Combination therapy for treating solid tumor

Abstract

Use or method of an HER2-targeting antibody that inhibits HER2 dimerization in combination with trastuzumab and chemotherapy for the treatment of HER2-positive breast cancer. In some embodiments, the HER2-targeting antibody that inhibits HER2 dimerization has a fucosylation level of 0-5%. In some embodiments, the HER2-targeting antibody that inhibits HER2 dimerization comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a sequence as set forth in SEQ ID NO: 7, and the light chain variable region comprises a sequence as set forth in SEQ ID NO: 8. In some embodiments, the HER2-targeting antibody that inhibits HER2 dimerization is BAT0303F.

Description

Combination therapy for solid tumors Technical Field

[0001] This invention relates to the field of drug treatment methods, specifically to the use or method of using a HER2-targeting antibody that inhibits HER2 dimerization in combination with trastuzumab and chemotherapy to treat patients with solid tumors. Background Technology

[0002] Cancer remains a leading cause of illness and death worldwide. HER2 is associated with a variety of cancers, including breast cancer, stomach cancer, colon cancer, bladder cancer, ovarian cancer, endometrial cancer, and lung cancer. Currently, there is no standard treatment for patients who have failed HER2-ADC therapy, and clinical exploration is very limited. There is an urgent need for new second-line treatment modalities to further improve patient benefits. Summary of the Invention

[0003] This invention provides a method or use of a HER2-targeting antibody that inhibits HER2 dimerization in combination with trastuzumab and chemotherapy for treating patients with solid tumors, including administering an effective amount of the HER2-targeting antibody that inhibits HER2 dimerization, trastuzumab, and chemotherapy to a patient in need; in some embodiments, the use of the HER2-targeting antibody that inhibits HER2 dimerization, trastuzumab, and chemotherapy for treating solid tumors is provided; in some embodiments, the use of the HER2-targeting antibody that inhibits HER2 dimerization, trastuzumab, and chemotherapy in the preparation of a medicament for treating solid tumors is provided; in some embodiments, the use of the HER2-targeting antibody that inhibits HER2 dimerization in the preparation of a medicament for treating solid tumors in combination with trastuzumab and chemotherapy is provided; wherein the antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the sequence shown in SEQ ID NO:7, and the light chain variable region comprising the sequence shown in SEQ ID NO:8. In some embodiments, the fucosylation level of the antibody is 0%-5%.

[0004] In some embodiments, the antibody comprises a heavy chain and a light chain, the heavy chain comprising the sequence shown in SEQ ID NO:9, and the light chain comprising the sequence shown in SEQ ID NO:10.

[0005] In some embodiments, the fucosylation level of the antibody is about 0, about 1%, about 2%, about 3%, about 4%, about 5%, or a range (including endpoints) of any two of these values, or any value therein. In some embodiments, the fucosylation level of the antibody is 0%-1%. In some embodiments, the fucosylation level of the antibody is 0%.

[0006] In some embodiments, the antibody contains at least 60% GO. In some embodiments, the antibody contains at least 70% GO. In some embodiments, the GO glycoform content is about 60%-80%. In some embodiments, the GO glycoform content is about 70%-80%.

[0007] In some embodiments, the antibody is an antibody that enhances ADCC (antibody-dependent cell-mediated cytotoxicity).

[0008] In some embodiments, the antibody is BAT0303F, a glycosylated recombinant humanized anti-HER2 monoclonal antibody with a sequence identical to that of pertuzumab, exhibiting low fucosylation levels, enhanced ADCC effect, and further improved efficacy.

[0009] For the preparation of BAT0303F, please refer to the preparation of BAT0303F in WO2022 / 022526.

[0010] In some implementations, the solid tumor is breast cancer.

[0011] In some implementations, the solid tumor is HER2-positive breast cancer.

[0012] In some implementations, the HER2 positivity is defined as an immunohistochemical staining result of 3+ (IHC3+) or an immunohistochemical staining result of 2+ and a positive fluorescence in situ hybridization result (IHC2+ and FISH+).

[0013] In some implementations, the chemotherapy is vinorelbine.

