RU2774721C2 - Use of combination treatment based on antibody to pd-1 and apatinib for treatment of triple negative breast cancer - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: present invention relates to biotechnology, in particular to the use of combination treatment based on an antibody to PD-1 and apatinib for the treatment of triple negative breast cancer. In particular, the present invention relates to the use of an antibody to PD-1 in combination with apatinib in the production of a drug against triple negative breast cancer.

EFFECT: treatment of triple negative breast cancer.

12 cl, 2 dwg, 2 tbl, 1 ex

Description

The field of technology to which the invention belongs

The present invention relates to the use of an antibody to PD-1 (programmed cell death protein 1) or an antigen-binding fragment thereof in combination with Apatinib or a pharmaceutically acceptable salt thereof in the manufacture of a drug for the treatment of triple negative breast cancer .

Prior Art

Breast cancer is the most common malignant tumor that threatens women's health, has the highest incidence rate among female cancers in China, and the number of cases is still on the rise. Breast cancer is a collection of diseases, at least can be divided into four molecular subtypes: luminal A, luminal B, HER2-expressing and triple negative. Triple-negative breast cancer accounts for approximately 15% of all breast cancers and is characterized by a high rate of early recurrence, a high rate of distant metastases, and a poor prognosis. In the absence of effective targeted therapies, ABC3 currently only recommends low-toxicity chemotherapy for triple-negative breast cancer. However, chemotherapy resistance is often encountered during treatment. Thus, finding effective targeted drugs for the treatment of triple-negative breast cancer has become an urgent and complex problem.

Apatinib, a small molecule tyrosine kinase inhibitor disclosed in WO 2005000232 A, highly selectively competes for an ATP-binding site with intramolecular VEGFR-2 (vascular endothelial growth factor), blocks subsequent signaling, inhibits neovascularization in tumors, and, ultimately achieves the goal of treating tumors. The structural formula of Apatinib is shown in Formula (I):

CN 101676267 A discloses a range of Apatinib salts such as mesylate, hydrochloride, maleate, etc. Preclinical animal experiments disclosed in CN 101675930 A also show that Apatinib in combination with cytotoxic drugs (such as oxaliplatin, 5 -Fu, docetaxel and doxorubicin) can significantly increase their effectiveness.

In recent years, breakthrough progress has been made in tumor immunotherapy. A number of clinical studies have shown that antibodies to PD-1/PD-L1 demonstrate significant efficacy in the case of a large number of common solid tumors (such as melanoma, kidney cancer, non-small cell lung cancer and breast cancer), with an overall response rate (ORR - from Overall Response Rate) is approximately 10%-40% against various solid tumors, and is most effective against malignant melanoma (approximately 36%-53%). WO 2015085847 A discloses a novel anti-PD-1 antibody which is currently in clinical trials and has shown some antitumor activity. However, anti-PD-1/PD-L1 antibody treatment alone has not achieved good efficacy in many patients with triple negative breast cancer (Nanda R, Chow LQ, Dees EC et al. Pembrolizumab in Patients with Advanced Triple Negative Breast Cancer: Phase lb KEYNOTE-012 Study J Clin Oncol 2016;34: 2460-2467). Thus, it is important to find targeted drugs that could increase the effectiveness of anti-PD-1/PD-L1 antibodies when administered in combination with antibodies.

Brief summary of the invention

The present invention provides the use of Apatinib or a pharmaceutically acceptable salt thereof in combination with an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for the treatment of triple negative breast cancer.

The present invention also provides the use of an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for the treatment of triple negative breast cancer.

As used herein, the term "triple-negative breast cancer" refers to breast cancer that is negative for all of the estrogen receptor (ER), progesterone receptor (PR), and Her-2 proto-oncogene.

In a preferred embodiment of the invention, the anti-PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of AMP-224, GLS-010, IBI-308, REGN-2810, PDR-001, BGB-A317, Pidilizumab, PF-06801591, Genolimzumab , CA-170, MEDI-0680, JS-001, TSR-042, Camrelizumab, Pembrolizumab, LZM-009, AK-103 and Nivolumab.

In a preferred embodiment of the present invention, the light chain variable region of an anti-PD-1 antibody or antigen-binding fragment thereof comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively; and the heavy chain variable region contains HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively.

Each CDR (complementary determining region) sequence described above is shown in the following table:

Preferably, the anti-PD-1 antibody is a humanized antibody.

