WO2021228069A1 - 抗vegf抗体和抗pd-1抗体组合用于预防或治疗疾病的应用 - Google Patents

抗vegf抗体和抗pd-1抗体组合用于预防或治疗疾病的应用 Download PDF

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WO2021228069A1
WO2021228069A1 PCT/CN2021/092987 CN2021092987W WO2021228069A1 WO 2021228069 A1 WO2021228069 A1 WO 2021228069A1 CN 2021092987 W CN2021092987 W CN 2021092987W WO 2021228069 A1 WO2021228069 A1 WO 2021228069A1
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antibody
seq
sequence
antigen
heavy chain
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PCT/CN2021/092987
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English (en)
French (fr)
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杨勇
王岩
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信达生物制药(苏州)有限公司
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Publication of WO2021228069A1 publication Critical patent/WO2021228069A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells

Definitions

  • the present invention relates to the treatment of tumors. Specifically, the present invention relates to a method for treating tumors by a combination of an anti-VEGF antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof.
  • liver cancer is the second leading cause of cancer-related death in the world and the sixth leading cause of cancer-related death in developed countries. It is estimated that in 2012, the number of new liver cancer cases worldwide reached 782,000, and liver cancer deaths were 745,000, of which about 50% occurred in China. Most primary liver cancers (70% to 90%) are hepatocellular carcinoma (HCC).
  • HCC hepatocellular carcinoma
  • HCC hepatitis B virus
  • HCV hepatitis C virus
  • the targets include VEGFR1, VEGFR2, VEGFR3, PDGFR- ⁇ , c-kit, FLT-3, RET
  • VEGFR1, VEGFR2, VEGFR3, PDGFR- ⁇ , c-kit, FLT-3, RET This is the first systemic drug or treatment program that has been proven to bring significant survival benefits to patients with advanced HCC, and it is also the current standard first-line treatment program.
  • the median OS of the sorafenib group was 10.7 months
  • the median PFS was 5.5 months
  • the effective rate was only 2%
  • the adverse event rate was as high as 80% (Llovet, JM, et al. Sorafenib in advanced hepatocellular carcinoma.
  • ORR is 7%
  • DCR is 48%
  • median OS is 11.4 months
  • median PFS is 3.2 months
  • Lenvatinib was also approved for first-line treatment of liver cancer, with an overall survival of 13.6 months
  • median PFS 7.4 months
  • the present invention provides a pharmaceutical combination comprising an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-VEGF antibody and its use and method for preventing or treating cancer.
  • the present invention provides the following embodiments:
  • a drug combination for preventing or treating tumors which is characterized in that it comprises an anti-VEGF antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the anti-VEGF antibody Preferably bevacizumab;
  • the anti-PD-1 antibody includes six CDRs: the heavy chain VH CDR1 includes SEQ ID NO:1, the heavy chain VH CDR2 includes SEQ ID NO: 2, and the heavy chain VH CDR3 includes SEQ ID NO: 3, the light chain VL CDR1 includes SEQ ID NO: 4, the light chain VL CDR2 includes SEQ ID NO: 5, and the light chain VL CDR3 includes SEQ ID NO: 6, which defines the rules for North.
  • the combination is characterized in that the anti-PD-1 antibody comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7 or It has a sequence that is at least 90% identical to it, and the light chain variable region includes the sequence of SEQ ID NO: 8 or a sequence that has at least 90% identity to it; or the anti-PD-1 antibody heavy chain includes SEQ ID NO: The sequence of 9 or a sequence with at least 90% identity with it, and wherein the light chain comprises the sequence of SEQ ID NO: 10 or a sequence with at least 90% identity with it; or the anti-PD-1 antibody is Xindi Lizumab.
  • the combination is characterized in that the weight of the anti-VEGF antibody drug is about 300-2700 mg, preferably 450 mg, 900 mg, 1800 mg, 2700 mg; the weight of the anti-PD-1 antibody drug is about 100 to 300 mg, preferably 200mg.
  • the combination is characterized in that the tumor is a solid tumor, hematological tumor, preferably hepatocellular carcinoma.
  • the combination is characterized in that the prevention or treatment can increase the tumor complete remission rate by 10% to 100%, increase the partial remission rate by 10% to 100%, and reduce the disease progression rate compared with the pre-treatment rate. The disease progresses slowly.
  • a method for preventing or treating tumor-related diseases comprises administering the above-mentioned anti-VEGF antibody or antigen-binding fragment thereof and anti-PD-1 antibody or antigen-binding fragment thereof to an individual,
  • a single dose of anti-VEGF antibody or antigen-binding fragment thereof is about 1-30 mg/kg body weight, preferably 7.5-15 mg/kg body weight, more preferably 7.5 mg/kg body weight, 15 mg/kg body weight, or about 60-1800 mg, preferably 450 ⁇ 900mg, more preferably 450mg, 900mg;
  • a single dose of anti-PD-1 antibody or its antigen-binding fragment is about 100-300mg, preferably 200mg, preferably once a week, once every two weeks, once every three weeks, every four weeks Once, once every five weeks or once every six weeks, and the interval between each dosing cycle can be the same or different; preferably, it is administered once or twice in each dosing cycle, more preferably once,
  • the method wherein the anti-VEGF antibody and anti-PD-1 antibody are administered simultaneously, separately or sequentially.
  • the method wherein the sequential administration is to administer PD-1 antibody first, then VEGF antibody, at an interval of no less than 5 minutes, preferably 5 minutes, 10 minutes, 30 hours, 1 Hours, 2 hours, 12 hours, 24 hours.
  • kits of medicines which contains an effective amount of the above-mentioned anti-VEGF antibody or antigen-binding fragment thereof and anti-PD-1 antibody or antigen-binding fragment thereof.
  • the above-mentioned drug combination or packaged drug package is used in the preparation of drugs for preventing or treating tumors, the tumors being solid tumors, hematological tumors, and preferably hepatocellular carcinoma.
  • the drug combination of the present invention has a good curative effect in the treatment of tumor diseases.
