WO2018072743A1 - Utilisation d'un anticorps anti-pd-1 conjugué à un inhibiteur de l'ido dans la préparation d'un médicament antitumoral - Google Patents

Utilisation d'un anticorps anti-pd-1 conjugué à un inhibiteur de l'ido dans la préparation d'un médicament antitumoral Download PDF

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WO2018072743A1
WO2018072743A1 PCT/CN2017/107051 CN2017107051W WO2018072743A1 WO 2018072743 A1 WO2018072743 A1 WO 2018072743A1 CN 2017107051 W CN2017107051 W CN 2017107051W WO 2018072743 A1 WO2018072743 A1 WO 2018072743A1
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cancer
seq
antibody
tumor
use according
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PCT/CN2017/107051
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English (en)
Chinese (zh)
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马珂
曹国庆
杨昌永
张连山
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苏州盛迪亚生物医药有限公司
江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN201780016510.XA priority Critical patent/CN108778332B/zh
Publication of WO2018072743A1 publication Critical patent/WO2018072743A1/fr

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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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a PD-1 antibody or antigen-binding fragment thereof and an IDO inhibitor compound (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindole) Use of indole-5-ylpiperidin-1-yl)phenyl)-1H-pyrazol-1-yl)ethanol in the preparation of antitumor drugs.
  • Indoleamine-pyrrole-2,3-dioxygenase is a heme-containing monomeric protein consisting of 403 amino acid residues, including two folds.
  • the alpha-helical domain, the large domain contains a catalytic pocket, and the substrate can be hydrophobic with the IDO in the catalytic pocket.
  • IDO is closely related to interferon (IFN), interleukin (IL), tumor necrosis factor and other cytokines, and they can activate IDO under certain conditions.
  • IFN interferon
  • IL interleukin
  • T-cells there is a regulation point that is very sensitive to tryptophan levels.
  • IDO depletes local tryptophan, causing T-cells to arrest in the middle of G1 phase, thereby inhibiting the proliferation of T cells;
  • IDO catalyzes the main product produced by the metabolism of tryptophan.
  • Canine urea is induced by oxygen free radicals to induce changes in intracellular oxidants and antioxidants to induce T-cell apoptosis, which is an intrinsic immunosuppressive mechanism present in the body.
  • IDO is highly expressed in leukemia cells, which inhibits the proliferation of local T cells, inhibits T-cell-mediated immune responses, and blocks T-cell activation signal transduction, thereby mediating tumor cell escape from the immune system. attack.
  • Most human tumors have been found to constitutively express IDO. Therefore, IDO is a potential target for cancer immunotherapy.
  • IDO inhibitors have a good application prospect in the pharmaceutical industry as a pharmaceutical, and a novel, highly effective and low toxicity selective IDO inhibitor compound is provided in the patent application PCT/CN2016/079054 (filed on Apr. 2016.04.12, publication No. WO2016169421A1). It has excellent effects and effects, especially excellent pharmacophore absorption activity, and its chemical name is (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1- a]isoindole-5-yl)piperidin-1-yl)phenyl)-1H-pyrazol-1-yl)ethanol, having the structure shown in the following formula (I)
  • PD-1 Programmed death-1
  • CTL-4 cytotoxic T Iymphocyte antigen 4
  • PD-1 has two ligands, PD-L1 and PD-L2.
  • PD-L1 is mainly expressed in T cells, On B cells, macrophages, and dendritic cells (DCs), expression on cells after activation can be up-regulated.
  • PD-L2 The expression of PD-L2 is relatively limited, mainly expressed on antigen presenting cells, such as activated macrophages and dendritic cells.
  • antigen presenting cells such as activated macrophages and dendritic cells.
  • the new study found that high PD-L1 protein expression was detected in human tumor tissues such as breast cancer, lung cancer, gastric cancer, colon cancer, kidney cancer, and melanoma, and the expression level of PD-L1 was closely related to the clinical and prognosis of patients. . Since PD-L1 acts as a second signaling pathway to inhibit T cell proliferation, PD-1/PD-L1 immunotherapy is currently a new class of anti-cancer immunotherapy aimed at using the body's own immune system to fight cancer.
