WO2025201363A1 - Anticorps bloquant les cytokines et son utilisation - Google Patents

Anticorps bloquant les cytokines et son utilisation

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Publication number
WO2025201363A1
WO2025201363A1 PCT/CN2025/084866 CN2025084866W WO2025201363A1 WO 2025201363 A1 WO2025201363 A1 WO 2025201363A1 CN 2025084866 W CN2025084866 W CN 2025084866W WO 2025201363 A1 WO2025201363 A1 WO 2025201363A1
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WIPO (PCT)
Prior art keywords
antibody
yervoy
ifn
metastatic
cancer
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PCT/CN2025/084866
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English (en)
Chinese (zh)
Inventor
庄智弘
黄奕中
赵士伟
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Kaohsiung Medical University
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Kaohsiung Medical University
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Publication of WO2025201363A1 publication Critical patent/WO2025201363A1/fr
Pending legal-status Critical Current
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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells

Definitions

  • the present invention relates to a specific selective antibody, in particular an antibody for improving the efficacy and safety of treating metastatic cancer.
  • Yervoy can lead to systemic immune overactivation and systemic autoimmune toxicity.
  • FDA reports and literature indicate that Yervoy administration may cause side effects such as enteritis, hepatitis, endocrine abnormalities, and toxic epidermolysis due to overactive immune system. Furthermore, it may cause inflammation of the nervous system, leading to paralysis. Therefore, increasing the selectivity of Yervoy for tumors to reduce side effects is urgently needed.
  • the term "antibody” refers to a protein comprising at least one heavy (H) chain and one light (L) chain interconnected by disulfide bonds.
  • Each heavy chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region (abbreviated herein as CH).
  • VH heavy chain variable region
  • CH heavy chain constant region
  • the heavy chain constant region comprises a hinge and three domains: CH1, CH2, and CH3.
  • each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region.
  • the light chain constant region comprises one domain (abbreviated herein as CL).
  • the peptide is an interferon.
  • the peptide comprises IFN- ⁇ , IFN- ⁇ or IFN- ⁇ .
  • the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition comprises: the antibody as described above; and a pharmaceutically acceptable carrier.
  • the effective dose is 0.1 mg/kg-6 mg/kg; in a preferred embodiment, the effective dose is 0.2 mg/kg-4.5 mg/kg; in an optimal embodiment, the effective dose is 0.5 mg/kg-3 mg/kg.
  • the present invention further provides a method of treating a subject having metastatic cancer, wherein the method comprises administering to the subject an effective amount of the above-described antibody.
  • the metastatic cancer is microsatellite instability-high (MSI-H) metastatic colorectal cancer, mismatch repair-deficient metastatic colorectal cancer, or metastatic melanoma.
  • the effective dose is 0.1 mg/kg-6 mg/kg; in a preferred embodiment, the effective dose is 0.2 mg/kg-4.5 mg/kg; in an optimal embodiment, the effective dose is 0.5 mg/kg-3 mg/kg.
  • FIG2 is a schematic diagram of the IFN- ⁇ -Yervoy antibody.
  • Figure 4 shows the binding ability analysis of IFN family proteins IFN- ⁇ , IFN- ⁇ and IFN- ⁇ with therapeutic antibodies Yervoy, Tremelimumab, Pembrolizumab, Nivolumab, Cemiplimab, Atezolizumab, Durvalumab or Avelumab, respectively.
  • Figure 5 shows the results of cytotoxicity analysis of IFN- ⁇ -Yervoy.
  • Figure 5A shows the cell viability assay of Yervoy, IFN- ⁇ -Yervoy, and Yervoy + IFN- ⁇ -Yervoy after reaction with MMP-2/9 at different times.
  • Figure 5B shows the MHC I level assay of SW480 cells treated with Yervoy and IFN- ⁇ -Yervoy with or without MMP-2/9.
