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WO2018032793A1 - Nouvel anticorps obtenu par couplage d'un immuno-agoniste à petite molécule et d'un anticorps pd-1, et son application dans la résistance tumorale - Google Patents

Nouvel anticorps obtenu par couplage d'un immuno-agoniste à petite molécule et d'un anticorps pd-1, et son application dans la résistance tumorale Download PDF

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Publication number
WO2018032793A1
WO2018032793A1 PCT/CN2017/081007 CN2017081007W WO2018032793A1 WO 2018032793 A1 WO2018032793 A1 WO 2018032793A1 CN 2017081007 W CN2017081007 W CN 2017081007W WO 2018032793 A1 WO2018032793 A1 WO 2018032793A1
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Prior art keywords
antibody
small molecule
immunoagonist
novel
compound
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Ceased
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Chinese (zh)
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靳广毅
王竹林
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Shenzhen Kangjuzheng Pharmaceutical Technology Co Ltd
Shenzhen University
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Shenzhen Kangjuzheng Pharmaceutical Technology Co Ltd
Shenzhen University
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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
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • 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
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily

Definitions

  • the present invention relates to the field of immunochemistry, and more particularly to a PD-1 antibody having an inhibitory effect on the immune system and a novel type of small molecule immunoagonist to form a novel antibody, and the preparation and resistance of the novel antibody Application in tumors.
  • PD-1 protein is an immunosuppressive protein that inhibits immune balance in normal human immunity.
  • PD-1 also inhibits the normal anti-tumor immune response; therefore, PD-1 antibodies can relieve this tumor's immunosuppressive effect (Chinese Journal of Biologicals, June 2014, Volume 27, Issue 6) 856-860), this effect has produced many long-term treatment effects in clinical treatment of tumors.
  • PD-1 antibodies have been marketed in the United States, Japan and other countries (see the following website: http://www.fiercebiotech.com/biotech/anti-pd-1-cancer-star-nivolumab-wins-world- S-first-regulatory-approval;http://www.pharmatimes.com/news/japan_approves_worlds_first_pd-1_drug%2C_nivolumab_1002153).
  • the role of the PD-1 antibody is only to relieve the "brake" of the immune system, so its efficacy is significant, but it is only effective in about 20% to 30% of patients.
  • a product is needed to simultaneously improve the autoimmune ability of tumor patients to produce synergistic effects and higher therapeutic effects.
  • the technical problem to be solved by the present invention is that the above-mentioned PD-1 antibody has a low therapeutic effect ratio, A novel antibody that conjugates a PD-1 antibody to a small molecule immunoagonist and provides its antitumor application.
  • the technical solution of the present invention is to provide a novel antibody of a small molecule immunoagonist coupled with a PD-1 antibody, which is obtained by coupling a small molecule immunoagonist and a PD-1 antibody.
  • the novel antibodies include the following compounds of the general formula [I]:
  • the X 2 represents a thiocarbonyl group:
  • the small molecule immunoagonist is a compound of formula 2-1, 2-2, 2-3:
  • the X 2 represents the following group:
  • u is an integer of 0 to 12;
  • X 2 represents the following groups:
  • u is an integer from 0 to 12;
  • X 2 represents the following groups:
  • PEG is a polyethylene glycol group
  • diethylene glycol groups Triethylene glycol group is Tetraethylene glycol group is