Preferably, the light chain variable region sequence of the humanized antibody is shown in SEQ ID NO: 10 or a variant thereof; preferably, said variant has 0-10 amino acid substitutions in the light chain variable region. More preferably, the amino acid substitution is A43S. The sequence of the heavy chain variable region of the humanized antibody is shown in SEQ ID NO: 9 or a variant thereof; preferably, said variant has 0-10 amino acid substitutions in the heavy chain variable region. More preferably, the amino acid substitution is G44R.

The sequences of the variable regions of the heavy and light chains of a humanized antibody are as follows:

Heavy chain variable region

Light chain variable region

The preferred light chain sequence of the humanized antibody is shown in SEQ ID NO: 8 or a variant thereof. Preferably, said variant has 0-10 amino acid substitutions in the light chain variable region. More preferably, the amino acid substitution is A43S. The heavy chain sequence of the humanized antibody is shown in SEQ ID NO: 7 or a variant thereof. Preferably, said variant has 0-10 amino acid substitutions in the heavy chain variable region. More preferably, the amino acid substitution is G44R.

In a preferred embodiment of the invention, the light chain sequence of the humanized antibody is shown in SEQ ID NO: 8 and the heavy chain sequence is shown in SEQ ID NO: 7.

The heavy and light chain sequences of a humanized antibody are as follows:

heavy chain

light chain

In a preferred embodiment of the present invention, the triple-negative breast cancer patient is a patient who has failed or is intolerant of chemotherapy.

In a preferred embodiment of the invention, the chemotherapeutic agent is one or more selected from the group consisting of anthracyclines, taxanes, vinorelbine, capecitabine, gemcitabine, and platinum-based drugs.

The anthracyclines of the present invention include doxorubicin, epirubicin, idarubicin, daunorubicin and derivatives thereof, and the like.

The taxanes of the present invention include paclitaxel, docetaxel, paclitaxel, liposomes, albumin-bound paclitaxel, and the like.

The platinum-based drugs of the present invention include carboplatin, cisplatin, oxaplatin, Nedaplatin, lobaplatin, satraplatin, cycloplatin, Miboplatin, Endoplatin, Iproplatin, Dicycloplatin, and the like.

In a preferred embodiment of the invention, the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 1 to 10 mg/kg, preferably 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg or 10 mg/kg, more preferably 1 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg /kg or 10 mg/kg.

In a preferred embodiment of the present invention, wherein the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 50 to 600 mg, preferably 50 mg, 60 mg, 70 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg or 600 mg, more preferably 60 mg, 100 mg, 200 mg, 400 mg or 600 mg.

In a preferred embodiment of the invention, where the dose of Apatinib or a pharmaceutically acceptable salt thereof is 100 to 500 mg, preferably 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg or 500 mg, more preferably 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg or 375 mg.

In a preferred embodiment of the present invention, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a frequency of once a week, once every two weeks, once every three weeks, or once a month, and Apatinib or a pharmaceutically acceptable salt thereof is administered at a frequency of one once a day, once every two days, once every three days, 5 days of administration and 2 days of withdrawal, or 7 days of administration and 7 days of withdrawal.

As used herein, the phrase "in combination with" refers to the route of administration, in particular, it refers to the administration of at least one dose of Apatinib and at least one dose of anti-PD-1 antibody over a period of the time at which both substances show pharmacological action. The time period may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours. Apatinib and anti-PD-1 antibody may be administered simultaneously or sequentially. The following treatments cover such periods: Apatinib and anti-PD-1 antibody are administered via the same route of administration or via different routes of administration. The co-administration method described herein is selected from the group consisting of simultaneous administration, co-administration of independent compositions, and sequential administration of independent compositions. The co-administration route described herein is selected from the group consisting of oral administration, parenteral administration, and transdermal administration, parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection.

In a preferred embodiment of the present invention, at the time of administration, the anti-PD-1 antibody, or antigen-binding fragment thereof, is administered in an amount of 60-600 mg, by intravenous infusion, once every one to three weeks; Apatinib or a pharmaceutically acceptable salt thereof is administered in an amount of 250 mg - 500 mg orally once every one to two days.

In a preferred embodiment of the present invention, at the time of administration, the anti-PD-1 antibody, or antigen-binding fragment thereof, is administered in an amount of 60-600 mg, by intravenous infusion, once every one to three weeks; Apatinib or a pharmaceutically acceptable salt thereof is administered in an amount of 250 mg - 500 mg, orally, 5 days of administration and 2 days of withdrawal.