  • Radiotherapy is effective in the treatment of localized cancer, but it is often a palliative treatment for the treatment of diffuse cancer. In these cases, chemotherapy remains the treatment of choice, but the serious toxic effects of chemotherapy on normal tissues often limit its clinical application.
  • Combination therapy is one of the important factors affecting the drug's effects.
  • IDO is highly expressed in antigen-presenting cells and tumor cells, and the IDO pathway down-regulates the body's immunity by inhibiting the proliferation of T cells.
  • CTLA-4, PD-1 and PD-L1 immunological checkpoint inhibitors
  • IDO is one of the important mechanisms by which tumors escape the immune system.
  • IDO inhibitors There are currently 4 IDO inhibitors for clinical trials. From the clinical perspective, if the IDO single-target effect is limited, the above-mentioned possible combination mechanism may be combined with an immunological checkpoint inhibitor to permit an increase in efficacy.
  • the technical problem to be solved by the present invention is to provide a use of a PD-1 antibody or an antigen-binding fragment thereof in combination with an IDO inhibitor compound, specifically a PD-1 antibody or antigen-binding fragment thereof and (S)-2-(4-(4) -(4-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)phenyl)-1H-pyrazol-1-yl)ethanol Use in the preparation of anti-tumor drugs.
  • the present invention provides a use of a PD-1 antibody or an antigen-binding fragment thereof in combination with an IDO inhibitor represented by the compound (I) for producing an antitumor drug, wherein the component PD-1 antibody or antigen-binding fragment thereof contain:
  • An antibody light chain variable region comprising at least one LCDR selected from the group consisting of: SEQ ID NO: 4, SEQ ID NO: 5 or SEQ ID NO: 6;
  • An antibody heavy chain variable region comprising at least one HCDR selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3,
  • the IDO inhibitor is a compound (S)-2-(4-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindole-5) represented by the formula (I).
  • the compound of the formula (I) is also represented by the code 41.
  • the antibody light chain variable region of the PD-1 antibody or antigen-binding fragment thereof of the invention comprises the LCDR1 as set forth in SEQ ID NO:4.
  • the antibody light chain variable region of the PD-1 antibody or antigen-binding fragment thereof of the invention comprises the LCDR2 as set forth in SEQ ID NO: 5.
  • the antibody light chain variable region of the PD-1 antibody or antigen-binding fragment thereof of the invention comprises the LCDR3 as set forth in SEQ ID NO: 6.
  • the antibody heavy chain variable region of the PD-1 antibody or antigen-binding fragment thereof of the invention comprises HCDR1 as set forth in SEQ ID NO: 1.
  • the antibody heavy chain variable region of the PD-1 antibody or antigen-binding fragment thereof of the invention comprises HCDR2 as set forth in SEQ ID NO:2.
  • the antibody heavy chain variable region of the PD-1 antibody or antigen-binding fragment thereof of the invention comprises the HCDR3 as set forth in SEQ ID NO:3.
  • the PD-1 antibody or antigen-binding fragment thereof of the invention is a humanized antibody or a fragment thereof.
  • the humanized antibody light chain sequence of the PD-1 antibody or antigen-binding fragment thereof of the invention is the sequence set forth in SEQ ID NO: 8 or a variant thereof;
  • the variant preferably has an amino acid change of 0-10 in the light chain variable region; more preferably an amino acid change of A43S.
  • the humanized antibody light chain sequence of the PD-1 antibody or antigen-binding fragment thereof of the present invention is the sequence shown in SEQ ID NO: 7 or a variant thereof;
  • the body preferably has an amino acid change of 0-10 in the heavy chain variable region; more preferably an amino acid change of G44R.
  • the humanized antibody light chain sequence is the sequence set forth in SEQ ID NO: 8
  • the heavy chain sequence is the sequence set forth in SEQ ID NO: 7.
  • sequences of the aforementioned humanized antibody heavy and light chains are as follows:
  • the tumor is selected from the group consisting of a PD-1 mediated related disease or condition and a disease characterized by the pathology of an IDO mediated tryptophan metabolism pathway.
  • the tumor is selected from the group consisting of an IDO overexpressing tumor.
  • the tumor is tolerant or insensitive to immunotherapy selected from the group consisting of PD-1 antibodies.
