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WO2025076288A1 - Polythérapie pour le traitement du cancer - Google Patents

Polythérapie pour le traitement du cancer Download PDF

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Publication number
WO2025076288A1
WO2025076288A1 PCT/US2024/049880 US2024049880W WO2025076288A1 WO 2025076288 A1 WO2025076288 A1 WO 2025076288A1 US 2024049880 W US2024049880 W US 2024049880W WO 2025076288 A1 WO2025076288 A1 WO 2025076288A1
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Prior art keywords
seq
kras
ccr8
antibody
inhibitor
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Inventor
Nathan William PIERCE
Daniel Lu
Chi-Ming Kevin Li
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Amgen Inc
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Amgen Inc
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    • 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
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • 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
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • C07K16/2818—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 against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
    • C07K2317/41—Glycosylation, sialylation, or fucosylation

Definitions

  • a method of treating a cancer patient comprising administering to the cancer patient an effective amount of a pharmaceutical composition comprising an anti-CCR8 antibody and a pharmaceutical composition comprising an effective amount of an inhibitor of KRAS.
  • the inhibitor of KRAS is sotorasib.
  • the present invention provides a method of treating a cancer patient, wherein said method comprises administering to the cancer patient a pharmaceutical composition comprising an anti-CCR8 antibody and a pharmaceutical composition comprising an inhibitor of KRAS.
  • the inhibitor of KRAS is sotorasib.
  • the present invention provides a method of treating a patient having a KRAS G12C-mutated cancer comprising administering to the patient an anti-CCR8 antibody and a KRAS G12C inhibitor.
  • the patient is determined to have a G12C-mutated cancer.
  • the cancer has KRAS G12C mutated.
  • the anti-CCR8 antibody comprises a heavy chain (HC) and a light chain (LC), wherein the HC comprises a heavy chain variable region (HCVR) and wherein the LC comprises a light chain variable region (LCVR), wherein the HCVR comprises HCDR1, HCDR2, and HCDR3 and the LCVR comprises LCDR1, LCDR2, and LCDR3, and wherein HCDR1 comprises SEQ ID NO: 1, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO: 3, LCDR1 comprises SEQ ID NO: 4 or SEQ ID NO: 11, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6.
  • LCDR1 comprises SEQ ID NO: 4.
  • the antibody comprises two HCs and two LCs, wherein each HC comprises SEQ ID NO: 9 and each LC comprises an amino acid sequence of SEQ ID NO: 10. In an embodiment, the antibody comprises two HCs and two LCs, wherein each HC comprises SEQ ID NO: 9 and each LC comprises an amino acid sequence of SEQ ID NO: 13. In an embodiment, the KRAS inhibitor is sotorasib. In an embodiment, the anti-CCR8 antibody binds human CCR8.
  • the anti-CCR8 antibody is IPG0521.
  • the anti-CCR8 antibody is an antibody disclosed in PCT Publication Number W02021260206A2. In an embodiment, the antibody is capable of depleting Tregs.
  • the anti-CCR8 antibody is an antibody disclosed in PCT Publication Number W02021260208A2. In an embodiment, the antibody is capable of depleting Tregs.
  • the anti-CCR8 antibody is an antibody disclosed in PCT Publication Number WO2022136649A1. In an embodiment, the antibody is capable of depleting Tregs. [0047] In an embodiment, the anti-CCR8 antibody is an antibody disclosed in PCT Publication Number WO2020138489. In an embodiment, the antibody is capable of depleting Tregs.
  • the KRAS inhibitor is an inhibitor disclosed in PCT
  • the KRAS inhibitor is an inhibitor disclosed in PCT Publication Number WO2023018812.
  • the KRAS inhibitor is an inhibitor disclosed in PCT Publication Number W02024076670.
  • the KRAS inhibitor is an inhibitor disclosed in PCT Application Number PCT/US2024/027587, filed May 3, 2024.
  • the KRAS inhibitor is glecirasib (JAB-21822).
  • the KRAS inhibitor is BI1823911.
  • the KRAS inhibitor is ZG19018.
  • the KRAS inhibitor is MK-1084. [0079] In an embodiment, the KRAS inhibitor is JNJ-74699157.
  • the KRAS inhibitor is MRTX-1133.
  • the KRAS inhibitor is ARS-1620.
  • the KRAS inhibitor is ASP2453.
  • the KRAS inhibitor is RMC-036.
  • the KRAS inhibitor is ERAS-3490.