In a preferred embodiment of the present invention, at the time of administration, the anti-PD-1 antibody, or antigen-binding fragment thereof, is administered in an amount of 60-600 mg, by intravenous infusion, once every one to three weeks; Apatinib or a pharmaceutically acceptable salt thereof is administered in an amount of 250 mg - 500 mg, orally, 7 days of administration and 7 days of withdrawal.

In a preferred embodiment of the present invention, at the time of administration, the anti-PD-1 antibody, or antigen-binding fragment thereof, is administered in an amount of 200 mg by intravenous infusion once every two weeks; Apatinib or a pharmaceutically acceptable salt thereof is administered in an amount of 375 mg, orally, once a day.

In a preferred embodiment of the present invention, at the time of administration, the anti-PD-1 antibody, or antigen-binding fragment thereof, is administered in an amount of 200 mg by intravenous infusion once every two weeks; Apatinib or a pharmaceutically acceptable salt thereof is administered in an amount of 375 mg orally for 5 days of administration and 2 days of withdrawal.

In a preferred embodiment of the present invention, at the time of administration, the anti-PD-1 antibody, or antigen-binding fragment thereof, is administered in an amount of 200 mg by intravenous infusion once every two weeks; Apatinib or a pharmaceutically acceptable salt thereof is administered in an amount of 375 mg orally for 7 days of administration and 7 days of withdrawal.

In a preferred embodiment of the present invention, at the time of administration, the anti-PD-1 antibody, or antigen-binding fragment thereof, is administered in an amount of 200 mg by intravenous infusion once every two weeks; Apatinib or a pharmaceutically acceptable salt thereof is administered in an amount of 250 mg, orally, once a day.

In a preferred embodiment of the present invention, at the time of administration, the anti-PD-1 antibody, or antigen-binding fragment thereof, is administered in an amount of 200 mg by intravenous infusion once every two weeks; Apatinib or a pharmaceutically acceptable salt thereof is administered in an amount of 250 mg orally for 5 days of administration and 2 days of withdrawal.

In a preferred embodiment of the present invention, at the time of administration, the anti-PD-1 antibody, or antigen-binding fragment thereof, is administered in an amount of 200 mg by intravenous infusion once every two weeks;

Apatinib or a pharmaceutically acceptable salt thereof is administered in an amount of 250 mg orally for 7 days of administration and 7 days of withdrawal.

In a preferred embodiment of the invention, the anti-PD-1 antibody is administered by injection, eg subcutaneous or intravenous injection, and the anti-PD-1 antibody must be formulated into an injectable form prior to injection. A particularly preferred injectable form of the anti-PD-1 antibody is an injectable solution or a lyophilized powder for injection containing the anti-PD-1 antibody, a buffer, a stabilizer and optionally a surfactant. The buffer may be one or more selected from the group consisting of acetate, citrate, succinate and phosphate. The stabilizer may be saccharides or amino acids, preferably disaccharides such as sucrose, lactose, trehalose, maltose. The surfactant is selected from the group consisting of polyoxyethylene hydrogenated castor oil, glycerol fatty acid esters and polyoxyethylene sorbitan fatty acid esters, preferably the polyoxyethylene sorbitan fatty acid esters are polysorbate 20, 40, 60 or 80, most preferably polysorbate 20. Most preferably, the injectable form of the anti-PD-1 antibody comprises the anti-PD-1 antibody, acetate buffer, trehalose, and polysorbate 20.

The present invention provides an anti-PD-1 antibody, or an antigen-binding fragment thereof, as described above, in combination with Apatinib or a pharmaceutically acceptable salt thereof, as a drug to reduce the adverse effects of the drug, the adverse effects being caused by the anti-PD-1 antibody or antigen-binding thereof. fragment or Apatinib or a pharmaceutically acceptable salt thereof.

In a preferred embodiment of the present invention, adverse drug effects mediated by an anti-PD-1 antibody or antigen-binding fragment and/or immunity can be reduced when the anti-PD-1 antibody or antigen-binding fragment thereof is used in combination with Apatinib or a pharmaceutically acceptable salt thereof; Preferably, the adverse effect is a vascular adverse effect.