  • the present invention relates to a drug combination for preventing or treating tumors, the combination comprising an anti-VEGF antibody and an anti-PD-1 antibody.
  • the anti-VEGF antibody is Bevacizumab.
  • the anti-PD-1 antibody comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7 or a sequence that is at least 90% identical to it , And the light chain variable region includes the sequence of SEQ ID NO: 8 or a sequence with at least 90% identity:
  • the anti-PD-1 antibody comprises:
  • the anti-PD-1 antibody is an IgG4 type antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the sequence of SEQ ID NO: 9 or a sequence having at least 90% identity therewith, and wherein the light chain comprises the sequence of SEQ ID NO: 10 or a sequence having at least 90% identity with it:
  • the anti-PD-1 antibody is the anti-PD-1 monoclonal antibody AntibodyD disclosed in PCT Publication No. WO2017025016A1.
  • the anti-PD-1 monoclonal antibody is also referred to as sintilimab in this application, and its preparation method is referred to WO2017025016A1.
  • the weight of the anti-VEGF antibody drug of the present invention is about 300-2700 mg, preferably 450 mg, 900 mg, 1800 mg, 2700 mg.
  • the weight of the anti-PD-1 antibody drug is about 100-300 mg, preferably 200 mg.
  • the tumor is a solid tumor or hematological tumor.
  • the solid tumor is hepatocellular carcinoma.
  • the present invention relates to a method of preventing or treating tumors in an individual, the method comprising administering an anti-VEGF antibody and an anti-PD-1 antibody to the individual.
  • the anti-VEGF antibody is Bevacizumab.
  • the anti-PD-1 antibody comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7 or a sequence that is at least 90% identical to it , And the light chain variable region includes the sequence of SEQ ID NO: 8 or a sequence that is at least 90% identical to it.
  • the anti-PD-1 antibody is an IgG4 type antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the sequence of SEQ ID NO: 9 or a sequence having at least 90% identity therewith, and wherein the light chain comprises the sequence of SEQ ID NO: 10 or a sequence with at least 90% identity with it.
  • the anti-PD-1 antibody includes six CDRs, wherein the heavy chain VH CDR1 includes SEQ ID NO: 1, and the heavy chain VH CDR2 includes SEQ ID NO: 2, and the heavy chain VH CDR3 includes SEQ ID NO. :3, the light chain VL CDR1 includes SEQ ID NO: 4, the light chain VL CDR2 includes SEQ ID NO: 5, and the light chain VL CDR3 includes SEQ ID NO: 6.
  • the anti-PD-1 antibody is the anti-PD-1 monoclonal antibody AntibodyD disclosed in PCT Publication No. WO2017025016A1.
  • the anti-PD-1 monoclonal antibody is also referred to as sintilimab in this application, and its preparation method is referred to WO2017025016A1.
  • the tumor is a solid tumor or hematological tumor.
  • the solid tumor is hepatocellular carcinoma.
  • the combination of the invention is administered topically.
  • the combination of the present invention is administered simultaneously, separately or sequentially. It is preferably administered sequentially. More preferably, sintilizumab is administered first, followed by bevacizumab.
  • the administration interval between sintilizumab and bevacizumab of the present invention is not less than 5 minutes, preferably 5 minutes, 10 minutes, 30 hours, 1 hour, 2 hours, 12 hours, 24 hours.
  • the combined administration cycle of the present invention is once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks, and between each dosing cycle
  • the interval can be the same or different.
  • it is administered once or twice in each dosing cycle, preferably once, and the mode of administration is administration on the first day of each cycle.
  • the single administration dose of the anti-PD-1 antibody of the present invention may be selected from about 100 to 300 mg, preferably 200 mg.
  • a single administration dose of anti-VEGF antibody is about 1-30 mg/kg body weight, preferably 7.5-15 mg/kg body weight, more preferably 7.5 mg/kg body weight, 15 mg/kg body weight, or about 60-1800 mg, preferably 450-900 mg, more preferably 450mg, 900mg.
  • it is administered by injection, and more preferably, it is administered by intravenous injection.
  • the individual is a human.
  • the present invention relates to the use of an anti-PD-1 antibody combined with an anti-VEGF antibody in the preparation of drugs for the prevention or treatment of tumors in individuals.
  • the present invention relates to an anti-PD-1 antibody combined with an anti-VEGF antibody, which is used to prevent or treat tumor diseases in an individual.
  • the anti-VEGF antibody is Bevacizumab.
  • the anti-PD-1 antibody comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7 or a sequence that is at least 90% identical to it , And the light chain variable region includes the sequence of SEQ ID NO: 8 or a sequence that is at least 90% identical to it.
  • the anti-PD-1 antibody is an IgG4 type antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the sequence of SEQ ID NO: 9 or a sequence having at least 90% identity therewith, and wherein the light chain comprises the sequence of SEQ ID NO: 10 or a sequence with at least 90% identity with it.
  • the anti-PD-1 antibody includes six CDRs, wherein the heavy chain VH CDR1 includes SEQ ID NO: 1, and the heavy chain VH CDR2 includes SEQ ID NO: 2, and the heavy chain VH CDR3 includes SEQ ID NO. :3, the light chain VL CDR1 includes SEQ ID NO: 4, the light chain VL CDR2 includes SEQ ID NO: 5, and the light chain VL CDR3 includes SEQ ID NO: 6.
  • the anti-PD-1 antibody is the anti-PD-1 monoclonal antibody AntibodyD disclosed in PCT Publication No. WO2017025016A1.
  • the anti-PD-1 monoclonal antibody is also referred to as sintilimab in this application, and its preparation method is referred to WO2017025016A1.
  • the weight of the anti-PD-1 antibody drug of the present invention is about 100-300 mg, preferably 200 mg.
  • the weight of the anti-VEGF antibody drug is about 60-1800 mg, preferably 450-900 mg, more preferably 450 mg, 900 mg.
  • the tumor is a solid tumor or hematoma, and the solid tumor is hepatocellular carcinoma.
  • the anti-PD-1 antibody and anti-VEGF antibody composition of the present invention can increase the tumor complete remission rate by 10% to 100%, increase the partial remission rate by 10% to 100%, and reduce the disease progression rate compared with the pre-treatment rate. The disease progresses slowly.