  • the cancer patient has a solid tumor.
  • the cancer patient has lung cancer, gastric cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, triple-negative breast cancer, colorectal cancer, pancreatic cancer, or metastatic castrate-resistant prostate cancer.
  • the cancer patient has pancreatic cancer.
  • the cancer patient has colorectal cancer.
  • the cancer patient has lung cancer.
  • the cancer patient has non-small cell lung cancer.
  • the cancer patient has lung cancer and is treated with an effective amount of an anti-CCR8 antibody and an effective amount of an inhibitor of KRAS.
  • the anti-CCR8 antibody comprises HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, HCDR3 comprising SEQ ID NO: 3, LCDR1 comprising SEQ ID NO: 4 or SEQ ID NO: 11, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO: 6.
  • LCDR1 comprises SEQ ID NO: 4.
  • LCDR1 comprises SEQ ID NO: 11.
  • the HCVR comprises SEQ ID NO: 7 and the LCVR comprises SEQ ID NO: 8 or SEQ ID NO: 12.
  • the LCVR comprises SEQ ID NO: 8. In an embodiment, the LCVR comprises SEQ ID NO: 12. In an embodiment, the HC comprises SEQ ID NO: 9 and the LC comprises SEQ ID NO: 10 or SEQ ID NO: 13. In an embodiment, the HC comprises SEQ ID NO: 27 and the LC comprises SEQ ID NO: 10 or SEQ ID NO: 13. In an embodiment, the LC comprises SEQ ID NO: 10. In an embodiment, the LC comprises SEQ ID NO: 13. In an embodiment, the antibody comprises two HCs and two LCs, wherein each HC comprises SEQ ID NO: 9 and each LC comprises an amino acid sequence of SEQ ID NO: 10.
  • the inhibitor of KRAS is sotorasib.
  • the anti-CCR8 antibody comprises HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, HCDR3 comprising SEQ ID NO: 3, LCDR1 comprising SEQ ID NO: 11, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO: 6.
  • the anti- CCR8 antibody comprises HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, HCDR3 comprising SEQ ID NO: 3, LCDR1 comprising SEQ ID NO: 11, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO: 6, and the inhibitor of KRAS is sotorasib.
  • the cancer patient has hepatocellular carcinoma and is treated with an effective amount of an anti-CCR8 antibody and an effective amount of an inhibitor of KRAS.
  • the anti-CCR8 antibody comprises HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, HCDR3 comprising SEQ ID NO: 3, LCDR1 comprising SEQ ID NO: 4 or SEQ ID NO: 11, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO: 6.
  • LCDR1 comprises SEQ ID NO: 4.
  • LCDR1 comprises SEQ ID NO: 11.
  • the HCVR comprises SEQ ID NO: 7 and the LCVR comprises SEQ ID NO: 8 or SEQ ID NO: 12. In an embodiment, the LCVR comprises SEQ ID NO: 8. In an embodiment, the LCVR comprises SEQ ID NO: 12. In an embodiment, the HC comprises SEQ ID NO: 9 and the LC comprises SEQ ID NO: 10 or SEQ ID NO: 13. In an embodiment, the HC comprises SEQ ID NO: 27 and the LC comprises SEQ ID NO: 10 or SEQ ID NO: 13. In an embodiment, the LC comprises SEQ ID NO: 10. In an embodiment, the LC comprises SEQ ID NO: 13.
  • the HC comprises SEQ ID NO: 9 and the LC comprises SEQ ID NO: 10 or SEQ ID NO: 13. In an embodiment, the HC comprises SEQ ID NO: 27 and the LC comprises SEQ ID NO: 10 or SEQ ID NO: 13. In an embodiment, the LC comprises SEQ ID NO: 10. In an embodiment, the LC comprises SEQ ID NO: 13. In an embodiment, the antibody comprises two HCs and two LCs, wherein each HC comprises SEQ ID NO: 9 and each LC comprises an amino acid sequence of SEQ ID NO: 10. In an embodiment, the antibody comprises two HCs and two LCs, wherein each HC comprises SEQ ID NO: 9 and each LC comprises an amino acid sequence of SEQ ID NO: 13.
  • the anti-CCR8 antibody comprises HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, HCDR3 comprising SEQ ID NO: 3, LCDR1 comprising SEQ ID NO: 4 or SEQ ID NO: 11, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO: 6.
  • LCDR1 comprises SEQ ID NO: 4.
  • LCDR1 comprises SEQ ID NO: 11.