  • the tumor may be selected from the group consisting of lung cancer, gastric cancer, colon cancer, colon cancer, breast cancer, cervical cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, Kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck cancer, leukemia , lymphoma, myeloma or non-small cell lung cancer.
  • a tumor expressing PD-L1 is preferred, and more preferably breast cancer, lung cancer, gastric cancer, intestinal cancer, colon cancer, renal cancer, melanoma or non-small cell lung cancer.
  • the amount of the PD-1 antibody or antigen-binding fragment thereof in the present invention is not particularly limited and may be, for example, 0.1 to 1000 mg, preferably 50 to 600 mg, preferably 50 mg, 60 mg, 70 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg.
  • the amount of IDO used in the present invention is not particularly limited, and may be, for example, 0.1 to 1000 mg, preferably 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg, 1000 mg, more preferably 50 mg, 100 mg, 200 mg, 400 mg, 800 mg, 1000 mg.
  • the weight ratio of the PD-1 antibody or the antigen-binding fragment thereof to the IDO inhibitor represented by the formula (I) is also not particularly limited, and may be, for example, 0.001 to 1000, preferably 10 mg, 20 mg, 25 mg, 50 mg. 75 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg, 1000 mg, more preferably 50 mg, 100 mg, 200 mg, 400 mg, 800 mg, 1000 mg.
  • the frequency of administration of both may be determined according to the condition of the patient.
  • the IDO inhibitor is BID (twice a day) or once a day
  • the PD-1 antibody is QOD (administered once a day) ) or Q3W (given once every three weeks) or Q2W (given once every 2 weeks).
  • the present invention also relates to the use of a PD-1 antibody or antigen-binding fragment thereof in combination with an IDO inhibitor represented by the general formula (I) for the preparation of an antitumor drug, wherein the PD-1 antibody or antigen-binding fragment thereof
  • IDO inhibitors of the formula (I) are each prepared as a pharmaceutical composition, for example, as a tablet, a capsule, a pill, a granule, a solution, a suspension, a syrup, an injection (including an injection, respectively). Sterile powder for injection and concentrated solution for injection), suppository, inhalation or spray.
  • the pharmaceutical preparation of the present invention can also be administered to a patient or subject in need of such treatment by any suitable mode of administration, such as oral, parenteral, rectal, pulmonary or topical administration.
  • the pharmaceutical composition can be formulated into an oral preparation, such as an oral solid preparation such as a tablet, a capsule, a pill, a granule, or the like; or an oral liquid preparation such as an oral solution or an oral mixture. Suspension, syrup, and the like.
  • the pharmaceutical preparation may further contain a suitable filler, binder, disintegrant, lubricant, and the like.
  • the pharmaceutical preparation When used for parenteral administration, the pharmaceutical preparation can be prepared as an injection, including an injection, a sterile powder for injection, and a concentrated solution for injection.
  • the pharmaceutical composition When formulated as an injection, the pharmaceutical composition can be produced by a conventional method in the existing pharmaceutical field.
  • an additional agent may be added to the pharmaceutical preparation, and a suitable additional agent may be added depending on the nature of the drug.
  • the pharmaceutical preparation When used for rectal administration, can be formulated into a suppository or the like.
  • the pharmaceutical preparation For pulmonary administration, the pharmaceutical preparation can be formulated as an inhalant or a spray.
  • a particularly preferred injectable form of the PD-1 antibody is an injection or lyophilized powder comprising a PD-1 antibody, a buffer, a stabilizer, and optionally a surfactant.
  • the buffering agent may be selected from one or more of the group consisting of acetate, citrate, succinate, and phosphate.
  • the stabilizer may be selected from sugars or amino acids, preferably disaccharides such as sucrose, lactose, trehalose, maltose.
  • the surfactant is selected from the group consisting of polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, preferably the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, 40, 60 or 80. Most preferred is polysorbate 20.
  • Injectable forms of the most preferred PD-1 antibodies comprise PD-1 antibody, acetate buffer, trehalose and polysorbate 20.
  • the term "combination” is a mode of administration which includes various conditions in which two drugs are administered sequentially or simultaneously.
  • simultaneous means that PD-1 antibody is administered and administered in the same administration cycle.
  • the IDO inhibitor for example, delivers both drugs within 2 days, or within 1 day.
