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WO2023160517A1 - Composition pharmaceutique comprenant des anticorps mixtes anti-ctla4 et anti-pd1 et son utilisation thérapeutique - Google Patents

Composition pharmaceutique comprenant des anticorps mixtes anti-ctla4 et anti-pd1 et son utilisation thérapeutique Download PDF

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Publication number
WO2023160517A1
WO2023160517A1 PCT/CN2023/077316 CN2023077316W WO2023160517A1 WO 2023160517 A1 WO2023160517 A1 WO 2023160517A1 CN 2023077316 W CN2023077316 W CN 2023077316W WO 2023160517 A1 WO2023160517 A1 WO 2023160517A1
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WO
WIPO (PCT)
Prior art keywords
antibody
seq
ctla4
heavy chain
light chain
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Ceased
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PCT/CN2023/077316
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English (en)
Chinese (zh)
Inventor
杨新爱
张英民
王培震
徐爱峰
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Qilu Pharmaceutical Co Ltd
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Qilu Pharmaceutical Co Ltd
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Filing date
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Priority to CN202380018913.3A priority Critical patent/CN118660720A/zh
Publication of WO2023160517A1 publication Critical patent/WO2023160517A1/fr
Anticipated expiration legal-status Critical
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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 disclosure relates to the treatment of cancer, particularly renal cancer, including immunotherapy and combination therapy. More specifically, the present disclosure relates to the use of a pharmaceutical composition comprising a mixed antibody against CTLA4 and anti-PD1 in the treatment of renal cancer.
  • the 5-year survival rate of surgical treatment of localized and locally advanced renal cancer can reach 93%, but about 20%-40% of early renal cancer will recur within 5 years after radical surgery.
  • Advanced RCC is mainly treated with medical treatment.
  • a total of 6 immunotherapy programs have been approved for marketing: 1) FDA approved Nivolumab for second-line treatment of advanced renal cancer in 2015; 2) FDA approved it in April 2018 Nivolumab combined with Ipilimumab for first-line treatment of advanced renal cancer; 3) FDA approved Pembrolizumab + axitinib in April and May 2019 and 4) Avelumab (anti-PD-L1 monoclonal antibody) + axitinib for advanced renal cancer First-line treatment; 5) In January 2021, the FDA approved Nivolumab + cabozantinib for the first-line treatment of advanced renal cancer; 6) In August 2021, the FDA approved pembrolizumab + lenvatinib for the first-line treatment of advanced renal cancer.
  • ZPML265 is a mixed antibody drug formulation consisting of a recombinant humanized IgG1 monoclonal antibody targeting human CTLA4 and a recombinant humanized IgG4 monoclonal antibody targeting human PD1, two different antibodies produced by a single host cell .
  • the mixed antibody can specifically bind CTLA4 and PD1 at the same time, thereby blocking the two immune checkpoint signaling pathways of CTLA4 and B7-1/B7-2 and PD1 and PDL1, releasing the inhibitory effect of the two pathways on T lymphocytes, and restoring Its functional activity and anti-tumor immune response enable the body to fight and kill tumors.
  • Lenvatinib is a multi-target tyrosine kinase inhibitor (TKI) with Has the following structural formula:
  • Lenvatinib has a novel binding mode, in addition to inhibiting other pro-angiogenic and oncogenic signaling pathway-related tyrosine kinases involved in tumor proliferation, it can also selectively inhibit the kinase activity of vascular endothelial growth factor (VEGF) receptors, such as VEGF-1, VEGF-2 and VEGF-3 etc.
  • VEGF vascular endothelial growth factor
  • the technical problem to be solved by the present disclosure is to provide a combination therapy of double immunity and targeting to fill the clinical gap in which combination therapy of double immunity and targeting has not yet been applied to kidney cancer, so as to solve such unmet clinical needs .
  • the present disclosure provides a pharmaceutical composition for treating renal cancer, comprising an effective amount of a mixed antibody of anti-CTLA4 and anti-PD1.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises additional therapeutic agents, including but not limited to chemotherapeutics, cytotoxic agents, radiotherapeutics, cancer vaccines, tumor reducing agents, targeted anticancer agents, antivascular Genetic agents, biological response modifiers, cytokines, hormones, anti-metastatic and immunotherapeutic agents.
  • additional therapeutic agents including but not limited to chemotherapeutics, cytotoxic agents, radiotherapeutics, cancer vaccines, tumor reducing agents, targeted anticancer agents, antivascular Genetic agents, biological response modifiers, cytokines, hormones, anti-metastatic and immunotherapeutic agents.
  • the additional therapeutic agent is preferably lenvatinib or a pharmaceutically acceptable salt thereof, more preferably lenvatinib mesylate.
  • the present disclosure preferably also provides a pharmaceutical composition for treating renal cancer, which contains an effective amount of a mixed antibody against CTLA4 and anti-PD1 and lenvatinib.
