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WO2025076288A1 - Combination therapy for cancer treatment - Google Patents

Combination therapy for cancer treatment 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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WIPO (PCT)
Prior art keywords
seq
kras
ccr8
antibody
inhibitor
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French (fr)
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

The present invention provides methods of treating a cancer patient with an inhibitor of KRAS and an anti-CCR8 antibody. These methods are useful for treating a number of cancers, including pancreatic, colorectal, and lung cancers.

Description

COMBINATION THERAPY FOR CANCER TREATMENT
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/542,870, filed October 6, 2023, which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] Provided herein are methods of treating a cancer patient with an inhibitor of KRAS and an anti-CCR8 antibody. These methods are useful for treating a number of cancers, including pancreatic, colorectal, and lung cancers.
DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY
[0003] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 10481-W001-SEC_ST26.xml, created October 1, 2024, which is 27,224 bytes in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0004] Cancer remains one of the leading causes of death worldwide. Lung cancer is the leading cause of cancer-related deaths worldwide, and it accounts for more deaths worldwide than colon cancer, breast cancer and prostate cancer together. Overall survival rates for non-small cell lung cancer (NSCLC) are improving but remain poor for patients with advanced disease, and 5-year survival is only 9% for those with metastatic disease. Colorectal cancer is the third leading cause of cancer-related deaths in the United States, and pancreatic cancer accounts for about 3% of all cancers in the United States. Despite recent advances in cancer therapeutics, there is a need for new medical treatments, such as combination therapy, for cancer patients.
SUMMARY OF THE INVENTION
[0005] The present invention provides a method of treating a cancer patient, wherein said method comprises administering to the cancer patient an anti-CCR8 antibody and an inhibitor of KRAS. In an embodiment, the inhibitor of KRAS is sotorasib. [0006] A method of treating a cancer patient, wherein said method comprises administering to the cancer patient an effective amount of an anti-CCR8 antibody and an effective amount of an inhibitor of KRAS. In an embodiment, the inhibitor of KRAS is sotorasib.
[0007] A method of treating a cancer patient, wherein said method comprises 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. In an embodiment, the inhibitor of KRAS is sotorasib.
[0008] 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. In an embodiment, the inhibitor of KRAS is sotorasib.
[0009] The present invention provides an anti-CCR8 antibody and an inhibitor of KRAS for combined use in a method of treating a cancer patient. In an embodiment, the inhibitor of KRAS is sotorasib.
[0010] The present invention provides an anti-CCR8 antibody and an inhibitor of KRAS in the manufacture of a medicament for treating cancer. In an embodiment, the inhibitor of KRAS is sotorasib.
[0011] The present invention provides an anti-CCR8 antibody and an inhibitor of KRAS for use in treating a cancer patient. In an embodiment, the inhibitor of KRAS is sotorasib.
[0012] The present invention provides an anti-CCR8 antibody and an inhibitor of KRAS for use in the treatment of cancer. In an embodiment, the inhibitor of KRAS is sotorasib.
[0013] 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. In an embodiment, the patient is determined to have a G12C-mutated cancer. In an embodiment, the cancer has KRAS G12C mutated.
[0014] In an embodiment, 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.
[0015] In an embodiment, 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.
[0016] The present invention provides a method of treating a cancer patient, the method comprising determining if the patient has a KRAS mutation, and if the patient has a KRAS mutation, treating the patient with an anti-CCR8 antibody and an inhibitor of KRAS. In an embodiment, the patient is determined to have a KRAS G12C mutation. In an embodiment, the patient is determined to have a G12D mutation. In an embodiment, the patient is determined to have a G12V mutation. In an embodiment, the patient is determined to have a G12A mutation. In an embodiment, the patient is determined to have a G12S mutation. In an embodiment, the patient is determined to have a G12R mutation. In an embodiment, the patient is determined to have a G13D mutation. In an embodiment, the patient is determined to have a Q61H mutation. In an embodiment, the patient is determined to have a Q61L mutation. In an embodiment, the patient is determined to have a Q61R mutation. In an embodiment, the inhibitor of KRAS is sotorasib. In an embodiment, the inhibitor of KRAS is an inhibitor disclosed herein. In an embodiment, the anti-CCR8 antibody is an anti-CCR8 antibody disclosed herein. In an embodiment, 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. In an embodiment, LCDR1 comprises SEQ ID NO: 4. In an embodiment, LCDR1 comprises SEQ ID NO: 11. In an embodiment, 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: 9 and the LC comprises SEQ ID NO: 13. In an embodiment, the HC comprises SEQ ID NO: 27 and the LC comprises 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. In embodiment, 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. [0017] In an embodiment, the anti-CCR8 antibody binds to an epitope of human CCR8 comprising a threonine at position 4 of SEQ ID NO: 14 or of SEQ ID NO: 15. In an embodiment, the anti-CCR8 antibody binds to an epitope of cynomolgus CCR8 comprising a threonine at position 4 of SEQ ID NO: 16. In an embodiment, the anti-CCR8 antibody binds to an epitope of human and/or cynomolgus monkey CCR8 as shown in SEQ ID NOs 14-16. In an embodiment, 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.