  • the HCVR comprises SEQ ID NO: 7 and the LCVR comprises SEQ ID NO: 8 or SEQ ID NO: 12.
  • the LCVR comprises SEQ ID NO: 8.
  • the LCVR comprises SEQ ID NO: 12.
  • the HC comprises SEQ ID NO: 9 and the LC comprises SEQ ID NO: 10 or SEQ ID NO: 13. In an embodiment, the HC comprises SEQ ID NO: 27 and the LC comprises SEQ ID NO: 10 or SEQ ID NO: 13. In an embodiment, the LC comprises SEQ ID NO: 10. In an embodiment, the LC comprises SEQ ID NO: 13. In an embodiment, the antibody comprises two HCs and two LCs, wherein each HC comprises SEQ ID NO: 9 and each LC comprises an amino acid sequence of SEQ ID NO: 10. In an embodiment, the antibody comprises two HCs and two LCs, wherein each HC comprises SEQ ID NO: 9 and each LC comprises an amino acid sequence of SEQ ID NO: 13.
  • the inhibitor of KRAS is sotorasib.
  • the anti-CCR8 antibody comprises HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, HCDR3 comprising SEQ ID NO: 3, LCDR1 comprising SEQ ID NO: 11, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO: 6.
  • the anti-CCR8 antibody comprises HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, HCDR3 comprising SEQ ID NO: 3, LCDR1 comprising SEQ ID NO: 11, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO: 6, and the inhibitor of KRAS is sotorasib.
  • the cancer patient has metastatic castrate-resistant prostate cancer and is treated with an effective amount of an anti-CCR8 antibody and an effective amount of an inhibitor of KRAS.
  • the anti-CCR8 antibody comprises HCDR1 comprising SEQ ID NO: 1, HCDR2 comprising SEQ ID NO: 2, HCDR3 comprising SEQ ID NO: 3, LCDR1 comprising SEQ ID NO: 4 or SEQ ID NO: 11, LCDR2 comprising SEQ ID NO: 5, and LCDR3 comprising SEQ ID NO: 6.
  • LCDR1 comprises SEQ ID NO: 4.
  • LCDR1 comprises SEQ ID NO: 11.
  • Figures 2A-2C depict scRNAseq data in tumor macrophages upon treatment with sotorasib.
  • Fig. 2A depicts UMAP projection;
  • Fig. 2B and 2C depict Violin plots.
  • Figures 3A-3F depict individual tumor volumes in a CT-26 KRAS p.G12C mouse model following treatment with vehicle and Isotype (mIgG2a) control (Fig. 3 A), vehicle and 300 pg anti-CCR8 mIgG2 afucosylated antibody (“CCR8 Antibody 1”; Fig. 3B), 30 mg/kg sotorasib and mIgG2a isotype control (Fig. 3C), sotorasib 100 mg/kg and mIgG2a isotype control (Fig. 3D), 30 mg/kg sotorasib and 300 pg CCR8 Antibody 1 (Fig. 3E), or 100 mg/kg sotorasib and 300 pg CCR8 Antibody 1 (Fig. 3F).
  • mIgG2a control Fig. 3 A
  • vehicle and 300 pg anti-CCR8 mIgG2 afucosylated antibody (“CCR8 Antibody 1”; Fig. 3B)
  • Figure 5 depicts percent survival of CT-26 KRAS p.G12C tumor-bearing mice following treatment with vehicle and isotype (mIgG2a) control, vehicle and 300 pg CCR8 Antibody 1, 30 mg/kg sotorasib and mIgG2a isotype control, 100 mg/kg sotorasib and mIgG2a isotype control, 30 mg/kg sotorasib and 300 pg CCR8 Antibody 1, or 100 mg/kg sotorasib and 300 pg CCR8 Antibody 1.
  • vehicle and isotype (mIgG2a) control vehicle and 300 pg CCR8 Antibody 1
  • 30 mg/kg sotorasib and mIgG2a isotype control 100 mg/kg sotorasib and mIgG2a isotype control
  • 30 mg/kg sotorasib and 300 pg CCR8 Antibody 1 100 mg/kg sotorasib and 300 pg CCR8 Antibody 1.
  • Figures 8A-8B depict the mean tumor volumes of the tumor volumes shown in Figure 7.