The present invention also provides a pharmaceutical kit or pharmaceutical package comprising the above anti-PD-1 antibody or antigen-binding fragment thereof and the above Apatinib or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for treating triple negative breast cancer comprising administering to a patient the above anti-PD-1 antibody or antigen-binding fragment thereof and the above Apatinib or a pharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical composition comprising an effective amount of an anti-PD-1 antibody or antigen-binding fragment thereof and Apatinib or a pharmaceutically acceptable salt thereof as described above and one or more pharmaceutically acceptable excipients, diluents or carriers.

Detailed description Terminology

For an easier understanding of the invention, certain technical and scientific terms are specifically defined below. All other technical and scientific terms used in this document have the meanings usually implied by one of the ordinary experts in the field to which this invention belongs, unless it is obvious that they are clearly defined in this document,

The term "humanized antibody", also known as CDR-grafted antibody (CDR-grafted antibody), refers to an antibody obtained by grafting murine CDR sequences into human antibody variable region frameworks, namely, obtained in different types of human germline antibody framework sequences. . Such humanized antibodies can overcome the strong antibody responses elicited by the large amounts of murine protein components carried by the chimeric antibodies. Such backbone sequences can be obtained from public DNA databases or published reference sequences, including germline antibody nucleotide sequences. For example, the DNA sequences of the human germline heavy and light chain variable regions can be found in "VBase", a database of human germline sequences (available on the Internet at www.mrccpe.com.ac.uk/vbase), and in Kabat, EA, et al, 1991 Sequences of Proteins of Immunological Interest, 5th Ed. In a preferred embodiment of the invention, the CDR sequences of the humanized anti-PD-1 antibody are selected from the group consisting of SEQ ID NOS: 1, 2, 3, 4, 5 and 6.

The term "antigen-binding fragment" refers to a Fab fragment, a Fab' fragment, and a F(ab')2 fragment having antigen-binding activity, as well as an Fv fragment and an sFv fragment that binds to human PD-1. An "antigen-binding fragment" contains one or more CDR regions selected from SEQ ID NO: 1 - SEQ ID NO: 6 of an antibody of the invention. The Fv fragment contains the antibody heavy chain variable region and the light chain variable region, without the constant region, and is the minimum antibody fragment with all antigen-binding sites. Typically, the Fv antibody also contains a polypeptide linker between the VH and VL domains capable of forming the structure required for antigen binding. Two variable regions of an antibody can also be joined by different linkers to form a polypeptide chain, referred to as a single chain antibody or single chain Fv (sFv). The term "binding to PD-1", as used herein, means capable of interacting with human PD-1. The term "antigen-binding sites", as used in the present invention, refers to individual three-dimensional sites on an antigen recognized by an antibody or antigen-binding fragment of the present invention.

As used herein, the term "treatment failure" means that the subject has a measurable tumor lesion at baseline, and refers to progressive disease (PD) or intolerable according to criteria for evaluating the effectiveness of RECIST 1.1 (from the English. Response Evaluation Criteria in Solid Tumors - Criteria for evaluating the response of solid tumors).

The term "intolerant", as used herein, means that treatment cannot be continued due to adverse drug-related effects.

Overall survival (OS - from the English. overall survival) refers to the time from the start of the study until death from any cause. For subjects who were still alive at the time of the last observation, OS was recorded as censored data at the time of the last observation. For subjects who dropped out of follow-up, OS was recorded as censored data at the time of the last survival confirmation, before dropping out of follow-up. OS with censored data is defined as the period from random grouping to data censoring.

The objective response rate (ORR) refers to the proportion of patients whose tumors are reduced to a certain extent and maintained at the same level for a certain period of time, including cases of CR and PR. Objective tumor response is assessed according to the criteria for evaluating tumor response (RECIST criteria 1.1). Subjects must have measurable tumor lesions at baseline, and efficacy was classified as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) according to RECIST 1.1 criteria.

Disease Control Rate (DCR) refers to the percentage of patients who have confirmed complete response, partial response, and stable disease (8 weeks or more) in patients for whom efficacy is measurable.

Complete Response (CR): All target lesions disappear and all pathological lymph nodes (including target and non-target nodules) have a short axis dimension of less than 10 mm.

Partial Response (PR): The sum of the target lesion diameters is reduced by at least 30% from baseline.