  • the so-called “sequential” administration includes the administration of PD-1 antibody and IDO inhibitor, respectively, in different administration cycles.
  • the present invention also provides a method of treating a tumor comprising administering a combination of the aforementioned PD-1 antibody and IDO inhibitor to a tumor patient.
  • the present invention provides the above PD-1 antibody in combination with the above IDO inhibitor as a medicament for treating antitumor.
  • the present invention also provides a pharmaceutical kit, or a pharmaceutical pack comprising the aforementioned IDO inhibitor and PD-1 antibody.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned effective amount of a PD-1 antibody and the aforementioned IDO inhibitor, and one or more pharmaceutically acceptable excipients, diluents or carriers.
  • the antibody of the present invention refers to an immunoglobulin, which is a tetrapeptide chain structure in which two identical heavy chains and two identical light chains are linked by interchain disulfide bonds.
  • the immunoglobulin heavy chain constant region has different amino acid composition and arrangement order, so its antigenicity is also different. Accordingly, immunoglobulins can be classified into five classes, or isoforms of immunoglobulins, namely IgM, IgD, IgG, IgA and IgE, and their corresponding heavy chains are ⁇ chain, ⁇ chain ⁇ , ⁇ , respectively. Chain, ⁇ chain.
  • IgG can be classified into IgG1, IgG2, IgG3, and IgG4.
  • Light chains are classified as either a kappa chain or a lambda chain by the constant region.
  • Each of the five types of Ig may have a kappa chain or a lambda chain.
  • the antibody light chain variable region of the present invention may further comprise a light chain constant region comprising a human or murine kappa, lambda chain or a variant thereof.
  • the antibody heavy chain variable region of the present invention may further comprise a heavy chain constant region comprising human or murine IgG1, 2, 3, 4 or a variant thereof.
  • variable region The sequence of about 110 amino acids near the N-terminus of the antibody heavy and light chains varies greatly, being the variable region (V region); the remaining amino acid sequence near the C-terminus is relatively stable and is a constant region (C region).
  • the variable region includes three hypervariable regions (HVR) and four relatively conserved framework regions (FR). The three hypervariable regions determine the specificity of the antibody, also known as the complementarity determining region (CDR).
  • Each of the light chain variable region (LCVR) and the heavy chain variable region (HCVR) consists of three CDR regions and four FR regions, and the order from the amino terminus to the carboxy terminus is: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the three CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the three CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3.
  • the CDR amino acid residues of the LCVR region and the HCVR region of the antibody or antigen-binding fragment of the invention conform to the known Kabat numbering rules (LCDR1-3, HCDE2-3) in number and position, or to the kabat and chothia numbering rules ( HCDR1).
  • humanized antibody also known as CDR-grafted antibody, refers to the transplantation of mouse CDR sequences into human antibody variable region frameworks, ie different types of humans.
  • An antibody produced in a germline antibody framework sequence It is possible to overcome the strong antibody variable antibody response induced by chimeric antibodies by carrying a large amount of mouse protein components.
  • framework sequences can be obtained from public DNA databases including germline antibody gene sequences or published references.
  • the germline DNA sequences of human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet at www.mrccpe.com.ac.uk/vbase), as well as in Kabat, EA, etc.
  • the CDR sequence of said PD-1 humanized antibody mouse is selected from the group consisting of SEQ ID NO: 1, 2, 3, 4, 5, 6.
  • the "antigen-binding fragment” as used in the present invention refers to a Fab fragment having antigen-binding activity, a Fab' fragment, an F(ab')2 fragment, and an Fv fragment sFv fragment which binds to human PD-1;
  • the antibody is selected from one or more of the CDR regions of SEQ ID NO: 1 to SEQ ID NO: 6.
  • the Fv fragment contains the antibody heavy chain variable region and the light chain variable region, but has no constant region and has the smallest antibody fragment of the entire antigen binding site.
  • Fv antibodies also comprise a polypeptide linker between the VH and VL domains and are capable of forming the desired structure for antigen binding.
  • the two antibody variable regions can also be joined by a different linker into a single polypeptide chain, referred to as a single chain antibody or a single chain Fv (sFv).
  • binding to PD-1 refers to the ability to interact with human PD-1.