  • the present invention relates to a kit of medicines, which is characterized in that it contains an anti-PD-1 antibody and an anti-VEGF antibody.
  • the present invention relates to the use of a kit of medicines in the preparation of drugs for the prevention or treatment of tumors, which is characterized by comprising anti-PD-1 antibodies and anti-VEGF antibodies.
  • the anti-PD-1 antibody is the anti-PD-1 monoclonal antibody Antibody D disclosed in the publication number WO2017025016A1.
  • the anti-PD-1 antibody comprises the following dosage: about 100-300 mg, preferably 200 mg.
  • the anti-VEGF antibody is bevacizumab.
  • the anti-VEGF antibody comprises the following dosage: about 60-1800 mg, preferably 450-900 mg, more preferably 450 mg, 900 mg.
  • the term “comprising” or “including” means including the stated elements, integers or steps, but does not exclude any other elements, integers or steps.
  • the term “comprises” or “includes” when used, unless otherwise specified, it also covers the combination of the stated elements, integers or steps.
  • an antibody variable region that "comprises” a specific sequence when referring to an antibody variable region that "comprises” a specific sequence, it is also intended to encompass the antibody variable region composed of the specific sequence.
  • “Individual” includes mammals. Mammals include, but are not limited to, domestic animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., human and non-human primates such as monkeys), rabbits, and rodents (e.g., , Mice and rats). In some embodiments, the individual is a human, including a child, adolescent, or adult.
  • administered in combination refers to the administration of two or more therapeutic agents to treat diseases as described in this disclosure.
  • Such administration includes co-administration of these therapeutic agents in a substantially simultaneous manner, for example, in a single composition having a fixed ratio of active ingredients.
  • such administration includes co-administration of the respective active ingredients in multiple or in separate containers (e.g., tablets, capsules, powders, and liquids).
  • the powder and/or liquid can be reconstituted or diluted to the desired dose before administration.
  • such administration also includes the use of each type of therapeutic agent in a sequential manner at approximately the same time or at different times. In either case, the treatment regimen will provide the beneficial effects of the drug combination in the treatment of the conditions or conditions described herein.
  • treatment refers to slowing, interrupting, blocking, alleviating, stopping, reducing, or reversing the progression or severity of an existing symptom, disorder, condition, or disease.
  • prevention includes the inhibition of the occurrence or development of a disease or condition or the symptoms of a specific disease or condition.
  • individuals with a family history are candidates for preventive regimens.
  • prevention refers to the administration of drugs before the onset of symptoms or symptoms, especially in individuals at risk.
  • the term "effective amount” refers to the amount or dose of the preparation or composition of the present invention, which produces the desired effect in the treated patient after being administered to the patient in single or multiple doses.
  • the effective amount can be easily determined by the attending physician as a person skilled in the art by considering various factors such as the species of mammal; its size, age and general health; the specific disease involved; the degree or severity of the disease; The response of the individual patient; the specific antibody administered; the mode of administration; the bioavailability characteristics of the administered formulation; the selected dosing regimen; and the use of any concomitant therapy.
  • Therapeutically effective amount refers to the amount that is effective to achieve the desired therapeutic result at the required dose and for the required period of time.
  • the therapeutically effective amount of the preparation, antibody or antibody fragment or conjugate or composition of the present invention can be based on various factors such as the disease state, the age, sex and weight of the individual, and the amount of the antibody or antibody portion that elicits the desired response in the individual. Ability to change.
  • a therapeutically effective amount is also an amount in which any toxic or harmful effects of the formulation, antibody or antibody fragment or conjugate or composition thereof are not as good as the therapeutically beneficial effects.
  • prophylactically effective amount refers to an amount that effectively achieves the desired preventive result at the required dose and for the required period of time. Generally, since the prophylactic dose is used in the subject before or at an earlier stage of the disease, the prophylactically effective amount will be less than the therapeutically effective amount.
  • the term “formulation” or “pharmaceutical composition” refers to a composition comprising at least one active ingredient and at least one inactive ingredient suitable for administration to animals, preferably mammals (including humans).
  • “Liquid formulation” or “liquid composition” refers to a formulation in liquid form.
  • the liquid composition of the present invention comprises (i) the anti-VEGF antibody and anti-PD-1 antibody of the present invention; (ii) a buffer; and (iii) a vehicle.
  • the composition of the formulation of the present invention may be as shown in the above embodiments related to liquid pharmaceutical compositions.
  • the liquid preparation of the present invention is preferably an injection.
  • buffering agent refers to a pH buffering agent.
  • the buffer is selected from histidine, glutamate, phosphate, acetate, citrate, and tris.
  • the term "vehicle” refers to a liquid used to dissolve or suspend active ingredients and inactive ingredients to form a liquid formulation.
  • the solvents that can be used in the present invention include, but are not limited to, water for injection, and organic solvents for injection include, but are not limited to, injection oil, ethanol, propylene glycol, etc., or a combination thereof.
  • Anti-PD-1 antibody Sintilimab injection, Sinda Biopharmaceutical (Suzhou) Co., Ltd. 10ml: 100mg.
  • bevacizumab injection, preparation method and preparation composition please refer to the patent publication number CN 104922668A. 4ml: 100mg.
  • Hepatocellular carcinoma diagnosed by histology/cytology, or liver cirrhosis meets the American Society for the Study of Liver Diseases (AASLD) clinical diagnostic criteria for hepatocellular carcinoma.
  • ECOG Electronic Cooperative Oncology Group
  • Child-Pugh (grading standard for liver cirrhosis) score ⁇ 7 points.
  • the laboratory test values within 7 days before entry into the group meet the following requirements (no blood components, cell growth factors, albumin and other intravenous or subcutaneous administrations are allowed within the first 14 days of obtaining laboratory tests.