  • CCR8 expression is a marker for tumor specific T regulatory (Treg) cells (see, e.g., Plitas et al. (2016) “Regulatory T Cells Exhibit Distinct Features in Human Breast Cancer”, Immunity; 45(5): 1122-1134; Villarreal et al. (Sept. 2018) “Targeting CCR8 Induces Protective Antitumor Immunity and Enhances Vaccine-Induced Responses in Colon Cancer” Tumor Biol. And Immun.). CCR8 is expressed with much higher prevalence and at higher levels on the surface of tumor-resident Tregs compared to circulating or normal tissue Tregs and conventional T effector (Teff) cells. Treg cell infiltration in solid tumors is associated with poor clinical outcome, and Tregs suppress the anti-cancer immune response through inhibition of Teff cell cytotoxicity.
  • Treg tumor specific T regulatory
  • Sotorasib (LUMAKRAS®), a KRAS G12C inhibitor, is approved in the United States for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.
  • the recommended dosage of LUMAKRAS is 960 mg orally once daily (Sotorasib (LUMAKRAS® [package insert; April 2023], U.S. Food and Drug Administration; the contents of which are incorporated by reference in its entirety).
  • the KRAS inhibitor is a KRAS G12C inhibitor disclosed in PCT Publication Number WO 2018217651, which is herein incorporated by reference in its entirety, especially as it relates to KRAS inhibitor compounds and methods of making and using said KRAS inhibitors.
  • Methods for detecting a mutation in a KRAS, HRAS or NRAS nucleotide sequence are known by those of skill in the art.
  • PCR-RFLP polymerase chain reaction-restriction fragment length polymorphism
  • PCR-SSCP polymerase chain reaction-single strand conformation polymorphism
  • MASA mutant allele-specific PCR amplification
  • direct sequencing primer extension reactions
  • electrophoresis oligonucleotide ligation assays
  • hybridization assays TaqMan assays
  • SNP genotyping assays high resolution melting assays and microarray analyses.
  • samples are evaluated for G12C KRAS, HRAS or NRAS mutations by real-time PCR.
  • Patent applications, patents, and references disclosing inhibitors of KRAS or anti- CCR8 antibodies are herein incorporated by reference, especially as it relates to specific inhibitors of KRAS or specific anti-CCR8 antibodies and methods of making and using said inhibitors of KRAS or anti-CCR8 antibodies.
  • the anti-CCR8 antibody is an antibody disclosed in PCT Publication Number WO 2022256563, which is herein incorporated by reference in its entirety, especially as it relates to CCR8 antibodies and methods of making and using said CCR8 antibodies.
  • the 3 CDRs of the LC are referred to as “LCDR1, LCDR2, and LCDR3,” and the 3 CDRs of the HC are referred to as “HCDR1, HCDR2, and HCDR3.”
  • the CDRs contain most of the residues which form specific interactions with the antigen.
  • the functional ability of an antibody to bind a particular antigen is, thus, largely influenced by the amino acid residues within the six CDRs. Assignment of amino acids to CDR domains within the LCVR and HCVR regions of the antibodies disclosed herein is based on the well-known Kabat numbering convention (Kabat, et al., Ann. NY Acad. Sci.
  • the present invention includes combinations of a KRAS inhibitor and an anti- CCR8 antibody, wherein the anti-CCR8 antibody may have posttranslational modifications such as clipping of the C-terminal lysine residue of the antibody HC and/or conversion of the antibody HC glutamate or glutamine to pyroglutamate.
  • Anti-CCR8 antibodies comprising these posttranslational modifications are also included to be used in combination with a KRAS inhibitor as part of the present invention.
  • CCR8 Antibody 1 and CCR8 Antibody 2 refer to two different anti-CCR8 antibodies that bind mouse CCR8.
  • CCR8 Antibody 1 and CCR8 Antibody 2 are depleting antibodies, which refers to their ability to reduce the number of regulatory T cells (Tregs). Depleting antibodies may deplete Tregs by ADCC.
  • Tregs regulatory T cells
  • Depleting antibodies may deplete Tregs by ADCC.
  • Antibody 1 had an ECso of 215 pm and Antibody 2 had an ECso value of 2.5 nM.
  • It is thought that the greater number of CCR8-positive Tregs that are depleted in the tumor results in greater tumor growth inhibition upon treatment with an anti-CCR8 antibody and a KRAS inhibitor.
