eribulin, every 3 weeks is a treatment cycle. In some specific embodiments, the antigen-binding construct targeting HER2 and eribulin have the same treatment cycle, for example, every 3 weeks is a treatment cycle.

[0202] In some embodiments, in the method or use, every 3 weeks is a treatment cycle, and the antigen-binding construct targeting HER2 and the chemotherapy drug are administered in each treatment cycle.

[0203] In some embodiments, in the methods or uses, one treatment cycle is three weeks, and an antigen-binding construct targeting HER2 and nab-paclitaxel are administered in each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is three weeks, and an antigen-binding construct targeting HER2 is administered once in each treatment cycle, and nab-paclitaxel is administered once in each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is three weeks, and an antigen-binding construct targeting HER2 is administered once on day 1 of each treatment cycle, and nab-paclitaxel is administered once on day 1 of each treatment cycle.

[0204] In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and an antigen-binding construct targeting HER2 and capecitabine are administered in each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, an antigen-binding construct targeting HER2 is administered once in each treatment cycle, and capecitabine is administered 28 times in each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, an antigen-binding construct targeting HER2 is administered once on day 1 of each treatment cycle, and capecitabine is administered twice daily on days 1-14 of each treatment cycle.

[0205] In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and an antigen-binding construct targeting HER2 and gemcitabine are administered in each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and an antigen-binding construct targeting HER2 is administered once in each treatment cycle, and gemcitabine is administered twice in each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and an antigen-binding construct targeting HER2 is administered once on day 1 of each treatment cycle, and gemcitabine is administered once on day 1 and day 8 of each treatment cycle.

[0206] In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and an antigen-binding construct targeting HER2 and vinorelbine are administered in each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and an antigen-binding construct targeting HER2 is administered once in each treatment cycle, and vinorelbine is administered twice in each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is 3 weeks, and an antigen-binding construct targeting HER2 is administered once on day 1 of each treatment cycle, and vinorelbine is administered once on day 1 and day 8 of each treatment cycle.

[0207] In some embodiments, in the methods or uses, one treatment cycle is three weeks, and an antigen-binding construct targeting HER2 and eribulin are administered during each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is three weeks, and an antigen-binding construct targeting HER2 is administered once during each treatment cycle, and eribulin is administered twice during each treatment cycle. In some embodiments, in the methods or uses, one treatment cycle is three weeks, and an antigen-binding construct targeting HER2 is administered once on day 1 of each treatment cycle, and eribulin is administered once on day 1 and once on day 8 of each treatment cycle.

[0208] In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered in each treatment cycle, and 130-260 mg, or 180-260 mg of nab-paclitaxel is administered in each treatment cycle. In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered in each treatment cycle, and 130 mg, 180 mg, 200 mg, 220 mg, or 260 mg of nab-paclitaxel is administered in each treatment cycle. In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered in each treatment cycle, and 260 mg of nab-paclitaxel is administered in each treatment cycle. In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered on day 1 of each treatment cycle, and 130-260 mg, or 180-260 mg of nab-paclitaxel is administered on day 1 of each treatment cycle. In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered on day 1 of each treatment cycle, and 130 mg, 180 mg, 200 mg, 220 mg, or 260 mg of nab-paclitaxel is administered on day 1 of each treatment cycle. In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered on day 1 of each treatment cycle, and 260 mg of nab-paclitaxel is administered on day 1 of each treatment cycle.

[0209] In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered in each treatment cycle, and 14-28 g / m 2 In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered in each treatment cycle, and 14 g / m 2 , 21g / m 2 or 28g / m 2 In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered in each treatment cycle, and 28 g / m 2In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered in each treatment cycle, and 16.8-64.4 g or 32.2-64.4 g of capecitabine is administered in each treatment cycle. In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered in each treatment cycle, and 16.8 g, 21 g, 22.4 g, 25.2 g, 28 g, 29.4 g, 30.8 g, 32.2 g, 33.6 g, 36.4 g, 39.2 g, 40.6 g, 42 g, 44.8 g, 49 g, 50.4 g, 56 g, 60.2 g or 64.4 g of capecitabine is administered in each treatment cycle. In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered in each treatment cycle, and 32.2 g, 36.4 g, 40.6 g, 44.8 g, 49 g, 50.4 g, 56 g, 60.2 g, or 64.4 g of capecitabine is administered in each treatment cycle. In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered on day 1 of each treatment cycle, and 1000-2000 mg / kg is administered daily on days 1-14 of each treatment cycle. 2 In some specific embodiments, in the methods or uses, one treatment cycle is 3 weeks, 30 mg / kg of the HER2-targeting antigen-binding construct is administered on day 1 of each treatment cycle, and 1000 mg / kg is administered daily on days 1-14 of each treatment cycle. 2 , 1500mg / m 2 or 2000 mg / m 2 In some specific embodiments, in the methods or uses, one treatment cycle is 3 weeks, 30 mg / kg of the HER2-targeting antigen-binding construct is administered on day 1 of each treatment cycle, and 2000 mg / kg is administered daily on days 1-14 of each treatment cycle. 2In some specific embodiments, in the methods or uses, one treatment cycle is three weeks, 30 mg / kg of the HER2-targeting antigen-binding construct is administered on day 1 of each treatment cycle, and 1200-4600 mg, or 2300-4600 mg, of capecitabine is administered daily on days 1-14 of each treatment cycle. In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered on day 1 of each treatment cycle, and 1200 mg, 1500 mg, 1600 mg, 1800 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2600 mg, 2800 mg, 2900 mg, 3000 mg, 3200 mg, 3500 mg, 3600 mg, 4000 mg, 4300 mg or 4600 mg of capecitabine is administered daily on days 1 to 14 of each treatment cycle. In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered on day 1 of each treatment cycle, and 2300 mg, 2600 mg, 2900 mg, 3200 mg, 3500 mg, 3600 mg, 4000 mg, 4300 mg or 4600 mg of capecitabine is administered daily on days 1 to 14 of each treatment cycle.

[0210] In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered in each treatment cycle, and 1500-2000 mg / m 2 In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered in each treatment cycle, and 1500 mg / m 2 or 2000 mg / m 2 In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 30 mg / kg of the HER2-targeting antigen-binding construct is administered in each treatment cycle, and 2000 mg / m 2 In some specific embodiments, in the methods or uses, one treatment cycle is 3 weeks, 30 mg / kg of the HER2-targeting antigen-binding construct is administered on day 1 of each treatment cycle, and 750-1000 mg / m2 is administered on day 1 and day 8 of each treatment cycle. 2In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, 30 mg / kg of the HER2-targeting antigen-binding construct is administered on the first day of each treatment cycle, and 750 mg / m is administered on the first day of each treatment cycle. 2 or 1000 mg / m 2 In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, 30 mg / kg of the HER2-targeting antigen-binding construct is administered on the first day of each treatment cycle, and 1000 mg / m 2 of gemcitabine.

[0211] In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered in each treatment cycle, and 50 mg / m 2 In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered on day 1 of each treatment cycle, and 25 mg / kg is administered on day 1 and day 8 of each treatment cycle. 2 of Changchunruibin.

[0212] In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered in each treatment cycle, and 1.4-2.8 mg / m 2 In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered in each treatment cycle, and 1.4 mg / m 2 , 2.2mg / m 2 or 2.8 mg / m 2 In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 30 mg / kg of the antigen-binding construct targeting HER2 is administered in each treatment cycle, and 2.8 mg / m 2 In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, 30 mg / kg of the HER2-targeting antigen-binding construct is administered on day 1 of each treatment cycle, and 0.7-1.4 mg / m is administered on day 1 and day 8 of each treatment cycle. 2In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, 30 mg / kg of the HER2-targeting antigen-binding construct is administered on day 1 of each treatment cycle, and 0.7 mg / m is administered on day 1 of each treatment cycle. 2 , 1.1mg / m 2 or 1.4 mg / m 2 In some specific embodiments, in the methods or uses, every 3 weeks is a treatment cycle, 30 mg / kg of the HER2-targeting antigen-binding construct is administered on day 1 of each treatment cycle, and 1.4 mg / m is administered on day 1 of each treatment cycle. 2 of Eriblin.

[0213] In some embodiments, in each treatment cycle, the antigen binding construct targeting HER2 and the chemotherapeutic drug are administered in multiple doses or a single dose. In some embodiments, in each treatment cycle, the antigen binding construct targeting HER2 and the chemotherapeutic drug are administered in multiple doses.

[0214] In some embodiments, the antigen-binding construct targeting HER2 and nab-paclitaxel are administered in multiple doses or a single dose in each treatment cycle. In some embodiments, the antigen-binding construct targeting HER2 and nab-paclitaxel are administered in multiple doses in each treatment cycle.

[0215] In some embodiments, in each treatment cycle, the antigen-binding construct targeting HER2 and capecitabine are administered in multiple doses or a single dose. In some embodiments, in each treatment cycle, the antigen-binding construct targeting HER2 and capecitabine are administered in multiple doses.

[0216] In some embodiments, in each treatment cycle, the antigen binding construct targeting HER2 and gemcitabine are administered in multiple doses or a single dose. In some embodiments, in each treatment cycle, the antigen binding construct targeting HER2 and gemcitabine are administered in multiple doses.

[0217] In some embodiments, in each treatment cycle, the antigen binding construct targeting HER2 and vinorelbine are administered in multiple doses or a single dose. In some embodiments, in each treatment cycle, the antigen binding construct targeting HER2 and vinorelbine are administered in multiple doses.

[0218] In some embodiments, the antigen-binding construct targeting HER2 and eribulin are administered in multiple doses or a single dose during each treatment cycle. In some embodiments, the antigen-binding construct targeting HER2 and eribulin are administered in multiple doses during each treatment cycle.

[0219] In some embodiments, in the methods or uses, the antigen-binding construct targeting HER2 can be administered to the subject at a dose selected from 0.01 to 50 mg / kg, 0.1 to 50 mg / kg, 1 to 50 mg / kg, 2.5 to 40 mg / kg, 5 to 40 mg / kg, 7.5 to 40 mg / kg, 10 to 40 mg / kg, 15 to 40 mg / kg, 20 to 40 mg / kg, 30 to 40 mg / kg, 2.5 to 30 mg / kg, 5 to 30 mg / kg, 7.5 to 30 mg / kg, 10 to 30 mg / kg, 15 to 30 mg / kg, and 20 to 30 mg / kg.

[0220] In some embodiments, in the methods or uses, the dosing regimen (e.g., treatment cycle, dosage, route of administration, intravenous infusion rate, etc.) of the antigen-binding construct targeting HER2 and / or chemotherapy drugs (e.g., albumin-paclitaxel, capecitabine, gemcitabine, vinorelbine or eribulin) 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, a treatment cycle of the antigen-binding construct targeting HER2 can be adjusted to 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks or 12 weeks. For another example, in some embodiments, the single administration dose of albumin-paclitaxel can be 260 mg / m 2 , 200mg / m 2 or 130 mg / m 2 , or from 260mg / m 2 Reduce to 220 mg / m 2 , or from 220mg / m 2 Reduce to 180 mg / m 2 For another example, in some embodiments, the single dose of capecitabine can be adjusted to 75% or 50% of the initial dose. For another example, in some embodiments, the single dose of gemcitabine can be adjusted to 75% of the initial dose. For another example, in some embodiments, the single dose of gemcitabine can be adjusted to 75% of the initial dose.

[0221] III. Antigen-binding constructs targeting HER2

[0222] In some embodiments, the HER2-targeting antigen-binding construct comprises a first antigen-binding fragment that monovalently and specifically binds to the ECD4 antigen of HER2 on HER2-expressing cells; the heavy chain variable region of the first antigen-binding fragment comprises an amino acid mutation at position 30 according to the Kabat numbering system, preferably, the mutated amino acid is E, or / and the light chain variable region of the first antigen-binding fragment comprises an amino acid mutation at position 53 according to the Kabat numbering system, preferably, the mutated amino acid is Y.

[0223] In some embodiments, the heavy chain variable region of the first antigen-binding fragment comprises a K30E mutation according to the Kabat numbering system, or / and the light chain variable region of the first antigen-binding fragment comprises a F53Y mutation according to the Kabat numbering system.

[0224] In some embodiments, the first antigen-binding fragment comprises a heavy chain CDR1 (HCDR1) of the amino acid sequence shown in SEQ ID NO:1, a HCDR2 of the amino acid sequence shown in SEQ ID NO:2, a HCDR3 of the amino acid sequence shown in SEQ ID NO:3, a light chain CDR1 (LCDR1) of the amino acid sequence shown in SEQ ID NO:4, a LCDR2 of the amino acid sequence shown in SEQ ID NO:5, and a LCDR3 of the amino acid sequence shown in SEQ ID NO:6.