  • Figure 5C shows the cytotoxicity analysis of PBMC, PBMC + Yervoy, and PBMC + IFN- ⁇ -Yervoy (with MMP-2/9) at different effector (E) to target (T) ratios. Values are mean ⁇ SEM. * indicates significant difference, P ⁇ 0.05. Error: standard error of triplicate determinations.
  • Figure 6 shows the efficacy evaluation of IFN- ⁇ -Yervoy in colorectal cancer.
  • Figure 6A is a flow chart for the human PBMC animal model.
  • Figure 6B shows the analysis of tumor volume on day 33 after treatment with PBS, different concentrations of Yervoy, and IFN- ⁇ -Yervoy.
  • Figure 6C shows an analysis of CD4 + , CD8 + , and MHC I expression in tumor masses on day 33.
  • Figure 6D shows a statistical plot of the stained area for CD4 + , CD8 + , and MHC I expression in tumor masses on day 33.
  • Figure 7 shows the toxicity assessment of IFN- ⁇ -Yervoy in a colorectal cancer study.
  • Figure 7A shows the survival rate of mice treated with PBS, different doses of Yervoy, and IFN- ⁇ -Yervoy.
  • Figure 7B shows the weight analysis of mice under different treatments.
  • Figure 7C shows the analysis of CD4 + expression in the blood of mice on days 1, 8, and 34.
  • Figure 7D shows the analysis of CD8 + expression in the blood of mice on days 1, 8, and 34.
  • Figure 7E shows the analysis of MHC I expression in the blood of mice on days 1, 8, and 34.
  • Figure 7F shows the staining of organ damage in mice under different treatments.
  • Figure 7G shows the statistical graph of the area of organ damage or bleeding in mice under different treatments.
  • Figure 8 shows the structural integrity of the IFN ⁇ -Nivolumab fusion antibody analyzed by SDS-PAGE.
  • Figure 8A shows that the IFN ⁇ -Nivolumab fusion antibody has heavy chain and light chain bands.
  • Figure 8B shows that the IFN ⁇ -Nivolumab fusion antibody has a higher molecular weight band.
  • Figure 11 shows an IFN ⁇ -Nivolumab trial conducted in an A375 melanoma cell mouse model.
  • Figure 11A shows a record of tumor volume monitored every 3 days.
  • Figure 11B shows an immunohistochemical staining image.
  • Figure 11C shows the MHC I expression area in the mouse model under different treatments.
  • Figure 11D shows the expression area of CD4 + T cell infiltration in the mouse model under different treatments.
  • Figure 11E shows the expression area of CD8 + T cell infiltration in the mouse model under different treatments.
  • Figure 11F measures the level of IFN ⁇ in tumor tissues using a sandwich ELISA.
  • Figure 11G measures the level of IFN ⁇ in tumor tissues using a sandwich ELISA. Data are expressed as mean ⁇ standard deviation; asterisks ( * ) indicate statistically significant differences (P ⁇ 0.05).
  • Figure 12 shows a PBMC-mediated cytotoxicity assay. The data are shown as mean ⁇ standard deviation, and asterisks ( * ) indicate statistically significant differences (P ⁇ 0.05).
  • this example constructed Yervoy and IFN- ⁇ -Yervoy, as shown in FIG1A .
  • the N-terminus of the IFN- ⁇ -Yervoy antibody structure contains Type I IFN or Type II IFN, such as IFN- ⁇ , and a cleavable polypeptide linker, such as an MMP-2/9 substrate.
  • IFN- ⁇ -Yervoy is inactivated in the blood.
  • IFN- ⁇ -Yervoy enters the tumor microenvironment, it is cleaved by MMP-2/9 into Yervoy and IFN- ⁇ .
  • Yervoy promotes the proliferation of CD8 + T cells
  • IFN- ⁇ increases the expression of MHC molecules in tumors. The synergistic effect of the two enhances the ability of CD8 + T cells to recognize and kill tumors.
  • IFN- ⁇ -Yervoy improves the limitations of immune checkpoint blockade therapy.
  • this example further reacted equal amounts of 5 ⁇ g of MMPs and 5 ⁇ g of Yervoy at 37°C for 10 minutes, and terminated the reaction with 10 ⁇ g of BSA. Then, they were added to the CTLA4 ELISA plate through serial dilution and reacted for 1 hour. Secondary antibody was added for 1 hour, and ABTS was added for 30 minutes. The absorbance value was analyzed using an ELISA analyzer.
  • the present invention also confirms that the IFN family also has the same effect.