[0014] In some embodiments, the present invention provides methods or uses of HER2-targeting antibodies (e.g., BAT0303F), trastuzumab, and vinorelbine for treating patients with HER2-positive breast cancer, including administering an effective amount of the HER2-targeting antibody (e.g., BAT0303F), trastuzumab, and vinorelbine to a patient in need. In some embodiments, the invention provides use of HER2-targeting antibodies (e.g., BAT0303F), trastuzumab, and vinorelbine for treating HER2-positive breast cancer. In some embodiments, the invention provides use of HER2-targeting antibodies (e.g., BAT0303F), trastuzumab, and vinorelbine in the preparation of a medicament for treating HER2-positive breast cancer. In some embodiments, the invention provides use of HER2-targeting antibodies (e.g., BAT0303F) in the preparation of a medicament for use in combination with trastuzumab and vinorelbine for treating HER2-positive breast cancer.

[0015] In some implementations, the HER2-positive breast cancer is HER2-positive locally advanced or metastatic breast cancer.

[0016] In some implementations, the HER2-positive locally advanced or metastatic breast cancer patient is a patient who cannot be cured by radical resection or radiation therapy.

[0017] In some implementations, the HER2-positive locally advanced or metastatic breast cancer patient has previously received two or more anti-HER2 therapies.

[0018] In some embodiments, the HER2-positive locally advanced or metastatic breast cancer patient has previously received at least one antibody-drug conjugate (ADC) treatment, or the patient has failed treatment with the ADC. In some embodiments, the HER2-ADC is selected from trastuzumab emtansine (T-DM1), vediclazumab (RC48), ARX788, detrastuzumab (DS-8201a), trastuzumab reconstituted (SHR-A1811), DB-1303, and other HER2-ADCs from clinical trials, or combinations thereof.

[0019] In some implementations, the HER2-positive locally advanced or metastatic breast cancer patients have not previously used vinorelbine or have experienced disease recurrence or progression within 6 months of their last vinorelbine chemotherapy.

[0020] In some embodiments, the HER2-targeting antibody that inhibits HER2 dimerization is administered at a dose of about 1-25 mg / kg per administration. In some embodiments, the HER2-targeting antibody that inhibits HER2 dimerization is administered at a dose of about 3-20 mg / kg per administration. In some embodiments, the HER2-targeting antibody that inhibits HER2 dimerization is administered at a dose of about 1 mg / kg, about 3 mg / kg, about 6 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, or about 25 mg / kg, or a range between any two of these values ​​(including the endpoints), or any value thereof. In some embodiments, the HER2-targeting antibody that inhibits HER2 dimerization is administered about once every 3 weeks at a dose of about 15 mg / kg per administration. In some embodiments, a treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or a range between any two of these values ​​(including the endpoints), or any value thereof. In some implementations, the medication is administered approximately once a week, or approximately every 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or 7 weeks. In some implementations, the medication is administered approximately once every 3 weeks. In some implementations, the treatment period is ± 3 days of the above-mentioned treatment periods.

[0021] In some implementations, the order of administration is: HER2-targeting antibody that inhibits HER2 dimerization (e.g., BAT0303F), trastuzumab, and vinorelbine.

[0022] In some embodiments, the HER2-targeting antibody (e.g., BAT0303F) that inhibits HER2 dimerization is administered at a dose of approximately 15 mg / kg, approximately every three weeks. In some embodiments, the HER2-targeting antibody (e.g., BAT0303F) that inhibits HER2 dimerization is administered via intravenous infusion.

[0023] In some embodiments, the trastuzumab is administered as an initial loading dose of about 8 mg / kg, followed by a maintenance dose of about 6 mg / kg, approximately every three weeks. In some embodiments, the trastuzumab is administered via intravenous infusion.

[0024] In some embodiments, the vinorelbine is vinorelbine injection, and the dosage is approximately 25 mg / m² per administration. 2 Treatment is administered approximately every three weeks, with the drug being given on days 1 and 8 of each cycle. In some embodiments, the vinorelbine injection is administered intravenously.

[0025] In some embodiments, the vinorelbine is vinorelbine tartrate, and the dosage is approximately 25 mg / m² per administration. 2Treatment is administered approximately every three weeks, with the drug being administered on days 1 and 8 of each cycle. In some embodiments, the vinorelbine tartrate injection is administered intravenously.

[0026] In some embodiments, the vinorelbine is vinorelbine soft capsules, and the dosage is approximately 60 mg / m² per administration. 2 The treatment cycle is approximately every three weeks, with administration on days 1 and 8 of each cycle. In some embodiments, the vinorelbine soft capsules are administered orally.