[0225] In some embodiments, the antigen-binding construct targeting HER2 comprises a first antigen-binding fragment that monovalently and specifically binds to the ECD4 antigen of HER2 on HER2-expressing cells, wherein the first antigen-binding fragment is a scFv; the first antigen-binding fragment comprises a HCDR1 with the amino acid sequence shown in SEQ ID NO:20, a HCDR2 with the amino acid sequence shown in SEQ ID NO:2, a HCDR3 with the amino acid sequence shown in SEQ ID NO:3, a LCDR1 with the amino acid sequence shown in SEQ ID NO:4, a LCDR2 with the amino acid sequence shown in SEQ ID NO:21, and a LCDR3 with the amino acid sequence shown in SEQ ID NO:6.

[0226] In some embodiments, the HER2-targeting antigen-binding construct further comprises a second antigen-binding fragment that monovalently and specifically binds to the ECD2 antigen of HER2 on HER2-expressing cells, wherein the second antigen-binding fragment is a Fab.

[0227] In some embodiments, the second antigen-binding fragment comprises HCDR1 of the amino acid sequence shown in SEQ ID NO:9, HCDR2 of the amino acid sequence shown in SEQ ID NO:10, HCDR3 of the amino acid sequence shown in SEQ ID NO:11, LCDR1 of the amino acid sequence shown in SEQ ID NO:12, LCDR2 of the amino acid sequence shown in SEQ ID NO:13, and LCDR3 of the amino acid sequence shown in SEQ ID NO:14.

[0228] In some embodiments, the antigen-binding construct targeting HER2 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.

[0229] In some embodiments, the antigen-binding construct targeting HER2 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: 20, 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: 21, 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.

[0230] Exemplary CDR sequences of antigen-binding constructs targeting HER2 are provided in Table 1.

[0231] Table 1. CDR sequences of antigen-binding constructs targeting HER2

[0232]

[0233]

[0234] 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 definitions of AbM, Kabat, Chothia, IMGT, CCG, or Contact, etc., which are well known in the art) should also fall within the scope of protection of the present disclosure.

[0235] 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 or 22, 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 or 23. In some embodiments, the first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 7, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 8. In some embodiments, the first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 22, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 23. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the first antigen-binding fragment is as set forth in SEQ ID NO: 7, and the amino acid sequence of the light chain variable region is as set forth in SEQ ID NO: 8. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the first antigen-binding fragment is as set forth in SEQ ID NO: 22, and the amino acid sequence of the light chain variable region is as set forth in SEQ ID NO: 23.

[0236] In some embodiments, the first antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1 of the amino acid sequence of SEQ ID NO: 1, HCDR2 of the amino acid sequence of SEQ ID NO: 2, and HCDR3 of the amino acid sequence of SEQ ID NO: 3, and the light chain variable region comprises LCDR1 of the amino acid sequence of SEQ ID NO: 4, LCDR2 of the amino acid sequence of SEQ ID NO: 5, and LCDR3 of 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, 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: 9 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.

[0237] In some embodiments, the first antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1 of the amino acid sequence of SEQ ID NO:20, HCDR2 of the amino acid sequence of SEQ ID NO:2, and HCDR3 of the amino acid sequence of SEQ ID NO:3, the light chain variable region comprises LCDR1 of the amino acid sequence of SEQ ID NO:4, LCDR2 of the amino acid sequence of SEQ ID NO:21, and LCDR3 of 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:22, and the light ... NO:23 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.

[0238] EVQLVESGGGLVQPGGSLRLSCAASGFNIEDTYIHWVRQAPGKGLEWVARIYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVT VSS(SEQ ID NO:7);

[0239] DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASYLYSGVP SRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK(SEQ ID NO:8);

[0240] EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYT RYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVT VSS(SEQ ID NO:22);

[0241] DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVP SRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK(SEQ ID NO:23)。

[0242] 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 set forth in SEQ ID NO: 15, and a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 16. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the second antigen-binding fragment is set forth in SEQ ID NO: 15, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO: 16.

[0243] In some embodiments, the second antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1 of the amino acid sequence of SEQ ID NO:9, HCDR2 of the amino acid sequence of SEQ ID NO:10, and HCDR3 of the amino acid sequence of SEQ ID NO:11, and the light chain variable region comprises LCDR1 of the amino acid sequence of SEQ ID NO:12, LCDR2 of the amino acid sequence of SEQ ID NO:13, and LCDR3 of 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 .... 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.

[0244] EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSG GSIYNQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVT VSS(SEQ ID NO:15);

[0245] DIQMTQSPSSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVEIK (SEQ ID NO: 16).

[0246] In some embodiments, the heavy chain variable region and the light chain variable region of the first antigen-binding fragment are connected by a linker to form an scFv. The linker can be any suitable, for example, charged and / or flexible linker. In a specific embodiment, the linker consists of 1 to 50 amino acids connected by peptide bonds, wherein the amino acids can be selected from 20 naturally occurring amino acids; in a more preferred embodiment, 1 to 50 amino acids are selected from glycine, alanine, proline, asparagine, glutamine and lysine; even more preferably, the linker consists of most sterically unhindered amino acids (such as glycine and alanine). A particularly useful flexible linker is (GGGGS)n (also known as (G4S)n). In some embodiments, n is any number between 1-10, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, or any range defined by any two of the foregoing numbers, for example, 1-5, 2-5, 3-6, 2-4, 1-4, etc. In some embodiments, the linker comprises the sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 25). In some embodiments, the VH and VL of the first antigen-binding fragment are arranged from N-terminus to C-terminus in the following order: VH-linker-VL. In some embodiments, the VH and VL of the first antigen-binding fragment are arranged from N-terminus to C-terminus in the following order: VL-linker-VH.

[0247] 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.

[0248] 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 or 24, 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 the amino acid sequence of SEQ ID NO: 19. 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 embodiments, the antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence as set forth in SEQ ID NO: 24, 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 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 specific embodiments, the antigen-binding construct targeting HER2 consists of three polypeptide chains, wherein the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO: 24, 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.

[0249] EVQLVESGGGLVQPGGSLRLSCAASGFNIEDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPCLLIYSASYLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGT KVEIKGEKPKSSDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGPYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLPGK(SEQ ID NO:17);

[0250] EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVCTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNRFTQKSLSLSPGK(SEQ ID NO:18);

[0251] DIQMTQSPSSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:19);

[0252] EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSG GGGSGGGGSGGGGSGGGGSDIQMTQSPSSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGT KVEIKGEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPCREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:24).

[0253] In some embodiments, the C-terminal lysine of the amino acid sequence set forth in SEQ ID NO: 17 is deleted. In some embodiments, the C-terminal lysine of the amino acid sequence set forth in SEQ ID NO: 18 is deleted. In some embodiments, the C-terminal lysine of the amino acid sequence set forth in SEQ ID NO: 24 is deleted. In some embodiments, the C-terminal lysine of the first polypeptide chain and / or the C-terminal lysine of the second polypeptide chain of the antigen-binding construct targeting HER2 is deleted.

[0254] In other embodiments, the HER2-targeting antigen-binding construct of the present disclosure is selected from Zanidatamab (ZW25), KN026, MBS301, KM257, or BCD-147.

[0255] Pharmaceutical compositions of antigen-binding constructs targeting HER2

[0256] In some embodiments, the antigen-binding construct targeting HER2 is formulated as a formulation for parenteral administration. In some specific embodiments, the antigen-binding construct targeting HER2 is formulated as a formulation for intravenous administration, such as for injection or infusion.

[0257] In some embodiments, the HER2-targeting antigen-binding construct is formulated with one or more pharmaceutically acceptable excipients to form a suitable pharmaceutical composition. Pharmaceutically acceptable excipients include, for example, excipients, diluents, encapsulating materials, fillers, buffers, or other agents.

[0258] In some embodiments, the unit dose of the pharmaceutical composition of the antigen-binding construct targeting HER2 is 100-600 mg, 200-600 mg, or 200-400 mg of the antigen-binding construct targeting HER2, for example, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg of the antigen-binding construct targeting HER2, or a range formed by any two of the above values.

[0259] In some embodiments, the pharmaceutical composition of the antigen-binding construct targeting HER2 is an injection. In some embodiments, the pharmaceutical composition of the antigen-binding construct targeting HER2 is an aqueous injection, including but not limited to an unlyophilized aqueous formulation or an aqueous formulation reconstituted from a lyophilized powder.

[0260] In some specific embodiments, the pharmaceutical composition of the antigen-binding construct targeting HER2 is a powder injection. In some specific embodiments, the pharmaceutical composition of the antigen-binding construct targeting HER2 is a lyophilized preparation (e.g., lyophilized powder injection). The lyophilized preparation refers to a preparation prepared by a freeze-drying process of an aqueous solution, in which the substance is first frozen, and then the solvent quantity is first reduced by sublimation (primary drying process), and then the solvent quantity is reduced by desorption (secondary drying process) until the solvent quantity is a value that no longer supports biological activity or chemical reaction. The lyophilized preparation of the present disclosure can also be dried by other methods known in the art, such as spray drying and bubbling drying (bubbledrying).

[0261] IV. Compounds of formula (I)

[0262] As used in this disclosure, the structural formula of the compound of formula (I) is as follows:

[0263]

[0264] The dosages of the compounds of formula (I) or pharmaceutically acceptable salts thereof referred to in the present disclosure are based on the molecular weight of the compounds of formula (I), unless otherwise stated.

[0265] The compound of formula (I) or a pharmaceutically acceptable salt thereof used in the present disclosure can be prepared by methods in the prior art, for example, by referring to the method of WO2016141881.

[0266] Pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0267] In some embodiments, the unit dose of the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is 50 mg or 60 mg of the compound of formula (I) or its pharmaceutically acceptable salt. In some embodiments, the unit dose of the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is 60 mg of the compound of formula (I) or its pharmaceutically acceptable salt. Wherein, the amount of the pharmaceutically acceptable salt of the compound of formula (I) is based on the compound of formula (I).

[0268] The method of administration can be determined comprehensively based on the activity, toxicity and patient tolerance of the drug.

[0269] In some embodiments, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt further comprises a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, adhesives, disintegrants, lubricants, etc. In some embodiments, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt includes but is not limited to preparations suitable for oral, parenteral, and topical administration. In some embodiments, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is a preparation suitable for oral administration. In some embodiments, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is a solid pharmaceutical composition suitable for oral administration. In some embodiments, the dosage form of the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt includes but is not limited to tablets and capsules.

[0270] The pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by methods well known in the art, such as conventional mixing, dissolving, granulating, making sugar-coated pills, grinding, emulsifying, freeze-drying, etc.

[0271] Solid pharmaceutical compositions suitable for oral administration can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets or dragee cores.

[0272] V. Fulvestrant

[0273] As used in the present disclosure, Fulvestrant is chemically named 7α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10)-triene-3,17β-diol, and has the structural formula shown in the following formula (II):

[0274]

[0275] Pharmaceutical composition of fulvestrant

[0276] In some embodiments, the pharmaceutical composition of fulvestrant further contains pharmaceutically acceptable excipients; preferably, the pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, water for injection, etc.

[0277] In some embodiments, the pharmaceutical composition of fulvestrant is an injection.

[0278] In some embodiments, the pharmaceutical composition of fulvestrant is an aqueous injection, which includes but is not limited to an unlyophilized aqueous preparation or an aqueous preparation reconstituted from a lyophilized powder.

[0279] In some embodiments, the unit dose of the pharmaceutical composition of fulvestrant is 250 mg or 500 mg of fulvestrant. In some embodiments, the unit dose of the pharmaceutical composition of fulvestrant is 250 mg of fulvestrant.