  • the present invention provides a novel bifunctional antibody 10, 12, 14, 16, 18 which has both an immunosuppressive release function (represented by a significantly enhanced antitumor effect) and an activated immune function.
  • the invention is created by providing both an immunosuppressive release function (with a significantly improved anti-tumor) The tumor effect is representative), and at the same time, it has a novel antibody that activates an immune function and a preparation method thereof.
  • the invention is created by providing a novel antibody having the above dual functions and promoting the proliferation of active T cells and a preparation method thereof.
  • Another object of the present invention is to provide a novel antibody prepared for use in the inhibition and stimulation of immunosuppression, antiviral, tumor immunomodulation and tumor bioimmunotherapy.
  • the novel conjugated antibody of the present invention can be used for immunotherapy and immunomodulation of malignant tumors, and the administration method can be intraperitoneal injection, subcutaneous injection, intramuscular injection, and intravenous injection; or the novel antibody and immune cells of the present invention can be used (for example, dendritic cells, natural killer cells NK, lymphocytes, monocytes/macrophages, granulocytes, etc. are co-cultured, and methods for isolating immune cells in vivo are isolated.
  • novel antibodies and the corresponding small molecule immunoagonist compounds or salts thereof for preparing the same can be formulated into various therapeutic drugs, can be combined with other drugs, synergistic drugs, or made pharmaceutically acceptable.
  • a complex or combination of carriers can be used to formulate various therapeutic drugs, can be combined with other drugs, synergistic drugs, or made pharmaceutically acceptable.
  • novel bifunctional antibodies of the invention or their salts can be used in the preparation of various ratios of therapeutic agents.
  • Figure 1 shows the interleukin-6 (IL-6) eliciting activity of novel antibodies 10, 12, 14, 16, 18.
  • FIG 2 is an interleukin-12 (IL-12)-stimulating activity of novel antibodies 10, 12, 14, 16, 18.
  • IL-12 interleukin-12
  • Figure 3 is the IFN- ⁇ eliciting activity of novel antibodies 10, 12, 14, 16, 18.
  • Figure 4 is the antitumor activity of novel antibodies 10, 12, 14, 16, 18.
  • Figure 5 is a graph showing the promotion of T cell proliferation activity of novel antibodies 10, 12, 14, 16, 18.
  • Figure 6 is the IFN- ⁇ -stimulating activity of small molecule immunoagonists 19, 20, 21, 22, 20-2.
  • Figure 7 shows interleukin-6 (IL-6) eliciting activity of small molecule immunoagonists 19, 20, 21, 22.
  • IL-6 interleukin-6
  • Figure 8 is a functional feature of the PD-1 antibody.
  • Figures 9, 10 and 11 are functional features of the PD-1 antibody of the novel antibodies of the present invention.
  • the present invention provides a novel antibody which conjugates a PD-1 antibody to a small molecule immunoagonist, and has the following structural formula [I]:
  • the X 2 represents a thiocarbonyl group:
  • the small molecule immunoagonist is a compound of formula 2-1, 2-2, 2-3:
  • the X 2 represents the following group:
  • u is an integer of 0 to 12;
  • X 2 represents the following groups:
  • u is an integer from 0 to 12;
  • X 2 represents the following groups:
  • PEG is a polyethylene glycol group
  • diethylene glycol groups Triethylene glycol group is Tetraethylene glycol group is Wait.
  • a small molecule immunoagonist is a compound represented by Formula 1, 2-1, 2-2, 2-3, and 4
  • a typical representative structural formula of a novel antibody formed by using a PD-1 antibody and other antibodies as an antibody moiety is as follows :
  • n is a number between 1 and 10.