[0027] In some embodiments, the intravenous infusion duration of the HER2-targeting antibody (or formulation) that inhibits HER2 dimerization is approximately 30 to 120 minutes, for example, approximately 30 minutes, approximately 35 minutes, approximately 40 minutes, approximately 45 minutes, approximately 50 minutes, approximately 55 minutes, approximately 60 minutes, approximately 65 minutes, approximately 70 minutes, approximately 75 minutes, approximately 80 minutes, approximately 85 minutes, approximately 90 minutes, approximately 95 minutes, approximately 100 minutes, approximately 105 minutes, approximately 110 minutes, approximately 105 minutes, approximately 120 minutes, or a range (including endpoints) or any of these values. In some embodiments, the initial intravenous infusion time of the HER2-targeting antibody (or formulation) that inhibits HER2 dimerization is 90 (±10) minutes. In some embodiments, if the initial intravenous infusion is well tolerated, the infusion time for subsequent treatment cycles may be shortened to 45 ± 15 minutes.

[0028] In some implementations, the infusion time of the trastuzumab is approximately 90 minutes, and subsequent infusions may be 30 minutes if the first infusion is well tolerated.

[0029] In some embodiments, the HER2-targeting antibody that inhibits HER2 dimerization of the present invention, in combination with trastuzumab and chemotherapy, is expected to have good safety and antitumor efficacy. In some embodiments, the HER2-targeting antibody that inhibits HER2 dimerization of the present invention, in combination with trastuzumab and chemotherapy, results in improvements in at least one of the following: objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

[0030] In some embodiments, the HER2-targeting antibody that inhibits HER2 dimerization of the present invention, in combination with trastuzumab and chemotherapy, prolongs patients' PFS and / or OS. Detailed Implementation

[0031] "Approximately" refers to a typical error range for a given value that is readily known to those skilled in the art. In some embodiments, "approximately" as used herein refers to the described value and its range of ±10%, ±5%, or ±1%.

[0032] The term "HER2-targeting antibody that inhibits HER2 dimerization" refers to an antibody that binds to the HER2 protein to inhibit the formation of heterodimers between HER2 and HER1, HER3, or HER4. The HER2-targeting antibody that inhibits HER2 dimerization in this invention is not limited, as long as it is an antibody with this function. Preferably, the HER2-targeting antibody that inhibits HER2 dimerization is an antibody capable of binding to subdomain II of the extracellular domain of the HER2 protein.

[0033] "Treatment" refers to therapeutic treatments and preventative or preventative measures aimed at preventing, mitigating, improving, or stopping adverse physiological changes or disorders, such as disease progression, including but not limited to the following, whether detectable or undetectable: symptom relief, reduction of disease severity, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement, mitigation, reduction, or disappearance of the disease state (whether partial or complete), and prolongation of expected survival without treatment. Patients requiring treatment include those already suffering from the condition or disorder, those susceptible to the condition or disorder, those needing prevention of the condition or disorder, and those who can or expect to benefit from the combined treatments disclosed in this invention.

[0034] The presence of HER2 expression can be examined, for example, by collecting tumor tissue from cancer patients and examining formalin-fixed paraffin-embedded samples (FFPE) at the level of gene products (proteins), such as immunohistochemistry (IHC), flow cytometry, Western blotting, or at the level of gene transcription, such as in situ hybridization (ISH), quantitative PCR (q-PCR), or microarray analysis; or, alternatively, by collecting cell-free circulating tumor DNA (ctDNA) from cancer patients and examining it using methods such as next-generation sequencing (NGS).

[0035] The term "HER2-positive" solid tumor or cancer refers to a solid tumor or cancer that tests positive for HER2. Examples of HER2-positive cancers can include cancers that score 3+ for HER2 expression in immunohistochemistry (IHC) and cancers that score 2+ for HER2 expression in IHC and are confirmed positive for HER2 expression in in situ hybridization (ISH). In some embodiments, HER2-positive solid tumors have an IHC score of 2+ or 3+ and / or an ISH amplification ratio of ≥2.0.