[0280] VI. Chemotherapy drugs

[0281] In some embodiments of the present disclosure, the chemotherapy drugs include but are not limited to platinum anti-tumor drugs (including but not limited to oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, miplatin, lobaplatin, picoplatin, lebaplatin, triplatin tetranitrate, phenanthreneplatin, satraplatin), camptothecin anti-tumor drugs (including but not limited to camptothecin, hydroxycamptothecin, aminocamptothecin, irinotecan, topotecan, exitecan, rubitecan, lurtotecan, gimatecan, karenitecin, 7-ethylcamptothecin, serotonin ... Taxanes (including but not limited to paclitaxel, liposome paclitaxel, albumin paclitaxel, cabazitaxel and docetaxel), nitrogen mustards (including but not limited to cyclophosphamide, ifosfamide, chlorambucil, carmustine, melphalan, bendamustine), antimetabolites (including but not limited to fluorouracils (including but not limited to carmofur, 5-fluorouracil, tegafur, capecitabine, S-1a, fufurantoin, doxifluridine, trifluridine), Cytosine anti-tumor drugs (including but not limited to cytarabine, gemcitabine, azacitidine, ancitabine), purine anti-tumor drugs (including but not limited to mercaptopurine, fludarabine), anti-folate anti-tumor drugs (including but not limited to methotrexate, pemetrexed)), anthracycline anti-tumor drugs (including but not limited to doxorubicin, epirubicin, pirarubicin, amrubicin, aclarubicin, idarubicin, daunorubicin, mitoxantrone, idarubicin, valrubicin, zorubicin, pixantrone, liposomal doxorubicin), vinca alkaloid anti-tumor drugs (including but not limited to vinblastine, vincristine , vindesine, vinflunine and vinorelbine), podophyllotoxin alkaloid anti-tumor drugs (including but not limited to etoposide and teniposide), hormone anti-tumor drugs (including but not limited to prednisone, prednisolone, dexamethasone, methylprednisolone sodium succinate), antibiotic anti-tumor drugs (including but not limited to mitomycin, actinomycin D, bleomycin, bleomycin, epirubicin, peplomycin), microtubule inhibitor anti-tumor drugs (including but not limited to eribulin, auristatin, maytansine) one or more.

[0282] In some embodiments, the chemotherapy drug is a taxane anti-tumor drug, an antimetabolite anti-tumor drug, a vinca alkaloid anti-tumor drug, or a tubulin inhibitor anti-tumor drug. In some embodiments, the chemotherapy drug is a taxane anti-tumor drug, a fluorouracil anti-tumor drug, a cytosine anti-tumor drug, a vinca alkaloid anti-tumor drug, or a tubulin inhibitor anti-tumor drug.

[0283] In some embodiments, the chemotherapy drug is nab-paclitaxel, capecitabine, gemcitabine, vinorelbine, or eribulin.

[0284] In some embodiments, the chemotherapy drug is administered according to a known administration regimen (including administration cycle, administration dosage and dosage adjustment, and administration route).

[0285] nab-paclitaxel

[0286] As used in the present disclosure, the albumin-paclitaxel is albumin-bound paclitaxel; the chemical name of the paclitaxel is 5β,20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytaxane-11-ene-9-one-4,10-diacetate-2-benzoate-13-(2R,3S)-N-benzoyl-3-phenylisoserine ester, which has the following structural formula (III):

[0287]

[0288] The dosages of nab-paclitaxel referred to in this disclosure, unless otherwise stated, are based on the molecular weight of the compound of formula (III).

[0289] Pharmaceutical composition of albumin-paclitaxel

[0290] In some embodiments, the unit dose of the pharmaceutical composition of albumin-paclitaxel is 100 mg of albumin-paclitaxel, which comprises 100 mg of paclitaxel and about 900 mg of human albumin.

[0291] In some embodiments, the pharmaceutical composition of nab-paclitaxel is an injection. In some embodiments, the pharmaceutical composition of nab-paclitaxel is an aqueous injection.

[0292] In some embodiments, the pharmaceutical composition of nab-paclitaxel is a powder for injection. In some embodiments, the pharmaceutical composition of nab-paclitaxel is a lyophilized preparation (eg, lyophilized powder for injection).

[0293] In addition, paclitaxel prepared in other formulations is also included in the scope of the present disclosure, such as paclitaxel injection, paclitaxel oral solution, paclitaxel liposomes, etc.

[0294] Capecitabine

[0295] As used in the present disclosure, the chemical name of capecitabine is 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine, which has the structural formula (IV):

[0296]

[0297] Pharmaceutical compositions of capecitabine

[0298] In some embodiments, the unit dose of the pharmaceutical composition of capecitabine is 150 mg or 500 mg of capecitabine. In some embodiments, the unit dose of the pharmaceutical composition of capecitabine is 500 mg of capecitabine.

[0299] In some embodiments, the pharmaceutical composition of capecitabine is a formulation suitable for oral administration. In some embodiments, the pharmaceutical composition of capecitabine is a solid pharmaceutical composition suitable for oral administration. In some embodiments, the pharmaceutical composition of capecitabine is a tablet.

[0300] Gemcitabine

[0301] As used in this disclosure, the chemical name of gemcitabine is 2'-deoxy-2',2'-difluorocytidine (β-isomer), which has the structural formula (V):

[0302]

[0303] As used in the present disclosure, the gemcitabine includes its free base form, also includes pharmaceutically acceptable salts, and the non-salt form or salt are all included in the protection scope of the present disclosure. Gemcitabine can be used in its free base form, and can also be used in the form of its pharmaceutically acceptable salt. For example, the pharmaceutically acceptable salt of gemcitabine is within the scope of the present disclosure, and can be produced by different organic acids and inorganic acids according to methods well known in the art. For example, the inorganic acid can be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, and the organic acid can be selected from succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid or methanesulfonic acid. In some embodiments, the pharmaceutically acceptable salt of gemcitabine can be the hydrochloride of gemcitabine.

[0304] In some embodiments, gemcitabine is administered as its hydrochloride salt. In some embodiments, gemcitabine is administered as its monohydrochloride salt.

[0305] The dosages of gemcitabine referred to in this disclosure, unless otherwise stated, are based on the molecular weight of the compound of formula (V).

[0306] Pharmaceutical compositions of gemcitabine

[0307] In some embodiments, the unit dose of the pharmaceutical composition of gemcitabine is 0.2 g or 1.0 g of gemcitabine.

[0308] In some embodiments, the pharmaceutical composition of gemcitabine is a powder injection. In some embodiments, the pharmaceutical composition of gemcitabine is a lyophilized preparation (eg, lyophilized powder injection).

[0309] Vinorelbine

[0310] As used in this disclosure, the chemical name of vinorelbine is 3',4'-didehydro-4'-deoxy-8'-norvinblastine, which has the structural formula (VI):

[0311]

[0312] As used in this disclosure, the vinorelbine includes pharmaceutically acceptable salts, which are also included in the scope of protection of this disclosure. Vinorelbine can be administered in the form of its pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt of vinorelbine can be tartrate of vinorelbine.

[0313] In some embodiments, vinorelbine is administered as its tartrate salt. In some embodiments, vinorelbine is administered as its bitartrate salt.

[0314] The dosages of vinorelbine referred to in this disclosure, unless otherwise stated, are based on the molecular weight of the compound of formula (VI).

[0315] Pharmaceutical composition of vinorelbine

[0316] In some embodiments, the unit dose of the pharmaceutical composition of vinorelbine is 10 mg of vinorelbine.

[0317] In some embodiments, the pharmaceutical composition of vinorelbine is an injection. In some embodiments, the pharmaceutical composition of vinorelbine is an aqueous injection.

[0318] Eribulin

[0319] As used in the present disclosure, the chemical name of Eribulin (also known as Eribulin, Eribulin) is 3',4'-didehydro-4'-deoxy-8'-norvinblastine, which has the structural formula (VII):

[0320]

[0321] As used herein, the term "eribulin" includes pharmaceutically acceptable salts, which are also encompassed within the scope of this disclosure. Eribulin can be administered in the form of its pharmaceutically acceptable salts. In some embodiments, the pharmaceutically acceptable salt of eribulin can be the mesylate salt of eribulin.

[0322] In some embodiments, eribulin is administered as its mesylate salt. In some embodiments, eribulin is administered as its monomesylate salt (ie, eribulin mesylate).

[0323] The dosages of eribulin referred to in this disclosure, unless otherwise stated, are based on the molecular weight of the following structural formula:

[0324]

[0325] Pharmaceutical composition of eribulin

[0326] In some embodiments, the unit dose of the pharmaceutical composition of eribulin is 1 mg of eribulin.

[0327] In some embodiments, the pharmaceutical composition of eribulin is an injection. In some embodiments, the pharmaceutical composition of eribulin is an aqueous injection.

[0328] VII. Mode of Administration

[0329] The following does not limit the mode of administration of the pharmaceutical combination of the present disclosure.

[0330] The components of the drug combination of the present disclosure can be each independently or partly or all of them together with suitable various approaches to use, including but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous route) administration. In some embodiments, the components of the drug combination of the present disclosure can be each independently or partly or all of them together orally administered or injected (e.g., intravenously or subcutaneously) for use. The components of the drug combination of the present disclosure can be each independently administered successively or at intervals of a period of time.

[0331] The components of the pharmaceutical combination of the present invention can be in the form of suitable dosage forms, either independently or in combination, including but not limited to tablets, buccal tablets, pills, capsules (e.g., hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal, subcutaneous), granules, emulsions, suspensions, solutions, dispersions and sustained-release preparations for oral or parenteral administration.

[0332] The components of the pharmaceutical combination of the present disclosure may each independently, or some or all of them may contain pharmaceutically acceptable excipients.

[0333] The pharmaceutical combination of the present disclosure may further comprise an additional therapeutic agent. In one embodiment, the additional therapeutic agent may be a tumor therapeutic agent known in the art.

[0334] VIII. Tumors

[0335] In certain aspects, the tumors disclosed herein are malignant tumors; malignant tumors refer to any malignant and / or invasive growth caused by abnormal cell growth. In some embodiments, the tumors are solid tumors. In some embodiments, the tumors are treatment-naive, refractory, recurrent, metastatic, and / or advanced solid tumors. In some embodiments, the tumors are treatment-naive, refractory, recurrent, metastatic, and / or locally advanced solid tumors. In some embodiments, the tumors are recurrent and / or metastatic solid tumors. In some embodiments, the tumors are HER2-expressing or amplified tumors. In some embodiments, the tumors are HER2-expressing or amplified solid tumors.

[0336] In some embodiments, the subject with the tumor has not been previously treated for a tumor (e.g., lacks an effective treatment regimen). In some embodiments, the subject with the tumor has previously been treated for a tumor (e.g., treatment failure or intolerance) with one or more different anti-tumor treatments.

[0337] In some embodiments, the tumor is breast cancer. In some embodiments, the tumor is treatment-naive, refractory, recurrent, metastatic, and / or advanced breast cancer. In some embodiments, the tumor is treatment-naive, refractory, recurrent, metastatic, and / or locally advanced breast cancer. In some embodiments, the tumor is advanced breast cancer. In some embodiments, the tumor is locally advanced breast cancer. In some embodiments, the tumor is recurrent breast cancer. In some embodiments, the tumor is metastatic breast cancer. In some embodiments, the tumor is recurrent and / or metastatic breast cancer. In some embodiments, the tumor is locally advanced, recurrent, and / or metastatic breast cancer.

[0338] In some embodiments, the tumor is HER2-positive breast cancer. In some embodiments, the tumor is HER2-positive recurrent breast cancer. In some embodiments, the tumor is HER2-positive metastatic breast cancer. In some embodiments, the tumor is HER2-positive recurrent and / or metastatic breast cancer. In some embodiments, the tumor is HER2-positive advanced breast cancer. In some embodiments, the tumor is HER2-positive locally advanced breast cancer. In some embodiments, the tumor is HER2-positive locally advanced, recurrent, and / or metastatic breast cancer. In some embodiments, the tumor is HER2-positive advanced, recurrent, and / or metastatic breast cancer. In some embodiments, the tumor is HR-positive and HER2-positive breast cancer. In some embodiments, the tumor is HR-positive and HER2-positive recurrent breast cancer. In some embodiments, the tumor is HR-positive and HER2-positive metastatic breast cancer. In some embodiments, the tumor is HR-positive and HER2-positive recurrent breast cancer. In some embodiments, the tumor is HR-positive and HER2-positive metastatic breast cancer. In some embodiments, the tumor is HR-positive and HER2-positive recurrent and / or metastatic breast cancer. In some embodiments, the tumor is HR-positive and HER2-positive advanced breast cancer. In some embodiments, the tumor is HR-positive and HER2-positive locally advanced breast cancer. In some embodiments, the tumor is HR-positive and HER2-positive locally advanced, recurrent and / or metastatic breast cancer. In some embodiments, the tumor is HR-positive and HER2-positive late-stage, recurrent and / or metastatic breast cancer. The HR-positive includes estrogen receptor (ER) positive and progesterone receptor (PR) positive. In some embodiments, the tumor is HR-negative and HER2-positive breast cancer. In some embodiments, the tumor is HR-negative and HER2-positive recurrent breast cancer. In some embodiments, the tumor is HR-negative and HER2-positive metastatic breast cancer. In some embodiments, the tumor is HR-negative and HER2-positive recurrent and / or metastatic breast cancer. In some embodiments, the tumor is HR-negative and HER2-positive late-stage breast cancer. In some embodiments, the tumor is HR-negative and HER2-positive locally advanced breast cancer. In some embodiments, the tumor is HR-negative and HER2-positive locally advanced breast cancer. In some embodiments, the tumor is HR-negative and HER2-positive locally advanced breast cancer. In some embodiments, the tumor is HR-negative and HER2-positive late-stage, recurrent and / or metastatic breast cancer. In some embodiments, the tumor is HR-negative and HER2-positive late-stage, recurrent and / or metastatic breast cancer. In some embodiments, the HER2 positive is 3+ (IHC3+) detected by standard immunohistochemistry (IHC). In some embodiments, the HER2 positive is IHC2+ and confirmed to be positive (ISH+) by in situ hybridization (ISH). In some embodiments, the HER2 positive is ISH+.