  • Drugs for corrective treatment as follows:
  • ANC absolute neutrophil count
  • platelet count platelet, PLT
  • hemoglobin content hemoglobin, HGB
  • Liver function serum total bilirubin (TBIL) ⁇ 2 ⁇ upper limit of normal value (ULN); alanine aminotransferase (ALT) and aspartate amino transfer Enzyme (aspartate transferase, AST) ⁇ 5 ⁇ ULN; serum albumin ⁇ 28g/L; alkaline phosphatase (ALP) ⁇ 5 ⁇ ULN.
  • TBIL serum total bilirubin
  • ALT alanine aminotransferase
  • AST aspartate amino transfer Enzyme
  • serum albumin serum albumin ⁇ 28g/L
  • ALP alkaline phosphatase
  • Renal function serum creatinine (Cr) ⁇ 1.5 ⁇ ULN or creatinine clearance (clearance of creatinine, CCr) ⁇ 50mL/min (Cockcroft-Gault formula); urine routine results show urine protein ⁇ 2+; against baseline Routine urine testing shows that patients with urine protein ⁇ 2+ should undergo 24-hour urine collection and 24-hour urine protein quantitative ⁇ 1g.
  • Coagulation function International normalized ratio (INR) and activated partial thromboplastin time (APTT) ⁇ 1.5 times ULN.
  • Female patients of childbearing age or male patients whose sexual partners are females of childbearing age should take effective contraceptive measures during the entire treatment period and 6 months after the last medication.
  • the study drugs used in the study were defined as Sintilimab, Bevacizumab, and Sorafenib.
  • the first administration of the study drug should be started on the day of randomization (cycle 1, day 1), but no later than 72 hours after the randomization date. If the drug is not taken after 72 hours, discuss with the sponsor. Every effort should be made to start trial treatment on the day of randomization.
  • the drug can be administered within 3 days after the scheduled dosing day of each cycle. In case of holidays, it can be postponed for no more than one week.
  • the treatment plan of this study is shown in Table 1.
  • the experimental results show that the Sintilizumab+bevacizumab composition of the present invention has a better therapeutic effect in the first-line treatment of ORR, DCR, OS and PFS of HCC.

Abstract

提供了一种抗VEGF抗体和抗PD-1抗体组合用于预防或治疗疾病的应用，一种用于预防或治疗肿瘤的药物组合，包含抗VEGF抗体或其抗原结合片段，抗PD-1抗体或其抗原结合片段，其中抗VEGF抗体优选贝伐单抗；抗PD-1抗体包含六个CDR；其中重链VH CDR1包含SEQ ID NO：1，且重链VH CDR2包含SEQ ID NO：2，重链VH CDR3包含SEQ ID NO：3，轻链VL CDR1包含SEQ ID NO：4，轻链VL CDR2包含SEQ ID NO：5，轻链VL CDR3包含SEQ ID NO：6，为North定义规则，所述药物组合在治疗肿瘤疾病方面具有较好的疗效。

Description

抗VEGF抗体和抗PD-1抗体组合用于预防或治疗疾病的应用
本申请要求申请日为2020/5/12的中国专利申请2020103957829、申请日为2020/10/15的中国专利申请2020111033790的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及肿瘤的治疗。具体的本发明涉及抗VEGF抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段的组合治疗肿瘤的方法。
背景技术
目前虽然总体癌症的发病率和死亡率在持续下降，但肝癌的发病率和死亡率却在增加。肝癌的男性发病率远远高于女性，在发展中国家的男性中，肝癌是全球第二大癌症相关死因，在发达国家是第六大癌症相关死因。据估算，2012年全球新发肝癌例数达78.2万，肝癌死亡病例74.5万，其中大约50％发生在中国。大多数原发性肝癌(70％～90％)是肝细胞癌(HCC)。