  • the mixed antibody is produced by a single host cell containing nucleic acids encoding two different anti-CTLA4 and anti-PD1 antibodies, wherein the sequences of the heavy chains HCDR1, HCDR2 and HCDR3 of the anti-CTLA4 antibody are SEQ ID NO: ID NO: 1, 2, 3, the sequences of anti-CTLA4 antibody light chain LCDR1, LCDR2 and LCDR3 are respectively shown in SEQ ID NO: 4, 5, 6, and the sequences of anti-PD1 antibody heavy chain HCDR1, HCDR2 and HCDR3 are respectively The sequences of the anti-PD1 antibody light chains LCDR1, LCDR2 and LCDR3 are shown in SEQ ID NO: 9, 10 and 11, and the sequences are shown in SEQ ID NO: 12, 13 and 14, respectively.
  • the heavy chain variable region sequence of the anti-CTLA4 antibody is shown in SEQ ID NO: 7
  • the light chain variable region sequence of the anti-CTLA4 antibody is shown in SEQ ID NO: 8
  • the heavy chain of the anti-PD1 antibody is shown in SEQ ID NO: 15
  • the light chain variable region sequence of the anti-PD1 antibody is shown in SEQ ID NO: 16.
  • the heavy chain sequence of the anti-CTLA4 antibody is shown in SEQ ID NO: 17
  • the light chain sequence of the anti-CTLA4 antibody is shown in SEQ ID NO: 18
  • the heavy chain sequence of the anti-PD1 antibody is SEQ ID NO: As shown in 19, the light chain sequence of the anti-PD1 antibody is shown in SEQ ID NO: 20.
  • the renal cancer is clear cell renal carcinoma.
  • the renal cancer is metastatic or recurrent renal cell carcinoma.
  • the dosage of the mixed antibody is 5 mg/kg, administered once every three weeks, by intravenous infusion; the initial dosage of lenvatinib mesylate is 20 mg or 14 mg or 10 mg, administered orally once a day.
  • the present disclosure also provides a method for treating renal cancer, the method comprising administering to a subject a pharmaceutical composition, the pharmaceutical composition being the aforementioned pharmaceutical composition comprising an effective amount of a mixed antibody of anti-CTLA4 and anti-PD1.
  • the present disclosure also provides a method for treating kidney cancer, the method comprising administering to a subject a pharmaceutical composition, the pharmaceutical composition being the aforementioned mixed antibody comprising an effective amount of anti-CTLA4 and anti-PD1 and lenval The pharmaceutical composition of Tini.
  • the present disclosure also provides the use of the pharmaceutical composition comprising an effective amount of the anti-CTLA4 and anti-PD1 mixed antibody and lenvatinib in the preparation of a drug for treating renal cancer.
  • the mixed antibody or the combined regimen of mixed antibody and lenvatinib provided by the present disclosure is expected to have controllable safety and good patient compliance for the medical treatment of advanced renal cell carcinoma, and can largely fill the dual There is a clinical gap in the treatment of kidney cancer with the combination of immunotherapy and targeted therapy, and it solves the urgent clinical needs that have not been met.
  • the term “about” is meant to include ⁇ 20%, or in some cases ⁇ 10%, or in some cases ⁇ 5%, or within ⁇ 1% in some cases, or ⁇ 0.1% in some cases.
  • antibody typically refers to a protein comprising two heavy (H) polypeptide chains (HC) and two light (L) polypeptide chains (LC) held together by covalent disulfide bonds and non-covalent interactions. ) Y-tetrameric protein. Natural IgG antibodies have such a structure. Each light chain consists of a variable domain (VL) and a constant domain (CL). Each heavy chain comprises a variable domain (VH) and constant region (CH).
  • IgA Five major classes of antibodies are known in the art: IgA, IgD, IgE, IgG, and IgM, and the corresponding heavy chain constant domains are called ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • IgG and IgA can be further divided into different For example, IgG can be divided into IgG1, IgG2, IgG3, IgG4, and IgA can be divided into IgA1 and IgA2.
  • the light chains of antibodies from any vertebrate species can be assigned to one of two distinct classes, called kappa and lambda, based on the amino acid sequence of their constant domains.
  • variable region exhibits significant variation in amino acid composition from one antibody to another and is primarily responsible for antigen recognition and binding.
  • the variable regions of each light chain/heavy chain pair form the antibody combining site such that an intact IgG antibody has two binding sites (ie it is bivalent).
  • the variable region (VH) of the heavy chain and the variable region (VL) of the light chain each contain three regions of extreme variability known as hypervariable regions (HVR) or, more commonly, Complementarity-determining regions (CDR), VH and VL each have four framework regions FR (or called framework regions), which are represented by FR1, FR2, FR3, and FR4, respectively.
  • the CDR and FR sequences typically appear in the following sequence of the heavy chain variable domain (VH) (or the light chain variable domain (VL)): FR1-HCDR1(LCDR1)-FR2-HCDR2(LCDR2)-FR3 -HCDR3 (LCDR3)-FR4.
  • VH heavy chain variable domain
  • VL light chain variable domain
  • antibodies in a broad sense include polyclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized antibodies and primatized antibodies, CDR-grafted antibodies, human antibodies (including recombinantly produced human antibodies), recombinantly produced antibodies, intrabodies, multispecific antibodies, bispecific antibodies, single chain antibodies, monovalent antibodies, multivalent antibodies, single domain antibodies, nanobodies, synthetic antibodies (including Mutant proteins and their variants) and so on.
  • monoclonal antibody refers to a substantially homogeneous antibody produced by a single cell clone that only targets a specific epitope.