[0339] In some embodiments, the subject with breast cancer is postmenopausal, premenopausal, or perimenopausal.

[0340] In some embodiments, the subject of the breast cancer has not previously been treated for breast cancer (e.g., lack of an effective treatment regimen). In some embodiments, the subject of the breast cancer has not previously received systemic therapy to treat breast cancer (e.g., lack of an effective treatment regimen). In some embodiments, the subject of the breast cancer has not previously received surgery, radiotherapy, chemotherapy, and / or immunotherapy to treat breast cancer (e.g., lack of an effective treatment regimen). In some embodiments, the subject of the breast cancer has not previously received surgery to treat breast cancer (e.g., lack of an effective treatment regimen). In some of these embodiments, the breast cancer is locally advanced, recurrent, and / or metastatic breast cancer that is HER2-positive. In some of these embodiments, the breast cancer is locally advanced, recurrent, and / or metastatic breast cancer that is HR-positive and HER2-positive. In some of these embodiments, the breast cancer is locally advanced, recurrent, and / or metastatic breast cancer that is HR-negative and HER2-positive. In some specific embodiments, the breast cancer is locally advanced, recurrent, and / or metastatic breast cancer that is HER2-positive, and is not suitable for surgical treatment. In some specific embodiments, the breast cancer is late, recurrent, and / or metastatic breast cancer that is HER2-positive, and is not suitable for surgical treatment. In some embodiments, the breast cancer is HR-positive and HER2-positive locally advanced, recurrent and / or metastatic breast cancer, and is not suitable for surgical treatment. In some embodiments, the breast cancer is HR-negative and HER2-positive locally advanced, recurrent and / or metastatic breast cancer, and is not suitable for surgical treatment. In some embodiments, the breast cancer is HR-positive and HER2-positive late-stage, recurrent and / or metastatic breast cancer, and is not suitable for surgical treatment. In some embodiments, the breast cancer is HR-negative and HER2-positive late-stage, recurrent and / or metastatic breast cancer, and is not suitable for surgical treatment.

[0341] In some embodiments, the subject of breast cancer has been treated with one or more different anti-tumor treatments for breast cancer (e.g., treatment failure or intolerance) in the past. In some embodiments, the subject of breast cancer has been treated with a systemic treatment regimen (e.g., HER2-targeted therapy and / or endocrine therapy) for breast cancer (e.g., treatment failure or intolerance) in the past. In some embodiments, the subject of breast cancer has been treated with a first-line systemic treatment regimen (e.g., HER2-targeted therapy and / or endocrine therapy) for breast cancer (e.g., treatment failure or intolerance) in the past. In some embodiments, the subject of breast cancer has been treated with a second-line systemic treatment regimen (e.g., HER2-targeted therapy and / or endocrine therapy) for breast cancer (e.g., treatment failure or intolerance) in the past. In some specific embodiments, the subject of breast cancer has been treated with a first-line and / or second-line HER2-targeted therapy and / or endocrine therapy regimen for breast cancer (e.g., treatment failure or intolerance) in the past. In some of these embodiments, previous treatment is performed in the metastasis stage. In some of these embodiments, the breast cancer is locally advanced, recurrent and / or metastatic breast cancer that is HR positive and HER2 positive. In some of these embodiments, the breast cancer is HR negative and HER2 positive locally advanced, recurrent and / or metastatic breast cancer. In some of these embodiments, the breast cancer is HR positive and HER2 positive late, recurrent and / or metastatic breast cancer. In some of these embodiments, the breast cancer is HR negative and HER2 positive late, recurrent and / or metastatic breast cancer.

[0342] In other specific embodiments, the subject of the breast cancer has previously received at least two lines of HER2 targeted therapy (e.g., trastuzumab, pertuzumab, pyrotinib, lapatinib, T-DM1, tucatinib) to treat breast cancer (e.g., treatment failure or intolerance). In other specific embodiments, the subject of the breast cancer has previously received no more than three lines of anti-tumor therapy (including but not limited to HER2 targeted therapy, chemotherapy) to treat breast cancer, and disease progression occurs during or after the last treatment. In some of these embodiments, previous treatment is carried out in the metastasis stage. In some of these embodiments, the breast cancer is HER2-positive recurrent and / or metastatic breast cancer. In some embodiments, the subject with breast cancer is a subject with HER2-positive recurrent and / or metastatic breast cancer who has previously received at least two lines of HER2-targeted therapy; or, the subject with breast cancer is a subject with HER2-positive locally advanced, recurrent and / or metastatic breast cancer who has previously received at least two lines of HER2-targeted therapy; or, the subject with breast cancer is a subject with HER2-positive advanced, recurrent and / or metastatic breast cancer who has previously received at least two lines of HER2-targeted therapy.

[0343] In other embodiments, the subject of the breast cancer has previously received a systemic treatment regimen (e.g., endocrine therapy) that is no more than two lines and has treated breast cancer (e.g., treatment failure or intolerance). In other specific embodiments, the subject of the breast cancer has previously received a systemic endocrine therapy regimen that is no more than two lines and has treated breast cancer (e.g., treatment failure or intolerance). In some of these embodiments, previous treatment is carried out in the late stage. In some of these embodiments, the breast cancer is locally advanced, recurrent and / or metastatic breast cancer that is HER2 positive. In some of these embodiments, the breast cancer is late, recurrent and / or metastatic breast cancer that is HER2 positive.

[0344] In some embodiments, the subject with breast cancer has been treated with localized radiation therapy for breast cancer, and the localized radiation therapy has been completed for more than 4 weeks (brain radiation therapy for more than 2 weeks); wherein, the subject's target lesion is not within the radiotherapy area, or the target lesion is within the radiotherapy area but has been confirmed to have progressed. In some of these embodiments, the breast cancer is recurrent and / or metastatic breast cancer. In some of these embodiments, the breast cancer is advanced breast cancer. In some of these embodiments, the breast cancer is locally advanced breast cancer. In some of these embodiments, the breast cancer is HER2-positive breast cancer. In some of these embodiments, the breast cancer is HR-positive and HER2-positive breast cancer. In some of these embodiments, the breast cancer is HR-negative and HER2-positive breast cancer. In some of these embodiments, the breast cancer is HER2-positive recurrent and / or metastatic breast cancer. In some of these embodiments, the breast cancer is HER2-positive locally advanced, recurrent and / or metastatic breast cancer. In some of these embodiments, the breast cancer is HR-positive and HER2-positive locally advanced, recurrent and / or metastatic breast cancer. In some of these embodiments, the breast cancer is HR-positive and HER2-positive locally advanced, recurrent and / or metastatic breast cancer. In some of these embodiments, the breast cancer is HR-positive and HER2-positive advanced, recurrent and / or metastatic breast cancer. In some of these embodiments, the breast cancer is advanced, recurrent, and / or metastatic breast cancer that is HR-negative and HER2-positive.

[0345] The present disclosure also provides the following specific implementation schemes, but the protection scope of the present disclosure is not limited thereto:

[0346] Embodiment 1. A pharmaceutical combination comprising an antigen-binding construct targeting HER2, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant

[0347]

[0348] Wherein, the antigen-binding construct targeting HER2 comprises a first antigen-binding fragment and a second antigen-binding fragment, the first antigen-binding fragment comprising: 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.

[0349] Embodiment 2. The drug combination according to embodiment 1, wherein the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region whose amino acid sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8.

[0350] Embodiment 3. The drug combination according to embodiment 1 or 2, wherein the second antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 15, and a light chain variable region whose amino acid sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 16.

[0351] Embodiment 4. The drug combination according to any one of Embodiments 1-3, wherein the antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 17, a second polypeptide chain having an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 18, and a third polypeptide chain having an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 19.

[0352] Embodiment 5. The drug combination according to any one of Embodiments 1-4, wherein the unit dose of the antigen-binding construct targeting HER2 is 100-600 mg, 200-600 mg, or 200-400 mg; preferably, the unit dose of the antigen-binding construct targeting HER2 is 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg and / or 600 mg; more preferably, the unit dose of the antigen-binding construct targeting HER2 is 200 mg.

[0353] Embodiment 6. The pharmaceutical combination according to any one of Embodiments 1-5, wherein the unit dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 50 mg, 60 mg, 100 mg, 120 mg, 150 mg and / or 180 mg; preferably, the unit dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 50 mg and / or 60 mg.

[0354] Embodiment 7. The pharmaceutical combination according to any one of embodiments 1-6, wherein the unit dose of fulvestrant is 250 mg or 500 mg.

[0355] Embodiment 8. The drug combination according to any one of Embodiments 1-7, wherein the drug combination is suitable for administration within a single treatment cycle, and comprises 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of an antigen-binding construct targeting HER2; preferably, the drug combination is suitable for administration within a single treatment cycle, and comprises 7.5 mg / kg, 15 mg / kg, 30 mg / kg or 40 mg / kg of an antigen-binding construct targeting HER2; more preferably, the drug combination is suitable for administration within a single treatment cycle, and comprises 40 mg / kg of an antigen-binding construct targeting HER2.

[0356] Embodiment 9. The pharmaceutical combination according to embodiment 8, wherein the pharmaceutical combination comprises 840-6720 mg, 1680-5040 mg, 2520-5040 mg, 3360-5040 mg, 4200-5040 mg, or 4200-6720 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; preferably, the pharmaceutical combination comprises 1680 mg, 3360 mg, 4200 mg, or 5040 mg, or a range formed by any two of the foregoing values, of the compound of formula (I) or a pharmaceutically acceptable salt thereof; more preferably, the pharmaceutical combination comprises 3360 mg, 4200 mg, or 5040 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0357] Embodiment 10. The pharmaceutical combination according to embodiment 8 or 9, wherein the pharmaceutical combination comprises 500-1000 mg of fulvestrant; preferably, the pharmaceutical combination comprises 500 mg or 1000 mg of fulvestrant.

[0358] Embodiment 11. The pharmaceutical combination according to embodiment 10, wherein the pharmaceutical combination is suitable for administration in a first treatment cycle and comprises 1000 mg of fulvestrant.

[0359] Embodiment 12. The pharmaceutical combination according to embodiment 10, wherein the pharmaceutical combination is suitable for administration in the second treatment cycle and subsequent single treatment cycles, and comprises 500 mg of fulvestrant.

[0360] Embodiment 13. The pharmaceutical combination according to any one of embodiments 8-12, wherein every 4 weeks is one treatment cycle.

[0361] Embodiment 14. The drug combination according to any one of embodiments 1-13, wherein the drug combination is used to treat a tumor; preferably, the tumor is a solid tumor; more preferably, the tumor is breast cancer;

[0362] Optionally, the subject with breast cancer is postmenopausal, premenopausal or perimenopausal.

[0363] Embodiment 15. The pharmaceutical combination according to embodiment 14, wherein the tumor is recurrent and / or metastatic breast cancer.

[0364] Embodiment 16. The pharmaceutical combination according to embodiment 14 or 15, wherein the tumor is advanced breast cancer or locally advanced breast cancer, preferably locally advanced breast cancer.

[0365] Embodiment 17. The pharmaceutical combination according to any one of Embodiments 14-16, wherein the tumor is HR-positive and HER2-positive breast cancer.

[0366] Embodiment 18. The pharmaceutical combination according to embodiment 14, wherein the tumor is HR-positive and HER2-positive locally advanced, recurrent and / or metastatic breast cancer.

[0367] Embodiment 19. A method of treating a tumor in a subject, comprising administering to the subject the pharmaceutical combination of any one of embodiments 1-13.

[0368] Embodiment 20. The method according to embodiment 19, wherein the tumor is a solid tumor; preferably, the tumor is breast cancer;

[0369] Optionally, the subject with breast cancer is postmenopausal, premenopausal or perimenopausal.

[0370] Embodiment 21. The method according to embodiment 19 or 20, wherein the tumor is recurrent and / or metastatic breast cancer.

[0371] Embodiment 22. The method according to any one of embodiments 19-21, wherein the tumor is advanced breast cancer or locally advanced breast cancer, preferably locally advanced breast cancer.

[0372] Embodiment 23. The method of any one of Embodiments 19-22, wherein the tumor is HR-positive and HER2-positive breast cancer.