Progressive disease (PD): the minimum value of the sum of the diameters of all measured target lesions during the experimental study is used as a reference, the sum of the diameters relatively increases by at least 20% (the value measured at baseline will be used as a reference if minimal); In addition, the absolute value of the sum of the diameters must increase by at least 5 mm (development of one or more new lesions is also considered a progressive disease).

Stable disease (SD): The degree of reduction of the target lesions does not correspond to the PR, and the degree of increase does not correspond to the PD. SD occupies an intermediate position between PR and PD. The minimum sum of the diameters can be used as a reference.

Description of graphic materials

On FIG. 1 shows changes in target lesion diameters between the continuous Apatinib group and baseline.

On FIG. 2 shows changes in target lesion diameters between the Apatinib group (7 days on and 7 days off) and baseline.

Detailed description of the disclosure

The invention is further described below within the scope of the examples, but these examples are not intended to limit the scope of the invention.

Example 1 Clinical Study of Anti-PD-1 Antibody in Combination with Apatinib Mesylate in Treatment of Triple Negative Breast Cancer

1. Antibodies and compounds to be analyzed

An anti-PD-1 antibody has a heavy chain and a light chain as shown in SEQ ID NO: 7 and SEQ ID NO: 8 in the present invention. 20 mg/ml anti-PD-1 antibody was prepared from 200 mg/vial for use.

Apatinib mesylate tablets are commercially available.

2. Selection criteria: (1) Recurrent and metastatic triple-negative breast cancer pathologically confirmed (ER - negative (percentage of ER-positive, according to IHC (from English immunohistochemistry - immunohistochemistry), less than 1%), PR-negative ( the percentage of PR-positive, according to IHC, is less than 1%), HER2-negative (IHC-/+ or IHC ++, but FISH (from the English fluorescence in situ hybridization - fluorescence hybridization in s / Ya) / CISH (from the English. Chromogenic in situ hybridization - Chromogenic hybridization in situ)-); (2) Patients were treated with anthracyclines and taxanes, but the treatment was unsuccessful. In the phase of relapse and metastasis, the chemotherapy courses used are less than 3 courses; (3) Patients have measurable lesions; (4 ) ECOG score is 0-1.

3. Exemplary anti-PD-1 antibody and Apatinib dosing schedules are as follows:

200 mg anti-PD-1 antibody given by intravenous infusion once every two weeks plus 375 mg Apatinib orally once daily;

200 mg anti-PD-1 antibody given by intravenous infusion once every two weeks plus apatinib 375 mg orally for 7 days on and 7 days off;

200 mg anti-PD-1 antibody given by intravenous infusion once every two weeks plus apatinib 250 mg orally once daily;

200 mg anti-PD-1 antibody given by intravenous infusion once every two weeks plus apatinib 250 mg orally for 7 days on and 7 days off.

4. Dosing schedule

Anti-PD-1 antibody was administered intravenously at a fixed dose of 200 mg, via intravenous drip over 30 minutes (no less than 20 minutes, no more than 60 minutes), once every 2 weeks, for a cycle of 4 weeks, with the maximum duration of administration is 2 years.

Apatinib was administered orally after meals, once a day, one tablet each time (250 mg/tablet or 375 mg/tablet), 7 days of administration, 7 or 14 days of withdrawal.

5. Dosage regulation

Based on the toxic and adverse effects of the investigational drug, the dosing of the investigational medicinal products may be suspended, reduced and discontinued during the study.

Suspension of anti-PD-1 antibody administration during the study was allowed for up to 8 weeks; when administration of anti-PD-1 antibody was delayed for more than 3 days, administration was not carried out for the current point, and a dose of 200 mg was administered until the next administration point, according to the schedule.

In addition to stopping dosing, the dose of anti-PD-1 antibody may be reduced to 3 mg/kg once every two weeks for underweight subjects.

Due to toxicity associated with Apatinib, dosage adjustments included: dosing suspension (no more than 28 days), dose reduction (375 mg/day dose group) and dosing cessation. Apatinib dose reduction was only allowed during the study, and the dose of Apatinib may be reduced from 375 mg/day to 250 mg/day. However, dose escalation of Apatinib was not allowed. When toxicity associated with Apatinib was observed, administration should first be withheld and then the initial dose administered, dose reduced, or discontinued, depending on recovery from toxicity. After cessation of the administration of Apatinib, monotherapy can be continued based on the introduction of antibodies against PD-1 to the subject.