  • IFN- ⁇ , IFN- ⁇ , and IFN- ⁇ were each combined with various therapeutic antibodies, including Yervoy (Ipilimumab), Tremelimumab, Pembrolizumab, Nivolumab, Cemiplimab, Atezolizumab, Durvalumab, and Avelumab, and the antigen-binding ability of the various therapeutic antibodies was tested. As shown in FIG4 , the results showed that the IFN family can reduce the antigen-binding ability of the therapeutic antibodies and restore the antigen-binding ability of the therapeutic antibodies through MMP-2/9 activation.
  • this example added Yervoy and IFN- ⁇ -Yervoy to SW480 cells, and then allowed IFN- ⁇ and Yervoy to bind to MMP-2 at different times.
  • the binding ability of IFN- ⁇ -Yervoy increased depending on the duration of the reaction with MMP-2, demonstrating that IFN- ⁇ -Yervoy of the present invention can bind to IFN receptors and stimulate downstream signaling.
  • IFN- ⁇ in IFN- ⁇ -Yervoy can increase MHC I expression in SW480 cells, this example also added Yervoy, Yervoy+IFN ⁇ , IFN- ⁇ -Yervoy+BSA, and IFN- ⁇ -Yervoy+MMP-2 to SW480 cells, respectively.
  • Yervoy+IFN ⁇ and IFN- ⁇ -Yervoy+MMP-2 had better ability to activate PBMC cytotoxicity in SW480 cells.
  • IFN- ⁇ -Yervoy can be activated by matrix metalloproteinases, such as MMP-2, thereby promoting the IFN ⁇ signaling pathway and enhancing the cytotoxicity of T cells.
  • this example first used ASID mice to establish a human PBMC heterotopic colorectal cancer mouse model.
  • PBS, Yervoy, and IFN- ⁇ -Yervoy were administered, respectively.
  • Blood was collected on Day 1 (D1), Day 8, and Day 34 to analyze human lymphocyte activation.
  • lymphocyte activation was higher on Day 33 compared to Day 1, Day 8, and Day 34, demonstrating that the present invention successfully established a human PBMC heterotopic colorectal cancer mouse model.
  • %ID/g Percent injected dose per gram.
  • AUC Area under the influence of the plasma concentration.
  • CI Interval.
  • Cmax Mean maximum serum concentration.
  • h Hours.
  • MRT Mean residence time.
  • this example analyzed lung, liver, kidney, and intestinal damage in the PBS, IFN- ⁇ -Yervoy, and Yervoy groups on day 34.
  • the organs in the IFN- ⁇ -Yervoy-treated group showed no significant differences from those in the PBS-treated group, whereas the organ tissues in the Yervoy-treated group were significantly damaged. This suggests that IFN- ⁇ -Yervoy can mitigate the side effects of Yervoy by reducing lymphocyte infiltration, normal tissue bleeding, and organ damage.
  • A375 melanoma cells were cultured and treated with IFN ⁇ , Nivolumab, IFN ⁇ -Nivolumab, and IFN ⁇ -Nivolumab+MMP-2/9, respectively.
  • the MHC I expression levels of the treated A375 melanoma cells were analyzed.
  • Example 10 Efficacy of IFN ⁇ -Nivolumab in a mouse model
  • a mouse A375 cell tumor model was established, and different treatments were given, and the tumor volume was measured every three days.
  • IHC immunohistochemistry
  • the levels of IFN ⁇ and TNF ⁇ were also significantly increased in the tumor tissues of the IFN ⁇ -Nivolumab group.
  • PBMCs Peripheral blood mononuclear cells
  • E:T ratios effector to target cell ratios
  • Interferon- ⁇ -nivolumab fusion antibodies either activated or not by MMP-2/9, were then added. After culture, A375 cell survival was measured to assess PBMC-mediated cytotoxicity.
  • IFN ⁇ -Nivolumab fusion antibody can enhance the killing effect of PBMC on tumor cells at an increased effector to target ratio.
  • Example 10 During the treatment of Example 10, the survival rate and individual body weight changes of each treatment group were monitored. After the treatment, the lungs, liver, kidneys, small intestine and other organs of the mice were removed and stained with hematoxylin and eosin (H&E) to observe the pathological changes in the organ tissues.
  • H&E hematoxylin and eosin
  • mice in the IFN ⁇ -Nivolumab group exhibited a higher survival rate and less change in body weight.
  • this example demonstrates that the IFN ⁇ -Nivolumab fusion protein can be cleaved by MMP-2/9, restoring the activity of Nivolumab, enhancing MHC-I expression, and improving the cytotoxicity of T cells. It also demonstrated good tumor suppression effects and safety in animal experiments.