[0373] Embodiment 24. The method of embodiment 19, wherein the tumor is HR-positive and HER2-positive locally advanced, recurrent and / or metastatic breast cancer.

[0374] Embodiment 25. The method according to any one of Embodiments 19-24, wherein the antigen-binding construct targeting HER2, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant are administered simultaneously, sequentially, and / or alternately; preferably, the antigen-binding construct targeting HER2, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant are administered sequentially.

[0375] Embodiment 26. A method according to any one of embodiments 19-25, wherein the antigen-binding construct targeting HER2 is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, optionally, at a dose of 2.5-50 mg / kg, 2.5-30 mg / kg, 2.5-10 mg / kg, 5-10 mg / kg, 10-30 mg / kg, or 20-30 mg / kg of the antigen-binding construct targeting HER2 each time; preferably, at a dose of 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg or 50 mg / kg of the antigen-binding construct targeting HER2 each time.

[0376] Embodiment 27. The method according to embodiment 26, wherein the antigen-binding construct targeting HER2 is administered once every 2 weeks at a dose of 20 mg / kg of the antigen-binding construct targeting HER2.

[0377] Embodiment 28. The method according to any one of embodiments 19-27, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day, optionally at a dose of 30-240 mg, 60-180 mg, 90-180 mg, 120-180 mg, 150-180 mg, or 150-240 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each time; preferably, at a dose of 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 180 mg or 240 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each time; more preferably, at a dose of 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each time.

[0378] Embodiment 29. The method according to any one of embodiments 19-28, wherein fulvestrant is administered twice in the first treatment cycle and once in the second treatment cycle and each subsequent treatment cycle; preferably, fulvestrant is administered once each on day 1 and day 15 of the first treatment cycle and once on day 1 of the second treatment cycle and each subsequent treatment cycle.

[0379] Embodiment 30. The method of embodiment 29, wherein 500 mg of fulvestrant is administered on each of days 1 and 15 of the first treatment cycle, and 500 mg of fulvestrant is administered on day 1 of the second treatment cycle and each subsequent treatment cycle.

[0380] Embodiment 31. The method of any one of embodiments 19-30, wherein one treatment cycle is every 4 weeks.

[0381] Embodiment 32. The method of any one of embodiments 19-31, wherein the drug combination is administered in a therapeutically effective amount.

[0382] Embodiment 33. A kit for treating a tumor, comprising the drug combination according to any one of embodiments 1-18; preferably, the tumor is a solid tumor; more preferably, the tumor is breast cancer;

[0383] Optionally, the subject with breast cancer is postmenopausal, premenopausal or perimenopausal.

[0384] Embodiment 34. The kit according to embodiment 33, wherein the tumor is recurrent and / or metastatic breast cancer.

[0385] Embodiment 35. The kit according to embodiment 33 or 34, wherein the tumor is advanced breast cancer or locally advanced breast cancer, preferably locally advanced breast cancer.

[0386] Embodiment 36. The kit of any one of Embodiments 33-35, wherein the tumor is HR-positive and HER2-positive breast cancer.

[0387] Embodiment 37. The kit according to embodiment 33, wherein the tumor is HR-positive and HER2-positive locally advanced, recurrent and / or metastatic breast cancer.

[0388] Embodiment 38. A kit according to any one of Embodiments 33-37, wherein the antigen-binding construct targeting HER2, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant in the drug combination are separately packaged in respective medicine boxes.

[0389] Embodiment 39. A drug combination comprising an antigen-binding construct targeting HER2 and a chemotherapy drug, wherein the antigen-binding construct targeting HER2 comprises a first antigen-binding fragment and a second antigen-binding fragment, the first antigen-binding fragment comprising: 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 comprising: 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.

[0390] Embodiment 40. A drug combination according to embodiment 39, wherein the first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8.

[0391] Embodiment 41. A drug combination according to embodiment 39 or 40, wherein the second antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 15, and a light chain variable region whose amino acid sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 16.

[0392] Embodiment 42. The drug combination of any one of Embodiments 39-41, wherein the antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 17, a second polypeptide chain having an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 18, and a third polypeptide chain having an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 19.

[0393] Embodiment 43. The drug combination according to any one of Embodiments 39 to 42, wherein the chemotherapy drug is a taxane anti-tumor drug, an antimetabolite anti-tumor drug, a vinca alkaloid anti-tumor drug, or a microtubule inhibitor anti-tumor drug.

[0394] Embodiment 44. The drug combination according to any one of Embodiments 39 to 43, wherein the chemotherapy drug is a taxane anti-tumor drug, a fluorouracil anti-tumor drug, a cytosine anti-tumor drug, a vinca alkaloid anti-tumor drug, or a microtubule inhibitor anti-tumor drug.

[0395] Embodiment 45. The drug combination according to any one of embodiments 39-44, wherein the chemotherapy drug is nab-paclitaxel, capecitabine, gemcitabine, vinorelbine or eribulin.

[0396] Embodiment 46. A drug combination according to any one of Embodiments 39 to 45, wherein the unit dose of the antigen-binding construct targeting HER2 is 100-600 mg, 200-600 mg, or 200-400 mg; preferably, the unit dose of the antigen-binding construct targeting HER2 is 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg and / or 600 mg; more preferably, the unit dose of the antigen-binding construct targeting HER2 is 200 mg.

[0397] Embodiment 47. The pharmaceutical combination according to any one of Embodiments 39-46, wherein the unit dose of nab-paclitaxel is 100 mg.

[0398] Embodiment 48. The pharmaceutical combination according to any one of embodiments 39-46, wherein the unit dose of capecitabine is 150 mg and / or 500 mg.

[0399] Embodiment 49. The pharmaceutical combination according to any one of embodiments 39-46, wherein the unit dose of gemcitabine is 0.2 g and / or 1 g.

[0400] Embodiment 50. The pharmaceutical combination according to any one of embodiments 39-46, wherein the unit dose of vinorelbine is 10 mg.

[0401] Embodiment 51. The pharmaceutical combination according to any one of embodiments 39-46, wherein the unit dose of eribulin is 1 mg.

[0402] Embodiment 52. A drug combination according to any one of embodiments 39-51, wherein the drug combination is suitable for administration within a single treatment cycle and comprises 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of an antigen-binding construct targeting HER2; preferably, the drug combination is suitable for administration within a single treatment cycle and comprises 7.5 mg / kg, 15 mg / kg, 30 mg / kg or 40 mg / kg of an antigen-binding construct targeting HER2; more preferably, the drug combination is suitable for administration within a single treatment cycle and comprises 30 mg / kg of an antigen-binding construct targeting HER2.

[0403] Embodiment 53. The drug combination according to embodiment 52, wherein the drug combination comprises 130-260 mg, or 180-260 mg of albumin-paclitaxel; preferably, the drug combination comprises 130 mg, 180 mg, 200 mg, 220 mg or 260 mg of albumin-paclitaxel; more preferably, the drug combination comprises 260 mg of albumin-paclitaxel.

[0404] Embodiment 54. The pharmaceutical combination according to embodiment 52, wherein the pharmaceutical combination comprises 14-28 g / m 2 Capecitabine; preferably, the drug combination includes 14g / m 2 , 21g / m 2 or 28g / m 2 More preferably, the drug combination comprises 28g / m 2 of capecitabine.

[0405] Embodiment 55. The drug combination according to embodiment 52 or 54, wherein the drug combination comprises 16.8-64.4g, or 32.2-64.4g of capecitabine; preferably, the drug combination comprises 16.8g, 21g, 22.4g, 25.2g, 28g, 29.4g, 30.8g, 32.2g, 33.6g, 36.4g, 39.2g, 40.6g, 42g, 44.8g, 49g, 50.4g, 56g, 60.2g or 64.4g of capecitabine; more preferably, the drug combination comprises 32.2g, 36.4g, 40.6g, 44.8g, 49g, 50.4g, 56g, 60.2g or 64.4g of capecitabine.

[0406] Embodiment 56. The drug combination according to embodiment 52, wherein the drug combination comprises 1500-2000 mg / m 2 Preferably, the drug combination includes 1500 mg / m 2 or 2000 mg / m 2 More preferably, the drug combination comprises 2000 mg / m 2 of gemcitabine.

[0407] Embodiment 57. The drug combination according to embodiment 52, wherein the drug combination comprises 50 mg / m 2 Changchunruibin.

[0408] Embodiment 58. The drug combination according to embodiment 52, wherein the drug combination comprises 1.4-2.8 mg / m 2 Preferably, the drug combination includes 1.4 mg / m 2 , 2.2mg / m 2 or 2.8 mg / m 2 More preferably, the drug combination comprises 2.8 mg / m 2 of Eriblin.

[0409] Embodiment 59. The pharmaceutical combination according to any one of embodiments 39-58, wherein every 3 weeks is one treatment cycle.

[0410] Embodiment 60. The drug combination according to any one of embodiments 39-59, wherein the drug combination is used to treat a tumor; preferably, the tumor is a solid tumor; more preferably, the tumor is breast cancer;

[0411] Optionally, the subject with breast cancer is postmenopausal, premenopausal or perimenopausal.

[0412] Embodiment 61. The pharmaceutical combination according to embodiment 60, wherein the tumor is recurrent and / or metastatic breast cancer.

[0413] Embodiment 62. The pharmaceutical combination according to embodiment 60 or 61, wherein the tumor is advanced breast cancer or locally advanced breast cancer, preferably locally advanced breast cancer.

[0414] Embodiment 63. The pharmaceutical combination according to any one of Embodiments 60-62, wherein the tumor is HER2-positive breast cancer.

[0415] Embodiment 64. The pharmaceutical combination according to embodiment 60, wherein the tumor is HER2-positive locally advanced, recurrent and / or metastatic breast cancer.

[0416] Embodiment 65. The pharmaceutical combination according to embodiment 60, wherein the tumor is HER2-positive recurrent and / or metastatic breast cancer.

[0417] Embodiment 66. A method of treating a tumor in a subject, comprising administering to the subject the pharmaceutical combination of any one of embodiments 39-59.

[0418] Embodiment 67. The method according to embodiment 66, wherein the tumor is a solid tumor; preferably, the tumor is breast cancer;

[0419] Optionally, the subject with breast cancer is postmenopausal, premenopausal or perimenopausal.

[0420] Embodiment 68. The method of embodiment 66 or 67, wherein the tumor is recurrent and / or metastatic breast cancer.

[0421] Embodiment 69. The method according to any one of embodiments 66-68, wherein the tumor is advanced breast cancer or locally advanced breast cancer, preferably locally advanced breast cancer.

[0422] Embodiment 70. The method of any one of Embodiments 66-69, wherein the tumor is HER2-positive breast cancer.

[0423] Embodiment 71. The method of embodiment 66, wherein the tumor is HER2-positive locally advanced, recurrent and / or metastatic breast cancer.

[0424] Embodiment 72. The method of embodiment 66, wherein the tumor is HER2-positive recurrent and / or metastatic breast cancer.

[0425] Embodiment 73. The method according to any one of Embodiments 66-72, wherein the antigen-binding construct targeting HER2 and the chemotherapy drug can be administered simultaneously, sequentially and / or alternately; preferably, the antigen-binding construct targeting HER2 and the chemotherapy drug are administered sequentially.

[0426] Embodiment 74. The method of any one of Embodiments 66-73, wherein the antigen-binding construct targeting HER2 is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, optionally, at a dose of 2.5-50 mg / kg, 2.5-30 mg / kg, 2.5-10 mg / kg, 5-10 mg / kg, 10-30 mg / kg, or 20-30 mg / kg of the antigen-binding construct targeting HER2 each time; preferably, at a dose of 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, or 50 mg / kg of the antigen-binding construct targeting HER2 each time.

[0427] Embodiment 75. The method according to embodiment 74, wherein the antigen-binding construct targeting HER2 is administered once every 3 weeks at a dose of 30 mg / kg of the antigen-binding construct targeting HER2.

[0428] Embodiment 76. The method according to any one of embodiments 66-75, wherein the albumin-paclitaxel is administered once every 3 weeks, optionally at a dose of 130-260 mg, or 180-260 mg of albumin-paclitaxel each time; preferably, at a dose of 130 mg, 180 mg, 200 mg, 220 mg or 260 mg of albumin-paclitaxel each time; more preferably, at a dose of 260 mg of albumin-paclitaxel each time.

[0429] Embodiment 77. The method according to any one of embodiments 66-75, wherein the capecitabine is administered twice daily, optionally at a dose of 500-1000 mg / m 2 Capecitabine is administered at a dose of 500 mg / m 2 , 750mg / m 2 or 1000 mg / m 2 Capecitabine is administered at a dose of 1000 mg / m 2 Dosage of capecitabine.