HCC的病因主要是乙型肝炎病毒(HBV)和丙型肝炎病毒(HCV)感染、酒精、饮食相关因素等。我国大部分HCC的发病是由于HBV的慢性感染引起肝硬化，最终发展成为HCC。多数HCC患者发病时已经是局部晚期或转移性疾病，不适于接受根治性治疗。这类患者预后较差，在支持性治疗的情况下，中位生存时间仅为7.9个月，对于主要为病毒性肝炎引起的亚太地区HCC患者，中位生存时间更是仅为4.2个月。因此，目前亟需有效的治疗手段以满足我国及世界范围的晚期HCC患者需求。
2007年FDA批准了多靶点激酶抑制剂药索拉非尼(Sorafenib)用于不可手术的晚期HCC患者，靶点包括VEGFR1、VEGFR2、VEGFR3，PDGFR-β，c-kit、FLT-3、RET，这是第一个被证明可为晚期HCC患者带来明显生存 获益的全身性药物或治疗方案，也是目前的标准一线治疗方案。但是，索拉非尼组的中位OS为10.7月，中位PFS为5.5个月，有效率仅为2％，而不良事件发生率高达80％(Llovet，J.M.，et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med 359，378-390(2008))。而在亚洲人群，中位OS则更低，仅6.5个月(Cheng，A.-L.，et al.Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma：a phase III randomised，double-blind，placebo-controlled trial.Lancet Oncol 10，25-34(2009))。Roche同样公布了索拉非尼治疗HCC的数据，其中ORR为12％，DCR为55％，中位OS为13.2月，中位PFS为4.3个月(ESMO Asia 2019 Congress(22-24 November，Singapore))；在中国人群数据更不理想，其中ORR为7％，DCR为48％，中位OS为11.4月，中位PFS为3.2个月(EASL Liver Cancer Summit 2020.OP02-02)。仑伐替尼也获批肝癌一线治疗，总生存13.6个月，中位PFS：7.4个月(Kudo，M.，et al.Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma：a randomised phase 3 non-inferiority trial.Lancet 391，1163-1173(2018))。目前，免疫检查点抑制剂也开始在晚期HCC中显示出治疗价值。在Check-Mate-459肝癌一线研究中，nivolumab单药ORR仅15％，对照组索拉非尼ORR为7％，中位PFS和对照组无差异(3.7个月vs.3.8个月)。OS的获益也并不显著(16.4个月vs.14.7个月)(T Yau.，et al.CheckMate 459：A randomized，multi-center phase III study of nivolumab(NIVO)vs sorafenib(SOR)as first-line(1L)treatment in patients(pts)with advanced hepatocellular carcinoma(aHCC).Annals of Oncology(2019)30(suppl_5)：v874-v875.)。因此，对于晚期HCC的治疗无论是多靶点的激酶抑制剂，还是免疫检查点抑制剂抗PD-1/PD-L1单抗，单药治疗总体客观缓解率有限，生存期改善不够理想，临床需要具有更高疗效的治疗方式，联合治疗将是最优的选择，值得进一步深入探索。
发明内容
本发明提供了包含抗PD-1抗体或其抗原结合片段和抗VEGF抗体的药物组合及其用于预防或治疗癌症的用途和方法。
具体而言，本发明提供了以下实施方案：
在一个具体实例中，提供一种用于预防或治疗肿瘤的药物组合，其特征在于，包含抗VEGF抗体或其抗原结合片段，抗PD-1抗体或其抗原结合片段，其中所述抗VEGF抗体优选为贝伐单抗；所述抗PD-1抗体包含六个CDR：其中重链VH CDR1包含SEQ ID NO：1，且重链VH CDR2包含SEQ ID NO：2，重链VH CDR3包含SEQ ID NO：3，轻链VL CDR1包含SEQ ID NO：4，轻链VL CDR2包含SEQ ID NO：5，轻链VL CDR3包含SEQ ID NO：6，为North定义规则。
在一个优选实例中，所述的组合，其特征在于，抗PD-1抗体包含重链可变区VH和轻链可变区VL，其中重链可变区包含SEQ ID NO：7的序列或与其具有至少90％同一性的序列，且轻链可变区包含SEQ ID NO：8的序列或与其具有至少90％同一性的序列；或所述抗PD-1抗体重链包含SEQ ID NO：9的序列或与其具有至少90％同一性的序列，且其中所述轻链包含SEQ ID NO：10的序列或与其具有至少90％同一性的序列；或所述抗PD-1抗体为信迪利单抗。
在一个优选实例中，所述的组合，其特征在于，所述的抗VEGF抗体药物重量约300～2700mg，优选450mg、900mg、1800mg、2700mg；抗PD-1抗体药物重量约100～300mg，优选200mg。
在一个优选实例中，所述的组合，其特征在于，所述的肿瘤为实体瘤、血液肿瘤，优选为肝细胞癌。
在一个优选实例中，所述的组合，其特征在于，所述预防或治疗可以较用药前肿瘤完全缓解率提高10％～100％，部分缓解率提高10％～100％，疾病进展速度降低或疾病发展缓慢。
在一个具体实例中，提供一种预防或治疗肿瘤相关疾病的方法，其特征在于，该方法包括像个体施用上述的抗VEGF抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段，抗VEGF抗体或其抗原结合片段单次给药剂量约1～30mg/kg体重，优选7.5～15mg/kg体重，更优选7.5mg/kg体重、15mg/kg体重，或约60～1800mg，优选450～900mg，更优选450mg、900mg；抗PD-1抗体或其抗原结合片段单次给药剂量约100～300mg，优选200mg，优选为每周一次、每两周一次、每三周一次、每四周一次、每五周一次或每六周一次，而且每个给药周期之间的间隔可以相同或不同；优选地，在每个给药周期给药一次或两次，更优选一次，给药方式是每个周期的第一天给药；优选地，采用注射给药，更优选地，采用静脉注射给药。
在一个优选实例中，所述的方法，其中所述抗VEGF抗体和抗PD-1抗体同时给药、分开给药或依次给药。