[0036] There are no particular limitations on the methods used to score the degree of HER2 expression by immunohistochemistry or to determine the positivity or negativity of HER2 expression by in situ hybridization, as long as they are recognized by those skilled in the art. Examples of such methods may include those described in the "Guidelines for HER2 Testing in Breast Cancer (2019 Edition)" and the "Guidelines for HER2 Testing in Gastric Cancer (2016 Edition)".

[0037] The in situ hybridization methods of this invention include fluorescence in situ hybridization (FISH) and bright-field in situ hybridization. Commonly used bright-field in situ hybridization methods include colorimetric in situ hybridization (CISH) and silver-enhanced in situ hybridization (SISH); in SISH detection, the most widely used method is currently two-color silver staining in situ hybridization (DSISH).

[0038] As used herein, the term "effective dose" or "therapeutic effective dose" refers to an amount of a drug, such as a HER2-targeting antibody, trastuzumab, or chemotherapeutic agent that inhibits HER2 dimerization, sufficient to reduce or improve the severity and / or duration of a condition (e.g., cancer) or one or more of its symptoms; prevent disease progression; induce disease remission; prevent recurrence, development, onset, or progression of one or more symptoms associated with the condition; detect the condition; or enhance or improve the preventive or therapeutic effect of another therapy (e.g., a prophylactic or therapeutic agent). For example, an effective dose of a HER2-targeting antibody, trastuzumab, or chemotherapeutic agent that inhibits HER2 dimerization can inhibit tumor growth (e.g., inhibit an increase in tumor volume); reduce tumor growth (e.g., reduce tumor volume); reduce the number of cancer cells; and / or alleviate one or more symptoms associated with cancer to some extent. For example, an effective dose can improve progression-free survival (PFS), overall survival (OS), objective response rate (ORR), duration of response (DOR), disease control rate (DCR), or reduce the likelihood of relapse.

[0039] The term "patient" refers to any mammal requiring diagnosis, prognosis, or treatment, including but not limited to humans, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, etc., and particularly animals with one or more conditions of HER2-expressing solid tumors. In one or more embodiments, the patient is a human.

[0040] The assessment of antitumor efficacy is divided into two categories: tumor imaging assessment (CT / MRI) and survival assessment. Antitumor efficacy indicators include: objective response rate (ORR) as defined in RECIST 1.1 (Eisenhauer, EA et al., Eur J Cancer. 2009; 45(2):228-247), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

[0041] Objective response rate (ORR): This refers to the proportion of patients whose tumors shrink to a certain extent and remain so for a certain period of time, including cases of complete response (CR) and partial response (PR). The RECIST version 1.1 criteria for evaluating response in solid tumors were used to assess objective response. Subjects must have measurable tumor lesions at baseline. The efficacy evaluation criteria, according to RECIST version 1.1, are divided into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD).

[0042] Duration of Response (DOR): DOR is defined as the time from the first assessment of objective response to the first assessment of disease progression (PD) or death from any cause prior to PD, reflecting the duration of ORR.

[0043] Disease control rate (DCR): The proportion of patients whose tumors shrink or stabilize for a certain period of time, including CR, PR and SD cases, also known as clinical benefit rate (CBR).

[0044] Progression-free survival (PFS): the time from the first dose to the occurrence of objective tumor progression or all-cause death (whichever comes first).

[0045] Overall survival (OS): The time from the date of first administration to death from any cause. For subjects still alive at the time of analysis, the cutoff date is the date of their last contact.

[0046] As used in this article, “administration” means the administration of a substance to achieve a therapeutic purpose (e.g., treating a tumor).

[0047] The Eastern Cooperative Oncology Group (ECOG) has developed a simplified activity status scoring system that classifies patients’ activity status into 6 levels from 0 to 5. The ECOG activity status scoring system is scored as 0, 1, 2, 3, 4, and 5.

[0048] Single-dose pharmacokinetic parameters: C max T max T 1 / 2 CL, Vd, Ke, MRT, AUC (0-τ) AUC (0-∞)。

[0049] Multiple-dose pharmacokinetic parameters: C max,ss C avg,ss C min,ss AUC (0-τ)ss AUC (0-∞)ss T max,ss T1 / 2,ss CL, V ss Ke, MRT, Accumulation Index (R) ac ), Volatility Index (DF).

[0050] All publications and patents cited in this document are incorporated herein by reference for all purposes.

[0051] Unless otherwise specified, the materials and reagents used in the following examples can be obtained commercially or by known methods.