[0430] Embodiment 78. The method according to any one of embodiments 66-75, wherein gemcitabine is administered once a week for two consecutive weeks followed by one week of rest, optionally at a dose of 750-1000 mg / m 2 The dose of gemcitabine is preferably 750 mg / m 2 or 1000 mg / m 2 The dose of gemcitabine is preferably 1000 mg / m 2 Dosage of gemcitabine.

[0431] Embodiment 79. The method according to any one of embodiments 66-75, wherein vinorelbine is administered once a week for two consecutive weeks followed by one week of rest, optionally at a dose of 25 mg / m 2 Dosage administration of vinorelbine.

[0432] Embodiment 80. The method according to any one of embodiments 66-75, wherein eribulin is administered once a week for two consecutive weeks followed by one week of rest, optionally at a dose of 0.7-1.4 mg / m 2 The dose of eribulin is preferably 0.7 mg / m 2 , 1.1mg / m 2 or 1.4 mg / m 2 The dosage of eribulin is preferably 0.7-1.4 mg / m 2 Dosage of eribulin.

[0433] Embodiment 81. The method of any one of embodiments 66-80, wherein one treatment cycle is every 3 weeks.

[0434] Embodiment 82. The method of any one of embodiments 66-81, wherein the drug combination is administered in a therapeutically effective amount.

[0435] Embodiment 83. A kit for treating a tumor, comprising the drug combination according to any one of embodiments 39-65; preferably, the tumor is a solid tumor; more preferably, the tumor is breast cancer;

[0436] Optionally, the subject with breast cancer is postmenopausal, premenopausal or perimenopausal.

[0437] Embodiment 84. The kit according to embodiment 83, wherein the tumor is recurrent and / or metastatic breast cancer.

[0438] Embodiment 85. The kit according to any one of Embodiments 83 or 84, wherein the tumor is advanced breast cancer or locally advanced breast cancer, preferably locally advanced breast cancer.

[0439] Embodiment 86. The kit of any one of Embodiments 83-85, wherein the tumor is HER2-positive breast cancer.

[0440] Embodiment 87. The kit of embodiment 83, wherein the tumor is HER2-positive locally advanced, recurrent and / or metastatic breast cancer.

[0441] Embodiment 88. The kit of embodiment 83, wherein the tumor is HER2-positive recurrent and / or metastatic breast cancer.

[0442] Embodiment 89. The kit according to any one of Embodiments 83-88, wherein the antigen-binding construct targeting HER2 and the chemotherapy drug in the drug combination are separately packaged in respective medicine boxes.

[0443] Embodiment 90. A method of treating a tumor in a subject, comprising administering to the subject an antigen-binding construct targeting HER2, wherein the antigen-binding construct targeting HER2 comprises a first antigen-binding fragment, the first antigen-binding fragment comprising: 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 comprising: 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.

[0444] Embodiment 91. A method according to embodiment 90, wherein the first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8.

[0445] Embodiment 92. A method according to embodiment 90 or 91, wherein the second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:15, and a light chain variable region having an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:16.

[0446] Embodiment 93. A method according to any one of embodiments 90-92, wherein the antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 17, a second polypeptide chain having an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 18, and a third polypeptide chain having an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 19.

[0447] Embodiment 94. The method of any one of Embodiments 90-93, wherein the tumor is a HER2-expressing or amplified tumor.

[0448] Embodiment 95. The method of any one of Embodiments 90-94, wherein the tumor is breast cancer; optionally, the subject with breast cancer is postmenopausal, premenopausal, or perimenopausal.

[0449] Embodiment 96. The method of any one of Embodiments 90-95, wherein the tumor is recurrent and / or metastatic breast cancer.

[0450] Embodiment 97. The method according to any one of embodiments 90-96, wherein the tumor is advanced breast cancer or locally advanced breast cancer, preferably locally advanced breast cancer.

[0451] Embodiment 98. The method of any one of Embodiments 90-97, wherein the tumor is HER2-positive breast cancer.

[0452] Embodiment 99. The method of any one of Embodiments 90-98, wherein the tumor is HR-positive HER2-positive breast cancer.

[0453] Embodiment 100. The method of any one of Embodiments 90-99, wherein the antigen-binding construct targeting HER2 is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, optionally at a dose of 2.5-50 mg / kg, 2.5-30 mg / kg, 2.5-10 mg / kg, 5-10 mg / kg, 10-30 mg / kg, or 20-30 mg / kg of the antigen-binding construct targeting HER2 each time; preferably, at a dose of 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, or 50 mg / kg of the antigen-binding construct targeting HER2 each time.

[0454] Embodiment 101. The method of embodiment 100, wherein the antigen-binding construct targeting HER2:

[0455] (1) once every week, at a dose of 2.5-10 mg / kg or 5-10 mg / kg of the HER2-targeting antigen-binding construct;

[0456] (2) once every week, each time at a dose of about 2.5 mg / kg, about 5 mg / kg, or about 10 mg / kg of the HER2-targeting antigen-binding construct;

[0457] (3) once every 2 weeks, each time at a dose of about 20 mg / kg of the HER2-targeting antigen-binding construct; or (4) once every 3 weeks, each time at a dose of about 30 mg / kg of the HER2-targeting antigen-binding construct.

[0458] Alternatively, as an alternative, the present disclosure further provides the following embodiments, but the protection scope of the present disclosure is not limited thereto:

[0459] Embodiment 1. A pharmaceutical combination comprising an antigen-binding construct targeting HER2, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant,

[0460]

[0461] Wherein, the antigen-binding construct targeting HER2 comprises a first antigen-binding fragment and a second antigen-binding fragment, the first antigen-binding fragment comprising: 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.

[0462] Embodiment 2. A drug combination comprising an antigen-binding construct targeting HER2 and a chemotherapy drug, wherein the antigen-binding construct targeting HER2 comprises a first antigen-binding fragment and a second antigen-binding fragment, the first antigen-binding fragment comprising: 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 comprising: 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.

[0463] Embodiment 3. The drug combination according to embodiment 1 or 2, wherein the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region whose amino acid sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8.

[0464] Embodiment 4. The drug combination according to any one of Embodiments 1-3, wherein the second antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 15, and a light chain variable region whose amino acid sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 16.

[0465] Embodiment 5. The drug combination according to any one of Embodiments 1-4, wherein the antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 17, a second polypeptide chain having an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 18, and a third polypeptide chain having an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 19.

[0466] Embodiment 6. The drug combination according to any one of Embodiments 1-5, wherein the unit dose of the antigen-binding construct targeting HER2 is 100-600 mg, 200-600 mg, or 200-400 mg; preferably, the unit dose of the antigen-binding construct targeting HER2 is 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg and / or 600 mg; more preferably, the unit dose of the antigen-binding construct targeting HER2 is 200 mg.

[0467] Embodiment 7. The pharmaceutical combination according to any one of Embodiments 1 and 3-6, wherein the unit dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 50 mg, 60 mg, 100 mg, 120 mg, 150 mg and / or 180 mg; preferably, the unit dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 50 mg and / or 60 mg.

[0468] Embodiment 8. The pharmaceutical combination according to any one of embodiments 1 and 3-7, wherein the unit dose of fulvestrant is 250 mg or 500 mg.

[0469] Embodiment 9. The drug combination according to any one of embodiments 1 and 3-8, wherein the drug combination is a formulation suitable for administration within a single treatment cycle, comprising 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of an antigen-binding construct targeting HER2; preferably, the drug combination is suitable for administration within a single treatment cycle, comprising 7.5 mg / kg, 15 mg / kg, 30 mg / kg or 40 mg / kg of an antigen-binding construct targeting HER2.

[0470] Embodiment 10. The pharmaceutical combination according to any one of embodiments 1 and 3-9, wherein the pharmaceutical combination is a formulation suitable for administration in a single treatment cycle, comprising 840-6720 mg, 1680-5040 mg, 2520-5040 mg, 3360-5040 mg, 4200-5040 mg, or 4200-6720 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; preferably, the pharmaceutical combination is a formulation suitable for administration in a single treatment cycle, comprising 1680 mg, 3360 mg, 4200 mg, or 5040 mg, or a range formed by any two of the above values, of the compound of formula (I) or a pharmaceutically acceptable salt thereof; more preferably, the pharmaceutical combination is a formulation suitable for administration in a single treatment cycle, comprising 3360 mg, 4200 mg, or 5040 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0471] Embodiment 11. The drug combination according to any one of embodiments 1 and 3-10, wherein the drug combination is a formulation suitable for administration within a single treatment cycle, which comprises 500-1000 mg of fulvestrant; preferably, the drug combination is a formulation suitable for administration within a single treatment cycle, which comprises 500 mg or 1000 mg of fulvestrant.

[0472] Embodiment 12. The pharmaceutical combination according to embodiment 11, wherein the pharmaceutical combination is a formulation suitable for administration in a first treatment cycle, comprising 1000 mg of fulvestrant; and / or

[0473] The drug combination is a formulation suitable for administration in the second treatment cycle and subsequent single treatment cycles, which includes 500 mg of fulvestrant.

[0474] Embodiment 13. The pharmaceutical combination according to any one of embodiments 9 to 12, wherein every 4 weeks is one treatment cycle.

[0475] Embodiment 14. The drug combination according to any one of embodiments 1 and 3-13, wherein the antigen-binding construct targeting HER2, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant in the drug combination are separately packaged in respective medicine boxes.

[0476] Embodiment 15. A drug combination according to any one of Embodiments 1 and 3-14, wherein the drug combination comprises a pharmaceutical composition of the antigen-binding construct targeting HER2, a pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition of fulvestrant.

[0477] Embodiment 16. The pharmaceutical combination according to Embodiment 15, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2, the pharmaceutical composition of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition of fulvestrant are separately packaged in respective medicine boxes.

[0478] Embodiment 17. The drug combination according to any one of Embodiments 2-6, wherein the chemotherapy drug is a taxane anti-tumor drug, a fluorouracil anti-tumor drug, a cytosine anti-tumor drug, a vinca alkaloid anti-tumor drug, or a microtubule inhibitor anti-tumor drug.

[0479] Embodiment 18. The drug combination according to any one of embodiments 2-6 and 17, wherein the chemotherapy drug is albumin-paclitaxel, capecitabine, gemcitabine, vinorelbine or eribulin.

[0480] Embodiment 19. The pharmaceutical combination according to any one of embodiments 2-6 and 17-18, wherein the unit dose of nab-paclitaxel is 100 mg;

[0481] The unit dose of capecitabine is 150 mg and / or 500 mg;

[0482] The unit dose of gemcitabine is 0.2g and / or 1g;

[0483] The unit dose of vinorelbine is 10 mg; and / or

[0484] The unit dose of eribulin is 1 mg.

[0485] Embodiment 20. The drug combination according to any one of embodiments 2-6 and 17-19, wherein the drug combination is a formulation suitable for administration within a single treatment cycle, which includes 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of an antigen-binding construct targeting HER2; preferably, the drug combination is a formulation suitable for administration within a single treatment cycle, which includes 7.5 mg / kg, 15 mg / kg, 30 mg / kg or 40 mg / kg of an antigen-binding construct targeting HER2.

[0486] Embodiment 21. The drug combination according to any one of embodiments 2-6 and 17-20, wherein the drug combination is a formulation suitable for administration in a single treatment cycle, comprising 130-260 mg / m 2 , or 180-260 mg / m 2 Preferably, the drug combination includes 130 mg / m 2 , 180mg / m 2 , 200mg / m 2 , 220mg / m 2 or 260 mg / m 2 More preferably, the drug combination includes 260 mg / m 2 of nab-paclitaxel;

[0487] The pharmaceutical composition is suitably a formulation for administration in a single treatment cycle comprising 14-28 g / m 2 Capecitabine; preferably, the drug combination includes 14g / m 2 , 21g / m 2 or 28g / m 2 More preferably, the drug combination comprises 28g / m 2 Capecitabine;

[0488] The drug combination is suitable for a formulation for administration in a single treatment cycle, comprising 16.8-64.4 g, or 32.2-64.4 g of capecitabine; preferably, the drug combination comprises 16.8 g, 21 g, 22.4 g, 25.2 g, 28 g, 29.4 g, 30.8 g, 32.2 g, 33.6 g, 36.4 g, 39.2 g, 40.6 g, 42 g, 44.8 g, 49 g, 50.4 g, 56 g, 60.2 g or 64.4 g of capecitabine; more preferably, the drug combination comprises 32.2 g, 36.4 g, 40.6 g, 44.8 g, 49 g, 50.4 g, 56 g, 60.2 g or 64.4 g of capecitabine;

[0489] The drug combination is suitably a formulation for administration in a single treatment cycle comprising 1500-2000 mg / m 2 Preferably, the drug combination includes 1500 mg / m 2 or 2000 mg / m 2 More preferably, the drug combination comprises 2000 mg / m 2 Gemcitabine:

[0490] The drug combination is a formulation suitable for administration in a single treatment cycle, comprising 50 mg / m 2 Vinorelbine;

[0491] The drug combination is a formulation suitable for administration in a single treatment cycle, comprising 1.4-2.8 mg / m 2 Preferably, the drug combination includes 1.4 mg / m 2 , 2.2mg / m 2 or 2.8 mg / m 2 More preferably, the drug combination comprises 2.8 mg / m 2 of Eriblin.