在一个优选实例中，所述的方法，其中所述依次给药是先施用PD-1抗体，再施用VEGF抗体，间隔时间不少于5分钟，优选为5分钟、10分钟、30小时、1小时、2小时、12小时、24小时。
在一个具体实例中，提供一种成套药物包装盒，其包含有效量的上述的抗VEGF抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段。
在一个优选实例中，上述的药物组合或权成套药物包装盒在制备预防或治疗肿瘤的药物的用途，所述肿瘤为实体瘤、血液肿瘤，优选为肝细胞癌。
令人惊奇的是，本发明的药物组合在治疗肿瘤疾病方面具有较好的疗效。
具体实施方式
以下结合实施例进一步说明本发明，下列实施例不应被理解为对本发明的限制。
药物组合
第一方面，本发明涉及一种预防或治疗肿瘤的药物组合，该组合包括抗 VEGF抗体和抗PD-1抗体。
在一个实施方案中，所述抗VEGF抗体是贝伐单抗(Bevacizumab)。
在一个实施方案中，抗PD-1抗体包含重链可变区VH和轻链可变区VL，其中重链可变区包含SEQ ID NO：7的序列或与其具有至少90％同一性的序列，且轻链可变区包含SEQ ID NO：8的序列或与其具有至少90％同一性的序列：
Figure PCTCN2021092987-appb-000001
在一个实施方案中，所述抗PD-1抗体包含：
-KASGGTFSSYAIS(SEQ ID NO：1)的重链VH CDR1；
-LIIPMFDTAGYAQKFQG(SEQ ID NO：2)的重链VH CDR2；
-ARAEHSSTGTFDY(SEQ ID NO：3)的重链VH CDR3；
-RASQGISSWLA(SEQ ID NO：4)的轻链VL CDR1；
-SAASSLQS(SEQ ID NO：5)的轻链VL CDR2；和
-QQANHLPFT(SEQ ID NO：6)的轻链VL CDR3；
为North定义规则。
在一个实施方案中，所述抗PD-1抗体是包含重链和轻链的IgG4型抗体，其中所述重链包含SEQ ID NO：9的序列或与其具有至少90％同一性的序列，且其中所述轻链包含SEQ IDNO：10的序列或与其具有至少90％同一性的序列：
Figure PCTCN2021092987-appb-000002
Figure PCTCN2021092987-appb-000003
优选地，所述抗PD-1抗体是PCT公开号WO2017025016A1中公开的抗PD-1单克隆抗体AntibodyD。为方便表述，该抗PD-1单抗在本申请中也称为信迪利单抗，其制备方法参见WO2017025016A1。
在一个实施方案中，本发明的抗VEGF抗体药物重量约300～2700mg，优选450mg、900mg、1800mg、2700mg。抗PD-1抗体药物重量约100～300mg，优选200mg。
在一个实施方案中，所述的肿瘤为实体瘤、血液肿瘤。
在一个实施方案中，所述的实体瘤为肝细胞癌。
治疗方法
第二方面，本发明涉及在个体中预防或治疗肿瘤的方法，该方法包括向所述个体施用抗VEGF抗体和抗PD-1抗体。
在一个实施方案中，所述抗VEGF抗体是贝伐单抗(Bevacizumab)。
在一个实施方案中，抗PD-1抗体包含重链可变区VH和轻链可变区VL， 其中重链可变区包含SEQ ID NO：7的序列或与其具有至少90％同一性的序列，且轻链可变区包含SEQ ID NO：8的序列或与其具有至少90％同一性的序列。
在一个实施方案中，所述抗PD-1抗体是包含重链和轻链的IgG4型抗体，其中所述重链包含SEQ ID NO：9的序列或与其具有至少90％同一性的序列，且其中所述轻链包含SEQ IDNO：10的序列或与其具有至少90％同一性的序列。
在一个实施方案中，所述抗PD-1抗体包含六个CDR，其中重链VH CDR1包含SEQ ID NO：1，且重链VH CDR2包含SEQ ID NO：2，重链VH CDR3包含SEQ ID NO：3，轻链VL CDR1包含SEQ ID NO：4，轻链VL CDR2包含SEQ ID NO：5，轻链VL CDR3包含SEQ ID NO：6。
优选地，所述抗PD-1抗体是PCT公开号WO2017025016A1中公开的抗PD-1单克隆抗体AntibodyD。为方便表述，该抗PD-1单抗在本申请中也称为信迪利单抗，其制备方法参见WO2017025016A1。
在一个实施方案中，所述的肿瘤为实体瘤、血液肿瘤。
在一个实施方案中，所述的实体瘤为肝细胞癌。
在一些实施方案中，本发明的组合通过局部施用。
在一些实施方案中，本发明的组合施用时，同时给药、分开给药或依次给药。优选为依次给药。更优选地，先施用信迪利单抗，再施用贝伐单抗。
在一些实施方案中，本发明的组合信迪利单抗和贝伐单抗给药间隔时间不少于5分钟，优选为5分钟、10分钟、30小时、1小时、2小时、12小时、24小时。
在一些实施方案中，本发明的组合给药周期为每周一次、每两周一次、每三周一次、每四周一次、每五周一次或每六周一次，而且每个给药周期之间的间隔可以相同或不同。在一个优选的实施方案中，在每个给药周期给药一次或两次，优选一次，给药方式是每个周期的第一天给药。
在上述的每个实施方案中，本发明的抗PD-1抗体单次给药剂量可选自约100～300mg，优选200mg。抗VEGF抗体单次给药剂量约1～30mg/kg体重，优选7.5～15mg/kg体重，更优选7.5mg/kg体重、15mg/kg体重，或约60～1800mg，优选450～900mg，更优选450mg、900mg。优选地，采用注射给药，更优选地，采用静脉注射给药。
在上述方法的一些实施方案中，所述个体是人。
用途
第三方面，本发明涉及抗PD-1抗体联合抗VEGF抗体在制备用于在个体中预防或治疗肿瘤的药物中的用途。
第四方面，本发明涉及抗PD-1抗体联合抗VEGF抗体，其用于在个体中预防或治疗肿瘤疾病。
对于第三到第四方面，对它们的进一步限定如下：
在一个实施方案中，所述抗VEGF抗体是贝伐单抗(Bevacizumab)。
在一个实施方案中，抗PD-1抗体包含重链可变区VH和轻链可变区VL，其中重链可变区包含SEQ ID NO：7的序列或与其具有至少90％同一性的序列，且轻链可变区包含SEQ ID NO：8的序列或与其具有至少90％同一性的序列。
在一个实施方案中，所述抗PD-1抗体是包含重链和轻链的IgG4型抗体，其中所述重链包含SEQ ID NO：9的序列或与其具有至少90％同一性的序列，且其中所述轻链包含SEQ IDNO：10的序列或与其具有至少90％同一性的序列。