  • the anti-CCR8 antibody depletes about 60% of CCR8- positive Tregs. In an embodiment, the anti-CCR8 antibody depletes about 70% of CCR8-positive Tregs. In an embodiment, the anti-CCR8 antibody depletes about 80% of CCR8-positive Tregs. In an embodiment, the anti-CCR8 antibody depletes about 90% of CCR8-positive Tregs. In an embodiment, the anti-CCR8 antibody depletes about 95% of CCR8-positive Tregs. Treg depletion can be determined following methods known in the art (see, e.g., Kidani et al., PNAS; 119(7) (Feb.
  • Adagrasib (also called MRTX849 or Krazati®) is an inhibitor of KRAS G12C that is approved in the United States for treatment of KRAS G12C-mutated NSCLC. In patients with previously treated KRASG12C-mutated NSCLC, adagrasib showed clinical efficacy (Janne et al., N Engl J Med 2022;387: 120-131). Said inhibitor is part of the present invention, in combination with an anti-CCR8 antibody.
  • G12 mutation is, for example, G12D, G12V, G12A, G12S, G13D, G12R, or G12C, or a Q61 mutation wherein the Q61 mutation is, for example, Q61H, Q61R, or Q61L
  • Such inhibitor is part of the present invention, in combination with an anti- CCR8 antibody.
  • An effective amount of an anti-CCR8 antibody or inhibitor of KRAS may be administered in a single dose or in multiple doses.
  • a number of factors are considered by the attending medical practitioner, including, but not limited to: the patient's size (e.g., weight or mass), body surface area, age, and general health; the specific disease or disorder involved; the degree of, or involvement, or the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances known to medical practitioners.
  • treatment and/or “treating” and/or “treat” are intended to refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, stopping, or reversing of the progression of the cancer described herein, but does not necessarily indicate a total elimination of all symptoms.
  • Treatment includes administration of an anti-CCR8 antibody and administration of an inhibitor of KRAS for treatment of a cancer in a human that would benefit from activity of both an anti-CCR8 antibody and inhibitor of KRAS, and includes: (a) inhibiting further progression of the cancer; and (b) relieving the cancer disease, i.e., causing regression of the cancer or alleviating symptoms or complications thereof.
  • Nonlimiting examples of treatment include inhibiting tumor growth, a reduction in tumor size, and/or a reduction in metastasis.
  • the cancer patient’s tumor size is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%.
  • the cancer patient’s tumor is reduced by 10%.
  • the cancer patient’s tumor is reduced by 20%.
  • the cancer patient’s tumor is reduced by 30%.
  • the cancer patient’s tumor is reduced by 40%.
  • the cancer patient’s tumor is reduced by 50%.
  • the cancer patient’s tumor is reduced by 60%.
  • the cancer patient’s tumor is reduced by 70%.
  • the cancer patient’s tumor is reduced by 80%.
  • the cancer patient’s tumor is reduced by 90%.
  • the cancer patient’s tumor is no longer detectable.
  • the cancer patient’s spread of cancer cells to another part(s) of the body is slowed or stopped.
  • the cancer patient has a solid tumor.
  • the cancer patient has lung cancer, gastric cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, triple-negative breast cancer, colorectal cancer, pancreatic cancer, or metastatic castrate-resistant prostate cancer.
  • the cancer patient has pancreatic cancer.
  • the cancer patient has colorectal cancer.
  • the cancer patient has lung cancer.
  • the cancer patient has non-small cell lung cancer.
  • the cancer patient has KRAS G12 and/or KRAS Q61 mutated.
  • the cancer patient has KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L. Q61R, or G12C mutated.
  • the cancer patient has KRAS G12C mutated.
  • the cancer is KRAS G12 and/or KRAS Q61 mutated.
  • the cancer is KRAS G12D, G12V, G12A, G12R, G12S, G13D, Q61H, Q61R, Q61L or G12C mutated.
  • the cancer is KRAS G12C mutated.
  • the size of a patient's tumor, such as prostate, and/or metastatic lesions can be determined by methods known in the art. Such methods include computer tomography (CT), magnetic resonance imagine (MRI), and/or bone scans.
  • CT computer tomography
  • MRI magnetic resonance imagine
  • PSA prostate-specific antigen
  • blood test known in the art.
  • the HC comprises SEQ ID NO: 27 and the LC comprises SEQ ID NO: 10 or SEQ ID NO: 13.
  • the antibody comprises two HCs and two LCs, wherein each HC comprises SEQ ID NO: 9 and each LC comprises an amino acid sequence of SEQ ID NO: 13.
  • the patient has a G12C mutation.
  • the patient has lung cancer.