[0052] BAT0303F is an anti-HER2 antibody with enhanced ADCC effect, exhibiting a fucosylation level of 0-5%, comprising a heavy chain as shown in SEQ ID NO:1 and a light chain as shown in SEQ ID NO:2. Its preparation and purification can be found in patent document WO2022 / 022526.

[0053] Example 1. A phase II / III study evaluating the safety and efficacy of BAT0303F in combination with trastuzumab and chemotherapy in the treatment of HER2-positive unresectable or metastatic breast cancer that has previously received antibody-drug conjugates (ADCs).

[0054] This study evaluated the safety and efficacy of BAT0303F in combination with trastuzumab + vinorelbine versus placebo + trastuzumab + vinorelbine for the treatment of HER2-positive unresectable or metastatic breast cancer patients who have previously received antibody-drug conjugates (ADCs).

[0055] Phase II study endpoint:

[0056] Primary endpoints: 1) Safety endpoints: vital signs and physical examination, adverse events (AEs), clinical laboratory tests, and clinical auxiliary examinations (such as electrocardiogram); 2) Efficacy endpoints: evaluated according to the RECIST V1.1 criteria for evaluating the efficacy of treatment in solid tumors, comparing progression-free survival (PFS) and objective response rate (ORR) of BAT0303F + trastuzumab + vinorelbine versus placebo + trastuzumab + vinorelbine.

[0057] Secondary endpoint:

[0058] 1) Pharmacokinetic parameters under single and multiple dosing (mainly including: C60°C of a single dose) max T max T 1 / 2 CL, Vd, Ke, MRT, AUC (0-τ) AUC (0-∞) ; Multiple doses of C max,ss C avg,ss Cmin,ss AUC (0-τ)ss AUC (0-∞)ss T max,ss T 1 / 2,ss CL, V ss Ke, MRT, Accumulation Index (R) ac ), Volatility Index (DF).

[0059] 2) Immunogenicity evaluation indicators: Anti-drug antibody (ADA) / neutralizing antibody (NAb).

[0060] 3) Clinical efficacy indicators: Duration of response (DOR), disease control rate (DCR), and overall survival (OS).

[0061] 4) Correlation between HER2 expression level (3+ / 2+) in tumor tissue specimens and treatment efficacy.

[0062] Phase III study endpoint:

[0063] Primary endpoint: Based on the RECIST V1.1 criteria for evaluating efficacy in solid tumors, compare PFS of BAT0303F + trastuzumab + vinorelbine versus placebo + trastuzumab + vinorelbine.

[0064] Secondary endpoint:

[0065] 1) Safety endpoints: vital signs and physical examination, adverse events (AEs), clinical laboratory tests, and clinical auxiliary examinations (such as electrocardiogram).

[0066] 2) Compare the overall survival (OS) of BAT0303F + trastuzumab + vinorelbine vs placebo + trastuzumab + vinorelbine in the treatment of advanced HER2-positive breast cancer;

[0067] 3) Efficacy evaluated according to the RECIST V1.1 criteria for evaluating the efficacy of treatment in solid tumors, including: ORR, DCR, DOR, TTP, etc.

[0068] 3) Antidrug-resistant antibodies (ADA) / neutralizing antibodies (NAb).

[0069] 4) Assess the correlation between HER2 expression levels (3+ / 2+) in tumor tissue specimens and treatment efficacy.

[0070] Research drug formulation and dosing plans:

[0071] The dosing order was as follows: 1) BAT0303F / placebo, 2) trastuzumab, 3) vinorelbine.

[0072] Each dosing cycle is 3 weeks (Q3W), and the dosing window can be ±3 days.

[0073] BAT0303F: The dosage is 15 mg / kg, administered once every three weeks. The prepared BAT0303F should be administered intravenously over a period of 90 ± 10 minutes. It should not be administered by intravenous bolus or a single rapid intravenous injection. If an infusion reaction occurs, the administration time may be appropriately extended. If the initial intravenous infusion is well tolerated, the infusion time for subsequent treatment cycles can be shortened to 45 ± 15 minutes. The patient should be observed for 30 ± 15 minutes after the infusion is completed.

[0074] The placebo component is the same as BAT0303F except for the BAT0303F monoclonal antibody, and its appearance is also consistent with the BAT0303F investigational drug. It is administered intravenously.