  • the small molecule of the novel antibody-conjugated precursor is a compound represented by Formula 1, 2-1, 2-2, 2-3, and 4, a typical representative of a novel antibody formed by using a PD-1 antibody as a representative antibody is exemplified.
  • the synthesis and its structural formula are as follows:
  • the antibody is selected from the group consisting of PD-1 mAb; it can also be applied to other similar immunosuppressive antibodies, such as PD-L1 antibody, CTLA-4 antibody, TIM-3 antibody, LAG3. Antibody, TIGIT antibody, etc.; PD-1 mAb includes various monoclonal antibodies (IgG1, IgG2, and IgG4) against human PD-1 protein, and the sequence of the PD-1 protein is as follows:
  • the PD-1 antibody is directed against the sequence as an epitope sequence of an antigen.
  • the preparation method, reaction conditions and feed ratio of the coupled precursor compound 15 and 17 are the same as those of the preparation of the compound 13, except that use replace;
  • the PD-1 antibody is preferably Nivolumab (BMS-936558), Pembrolizumab (MK-3475), AMP-514, AMP-224, Pidilizumab; but is also applicable to PD-1 antibodies from other sources.
  • Nivolumab According to the method of preparing 5C4, 17D8, 2D3, 4H1, 4A11, 7D3 and 5F4 in the patent WO2006121168; and the method disclosed in CN201380062005.0.
  • Pembrolizumab is in accordance with the method disclosed in the patent WO2008156712 (A1), the preparation of h409A11, and its US Pat. No. 8,354,509 and US Pat. No. 8,900,587.
  • Pidilizumab is in accordance with the methods disclosed in the patents WO2009014708 and WO2009114335.
  • the method of preparing the PD-1 antibody can also employ other disclosed methods known in the art, such as those disclosed in Chinese Patent No. CN201410838610.9; CN201310199947.5; CN201380079581.6; CN201480011008.6; CN201310258289.2.
  • PD-1 antibody can also be purchased from the market, such as the PD-1 antibody from BioXCell, USA, name: anti h PD-1 (h CD279) IgG1, content 95%; Beijing Kehao Biotechnology Co., Ltd. anti-PD-1 Fully monoclonal antibody.
  • the source of the PD-1 antibody in the novel antibody synthesis method of the present invention is not limited thereto.
  • reaction concentrations of the following PD-1 antibodies were all 1 equivalent (1 eq, relative to other reactants).
  • Preferred antibody concentration stimulation with 0.1 ⁇ M for 24 h.
  • Peripheral monocytes were taken from volunteers, and T cells (suspended cells) were isolated and cultured at 37 ° C, 5% CO 2 serum-containing medium for 7 days, and plated at 1 ⁇ 10 6 /ml/well.
  • Preferred antibody concentration stimulation with 0.1 ⁇ M for 24 h.
  • mice 6-8 week old Balb/C mice were randomly divided into 7 groups. 2.5x10 5 4T1 tumor cells were implanted subcutaneously in the back of the mouse. The PBS blank control and 10 mg/kg of PD-1 antibody were administered respectively. The control drug and the novel antibody 10, 12, 14, 16, 18 were administered at a dose of 10 mg/kg and a volume of 100 ⁇ L. Intraperitoneal injection. On the first day after tumor implantation, each group was administered on days 7, 15, 22, and 29, respectively. Mice were euthanized when the tumor reached 1500 mm 3 or greater than 15% of body weight. Tumor inhibition results are shown in Figure 4. It can be seen that the novel antibody-treated group of the present invention has a markedly enhanced antitumor effect.
  • T cells (suspended cells) were isolated and cultured at 37 ° C, 5% CO 2 serum-containing medium for 7 days, and serum-free medium was added simultaneously with the novel antibody and PD-1 of the present invention. (All concentrations were 1 ⁇ M), and CCK-8 cells staining method was detected 3 days later. It can be seen that the novel antibodies of the present invention can promote T cell proliferation by potentiating blocking PD-1 and activating innate immunity. The result is shown in Figure 5.
  • the isolated peripheral blood lymphocytes were resuspended in physiological saline at 900 g for 10 min. Wash twice.