  • antigen binding site refers to a three-dimensional spatial site that is discrete on an antigen and is recognized by an antibody or antigen-binding fragment of the present invention.
  • administering when applied to an animal, human, experimental subject, cell, tissue, organ or biological fluid, refers to an exogenous drug, therapeutic agent, diagnostic agent or composition and animal, human, subject Contact of the test subject, cell, tissue, organ or biological fluid.
  • administering can refer to, for example, therapeutic, pharmacokinetic, diagnostic, research, and experimental methods.
  • Treatment of the cells includes contact of the reagents with the cells, and contact of the reagents with the fluid, wherein the fluids are in contact with the cells.
  • administeristering and “treating” also means treating, for example, cells in vitro and ex vivo by reagents, diagnostics, binding compositions, or by another cell.
  • Treatment when applied to a human, veterinary or research subject, refers to therapeutic treatment, prophylactic or preventive measures, research and diagnostic applications.
  • Treatment means administering to a patient a therapeutic agent for internal or external use, such as a composition comprising any of the binding compounds of the present invention, the patient having one or more symptoms of the disease, and the therapeutic agent is known to have Therapeutic effect.
  • a therapeutic agent is administered in a subject or population to be treated to effectively alleviate the symptoms of one or more diseases, whether by inducing such symptoms to degenerate or inhibiting the progression of such symptoms to any degree of clinical right measurement.
  • the amount of therapeutic agent also referred to as "therapeutically effective amount” effective to alleviate the symptoms of any particular disease can vary depending on a variety of factors, such as the patient's disease state, age and weight, and the ability of the drug to produce a desired effect in the patient.
  • Whether the symptoms of the disease have been alleviated can be assessed by any clinical test method commonly used by a physician or other professional health care provider to assess the severity or progression of the condition.
  • Embodiments of the invention e.g., methods of treatment or preparations
  • an "effective amount” includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition.
  • An effective amount also means sufficient The amount that allows or facilitates the diagnosis.
  • An effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the overall health of the patient, the route and dosage of the method of administration, and the severity of the side effects.
  • An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • the expression "cell”, “cell line” and “cell culture” are used interchangeably and all such names include progeny.
  • the words “transformants” and “transformed cells” include primary test cells and cultures derived therefrom, regardless of the number of transfers. It should also be understood that all offspring may not be exactly identical in terms of DNA content due to intentional or unintentional mutations. Mutant progeny having the same function or biological activity as screened for in the originally transformed cell are included. In the case of a different name, it is clearly visible from the context.
  • the PD-1 antibody or antigen-binding fragment thereof of the present invention and the IDO inhibitor composition represented by the compound (I) can effectively solve the tumor heterogeneity, exert a remarkable effect of inhibiting tumor cells, and effectively inhibit the proliferation, migration or invasion of tumor cells.
  • Figure 1 is a graph showing the inhibitory effect of the PD-1 antibody of the present invention on the growth of MC38 tumors in combination with the IDO inhibitor of the formula (I) (also referred to as compound 41 in the examples).
  • the invention is further described in the following examples, which are not intended to limit the scope of the invention.
  • the experimental methods in the examples of the present invention which do not specify the specific conditions are usually in accordance with conventional conditions, such as the cold spring harbor antibody technology experiment manual, molecular cloning manual; or according to the conditions recommended by the raw material or commodity manufacturer.
  • Reagents without specific source are routine reagents purchased from the market.
  • the HC sequence of PD-1 of the present invention is (SEQ ID NO: 7), and the LC sequence is (SEQ ID NO: 8) as follows:
  • Lithium diisopropylamide (32.5 mL, 65.0 mmol) was added to tetrahydrofuran (50 mL), and pre-prepared 1-bromo-3-fluorobenzene 1a (8.75 g, 50.0 mmol, 25 mL) in tetrahydrofuran was added dropwise at -78 °C. Stir at -78 ° C for 1 hour. Further, a pre-formed solution of tert-butyl 4-formylpiperidine-1-carboxylate 1b (8.75 g, 50.0 mmol, 25 mL) in THF was added dropwise at -78 ° C, and stirred at -78 ° C for one hour. After the reaction, at -78 ° C The reaction was quenched with EtOAc (EtOAc) (EtOAc) (EtOAc) , yield 84.0%).