  • Monoclonal antibodies can be prepared using various techniques known in the art, including hybridoma technology, recombinant technology, phage display technology, transgenic animals, synthetic technology or a combination of the above technologies, etc.
  • an antigen refers to a substance that is recognized and specifically bound by an antibody or a binding fragment in an antibody.
  • an antigen can include any immunogenic fragment or determinant of a selected target, including single-epitope, multi-epitope, Single domain, multi-domain, or complete extracellular domain (ECD) or protein.
  • polypeptide polypeptide
  • peptide protein
  • polymer may be linear, cyclic or branched, it may comprise modified amino acids, especially conservatively modified amino acids, and it may be interrupted by non-amino acids.
  • the term also includes amino acid polymers that have been modified, for example, by glycosylation, lipidation, acetylation, phosphorylation, methylation, and the like.
  • the term "mixed antibody” refers to a mixture of antibodies from a host cell (any antibody) that has been transfected with DNA encoding at least two different antibodies with different binding optionally cells from a single host cell line) produce a limited number of primary antibody species, optionally no more than two, three, four, five, six, seven, eight, nine or ten kinds.
  • DNA encoding at least two different heavy chains (HC) and at least two different light chains (LC) can be introduced into the same host cell, for example, a host cell can be encoded with at least two but no more than four DNA transfection of different antibodies with different binding specificities.
  • the sequences of all transfected DNA encoding HC and LC can be mutated, thereby altering the amino acid sequence of the antibody to disfavor non-cognate HC/LC pairing and strongly favor homologous HC/LC pairing.
  • one or both of the two different HCs may optionally be altered so as to disfavor heterodimer formation.
  • only one heavy chain is altered to prevent heterodimer formation.
  • DNA encoding only two different antibodies is introduced into a host cell, only one of the antibodies encoded by the DNA contains one or more partner orientation changes such that homologous HC/LC pairing, while the other antibody does not contain such changes.
  • the host cell produces only two major antibody species, where each HC is predominantly paired with its cognate LC, and the majority of the antibodies are two heavy chains with the same amino acid sequence and two heavy chains with the same amino acid sequence. Tetramers of light chains (see PCT/US2017/030676).
  • pharmaceutically acceptable salt refers to a salt of a compound, prepared from a compound having specified substituents and a relatively non-toxic acid or base.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
  • composition refers to a preparation or combination of preparations containing one, two or more active ingredients, which allows the active ingredients contained therein to exist in a form effective for biological activity, and does not contain any necessary ingredients for administration. Subjects of the formulation described above had unacceptably toxic additional ingredients.
  • pharmaceutical composition exists in the form of a combination of different separate preparations containing two or more active ingredients, they can be administered simultaneously, sequentially, separately or at intervals, the purpose of which is to exert the biological activities of multiple active ingredients and to use them together. Yu Zhi cure disease.
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant (eg, Freund's adjuvant (complete and incomplete)), excipient or vehicle with which the therapeutic agent is administered.
  • adjuvant eg, Freund's adjuvant (complete and incomplete)
  • an effective amount refers to the dose of a pharmaceutical formulation comprising an active ingredient of the present disclosure which, when administered to a patient in single or multiple doses, produces the desired effect in a treated patient.
  • An effective amount can be readily determined by the attending physician, who is skilled in the art, by considering various factors such as ethnic differences; body weight, age and health; the particular disease involved; the severity of the disease; the response of the individual patient; The specific antibody administered; the mode of administration; the bioavailability characteristics of the formulation administered; the chosen dosing regimen; and the use of any concomitant therapy.
  • host cell refers to a cell into which exogenous nucleic acid has been introduced, including the progeny of such a cell.
  • Host cells include “transformants” and “transformed cells,” which include the primary transformed cell and progeny derived therefrom, regardless of the number of passages. Progeny may not be identical in nucleic acid content to the parent cell, but may contain mutations. Included herein are mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell.
  • transfection refers to the introduction of exogenous nucleic acid into eukaryotic cells. Transfection can be achieved by various means known in the art, including electroporation, microinjection, liposome fusion, and the like.
  • nucleic acid molecule encoding refers to the sequence of deoxyribonucleotides along a deoxyribose nucleic acid chain. The order of these deoxyribonucleotides determines the order of amino acids along the polypeptide (protein) chain. Thus, a nucleic acid sequence encodes an amino acid sequence.