[0492] Embodiment 22. The pharmaceutical combination according to embodiment 20 or 21, wherein every 3 weeks is one treatment cycle.

[0493] Embodiment 23. The pharmaceutical combination according to any one of embodiments 2-6 and 17-22, wherein the antigen-binding construct targeting HER2 and the chemotherapy drug are each in the form of a pharmaceutical composition and are separately packaged in respective medicine boxes.

[0494] Embodiment 24. Use of the pharmaceutical combination of any one of Embodiments 1-23 for the preparation of a medicament for treating a tumor in a subject, wherein the tumor is breast cancer.

[0495] Embodiment 25. Use of an antigen-binding construct targeting HER2, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant in the preparation of a medicament for the combined treatment of a tumor in a subject,

[0496]

[0497] Wherein, the antigen-binding construct targeting HER2 comprises a first antigen-binding fragment and a second antigen-binding fragment, the first antigen-binding fragment comprising: 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 comprising: 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;

[0498] The tumor is breast cancer.

[0499] Embodiment 26. Use of an antigen-binding construct targeting HER2 in the preparation of a medicament for treating a tumor in a subject in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof and fulvestrant,

[0500]

[0501] Wherein, the antigen-binding construct targeting HER2 comprises a first antigen-binding fragment and a second antigen-binding fragment, the first antigen-binding fragment comprising: 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 comprising: 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;

[0502] The tumor is breast cancer.

[0503] Embodiment 27. Use of an antigen-binding construct targeting HER2 and a chemotherapy drug in the preparation of a medicament for combined treatment of a tumor in a subject, wherein the antigen-binding construct targeting HER2 comprises a first antigen-binding fragment, the first antigen-binding fragment comprising: 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 comprising: 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;

[0504] The tumor is breast cancer.

[0505] Embodiment 28. Use of an antigen-binding construct targeting HER2 in the preparation of a medicament for treating a tumor in a subject in combination with a chemotherapeutic agent, wherein the antigen-binding construct targeting HER2 comprises a first antigen-binding fragment, the first antigen-binding fragment comprising: 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 comprising: 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;

[0506] The tumor is breast cancer.

[0507] Embodiment 29. The use according to any one of embodiments 24-28, wherein the tumor is recurrent and / or metastatic breast cancer;

[0508] The tumor is advanced breast cancer or locally advanced breast cancer;

[0509] The tumor is HER2-positive breast cancer: and / or

[0510] The tumor is HR-positive or HR-negative breast cancer.

[0511] Embodiment 30. The use according to any one of embodiments 24-29, wherein the tumor is HER2-positive locally advanced, recurrent and / or metastatic breast cancer;

[0512] The tumor is HER2-positive advanced, recurrent and / or metastatic breast cancer; or

[0513] The tumor is HER2-positive recurrent and / or metastatic breast cancer.

[0514] Embodiment 31. The use according to any one of embodiments 24-30, wherein the subject is postmenopausal, premenopausal or perimenopausal;

[0515] The subject is a HER2-positive recurrent and / or metastatic breast cancer subject who has previously received at least two lines of HER2-targeted therapy;

[0516] The breast cancer subject is a HER2-positive locally advanced, recurrent and / or metastatic breast cancer subject who has previously received at least two lines of HER2-targeted therapy; and / or

[0517] The breast cancer subject is a HER2-positive advanced, recurrent and / or metastatic breast cancer subject who has previously received at least two lines of HER2-targeted treatment.

[0518] Embodiment 32. The use according to any one of embodiments 24-31, wherein the breast cancer is not amenable to surgical treatment.

[0519] Embodiment 33. The use according to any one of embodiments 24-32, wherein the first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region whose amino acid sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8.

[0520] Embodiment 34. The use according to any one of embodiments 24-33, wherein the second antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 15, and a light chain variable region whose amino acid sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 16.

[0521] Embodiment 35. The use according to any one of Embodiments 24 to 34, wherein the antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 17, a second polypeptide chain having an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 18, and a third polypeptide chain having an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 19.

[0522] Embodiment 36. The use according to any one of Embodiments 24-35, wherein the unit dose of the antigen-binding construct targeting HER2 is 100-600 mg, 200-600 mg, or 200-400 mg; preferably, the unit dose of the antigen-binding construct targeting HER2 is 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg and / or 600 mg; more preferably, the unit dose of the antigen-binding construct targeting HER2 is 200 mg.

[0523] Embodiment 37. The use according to any one of embodiments 24-26 and 29-36, wherein the unit dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 50 mg, 60 mg, 100 mg, 120 mg, 150 mg and / or 180 mg; preferably, the unit dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 50 mg and / or 60 mg.

[0524] Embodiment 38. The use according to any one of embodiments 24-26 and 29-37, wherein the unit dose of fulvestrant is 250 mg or 500 mg.

[0525] Embodiment 39. The use according to any one of embodiments 24-26 and 29-38, wherein the drug is a formulation suitable for administration within a single treatment cycle, which comprises 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of an antigen-binding construct targeting HER2; preferably, the drug is suitable for administration within a single treatment cycle, which comprises 7.5 mg / kg, 15 mg / kg, 30 mg / kg or 40 mg / kg of an antigen-binding construct targeting HER2.

[0526] Embodiment 40. The use according to any one of embodiments 24-26 and 29-39, wherein the drug is a formulation suitable for administration in a single treatment cycle, comprising 840-6720 mg, 1680-5040 mg, 2520-5040 mg, 3360-5040 mg, 4200-5040 mg, or 4200-6720 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; preferably, the drug is a formulation suitable for administration in a single treatment cycle, comprising 1680 mg, 3360 mg, 4200 mg, or 5040 mg, or a range formed by any two of the above values, of the compound of formula (I) or a pharmaceutically acceptable salt thereof; more preferably, the drug is a formulation suitable for administration in a single treatment cycle, comprising 3360 mg, 4200 mg, or 5040 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0527] Embodiment 41. The use according to any one of embodiments 24-26 and 29-40, wherein the drug is a formulation suitable for administration in a single treatment cycle, which comprises 500-1000 mg of fulvestrant; preferably, the drug is a formulation suitable for administration in a single treatment cycle, which comprises 500 mg or 1000 mg of fulvestrant.

[0528] Embodiment 42. The use according to embodiment 41, wherein the medicament is a formulation suitable for administration in a first treatment cycle, comprising 1000 mg of fulvestrant; and / or

[0529] The drug is a preparation suitable for administration in the second treatment cycle and subsequent single treatment cycles, which comprises 500 mg of fulvestrant.

[0530] Embodiment 43. The use according to any one of Embodiments 24-26 and 29-42, wherein the antigen-binding construct targeting HER2, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant are administered simultaneously, sequentially, and / or alternately; preferably, the antigen-binding construct targeting HER2, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant are administered sequentially.

[0531] Embodiment 44. The use according to any one of embodiments 24-26 and 29-43, wherein the antigen-binding construct targeting HER2 is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, optionally, at a dose of 2.5-50 mg / kg, 2.5-30 mg / kg, 2.5-10 mg / kg, 5-10 mg / kg, 10-30 mg / kg, or 20-30 mg / kg of the antigen-binding construct targeting HER2 each time; preferably, at a dose of 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg or 50 mg / kg of the antigen-binding construct targeting HER2 each time; more preferably, the antigen-binding construct targeting HER2 is administered once every 2 weeks, at a dose of 20 mg / kg of the antigen-binding construct targeting HER2 each time.

[0532] Embodiment 45. The use according to any one of embodiments 24-26 and 29-44, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day, optionally at a dose of 30-240 mg, 60-180 mg, 90-180 mg, 120-180 mg, 150-180 mg, or 150-240 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each time; preferably, at a dose of 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 180 mg or 240 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each time; more preferably, at a dose of 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof each time.

[0533] Embodiment 46. The use according to any one of embodiments 24-26 and 29-45, wherein fulvestrant is administered twice in the first treatment cycle and once in the second treatment cycle and each subsequent treatment cycle; preferably, fulvestrant is administered once on day 1 and day 15 of the first treatment cycle, and once on day 1 of the second treatment cycle and each subsequent treatment cycle; more preferably, 500 mg of fulvestrant is administered on day 1 and day 15 of the first treatment cycle, and 500 mg of fulvestrant is administered on day 1 of the second treatment cycle and each subsequent treatment cycle.

[0534] Embodiment 47. The use according to any one of embodiments 24-26 and 29-46, wherein one treatment cycle is every 4 weeks.

[0535] Embodiment 48. The use according to any one of embodiments 24-26 and 29-47, wherein the antigen-binding construct targeting HER2, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant are separately packaged in respective medicine boxes.

[0536] Embodiment 49. The use according to any one of Embodiments 24-26 and 29-48, wherein the medicament comprises a pharmaceutical composition of the antigen-binding construct targeting HER2, a pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition of fulvestrant.

[0537] Embodiment 50. The use according to Embodiment 49, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition of fulvestrant are separately packaged in respective medicine boxes.

[0538] Embodiment 51. The use according to any one of Embodiments 24 and 27-36, wherein the chemotherapy drug is a taxane anti-tumor drug, a fluorouracil anti-tumor drug, a cytosine anti-tumor drug, a vinca alkaloid anti-tumor drug, or a microtubule inhibitor anti-tumor drug.

[0539] Embodiment 52. The use according to any one of embodiments 24, 27-36 and 51, wherein the chemotherapy drug is nab-paclitaxel, capecitabine, gemcitabine, vinorelbine or eribulin.

[0540] Embodiment 53. The use according to any one of embodiments 24, 27-36 and 51-52, wherein the unit dose of nab-paclitaxel is 100 mg;

[0541] The unit dose of capecitabine is 150 mg and / or 500 mg;

[0542] The unit dose of gemcitabine is 0.2g and / or 1g;

[0543] The unit dose of vinorelbine is 10 mg; and / or

[0544] The unit dose of eribulin is 1 mg.

[0545] Embodiment 54. The use according to any one of Embodiments 24, 27-36 and 51-53, wherein the drug is a formulation suitable for administration within a single treatment cycle, which comprises 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of an antigen-binding construct targeting HER2; preferably, the drug is a formulation suitable for administration within a single treatment cycle, which comprises 7.5 mg / kg, 15 mg / kg, 30 mg / kg or 40 mg / kg of an antigen-binding construct targeting HER2.

[0546] Embodiment 55. The use according to any one of embodiments 24, 27-36 and 51-54, wherein the medicament is a formulation suitable for administration in a single treatment cycle comprising 130-260 mg / m 2 , or 180-260 mg / m 2 Preferably, the drug includes 130mg / m 2 , 180mg / m 2 , 200mg / m 2 , 220mg / m 2 or 260 mg / m 2 More preferably, the drug comprises 260 mg / m 2 of nab-paclitaxel;

[0547] The drug is suitable for administration in a single treatment cycle, which comprises 14-28 g / m 2 Capecitabine; preferably, the drug includes 14g / m 2 , 21g / m 2 or 28g / m 2 More preferably, the drug comprises 28g / m 2 Capecitabine;

[0548] The medicament is a formulation suitable for administration in a single treatment cycle, comprising 16.8-64.4 g, or 32.2-64.4 g of capecitabine; preferably, the medicament comprises 16.8 g, 21 g, 22.4 g, 25.2 g, 28 g, 29.4 g, 30.8 g, 32.2 g, 33.6 g, 36.4 g, 39.2 g, 40.6 g, 42 g, 44.8 g, 49 g, 50.4 g, 56 g, 60.2 g or 64.4 g of capecitabine; more preferably, the medicament comprises 32.2 g, 36.4 g, 40.6 g, 44.8 g, 49 g, 50.4 g, 56 g, 60.2 g or 64.4 g of capecitabine;

[0549] The drug is suitable for administration in a single treatment cycle, which comprises 1500-2000 mg / m 2 Gemcitabine; preferably, the drug includes 1500 mg / m 2 or 2000 mg / m 2 More preferably, the drug comprises 2000 mg / m 2 Gemcitabine:

[0550] The drug is a formulation suitable for administration in a single treatment cycle, comprising 50 mg / m 2 Vinorelbine;

[0551] The drug is a formulation suitable for administration in a single treatment cycle, which includes 1.4-2.8 mg / m 2 Preferably, the drug includes 1.4 mg / m 2 , 2.2mg / m 2 or 2.8 mg / m 2 More preferably, the drug comprises 2.8 mg / m 2 of Eriblin.