  • Tris(dibenzylideneacetone)dipalladium (2.92 g, 3.19 mmol) was added, and the reaction mixture was heated to 110 ° C, and the reaction was stirred for 2 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was evaporated to dryness crystals crystals. 6.38 g, gray oil, yield: 29%).
  • the compound 40b (9 g, 17.1 mmol) was dissolved in methanol (100 mL), and concentrated hydrochloric acid (12M, 5.7 mL) was added, and the reaction mixture was warmed to 45 ° C, and the reaction was stirred for 1 hour. After the reaction is completed, the reaction solution is cooled to The reaction mixture was stirred at room temperature, and then the mixture was filtered and evaporated. Solid, yield: 65%).
  • Test sample PD-1 antibody lyophilized powder (prepared according to the method of Patent Application PCT/CN2016/098982, Application No. 2016.09.14, Publication No. WO2017054646A1), IDO inhibitor compound 41, and the preparation method thereof are shown in the preparation examples.
  • Control drug IDO inhibitor compound INCB024360 (structure is Prepared according to the method disclosed in Example 3 on page 51 of the patent WO2010005958A1 (publication date 2010.01.14); NLG0919 (structure is It is prepared by the method disclosed in Example 25 of the specification of WO2012142237A1 (Publication Day 2010.10.18).
  • mice human PD-1 transgenic mice, 7-16 weeks, 80 rats, half male and half female.
  • the transgenic mouse was purchased from Cephrim. All of these human PD-1 mice were bred in a barrier environment provided by INNOVIVE in a special pathogen free (SPF) experimental animal. The feeding of experimental animals was carried out in accordance with laboratory standards approved by the Laboratory Animal Care and Use Committee (IACUC).
  • IACUC Laboratory Animal Care and Use Committee
  • ⁇ -cyclodextrin HPB, oral was purchased from Roquette;
  • CMC-Na Sodium carboxymethyl cellulose
  • DMA N,N-dimethylacetamide
  • IgG derived from human serum was purchased from Sigma-Aldrich;
  • DMEM high glucose
  • bovine serum containing 10% bovine serum, 1% streptomycin, 2 mM glutamine, 1% sodium pyruvate, 1% non-essential amino acids, and 1% vitamin
  • the culture medium was changed twice a week. Cells are passaged until sufficient numbers of cells can be planted in the mice. The requirements for planting cells are: 1) in the fast growing season (usually 70% to 90% of the bottom area saturation); 2) low passage times (usually in 2 to 4 generations); 3) must be changed the day before inoculation New culture solution; 4) Survival rate of 95% or more.
  • MC38 cells When transplanting MC38 cells into mice (Day 0), MC38 cells were first digested according to the standard steps of cell culture, washed twice with PBS, then counted, and finally mixed with PBS to a concentration of 5 ⁇ 10 6 MC38 single cell suspension. Prior to inoculation, the cell suspension was placed in an ice bath. Each hPD-1 transgenic mouse was inoculated with 0.1 mL of 500,000 (5 x 10 5 ) MC38 cells subcutaneously on the right side.
  • CMC-Na 0.5% CMC-Na, 10% cyclodextrin and 5% dextrose aqueous solution were prepared in advance and stored in a 4 ° C refrigerator.
  • PD-1 antibody PD-1 antibody lyophilized powder (200 mg) Firstly, water for injection (5 mL) was added to obtain a 40 mg/mL PD-1 antibody concentrate. The PD-1 antibody solution administered is prepared freshly at each administration. The PD-1 antibody concentrate (100 tL) was taken, and 13.2 mL of a 5% glucose solution (1:133.3 fold dilution) was added thereto, and the mixture was uniformly mixed to obtain a solution of 0.3 mg/mL. Each mouse was intraperitoneally injected (ip) with a volume of 10 mL/Kg and a final dose of 3 mg/kg/time.
  • ip intraperitoneally injected
  • Human plasma IgG IgG lyophilized powder (21 mg) was dissolved in physiological saline (7 mL) to obtain a 3 mg/mL IgG concentrate. The concentrate was dispensed into 7 1 mL tubes and stored at -20 °C. At each administration, one tube of the concentrate was dissolved at room temperature. It was diluted 1:10 with physiological saline (0.5 mL + 4.5 mL of physiological saline). After mixing well, a solution of 0.3 mg/mL was obtained. Each mouse was intraperitoneally injected (ip) with a volume of 10 mL/Kg and a final dose of 3 mg/kg/time.