[0075] Trastuzumab: Use according to the trastuzumab package insert. The recommended initial loading dose is 8 mg / kg, followed by a maintenance dose of 6 mg / kg every three weeks, with an infusion time of approximately 90 minutes. If the first infusion is well tolerated, subsequent infusions can be administered over 30 minutes.

[0076] Changchun Ruibin: Soft capsules 60mg / m² 2 Or injection 25mg / m 2 Each treatment cycle consists of 3 weeks, with medication administered on days 1 and 8 of each cycle until disease progression.

[0077] Study population:

[0078] Selection criteria:

[0079] To be eligible to enroll in this study, participants must meet all of the following inclusion criteria:

[0080] 1. Age ≥ 18 years old, gender not limited;

[0081] 2. Voluntarily sign the informed consent form;

[0082] 3. Subjects with locally advanced or metastatic breast cancer confirmed by histological or cytological examination, and who are ineligible for radical resection or radiation therapy. They must also meet the following criteria: a. HER2-positive (IHC 3+ or IHC 2+ and FISH+) specimen confirmed by histopathology and / or cytology within the past five years; b. Previously received two or more anti-HER2 therapies; c. Patients previously received at least one HER2-ADC therapy (including T-DM1, RC48, ARX788, DS-8201a, SHR-A1811, DB-1303, and other HER2-ADCs in clinical trials) and the treatment failed.

[0083] 4. According to RECIST 1.1 criteria, at least one measurable tumor lesion must be present;

[0084] 5. The Eastern Cooperative Oncology Group (ECOG) performance status score requirement is 0 or 1.

[0085] 6. The investigator's assessment of expected survival is ≥12 weeks;

[0086] 7. Possess sufficient organ and bone marrow reserves.

[0087] 8. Female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose and agree to use effective contraception to prevent pregnancy during the study period and for 6 months after the last dose. Male patients must agree to use effective contraception during the study period and for 6 months after the last dose; postmenopausal women must have been without menstruation for at least 12 months to be considered infertile.

[0088] 9. Echocardiography shows a left ventricular ejection fraction (LVEF) ≥ 55%;

[0089] 10. Able to understand the test requirements and willing and able to comply with the test and follow-up procedures.

[0090] Exclusion criteria:

[0091] Patients meeting any of the following exclusion criteria will be excluded from the study:

[0092] 1. Within 4 weeks prior to the first administration of the investigational drug, the individual had received treatment with an experimental drug or participated in a clinical trial of a medical device;

[0093] 2. Patients who have previously used vinorelbine and whose disease relapsed or progressed within 6 months after their last vinorelbine chemotherapy session;

[0094] 3. 1) Patients who have received chemotherapy, radical radiotherapy (palliative radiotherapy must be completed within 2 weeks before the first dose), biotherapy, endocrine therapy, immunotherapy, or other anti-tumor treatments within 4 weeks prior to the first dose; 2) For fluorouracil and small molecule targeted drugs, the first dose must be within 2 weeks prior to the first use of the investigational drug or within 5 half-lives of the drug (whichever is longer); 3) For nitrosoureas or mitomycin C, the first dose must be within 42 days prior to the first use of the investigational drug.

[0095] 4. Those who have received traditional Chinese medicine or treatment with anti-tumor related functions as specified in the drug instructions of NMPA within one week prior to administration, or those whose medical records clearly record traditional Chinese herbal medicine treatment for anti-tumor purposes;

[0096] 5. Prior to the first administration of the study drug, if there are still AEs (CTCAE 5.0) greater than grade 1 caused by previous antitumor therapy, except for toxicities that the investigator judges to pose no safety risk, such as hair loss, grade 2 peripheral neurotoxicity, etc.

[0097] 6. If a major surgery (excluding diagnostic procedures) is required within 4 weeks prior to the first administration of the investigational drug, or if a major surgery is expected to be required during the study period;

[0098] 7. Individuals with a history of allogeneic cell or solid organ transplantation surgery;

[0099] 8. Patients with primary central nervous system tumors or symptomatic central nervous system metastases, those with past or present meningeal metastases, or those with a history of epilepsy. If the brain metastases are stable after treatment, and the lesions have been stable for at least 4 weeks prior to drug administration with no new lesions, or if an asymptomatic lesion is first discovered within 4 weeks and the investigator determines the condition is stable, or if the investigator determines that corticosteroid treatment was discontinued 7 days before the first administration of the study drug, then this is permitted.