[0552] Embodiment 56. The use according to any one of Embodiments 24, 27-36 and 51-55, wherein the antigen-binding construct targeting HER2 and the chemotherapy drug can be administered simultaneously, sequentially and / or alternately; preferably, the antigen-binding construct targeting HER2 and the chemotherapy drug are administered sequentially.

[0553] Embodiment 57. The use according to any one of embodiments 24, 27-36 and 51-56, wherein the antigen-binding construct targeting HER2 is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, optionally, at a dose of 2.5-50 mg / kg, 2.5-30 mg / kg, 2.5-10 mg / kg, 5-10 mg / kg, 10-30 mg / kg, or 20-30 mg / kg of the antigen-binding construct targeting HER2 each time; preferably, at a dose of 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg or 50 mg / kg of the antigen-binding construct targeting HER2 each time.

[0554] Embodiment 58. The use according to embodiment 57, wherein the antigen-binding construct targeting HER2 is administered once every 3 weeks, each time at a dose of 30 mg / kg of the antigen-binding construct targeting HER2.

[0555] Embodiment 59. The use according to any one of embodiments 24, 27-36 and 51-58, wherein the albumin-paclitaxel is administered once every 3 weeks, optionally at a dose of 130-260 mg, or 180-260 mg of albumin-paclitaxel each time; preferably, at a dose of 130 mg, 180 mg, 200 mg, 220 mg or 260 mg of albumin-paclitaxel each time; more preferably, at a dose of 260 mg of albumin-paclitaxel each time.

[0556] Embodiment 60. The use according to any one of embodiments 24, 27-36 and 51-59, wherein the capecitabine is administered twice daily, optionally at a dose of 500-1000 mg / m 2 Capecitabine is administered at a dose of 500 mg / m 2 , 750mg / m 2 or 1000 mg / m 2 Capecitabine is administered at a dose of 1000 mg / m 2 Dosage of capecitabine.

[0557] Embodiment 61. The use according to any one of embodiments 24, 27-36 and 51-60, wherein gemcitabine is administered once a week for two consecutive weeks followed by one week of rest, optionally at a dose of 750-1000 mg / m 2 The dose of gemcitabine is preferably 750 mg / m 2 or 1000 mg / m2 The dose of gemcitabine is preferably 1000 mg / m 2 Dosage of gemcitabine.

[0558] Embodiment 62. The use according to any one of embodiments 24, 27-36 and 51-61, wherein vinorelbine is administered once a week for two consecutive weeks followed by one week of rest, optionally at a dose of 25 mg / m 2 Dosage administration of vinorelbine.

[0559] Embodiment 63. The use according to any one of embodiments 24, 27-36 and 51-62, wherein eribulin is administered once a week for two consecutive weeks followed by one week of rest, optionally at a dose of 0.7-1.4 mg / m 2 The dose of eribulin is preferably 0.7 mg / m 2 , 1.1mg / m 2 or 1.4 mg / m 2 Dosage administration of eribulin;

[0560] More preferably, 0.7-1.4 mg / m 2 Dosage of eribulin.

[0561] Embodiment 64. The use according to any one of embodiments 24, 27-36, and 51-63, wherein one treatment cycle is every 3 weeks.

[0562] Embodiment 65. The use according to any one of embodiments 24, 27-36 and 51-64, wherein the antigen-binding construct targeting HER2 and the chemotherapy drug are separately packaged in respective medicine kits.

[0563] Embodiment 66. The use according to any one of Embodiments 24, 27-36, and 51-65, wherein the medicament comprises a pharmaceutical composition of the antigen-binding construct targeting HER2 and a pharmaceutical composition of the chemotherapy drug.

[0564] Embodiment 67. The use according to Embodiment 66, wherein the pharmaceutical composition of the antigen-binding construct targeting HER2 and the pharmaceutical composition of the chemotherapy drug are separately packaged in respective medicine boxes.

[0565] IX. Technical Effects

[0566] In general, use of the above-described pharmaceutical combinations of the present disclosure will help:

[0567] (1) Produce a better therapeutic effect in reducing tumor growth or even eliminating tumors compared to administering either drug alone;

[0568] (2) provide for administration of a smaller amount of the drug than would be possible with either drug alone;

[0569] (3) provide a treatment that is well tolerated by patients and has fewer adverse effects and / or complications than either drug given alone;

[0570] (4) provide better disease control rate (DCR) among treated patients;

[0571] (5) provide longer survival (e.g., median survival, progression-free survival (PFS), or overall survival (OS)) in treated patients;

[0572] (6) provide longer survival (e.g., median survival, progression-free survival, or overall survival) for treated patients compared to standard chemotherapy;

[0573] (7) provide a longer duration of disease remission (DOR); and / or

[0574] (8) Compared with the administration of any drug in the combination alone, it has good anti-tumor activity and shows a more excellent anti-tumor synergistic effect.

[0575] The drug combination and treatment regimen disclosed herein have good efficacy in treating breast cancer, and have beneficial effects on at least one of objective response rate (ORR), DCR, DOR, PFS, OS, tolerability, and side effects.

[0576] X. Definitions and Explanations

[0577] 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.

[0578] As used herein, the term "drug combination" refers to a combination of two or more active ingredients (including administration in the form of the respective active ingredients themselves, or in the form of their respective pharmaceutically acceptable salts or esters, derivatives, prodrugs or compositions) administered simultaneously or sequentially, and may also be referred to as a "drug combination product", which covers the use of two or more active ingredients or drugs in combination. The active ingredients can each be administered to the subject simultaneously as a single formulation, or each as a single formulation in any order. The two or more active ingredients or drugs in the drug combination are mentioned together only because they are used in combination, but it does not mean that these active ingredients or drugs must be packaged together, but can be packaged separately in different units (for example, in different medicine boxes).

[0579] The term "fixed combination" means that the active ingredients are administered to a subject simultaneously in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation.

[0580] The term "non-fixed combination" refers to two or more active ingredients administered to a subject as independent entities (e.g., pharmaceutical compositions, formulations) simultaneously, concurrently or sequentially, wherein the active ingredients administered to the subject reach a therapeutically effective level. An example of a non-fixed combination is cocktail therapy, e.g., administration of three or more active ingredients. In a non-fixed combination, the individual active ingredients may be packaged, sold or administered as completely independent pharmaceutical compositions. The "non-fixed combination" also includes the combined use of "fixed combinations" or "fixed combinations" with any one or more independent entities of the active ingredients.

[0581] 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, or protein or peptide complex, an antibody or its antigen binding fragment, scFv, 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.

[0582] The term "bispecific" is intended to describe any agent, such as an antigen-binding construct, comprising two antigen-binding fragments, each of which has a unique binding specificity. For example, the first antigen-binding fragment binds to an epitope on a first antigen, while the second antigen-binding fragment binds to an epitope on a second antigen. In another example, the first antigen-binding fragment and the second antigen-binding fragment each bind to a different epitope on the same antigen.

[0583] An "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). It has been demonstrated that the antigen-binding function of an antibody can be performed by fragments of the entire antibody. Examples encompassed by the term "antigen-binding fragment" of an antibody include: (i) Fab fragments: consisting of V L 、V H The invention relates to a monovalent fragment consisting of a single variable domain (VL), a monovalent fragment consisting of a CL and a CH1 domain; (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 the VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment consisting of a VH domain (see Ward et al., Nature. 341:544-546 (1989)); (vi) an isolated complementarity determining region (CDR); and (vii) a nanobody, a heavy chain variable region 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, recombinant methods can be used to connect VH and VL to a single protein chain through a synthetic linker, wherein VL and VH pair to form a monovalent molecule (called single-chain Fv (scFv); see, for example, Bird et al., Science. 242: 423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. 85: 5879-5883 (1988)). These single-chain antibodies are also encompassed by the term antigen-binding fragment.

[0584] The term "HER2" refers to the second member of the EGFR family that has tyrosine kinase activity.

[0585] The term "identity" is also known as consistency. The "percent 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 aligning 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. 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 appropriate parameters for aligning sequences, including any algorithm needed to achieve maximum alignment over the full length of the compared sequences.

[0586] The term "treatment" refers to an attempt to change the natural course of a disease in a treatment individual, and can be for the purpose of preventing, improving or eliminating a disease or one or more symptoms associated with the disease, including but not limited to preventing the occurrence or recurrence of the disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, improving or alleviating the disease state, and resolving or improving the prognosis. The term "therapeutically effective amount" means (i) treating a specific disease, condition or disorder, (ii) alleviating, improving or eliminating one or more symptoms of a specific disease, condition or disorder, or (iii) preventing or delaying the onset of one or more symptoms of a specific disease, condition or disorder described herein. The amount of the active substance (e.g., antigen-binding construct of the present invention) constituting a "therapeutically effective amount" can vary according to factors such as the disease state, age, sex and weight of the individual, and the ability of the therapeutic agent or therapeutic agent combination to induce a desired response in the individual. A therapeutically effective amount can also be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0587] The terms "administration," "administering," or "administering" refer to the physical introduction of a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.

[0588] The administration route of antigen-binding construct (for example, the antigen-binding construct of targeting HER2) includes intravenous, intramuscular, subcutaneous, intraperitoneal, spinal column or other parenteral administration routes, for example, by injection or infusion.Phrase " parenteral administration " used herein refers to, the administration mode except enteral and topical application 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, under capsule, under the arachnoid, 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.

[0589] 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.

[0590] As used herein, the terms "subject," "patient," or "subject" are used interchangeably. In some embodiments, the term "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.

[0591] 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, the values ​​of step parameters or conditions are modified by "about" by default.

[0592] As used herein, "combination", "co-administration" or "combined use" means that two or more active substances can be administered to a subject simultaneously, each as a single formulation, or sequentially in any order, each as a single formulation.

[0593] The term "single dose" refers to the smallest packaging unit containing a certain amount of a drug, for example, a vial of injection is a singl...

Claims

1. A pharmaceutical combination comprising an antigen-binding construct targeting HER2, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and fulvestrant, in, 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.

2. A drug combination comprising an antigen-binding construct targeting HER2 and a chemotherapy drug, wherein: 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.

3. The pharmaceutical combination according to claim 1 or 2, wherein The first antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region whose amino acid sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO:

8.

4. The pharmaceutical combination according to any one of claims 1 to 3, wherein The second antigen-binding fragment comprises a heavy chain variable region whose amino acid sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 15, and a light chain variable region whose amino acid sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO:

16.

5. The pharmaceutical combination according to any one of claims 1 to 4, wherein The HER2-targeting antigen-binding construct comprises a first polypeptide chain having an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 17, a second polypeptide chain having an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 18, and a third polypeptide chain having an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO:

19.

6. The pharmaceutical combination according to any one of claims 1 to 5, wherein The unit dose of the antigen-binding construct targeting HER2 is 100-600 mg, 200-600 mg, or 200-400 mg; preferably, the unit dose of the antigen-binding construct targeting HER2 is 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg and / or 600 mg; more preferably, the unit dose of the antigen-binding construct targeting HER2 is 200 mg.

7. The pharmaceutical combination according to any one of claims 1 and 3-6, wherein The unit dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 50 mg, 60 mg, 100 mg, 120 mg, 150 mg and / or 180 mg; preferably, the unit dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 50 mg and / or 60 mg.

8. The pharmaceutical combination according to any one of claims 1 and 3-7, wherein The unit dose of fulvestrant is 250 mg or 500 mg.

9. The pharmaceutical combination according to any one of claims 1 and 3-8, wherein The drug combination is a preparation suitable for administration within a single treatment cycle, which includes 7.5-50 mg / kg, 7.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, or 30-40 mg / kg of an antigen-binding construct targeting HER2; preferably, the drug combination is suitable for administration within a single treatment cycle, which includes 7.5 mg / kg, 15 mg / kg, 30 mg / kg or 40 mg / kg of an antigen-binding construct targeting HER2.

10. The pharmaceutical combination according to any one of claims 1 and 3-9, wherein The drug combination is a preparation suitable for administration within a single treatment cycle, which includes 840-6720 mg, 1680-5040 mg, 2520-5040 mg, 3360-5040 mg, 4200-5040 mg, or 4200-6720 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; preferably, the drug combination is a preparation suitable for administration within a single treatment cycle, which includes 1680 mg, 3360 mg, 4200 mg, or 5040 mg, or a range formed by any two of the above values, or a pharmaceutically acceptable salt thereof; more preferably, the drug combination is a preparation suitable for administration within a single treatment cycle, which includes 3360 mg, 4200 mg or 5040 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

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