  • ip intraperitoneally injected
  • INCB024360DMA solution First, weighed INCB024360 compound (300mg), then added DMA (0.9mL), fully mixed, completely dissolved, to obtain 333mg / mL INCB024360 concentrate, placed at room temperature. Every other day, INCB024360 concentrate (240 mL) was taken and a 10% cyclodextrin aqueous solution (3.76 mL) was slowly added during low speed rotation. If it does not dissolve, it can be dissolved in a short-term ultrasonic water bath. A dosing solution of 20 mg/mL was obtained. Each mouse was orally administered with a volume of 5 mL/Kg, and the final dose was 100 mg/Kg/time.
  • NLG0919 suspension NLG0919 compound (120 mg) was weighed in 0.5% CMC-Na (6 mL). The bath was then ultrasonicated to give a 20 mg/mL fine particle NLG0919 suspension. Place at room temperature. Each mouse was orally administered with a volume of 5 mL/Kg, and the final dose was 100 mg/Kg/time.
  • Compound 41 suspension Compound 41 compound (120 mg) was weighed and 0.5% CMC-Na (15 mL) was added. The bath was then ultrasonicated to obtain 8 mg/mL fine particles of NLG0919 suspension. The above suspension was diluted 1:2 times (3 mL plus 3 mL) and 1:4 times (1.5 mL plus 4.5 mL) with 0.5% CMC-Na, correspondingly obtained 4 mg/mL and 2 mg/mL fine particles of compound 41 Suspension. Place at room temperature. Each mouse was orally administered in a volume of 5 mL/Kg, and the final doses were 40, 20 and 10 mg/Kg/time.
  • the PD-1 antibody or hIgG is given once every other day for the morning.
  • the other three compounds, INCB024360, NLG0919, and Compound 41 were administered twice in the morning and evening, and the interval between morning and evening was 8 hours.
  • Sixty-four of the 80 mice transplanted with MC38 cells were randomly divided into 8 groups (4 per sex, #1 to #4 are female; #5 to #8 are male). This day is scheduled for the 8th day.
  • the specific experimental scheme of the test article according to the preset single use or combination, dose and route administration is as follows:
  • Ip is injected intraperitoneally; po is oral.
  • mice On the 2nd day after the end of the experiment (the 22nd day of the experiment), all the experimental mice continued the PK/PD study. Briefly, six groups of mice (Groups 3 through 8) were given a single dose (INCB024360, NLG0919, and Compound 41) according to the oral dose of this group. Of the 8 mice in each group, the first and second mice did not give any medicine, only as a zero point control. The third to fifth mice were orally administered 2 hours earlier, and the sixth to eighth mice were orally administered 8 hours earlier. Thus the mice terminate their lives with carbon dioxide at about the same time. Mouse whole blood samples were immediately removed through a cardiac needle, placed in an anticoagulation tube, and placed in an ice bath until centrifugation.
  • the blood sample was centrifuged at 15,000 rpm for 5 minutes in a centrifuge, and the supernatant (serum) in the test tube was taken out and placed in a new set of test tubes. Finally, all serum samples were stored in an ultra-low temperature freezer at -80 °C until they were sent to Shanghai Hengrui Pharmaceutical Co., Ltd. At the same time, the tumors in all mice were stripped, weighed on a balance, and recorded. After all the tumors were removed, the individual tumors were photographed and the tumors were then packaged separately and stored in an ultra-low temperature freezer at -80 °C.
  • Tumor volume and body weight of mice were measured twice a week.
  • mice If any of the mice has one of the following conditions, then the mouse will be aborted and removed from the data collection:
  • the grouping and treatment started from the 8th day after the inoculation (D8).
  • the experimental data of Table 1 above showed that the maximum tumor inhibition rate of PD-1 antibody or Compound 41 alone was 41.9% and 43.3%, PD-1.
  • the maximum tumor inhibition rate of the antibody combined with the IDO inhibitor compound 41 was the tumor inhibition rate of the reference IDO inhibitor compound INCB024360 (100 mg/kg) and NLG0919 (100 mg/kg) combined with PD-1 antibody on the 22nd day.