  • Antibodies or antigen-binding fragments thereof engineered in the present disclosure can be prepared and purified using conventional methods.
  • cDNA sequences encoding heavy and light chains can be cloned and recombined into expression vectors.
  • the recombinant immunoglobulin expression vector can stably transfect CHO cells.
  • Stable clones are obtained by expressing antibodies that specifically bind to human antigens.
  • Positive clones are expanded in serum-free medium in bioreactors for antibody production.
  • the culture fluid that secretes the antibody can be purified and collected using conventional techniques.
  • Antibodies can be concentrated by filtration using conventional methods. Soluble mixtures and aggregates can also be removed by conventional methods such as molecular sieves and ion exchange.
  • subject refers to any animal, such as a mammal or a marsupial.
  • Subjects of the present disclosure include, but are not limited to, humans, non-human primates (such as cynomolgus or rhesus or other types of rhesus monkeys), mice, pigs, horses, donkeys, cows, sheep, rats, and any species poultry.
  • the term “disease” or “condition” or “disorder” and the like refers to any change or disorder that damages or interferes with the normal function of a cell, tissue or organ.
  • the “disease” includes but is not limited to: tumor, pathogenic infection, autoimmune disease, T cell dysfunction disease, or immune tolerance defect (such as transplant rejection), etc.
  • tumor refers to a disease characterized by the pathological proliferation of cells or tissues, and their subsequent migration or invasion of other tissues or organs. Tumor growth is usually uncontrolled and progressive, without inducing or inhibiting normal cell proliferation. Tumor includes “cancer”, which generally refers to all malignant tumors.
  • kidney cancer used in this article is also called "renal cell carcinoma", which is a malignant tumor originating from the renal tubular epithelium, accounting for 80% to 90% of renal malignant tumors.
  • the most common histopathological type of RCC is clear cell RCC.
  • treatment refers to clinical intervention in an attempt to alter the course of a disease caused by an individual or a cell, either for prevention or for intervention in the course of clinical pathology.
  • Therapeutic effects include, but are not limited to, preventing the occurrence or recurrence of the disease, relieving symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing down the progression of the disease, improving or relieving the disease, remission or improving the prognosis, etc.
  • the term "combination” relates to a treatment regimen that provides at least two or more different therapies, either physical, such as radiotherapy, or chemical, such as administration of Drugs for the subject, which also include combination drugs.
  • “Combined drug” refers to a combination comprising two or more pharmaceutical preparations each having an active ingredient, which need to be used in combination when administered to a subject.
  • the active ingredients can be mixed together to form a single administration unit, or they can be independently used as administration units and used separately; when administered, different pharmaceutical preparations can be administered substantially synchronously, simultaneously or sequentially.
  • OS Overall survival
  • PFS Progression-free survival
  • ORR Objective response rate
  • DCR Disease control rate
  • CR Complete remission
  • Partial Response The sum of the target lesion diameters is reduced by at least 30% compared with the baseline level.
  • Progression of disease taking the minimum value of the sum of the diameters of all target lesions measured throughout the experimental study as a reference, the sum of the diameters increased by at least 20% (if the baseline measurement value is the smallest, the baseline value is used as a reference); otherwise
  • the absolute value of the sum of diameters must increase by at least 5mm (the appearance of one or more new lesions is also considered as disease progression).
  • Stable disease The degree of reduction of the target lesion does not reach the PR level, and the degree of increase does not reach the PD level, in between, The minimum value of the sum of diameters can be used as a reference during research.
  • Duration of response was defined as the time between when the tumor was first assessed as CR or PR (whichever was recorded first) and when it was first assessed as PD or death.
  • TEAE Adverse events during treatment
  • Treatment-related adverse events refer to adverse events related to the study drug that occurred during treatment.
  • SAE Serious adverse event
  • AST Alanine aminotransferase
  • ALT aspartate aminotransferase
  • Dosing regimen The dose of ZPML265 is 5mg/kg, administered by intravenous infusion once every three weeks.
  • Table 2 lists the comparison of Nivolumab combined with Ipilimumab in the Checkmate214 study and ZPML265 monotherapy in advanced renal cancer with an incidence of ⁇ 10% of TRAEs.
  • Example 3 An evaluation of the tolerance, safety, and pharmacokinetics of ZPML265 combined with lenvatinib in patients with advanced renal cell carcinoma Phase Ib clinical study of preliminary efficacy
  • Dosing regimen The initial dose of lenvatinib mesylate is 20 mg or 14 mg or 10 mg, administered orally once a day; the dose of ZPML265 is 5 mg/kg, administered by intravenous infusion once every three weeks.
  • Evaluation indicators The endpoints of this study are safety and efficacy indicators and other indicators.