  • Tumor volume was measured twice per week. Individual tumor growth for the treatment groups is depicted as spider plots in Figures 3 A-3F or group mean panel in Figure 4A and Figure 4B ⁇ SEM for each group until the last timepoint when all animals were on study (day 32). Statistical analysis to evaluate effect of treatment on tumor size over time relative to control group was performed using Linear Mixed Effects (LME) model with Dunnett’s post-hoc analysis. Statistical analysis was also performed to evaluate differences between the combination group versus either single agent.
  • LME Linear Mixed Effects
  • the number of CRs in each treatment group are as follows: 3 CRs (CCR8 Antibody 1), 2 CRs (Sotorasib 100 mg/kg), 9 CRs (sotorasib 30 mg/kg + CCR8 Antibody 1), and 10 CRs (Sotorasib lOOmg/kg + CCR8 Antibody 1).
  • CT-26 KRAS p.G12C tumor bearing animals were treated with 300 pg doses of either control isotype mIgG2a or CCR8 Antibody 1 intra-peritoneally on study day 21 and 24 as well as 30 mg/kg doses of either Vehicle or sotorasib dosed orally daily on study days 21-25 (QD x 5). Pharmacodynamic evaluation was performed one hour after final dose of sotorasib treatment on study day 25. Tumor weights were collected during harvest for the different groups and used for normalization to determine absolute cell counts in tumors. Single cell suspensions of tumors were prepared for flow cytometry analysis of T cell characterization. Total T cells were gated on Live CD45+ TCRP+ Thy 1.2+ staining.
  • CD8+ T cells were gated on total T cells and CD8/Treg ratios in tumor were calculated as depicted in panel (C). Percentage and absolute numbers of CD8+ PD1+ Ki67+ cells were assessed within the CD8+ T cell compartment in panel (D). Each dot represents data obtained from individual mouse. Scatter dot plot graphs are displayed where lines are mean with SEM. Statistical analysis was performed using standard one-way ANOVA (* p ⁇ 0.05, ** p ⁇ 0.01, *** p ⁇ 0.001, **** p ⁇ 0.0001). P values of panels (B-D) were obtained from log transformation of the data.
  • CCR8 Antibody 2 (anti-CCR8 afucosylated antibody) comprises HCDR1 comprising SEQ ID NO: 17, HCDR2 comprising SEQ ID NO: 18, HCDR3 comprising SEQ ID NO: 19, LCDR1 comprising SEQ ID NO: 20, LCDR2 comprising SEQ ID NO: SEQ ID NO: 21, LCDR3 comprising SEQ ID NO: 22.
  • Tumor volume was measured twice per week. Individual tumor growth for the treatment groups is depicted as spider plots in Figures 7A-7F or group means in Figures 8A-8B ⁇ SEM for each group until the last timepoint when all animals were on study (day 31).
  • LME Linear Mixed Effects
  • the number of CRs was as follows: 4 CRs (Sotorasib 100 mg/kg) and 9 CRs (Sotorasib lOOmg/kg + CCR8 Antibody 2). Not shown in the graph is p ⁇ 0.0001 CCR8 Antibody 2 versus CCR8 Antibody 2 and 30 mg/kg sotorasib; and p ⁇ 0.0001 CCR8 Antibody 2 versus CCR8 Antibody 2 and 100 mg/kg sotorasib. [00164] These data demonstrate that CT-26 KRAS p.G12C tumor-bearing animals had a reduction in tumor volume following treatment with a combination of sotorasib and CCR8 Antibody 2.
  • E10 The method of any one of El-9, wherein the cancer patient has pancreatic cancer, colorectal cancer, or lung cancer.
  • E12 The method of any one of El-11, wherein the cancer is KRAS G12D, G12V, G12A, G12R, G12S, G13D, Q61H, Q61R, Q61L or G12C mutated.
  • E16 The method of any one of El-13, wherein the cancer patient has a reduction in tumor size of at least 40%.
  • E27 The method of E6 or E9, wherein the anti-CCR8 antibody HC comprises SEQ ID NO: 9.

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Abstract

La présente invention concerne des méthodes de traitement d'un patient cancéreux avec un inhibiteur de KRAS et un anticorps anti-CCR8. Ces inhibiteurs sont utiles pour traiter un certain nombre de cancers, notamment le cancer du pancréas, le cancer colorectal et le cancer des poumons.
PCT/US2024/049880 2023-10-06 2024-10-04 Polythérapie pour le traitement du cancer Pending WO2025076288A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

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