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Abstract

L'invention concerne un anticorps couplé obtenu par couplage d'un immuno-agoniste à petite molécule et d'un anticorps PD-1, et son application. L'anticorps couplé est obtenu au moyen d'une réaction de couplage entre un immuno-agoniste à petite molécule et un anticorps PD-1. Il comprend un composé de formule [I] et peut être utilisé dans l'immunothérapie et l'immunomodulation des tumeurs malignes.
PCT/CN2017/081007 2016-08-15 2017-04-19 Nouvel anticorps obtenu par couplage d'un immuno-agoniste à petite molécule et d'un anticorps pd-1, et son application dans la résistance tumorale Ceased WO2018032793A1 (fr)

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CN2016106719718 2016-08-15
CN201610671971.8A CN106267188B (zh) 2016-08-15 2016-08-15 小分子免疫激动剂偶联pd-1抗体的新型抗体及其在抗肿瘤中的应用

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US11130796B2 (en) 2017-01-05 2021-09-28 Kahr Medical Ltd. SIRPalpha-41BBL fusion protein and methods of use thereof
US11299530B2 (en) 2017-01-05 2022-04-12 Kahr Medical Ltd. SIRP alpha-CD70 fusion protein and methods of use thereof
US11566060B2 (en) 2017-01-05 2023-01-31 Kahr Medical Ltd. PD1-CD70 fusion protein and methods of use thereof
US11702458B2 (en) 2017-01-05 2023-07-18 Kahr Medical Ltd. PD1-41BBL fusion protein and methods of use thereof
US12134638B2 (en) 2018-07-11 2024-11-05 Kahr Medical Ltd. SIRPalpha-4-1BBL variant fusion protein and methods of use thereof
US12281117B2 (en) 2018-04-03 2025-04-22 Shenzhen University Small molecule immune agonists and immune targeting compounds and application thereof
US12286466B2 (en) 2018-07-11 2025-04-29 Kahr Medical Ltd. PD1-4-1BBL variant fusion protein and methods of use thereof

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CN106267188B (zh) * 2016-08-15 2025-06-17 深圳大学 小分子免疫激动剂偶联pd-1抗体的新型抗体及其在抗肿瘤中的应用
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CN111704614B (zh) * 2020-04-15 2021-10-22 深圳大学 一种系列免疫激动剂
CN115068625B (zh) * 2021-03-16 2024-07-02 中国科学院上海药物研究所 Pd-l1和tlr7双靶向纳米抗体偶联药物及其在抗肿瘤中的应用
WO2023174312A1 (fr) * 2022-03-15 2023-09-21 中国科学院上海药物研究所 Médicament conjugué à nanocorps à double ciblage anti-pd-l1 humain et tlr7 et son utilisation dans la résistance à une tumeur
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CN116966313A (zh) * 2023-04-27 2023-10-31 深圳市康居正医药科技有限公司 偶联抗体的免疫激活型小分子化合物及应用

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CN106267188A (zh) * 2016-08-15 2017-01-04 深圳大学 小分子免疫激动剂偶联pd‑1抗体的新型抗体及其在抗肿瘤中的应用

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11130796B2 (en) 2017-01-05 2021-09-28 Kahr Medical Ltd. SIRPalpha-41BBL fusion protein and methods of use thereof
US11299530B2 (en) 2017-01-05 2022-04-12 Kahr Medical Ltd. SIRP alpha-CD70 fusion protein and methods of use thereof
US11566060B2 (en) 2017-01-05 2023-01-31 Kahr Medical Ltd. PD1-CD70 fusion protein and methods of use thereof
US11702458B2 (en) 2017-01-05 2023-07-18 Kahr Medical Ltd. PD1-41BBL fusion protein and methods of use thereof
US11897937B2 (en) 2017-01-05 2024-02-13 Kahr Medical Ltd. SIRPalpha-41BBL fusion protein and methods of use thereof
US12331098B2 (en) 2017-01-05 2025-06-17 Kahr Medical Ltd. SIRPalpha-41BBL fusion protein and methods of use thereof
US12281117B2 (en) 2018-04-03 2025-04-22 Shenzhen University Small molecule immune agonists and immune targeting compounds and application thereof
US12134638B2 (en) 2018-07-11 2024-11-05 Kahr Medical Ltd. SIRPalpha-4-1BBL variant fusion protein and methods of use thereof
US12286466B2 (en) 2018-07-11 2025-04-29 Kahr Medical Ltd. PD1-4-1BBL variant fusion protein and methods of use thereof

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