[0100] 9. Having other active malignant tumors within 5 years prior to the first dose. This excludes locally cured tumors (e.g., basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or breast carcinoma in situ, etc.).

[0101] 10. The following cardiovascular diseases occurred within 6 months prior to the first use of medication: symptomatic heart failure of NYHA class 2 or above, left ventricular ejection fraction (LVEF) <50%, unstable arrhythmia or unstable angina, myocardial infarction requiring treatment, pulmonary embolism, uncontrolled hypertension (defined in this protocol as systolic blood pressure >160 mmHg and / or diastolic blood pressure >100 mmHg after treatment with optimal antihypertensive therapy, and clinically significant as assessed by the investigator), and QTcF >480 ms as obtained from a 12-lead electrocardiogram (QTcF is corrected using the Fridericia formula);

[0102] 11. Subjects with any other serious underlying diseases (e.g., Gilbert's syndrome, uncontrolled diabetes, uncontrolled hypertension, active gastric ulcer, uncontrolled seizures, cerebrovascular events / gastrointestinal bleeding within 3 months prior to first administration, or coagulation disorders with severe symptoms or signs) that, in the investigator's opinion, may affect the subject's participation in the study, treatment, and follow-up, affect subject compliance, or may lead to complications related to the study drug;

[0103] 12. Active autoimmune diseases requiring systemic treatment (e.g., using disease-modifying drugs, corticosteroids, or immunosuppressive drugs) may be accompanied by relevant replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency).

[0104] 13. Subjects with tuberculosis who are either untreated or currently undergoing treatment, including but not limited to pulmonary tuberculosis; those who have undergone standard anti-tuberculosis treatment and have been confirmed cured by the investigator may be included;

[0105] 14. A serious infection occurred within 4 weeks prior to the first use of medication, or an active infection occurred within 2 weeks prior to the first use of medication;

[0106] 15. Individuals with the following infections: Human Immunodeficiency Virus (HIV) infection; Active Hepatitis B Virus (HBV) infection [HBsAg positive, and HBV-DNA levels >200 IU / ml or 10...]. 3 [Copies / ml or upper limit of normal value for research center testing]; Hepatitis C virus infected individuals [positive HCV antibody and viral ribonucleic acid (HCV-RNA) test results]; Treponema pallidum antibody positive and RPR / TRUST positive;

[0107] 16. Newly diagnosed thromboembolic events requiring treatment within 6 months (patients with stable venous thrombosis and patients with port-of-care thrombosis are allowed to be included);

[0108] 17. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring repeated drainage procedures (once a month or more);

[0109] 18. It is known that there is a hypersensitivity reaction or delayed-type hypersensitivity reaction to any component of the research drug;

[0110] 19. Individuals who have a known history of grade ≥3 allergic reactions to trastuzumab or pertuzumab;

[0111] 20. Known history of mental illness, drug abuse, alcoholism, or drug use that may affect the test results;

[0112] 21. Pregnant or breastfeeding women, or women or men planning to give birth;

[0113] 22. Other circumstances where the researchers deem it unsuitable for participation in this trial.

[0114] Currently, all 6 subjects in the safe introduction phase have received the aforementioned BAT0303F combination therapy. These 6 subjects are all patients with advanced breast cancer who had received at least 3 lines of systemic anti-tumor therapy prior to enrollment, had multiple lines of anti-HER2 targeted therapy experience, and lacked effective standard treatment options. Preliminary anti-tumor efficacy after 6 weeks of treatment: 1 case of PR, 4 cases of SD, and 1 case of PD.

[0115] Safety: No DLT occurred, AE incidence was 100%, ≥ grade 3 AE incidence was 67% (all were decreased white blood cell count and decreased neutrophil count), no SAE occurred, and no AEs leading to death or discontinuation of treatment occurred.

[0116] The results showed that the combined administration of BAT0303F of the present invention with trastuzumab and chemotherapy had good safety, tolerability and certain anti-tumor efficacy.