  • Compound 41 and PD-1 antibody inhibited tumor growth in a dose-dependent manner (10, 20, 40 mg/kg), and the maximum tumor inhibition rates were 63.7%, 69.0% and 84.3%, respectively.
  • the above combination group was statistically significant on day 22 compared with the control group or the PD-1 antibody alone group, and the 10 mg/kg IDO inhibitor compound 41 was equivalent to the 100 mg/kg IDO/TDO inhibitor NLG0919. Better than 100 mg/kg IDO inhibitor INCB024360.
  • the PD-1 antibody of the present invention combined with the IDO inhibitor compound 41 has a significantly better inhibitory effect on colon cancer (MC38) cells than the single component PD-1 antibody or compound 41, and is superior to the control group PD.

Abstract

L'invention concerne une utilisation d'un anticorps anti-PD-1, ou d'un fragment de liaison à l'antigène de ce dernier, conjugué à un inhibiteur de l'IDO dans la préparation d'un médicament antitumoral.
PCT/CN2017/107051 2016-10-21 2017-10-20 Utilisation d'un anticorps anti-pd-1 conjugué à un inhibiteur de l'ido dans la préparation d'un médicament antitumoral WO2018072743A1 (fr)

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CN108440388A (zh) * 2018-05-21 2018-08-24 上海再启生物技术有限公司 一种(s)-4-((2-溴-6-氟苯基)羟基甲基)哌啶-1-甲酸叔丁酯的制备方法
CN110664812A (zh) * 2018-07-02 2020-01-10 江苏恒瑞医药股份有限公司 一种包含咪唑并异吲哚类衍生物的药物组合物
WO2020239558A1 (fr) 2019-05-24 2020-12-03 Pfizer Inc. Polythérapies faisant appel à des inhibiteurs de cdk
WO2022118197A1 (fr) 2020-12-02 2022-06-09 Pfizer Inc. Délai de résolution d'événements indésirables liés à l'axitinib
WO2023057882A1 (fr) 2021-10-05 2023-04-13 Pfizer Inc. Combinaisons de composés d'azalactam avec un antagoniste de liaison à l'axe pd-1 pour le traitement du cancer
WO2023079428A1 (fr) 2021-11-03 2023-05-11 Pfizer Inc. Polythérapies utilisant un agoniste de tlr7/8

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WO2015085847A1 (fr) * 2013-12-12 2015-06-18 上海恒瑞医药有限公司 Anticorps anti-pd-1, son fragment de liaison à l'antigène, et son application médicale
WO2015119944A1 (fr) * 2014-02-04 2015-08-13 Incyte Corporation Combinaison d'un antagoniste de pd-1 et d'un inhibiteur de ido1 pour traiter le cancer
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WO2015085847A1 (fr) * 2013-12-12 2015-06-18 上海恒瑞医药有限公司 Anticorps anti-pd-1, son fragment de liaison à l'antigène, et son application médicale
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CN108440388A (zh) * 2018-05-21 2018-08-24 上海再启生物技术有限公司 一种(s)-4-((2-溴-6-氟苯基)羟基甲基)哌啶-1-甲酸叔丁酯的制备方法
CN110664812A (zh) * 2018-07-02 2020-01-10 江苏恒瑞医药股份有限公司 一种包含咪唑并异吲哚类衍生物的药物组合物
CN110664812B (zh) * 2018-07-02 2023-04-07 江苏恒瑞医药股份有限公司 一种包含咪唑并异吲哚类衍生物的药物组合物
WO2020239558A1 (fr) 2019-05-24 2020-12-03 Pfizer Inc. Polythérapies faisant appel à des inhibiteurs de cdk
WO2022118197A1 (fr) 2020-12-02 2022-06-09 Pfizer Inc. Délai de résolution d'événements indésirables liés à l'axitinib
WO2023057882A1 (fr) 2021-10-05 2023-04-13 Pfizer Inc. Combinaisons de composés d'azalactam avec un antagoniste de liaison à l'axe pd-1 pour le traitement du cancer
WO2023079428A1 (fr) 2021-11-03 2023-05-11 Pfizer Inc. Polythérapies utilisant un agoniste de tlr7/8

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