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Abstract

La présente invention concerne l'utilisation d'une composition pharmaceutique comprenant des anticorps mixtes anti-CTLA4 et anti-PD1 en combinaison avec le lenvatinib pour traiter le cancer du rein.
PCT/CN2023/077316 2022-02-22 2023-02-21 Composition pharmaceutique comprenant des anticorps mixtes anti-ctla4 et anti-pd1 et son utilisation thérapeutique Ceased WO2023160517A1 (fr)

Priority Applications (1)

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CN202380018913.3A CN118660720A (zh) 2022-02-22 2023-02-21 包含抗ctla4和抗pd1的混合抗体的药物组合物及其治疗用途

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CN202210164234 2022-02-22

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017205014A1 (fr) * 2016-05-26 2017-11-30 Qilu Puget Sound Biotherapeutics Corporation Mélanges d'anticorps
US20190276542A1 (en) * 2016-11-08 2019-09-12 Qilu Puget Sound Biotherapeutics Corporation Anti-pd1 and anti-ctla4 antibodies
CN110404066A (zh) * 2018-04-28 2019-11-05 齐鲁制药有限公司 一种抗人pd-1的单克隆抗体制剂、联合用药物及其用途
WO2021143799A1 (fr) * 2020-01-17 2021-07-22 嘉和生物药业有限公司 Utilisation d'un anticorps anti-pd-1 en combinaison avec du fruquintinib dans la préparation de médicaments pour le traitement du cancer
WO2021178657A1 (fr) * 2020-03-05 2021-09-10 Merck Sharp & Dohme Corp. Méthodes de traitement du cancer à l'aide d'une combinaison d'un antagoniste de pd-1, d'un antagoniste de ctla4 et de lenvatinib ou d'un sel pharmaceutiquement acceptable associé
WO2021219138A1 (fr) * 2020-04-30 2021-11-04 正大天晴药业集团股份有限公司 Médicament combiné pour le traitement du cancer du rein

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017205014A1 (fr) * 2016-05-26 2017-11-30 Qilu Puget Sound Biotherapeutics Corporation Mélanges d'anticorps
US20190276542A1 (en) * 2016-11-08 2019-09-12 Qilu Puget Sound Biotherapeutics Corporation Anti-pd1 and anti-ctla4 antibodies
CN110312523A (zh) * 2016-11-08 2019-10-08 齐鲁皮吉特湾生物治疗有限公司 抗pd1和抗ctla4抗体
CN110404066A (zh) * 2018-04-28 2019-11-05 齐鲁制药有限公司 一种抗人pd-1的单克隆抗体制剂、联合用药物及其用途
WO2021143799A1 (fr) * 2020-01-17 2021-07-22 嘉和生物药业有限公司 Utilisation d'un anticorps anti-pd-1 en combinaison avec du fruquintinib dans la préparation de médicaments pour le traitement du cancer
WO2021178657A1 (fr) * 2020-03-05 2021-09-10 Merck Sharp & Dohme Corp. Méthodes de traitement du cancer à l'aide d'une combinaison d'un antagoniste de pd-1, d'un antagoniste de ctla4 et de lenvatinib ou d'un sel pharmaceutiquement acceptable associé
WO2021219138A1 (fr) * 2020-04-30 2021-11-04 正大天晴药业集团股份有限公司 Médicament combiné pour le traitement du cancer du rein

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