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Abstract

L'invention concerne un anticorps activé sélectivement dans une cellule ou un tissu cible pour traiter l'un des symptômes. L'anticorps comprend un anticorps fonctionnel qui contient au moins une chaîne légère et au moins une chaîne lourde et peut être utilisé pour traiter une pathologie dans un état activé ; au moins un peptide qui peut se lier à un récepteur d'interféron selon les besoins et activer une voie de signalisation du peptide ; et au moins un lieur polypeptidique clivable, chaque lieur polypeptidique clivable contenant un peptide substrat qui peut être clivé au moyen d'une enzyme, l'enzyme étant spécifiquement ou hautement exprimée dans une cellule ou un tissu cible et le lieur polypeptidique clivable liant l'un des peptides au domaine N-terminal de l'une de la ou des chaînes légères et de la ou des chaînes lourdes de l'anticorps fonctionnel.
PCT/CN2025/084866 2024-03-27 2025-03-26 Anticorps bloquant les cytokines et son utilisation Pending WO2025201363A1 (fr)

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Citations (7)

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CN115175926A (zh) * 2019-11-14 2022-10-11 狼人治疗公司 可激活细胞因子多肽及其使用方法
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CN111050803A (zh) * 2017-06-20 2020-04-21 德克萨斯大学系统董事会 用于治疗癌症的干扰素前药
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CN115175926A (zh) * 2019-11-14 2022-10-11 狼人治疗公司 可激活细胞因子多肽及其使用方法
US20240076355A1 (en) * 2021-01-14 2024-03-07 AskGene Pharma, Inc. Interferon Prodrugs and Methods of Making and Using the Same
CN116574192A (zh) * 2023-03-30 2023-08-11 上海妙聚生物科技有限公司 一种可条件性释放并激活的细胞因子融合蛋白及其制备和用途

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SHANG PENGZHAO, GAO RUI, ZHU YIJIA, ZHANG XIAORUI, WANG YANG, GUO MINJI, PENG HUI, WANG MIN, ZHANG JUAN: "VEGFR2-targeted antibody fused with IFN mut regulates the tumor microenvironment of colorectal cancer and exhibits potent anti-tumor and anti-metastasis activity", ACTA PHARMACEUTICA SINICA B, vol. 11, no. 2, 1 February 2021 (2021-02-01), pages 420 - 433, XP093359985, ISSN: 2211-3835, DOI: 10.1016/j.apsb.2020.09.008 *

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