[0117] The combination therapy of BAT0303F of the present invention with trastuzumab and chemotherapy is expected to have good safety and anti-tumor efficacy, for example, it is expected to lead to at least one improvement selected from the following: objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

Claims

1. The use of HER2-targeting antibodies that inhibit HER2 dimerization in the preparation of drugs for use in combination with trastuzumab and chemotherapy for the treatment of patients with solid tumors, wherein, The antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the sequence shown in SEQ ID NO:7, the light chain variable region comprising the sequence shown in SEQ ID NO:8, and the fucosylation level of the antibody is 0%-5%.

2. The use according to claim 1, wherein the fucosylation level of the antibody is 0%-1%.

3. The use according to claim 1 or 2, wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprising the sequence shown in SEQ ID NO:9, and the light chain comprising the sequence shown in SEQ ID NO:

10.

4. The use according to any one of claims 1-3, wherein the antibody is BAT0303F.

5. The use according to any one of claims 1-4, wherein the solid tumor is breast cancer.

6. The use according to any one of claims 1-5, wherein the solid tumor is HER2-positive breast cancer.

7. The use according to any one of claims 1-6, wherein the chemotherapy is vinorelbine.

8. The use of HER2-targeting antibodies that inhibit HER2 dimerization in the preparation of drugs for the combined treatment of HER2-positive breast cancer patients with trastuzumab and vinorelbine, wherein... The antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the sequence shown in SEQ ID NO:7, the light chain variable region comprising the sequence shown in SEQ ID NO:8, and the fucosylation level of the antibody is 0%-5%.

9. The use according to claim 8, wherein the fucosylation level of the antibody is 0%-1%.

10. The use as described in claim 8 or 9, wherein the antibody is BAT0303F.

11. The use according to any one of claims 6, 8-10, wherein the HER2-positive breast cancer is HER2-positive locally advanced or metastatic breast cancer.

12. The use according to any one of claims 6, 8-11, wherein the HER2-positive breast cancer patient is a patient who cannot be cured by radical resection or radiation therapy.

13. The use according to any one of claims 6, 8-12, wherein the HER2-positive breast cancer patient has previously received two or more anti-HER2 therapies.

14. The use according to any one of claims 6, 8-13, wherein the HER2-positive breast cancer patient has previously received at least one anti-HER2 antibody-drug conjugate treatment and the treatment has failed.

15. The use as described in claim 14, wherein the anti-HER2 antibody drug conjugate is selected from T-DM1, RC48, ARX788, DS-8201a, SHR-A1811, DB-1303 and other anti-HER2 antibody drug conjugates in clinical trials, or combinations thereof.

16. The use according to any one of claims 6, 8-15, wherein the HER2-positive breast cancer patient has not previously used vinorelbine or has experienced disease recurrence or progression within 6 months of the last vinorelbine chemotherapy.

17. The use according to any one of claims 1-16, wherein the antibody is administered at a dose of about 1-25 mg / kg, or about 3-20 mg / kg, or about 15 mg / kg per administration.

18. The use according to any one of claims 1-17, wherein the antibody is administered about once a week, or about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, or about once every 7 weeks.

19. The use according to any one of claims 1-18, wherein the antibody is administered approximately every 3 weeks.

20. The use according to any one of claims 1-19, wherein the antibody is administered at a dose of about 15 mg / kg once every three weeks.

21. The use according to any one of claims 1-20, wherein the antibody is administered via intravenous infusion.

22. The use according to any one of claims 1-21, wherein the trastuzumab is administered at an initial loading dose of about 8 mg / kg, followed by a maintenance dose of about 6 mg / kg, once every three weeks.

23. The use according to any one of claims 1-22, wherein the trastuzumab is administered via intravenous infusion.

24. The use according to any one of claims 1-23, wherein the chemotherapy is vinorelbine, and the vinorelbine is vinorelbine injection, with a dose of approximately 25 mg / m² per administration. 2 Each treatment cycle consists of three weeks, with the medication administered on day 1 and day 8 of each cycle.

25. The use as described in claim 24, wherein the vinorelbine injection is administered intravenously.

26. The use according to any one of claims 1-23, wherein the chemotherapy is vinorelbine, the vinorelbine is vinorelbine soft capsules, and the dosage per administration is approximately 60 mg / m². 2 Each treatment cycle consists of three weeks, with the medication administered on day 1 and day 8 of each cycle.

27. The use as described in claim 26, wherein the vinorelbine soft capsules are administered orally.

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