在一个实施方案中，所述抗PD-1抗体包含六个CDR，其中重链VH CDR1包含SEQ ID NO：1，且重链VH CDR2包含SEQ ID NO：2，重链VH CDR3包含SEQ ID NO：3，轻链VL CDR1包含SEQ ID NO：4，轻链VL CDR2包含SEQ ID NO：5，轻链VL CDR3包含SEQ ID NO：6。
优选地，所述抗PD-1抗体是PCT公开号WO2017025016A1中公开的 抗PD-1单克隆抗体AntibodyD。为方便表述，该抗PD-1单抗在本申请中也称为信迪利单抗，其制备方法参见WO2017025016A1。
在上述的每个实施方案中，本发明的抗PD-1抗体药物重量约100～300mg，优选200mg。抗VEGF抗体药物重量约60～1800mg，优选450～900mg，更优选450mg、900mg。
在一个实施方案中，所述的肿瘤为实体瘤或血液瘤，所述实体瘤为肝细胞癌。
在一些实施方案中，本发明的抗PD-1抗体和抗VEGF抗体组合物可以较用药前肿瘤完全缓解率提高10％～100％，部分缓解率提高10％～100％，疾病进展速度降低或疾病发展缓慢。
成套药物包装盒
在第五方面，本发明涉及一种成套药物包装盒，其特征在于，包含抗PD-1抗体和抗VEGF抗体。
在第六方面，本发明涉及成套药盒在制备预防或治疗肿瘤的药物中的用途，其特征在于包含抗PD-1抗体和抗VEGF抗体。
对于第五到第六方面，对它们的进一步限定如下：
所述抗PD-1抗体为公开号WO2017025016A1中公开的抗PD-1单克隆抗体Antibody D。
所述抗PD-1抗体包含以下剂量：约100～300mg，优选200mg。
所述抗VEGF抗体为贝伐单抗。
所述抗VEGF抗体包含以下剂量：约60～1800mg，优选450～900mg，更优选450mg、900mg。
定义
本文所使用的术语具有如下的定义。若本文没有定义，可适用专利申请WO2017025016A1中的定义。如果在两者中都没有给出定义，则本发明中所使用的术语具有本领域所通常理解的含义。
如本文所用，术语“和/或”是指可选项中的任一项或可选项的两项或更多项。
如本文所用，术语“包含”或“包括”是指包括所述的要素、整数或步骤，但是不排除任意其他要素、整数或步骤。在本文中，当使用术语“包含”或“包括”时，除非另有指明，否则也涵盖由所述及的要素、整数或步骤组合的情形。例如，当提及“包含”某个具体序列的抗体可变区时，也旨在涵盖由该具体序列组成的抗体可变区。
“个体”包括哺乳动物。哺乳动物包括但不限于，家养动物(例如，牛，羊，猫，狗和马)，灵长类动物(例如，人和非人灵长类动物如猴)，兔，以及啮齿类动物(例如，小鼠和大鼠)。在一些实施方案中，个体是人，包括儿童、青少年或成人。
术语“组合施用”是指施用两种或更多种治疗剂以治疗如本公开所述的疾病。这种施用包括以基本上同时的方式共同施用这些治疗剂，例如以具有固定比例的活性成分的单一组合物。或者，这种施用包括对于各个活性成分在多种或在分开的容器(例如片剂、胶囊、粉末和液体)中的共同施用。粉末和/或液体可以在施用前重构或稀释至所需剂量。此外，这种施用还包括以大致相同的时间或在不同的时间以顺序的方式使用每种类型的治疗剂。在任一情况下，治疗方案将提供药物组合在治疗本文所述的病症或病状中的有益作用。
用于本文时，“治疗”指减缓、中断、阻滞、缓解、停止、降低、或逆转已存在的症状、病症、病况或疾病的进展或严重性。
用于本文时，“预防”包括对疾病或病症或特定疾病或病症的症状的发生或发展的抑制。在一些实施方式中，具有家族病史的个体是预防性方案的候选。通常，术语“预防”是指在病征或症状发生前，特别是在具有风险的个体中发生前的药物施用。
术语“有效量”指本发明的制剂或组合物的量或剂量，其以单一或多次剂 量施用患者后，在治疗的患者中产生预期效果。有效量可以由作为本领域技术人员的主治医师通过考虑以下多种因素来容易地确定：诸如哺乳动物的物种；它的大小、年龄和一般健康；涉及的具体疾病；疾病的程度或严重性；个体患者的应答；施用的具体抗体；施用模式；施用制剂的生物利用率特征；选择的给药方案；和任何伴随疗法的使用。
“治疗有效量”指以需要的剂量并持续需要的时间段，有效实现所需治疗结果的量。本发明的制剂、抗体或抗体片段或其缀合物或组合物的治疗有效量可以根据多种因素如疾病状态、个体的年龄、性别和重量和抗体或抗体部分在个体中激发所需反应的能力而变动。治疗有效量也是这样的一个量，其中制剂、抗体或抗体片段或其缀合物或组合物的任何有毒或有害作用不及治疗有益作用。
“预防有效量”指以需要的剂量并持续需要的时间段，有效实现所需预防结果的量。通常，由于预防性剂量在对象中在疾病较早阶段之前或在疾病较早阶段使用，故预防有效量将小于治疗有效量。
如文中所用，术语“制剂”或“药物组合物”指适合于向动物优选哺乳动物(包括人)施用的包含至少一种活性成分和至少一种非活性成分的组合物。“液体制剂”或“液体组合物”是指液体形式的制剂。本发明的液体组合物包含(i)本发明所述的抗VEGF抗体、抗PD-1抗体；(ii)缓冲剂；和(iii)溶媒。本发明的制剂的组成可如上面涉及液体药物组合物的实施方案中所示。本发明的液体制剂优选为注射剂。
如文中所用，“缓冲剂”是指pH缓冲剂。例如，缓冲剂选自组氨酸、谷氨酸盐、磷酸盐、乙酸盐、柠檬酸盐和三羟甲基氨基甲烷。
如文中所用，术语“溶媒”是指用于溶解或悬浮活性成分和非活性成分以形成液体制剂的液体。可用于本发明的溶媒包括但不限于注射用水、注射用有机溶剂包括但不限于注射用油、乙醇、丙二醇等，或其组合。
术语“约”在与数字数值联合使用时意为涵盖具有比指定数字数值小10％ 的下限和比指定数字数值大10％的上限的范围内的数字数值。
缩写语
Figure PCTCN2021092987-appb-000004
实施例1
一、受试药物
抗PD-1抗体，信迪利单抗注射液，信达生物制药(苏州)有限公司。10ml∶100mg。
抗VEGF抗体，贝伐单抗注射液，制备方法及制剂组成参见专利公开号为CN 104922668A。4ml∶100mg。
索拉非尼，拜耳股份有限公司。0.2g/片。
二、入组标准
1.经组织学/细胞学确诊的肝细胞癌，或肝硬化者符合美国肝病研究学会(AASLD)肝细胞癌的临床诊断标准。
2.年龄≥18周岁。
3.ECOG(Eastern Cooperative Oncology Group)体力状态评分0或1分。
4.巴塞罗那临床肝癌(Barcelona Clinic Liver Cancer，BCLC)分期为C期。不适合根治性手术和/或局部治疗的B期。
5.首次给药前未接受过针对肝细胞癌的全身系统性抗肿瘤治疗。