6. Results

Two groups of patients received 200 mg of anti-PD-1 antibody, iv. (intravenously), once every two weeks; Apatinib 250 mg daily, orally; and anti-PD-1 antibody, iv, once every two weeks; Apatinib 250 mg administered over a 14-day cycle (including 7 days of administration, 7 days of withdrawal), respectively. 19 patients were recruited, 10 patients received continuous administration, and 9 patients were administered for 7 days with 7 days of withdrawal. Seventeen patients were eligible for evaluation, of which eight patients were in the continuous administration group and nine patients were in the 7 days of administration plus 7 days of withdrawal group. The first efficacy evaluation was performed in the continuous administration group, where PR: 3 patients, SD: 2 patients, PD 3 patients, ORR was 37.5%, DCR was 62.5%; As in the case of the group 7 days of introduction plus 7 days of withdrawal, where SD: 4 patients, PD: 5 patients, ORR was 0%, DCR was 44.4%.

Some subjects were subsequently recruited up to a total of 23 patients, with the following results:

The co-administration of an anti-PD-1 antibody and Apatinib in the present invention was tolerable and safe in subjects with triple negative breast cancer. Most subjects discontinued treatment due to progressive disease. Capillary hemangioma was essentially not observed in the continuous administration group, which is significantly better than the number of cases of capillary hemangioma encountered with anti-PD-1 antibody monotherapy used in the Phase I clinical trial.

Claims (12)

1. Use of an anti-PD-1 antibody or antigen-binding fragment thereof in combination with apatinib or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of triple negative breast cancer, wherein the light chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof contains LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively, and the heavy chain variable region of an anti-PD-1 antibody contains HCDR1, HCDR2, and HCDR3, as shown in SEQ ID NO: : 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively. 2. Use according to claim 1, wherein the anti-PD-1 antibody is a humanized antibody. 3. Use according to claim 2, wherein the light chain variable region sequence of the humanized antibody is shown in SEQ ID NO: 10 or a variant thereof, wherein said variant preferably has 0-10 amino acid substitutions in the light chain variable region, more preferably , the amino acid substitution is A43S; the heavy chain variable region sequence is shown in SEQ ID NO: 9 or a variant thereof, preferably having 0-10 amino acid substitutions in the heavy chain variable region, more preferably the amino acid substitution is G44R. 4. Use according to claim 3, wherein the light chain sequence of the humanized antibody is shown in SEQ ID NO: 8 or a variant thereof, wherein said variant preferably has 0-10 amino acid substitutions in the light chain variable region, more preferably an amino acid the replacement is A43S; the heavy chain sequence is shown in SEQ ID NO: 7 or a variant thereof, preferably having 0-10 amino acid substitutions in the heavy chain variable region, more preferably the amino acid substitution is G44R. 5. Use according to claim 4, wherein the light chain sequence of the humanized antibody is shown in SEQ ID NO: 8 and the heavy chain sequence is shown in SEQ ID NO: 7. 6. Application according to any one of paragraphs. 1-5 where chemotherapy was unsuccessful in treating triple negative breast cancer. 7. Use according to claim 6, wherein the chemotherapeutic agent is one or more selected from the group consisting of anthracyclines, taxanes, vinorelbine, capecitabine, gemcitabine, and platinum-based drugs. 8. Application according to any one of paragraphs. 1-7, wherein the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 1 to 10 mg/kg, preferably 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg , 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg or 10 mg/kg, more preferably 1 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg or 10 mg/kg. 9. Application according to any one of paragraphs. 1-7, wherein the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 50 to 600 mg, preferably 50 mg, 60 mg, 70 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg , 225 mg, 250 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg or 600 mg, more preferably 60 mg, 100 mg, 200 mg, 400 mg or 600 mg. 10. Application according to any one of paragraphs. 1-7, wherein the dose of apatinib or a pharmaceutically acceptable salt thereof is 100 to 500 mg, preferably 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg , 350 mg, 375 mg, 400 mg or 500 mg, more preferably 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg or 375 mg. 11. Pharmaceutical packaging for use in the treatment of triple negative breast cancer containing apatinib or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or antigen-binding fragment thereof according to any one of paragraphs. 1-10. 12. Pharmaceutical composition for use in the treatment of triple negative breast cancer, containing an effective amount of an antibody to PD-1 or its antigen-binding fragment and apatinib or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-10 and one or more pharmaceutically acceptable excipients, diluents or carriers.

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