6.根据实体瘤疗效评价标准1.1版(RECIST V1.1，Response Evaluation Criteria in Solid Tumors V1.1)，至少有1个可测量病灶，或经过局部治疗后明确进展(基于RECIST V1.1标准)的可测量病灶。
7.Child-Pugh(肝硬化分级标准)评分≤7分。
8.具有充分的器官和骨髓功能，入组前7天内实验室检查值符合下列要求(获得实验室检查的前14天内不允许给予任何血液成分、细胞生长因子、白蛋白及其他静脉或皮下给药的纠正治疗的药物)，具体如下：
1)血常规：绝对中性粒细胞计数(absolute neutrophil count，ANC)≥1.5×10 9/L；血小板计数(platelet，PLT)≥75×10 9/L；血红蛋白含量(hemoglobin，HGB)≥9.0g/dL。
2)肝功能：血清总胆红素(total bilirubin，TBIL)≤2×正常上限(upper limit of normal value，ULN)；丙氨酸氨基转移酶(alanine aminotransferase，ALT)和天门冬氨酸氨基转移酶(aspartate transferase，AST)≤5×ULN；血清白蛋白≥28g/L；碱性磷酸酶(alkaline phosphatase，ALP)≤5×ULN。
3)肾功能：血清肌酐(creatinine，Cr)≤1.5×ULN或肌酐清除率(clearance of creatinine，CCr)≥50mL/min(Cockcroft-Gault公式)；尿常规结果显示尿蛋白＜2+；对基线时尿常规检测显示尿蛋白≥2+的患者，应进行24小时尿液采集且24小时尿蛋白定量＜1g。
4)凝血功能：国际标准化比率(INR)和活化部分凝血活酶时间(APTT)≤1.5倍ULN。
9.预期生存时间≥12周。
10.育龄期女性患者或性伴侣为育龄期女性的男性患者，需在整个治疗期及末次用药后6个月采取有效的避孕措施。
11.签署书面知情同意书，而且能够遵守方案规定的访视及相关程序。
三、治疗方案
研究中研究用药定义为信迪利单抗、贝伐单抗和索拉非尼。研究药物的 首次给药应在随机分组当日(第1周期，第1天)开始，但不能晚于随机分组日期72小时，超出72小时仍未用药需与申办方讨论。应尽所有努力在随机分组当日开始试验治疗。对于所有其他研究治疗周期，可根据研究者的判断，出于管理方面的原因，可在每周期计划给药日的后3天内给药，如遇节假日，可顺延不超过一周。本研究的治疗方案如表1所示。
表1治疗方案和给药顺序
Figure PCTCN2021092987-appb-000005
四、实验结果
1.II/III期临床研究结果
本次研究的主要分析，采用RECIST标准评估，确定ORR、DCR、OS、PFS、HR。
Figure PCTCN2021092987-appb-000006
Figure PCTCN2021092987-appb-000007
*NE，not estimable，表示无法评估
实验结果表明，本发明信迪利单抗+贝伐单抗组合物一线治疗HCC的ORR、DCR、OS及PFS具有较好的治疗效果。

Claims (10)

  1. 一种用于预防或治疗肿瘤的药物组合，其特征在于，包含抗VEGF抗体或其抗原结合片段，抗PD-1抗体或其抗原结合片段，其中所述抗VEGF抗体优选为贝伐单抗；
    所述抗PD-1抗体包含六个CDR：
    其中重链VH CDR1包含SEQ ID NO：1，且重链VH CDR2包含SEQ ID NO：2，重链VH CDR3包含SEQ ID NO：3，轻链VL CDR1包含SEQ ID NO：4，轻链VL CDR2包含SEQ ID NO：5，轻链VL CDR3包含SEQ ID NO：6，为North定义规则。
  2. 根据权利要求1所述的药物组合，其特征在于，抗PD-1抗体包含重链可变区VH和轻链可变区VL，其中重链可变区包含SEQ ID NO：7的序列或与其具有至少90％同一性的序列，且轻链可变区包含SEQ ID NO：8的序列或与其具有至少90％同一性的序列；或
    所述抗PD-1抗体重链包含SEQ ID NO：9的序列或与其具有至少90％同一性的序列，且其中所述轻链包含SEQ ID NO：10的序列或与其具有至少90％同一性的序列；或
    所述抗PD-1抗体为信迪利单抗。
  3. 根据权利要1或2所述的药物组合，其特征在于，所述的抗VEGF抗体药物重量约300～2700mg，优选450mg、900mg、1800mg、2700mg；抗PD-1抗体药物重量约100～300mg，优选200mg。
  4. 根据权利要求1-3任一所述的药物组合，其特征在于，所述的肿瘤为实体瘤、血液肿瘤，优选为肝细胞癌。
  5. 根据权利要求4所述的药物组合，其特征在于，所述预防或治疗可以较用药前肿瘤完全缓解率提高10％～100％，部分缓解率提高10％～100％，疾病进展速度降低或疾病发展缓慢。
  6. 一种预防或治疗肿瘤相关疾病的方法，其特征在于，该方法包括像个体施用权利要求1-5任一项所述的抗VEGF抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段，抗VEGF抗体或其抗原结合片段单次给药剂量约1～30mg/kg体重，优选7.5～15mg/kg体重，更优选7.5mg/kg体重、15mg/kg体重，或约60～1800mg，优选450～900mg，更优选450mg、900mg；抗PD-1抗体或其抗原结合片段单次给药剂量约100～300mg，优选200mg，优选为每周一次、每两周一次、每三周一次、每四周一次、每五周一次或每六周一次，而且每个给药周期之间的间隔可以相同或不同；优选地，在每个给药周期给药一次或两次，更优选一次，给药方式是每个周期的第一天给药；
    优选地，采用注射给药，更优选地，采用静脉注射给药。
  7. 权利要求6所述的方法，其中所述抗VEGF抗体和抗PD-1抗体同时给药、分开给药或依次给药。
  8. 根据权利要求6或7所述的方法，其中所述依次给药是先施用PD-1抗体，再施用VEGF抗体，间隔时间不少于5分钟，优选为5分钟、10分钟、30小时、1小时、2小时、12小时、24小时。
  9. 一种成套药物包装盒，其包含有效量的权利要求1-5所述的抗VEGF抗体或其抗原结合片段和抗PD-1抗体或其抗原结合片段。
  10. 根据权利要求1-5任一项所述的药物组合或权利要求9所述的成套药物包装盒在制备预防或治疗肿瘤的药物的用途，所述肿瘤为实体瘤、血液肿瘤，优选为肝细胞癌。
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