[0018] In an embodiment, 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. In an embodiment, LCDR1 comprises SEQ ID NO: 4. In an embodiment, LCDR1 comprises SEQ ID NO: 11. In an embodiment, 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: 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. In an embodiment, the KRAS inhibitor is sotorasib. In an embodiment, the anti-CCR8 antibody binds human CCR8. In embodiment, 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.
[0019] In an embodiment, the anti-CCR8 antibody is an afucosylated antibody.
[0020] In an embodiment, the anti-CCR8 antibody is a depleting antibody.
[0021] In an embodiment, the anti-CCR8 antibody has ADCC activity.
[0022] In an embodiment, the anti-CCR8 antibody is a neutralizing antibody.
[0023] In an embodiment, the anti-CCR8 antibody is not a neutralizing antibody.
[0024] In an embodiment, the anti-CCR8 antibody is BMS-986340.
[0025] In an embodiment, the anti-CCR8 antibody is GS-1811.
[0026] In an embodiment, the anti-CCR8 antibody is ABBV-514. [0027] In an embodiment, the anti-CCR8 antibody is LM-108.
[0028] In an embodiment, the anti-CCR8 antibody is S-531011.
[0029] In an embodiment, the anti-CCR8 antibody is BAY3375968.
[0030] In an embodiment, the anti-CCR8 antibody is SRF114.
[0031] In an embodiment, the anti-CCR8 antibody is CM369.
[0032] In an embodiment, the anti-CCR8 antibody is ZL-1218.
[0033] In an embodiment, the anti-CCR8 antibody is IPG0521.
[0034] In an embodiment, the anti-CCR8 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. In an embodiment, the anti-CCR8 antibody comprises an HCVR comprising SEQ ID NO: 23, and an LCVR comprising SEQ ID NO: 24. In an embodiment, the anti-CCR8 antibody comprises a HC comprising SEQ ID NO: 25, and an LC comprising SEQ ID NO: 26.
[0035] In an embodiment, 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. In an embodiment, LCDR1 comprises SEQ ID NO: 4. In an embodiment, LCDR1 comprises SEQ ID NO: 11. In an embodiment, 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. 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. In embodiment, 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. [0036] In an embodiment, the anti-CCR8 antibody is an antibody disclosed in PCT Publication Number WO2022256563A1. In an embodiment, the antibody is capable of depleting Tregs.
[0037] In an embodiment, the anti-CCR8 antibody is an antibody disclosed in PCT Publication Number WO2018181425A1. In an embodiment, the antibody is capable of depleting Tregs.
[0038] In an embodiment, the anti-CCR8 antibody is an antibody disclosed in PCT Publication Number WO2021142002A1. In an embodiment, the antibody is capable of depleting Tregs.
[0039] In an embodiment, the anti-CCR8 antibody is an antibody disclosed in PCT Publication Number WO2021194942A1. In an embodiment, the antibody is capable of depleting Tregs.
[0040] In an embodiment, the anti-CCR8 antibody is an antibody disclosed in PCT Publication Number W02021260206A2. In an embodiment, the antibody is capable of depleting Tregs.
[0041] In an embodiment, the anti-CCR8 antibody is an antibody disclosed in PCT Publication Number W02021260208A2. In an embodiment, the antibody is capable of depleting Tregs.
[0042] In an embodiment, the anti-CCR8 antibody is an antibody disclosed in PCT Publication Number W02021260210A2. In an embodiment, the antibody is capable of depleting Tregs.
[0043] In an embodiment, the anti-CCR8 antibody is an antibody disclosed in PCT Publication Number W02021260209A. In an embodiment, the antibody is capable of depleting Tregs.
[0044] In an embodiment, the anti-CCR8 antibody is an antibody disclosed in PCT Publication Number WO2021152186A2. In an embodiment, the antibody is capable of depleting Tregs.
[0045] In an embodiment, the anti-CCR8 antibody is an antibody disclosed in PCT Publication Number W02022004760A1. In an embodiment, the antibody is capable of depleting Tregs.
[0046] In an embodiment, 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.
[0048] In an embodiment, the anti-CCR8 antibody binds mouse CCR8. In an embodiment, the anti-CCR8 antibody does not bind mouse CCR8. In an embodiment, the anti- CCR8 antibody blocks ligand binding to CCR8. In an embodiment, the anti-CCR8 antibody blocks CCL1 binding to CCR8. In an embodiment, the anti-CCR8 antibody does not block ligand binding to CCR8. In an embodiment, the anti-CCR8 antibody does not block CCL1 binding to CCR8.
[0049] In an embodiment, the KRAS inhibitor is an inhibitor of KRAS G12D, G12V, G12A, G12R, G12S, G13D, Q61H, Q61L, Q61R, or G12C. In an embodiment, the KRAS inhibitor is an inhibitor of KRAS G12C. In an embodiment, the KRAS inhibitor is an inhibitor disclosed in WO2018217651. In an embodiment, the KRAS inhibitor is sotorasib. In an embodiment, the KRAS inhibitor is a compound having a structure of Formula 1:
Figure imgf000008_0001
[0050] In an embodiment, 960 mg of sotorasib is administered to the patient orally once daily.
[0051] In an embodiment, the KRAS inhibitor is an inhibitor disclosed in PCT Publication Number WO2022232331.
[0052] In an embodiment, the KRAS inhibitor is an inhibitor disclosed in PCT Publication Number WO2022232332.
[0053] In an embodiment, the KRAS inhibitor is an inhibitor disclosed in PCT
Publication Number W02023018809. [0054] In an embodiment, the KRAS inhibitor is an inhibitor disclosed in PCT Publication Number W02023018810.
[0055] In an embodiment, the KRAS inhibitor is an inhibitor disclosed in PCT Publication Number WO2023018812.
[0056] In an embodiment, the KRAS inhibitor is an inhibitor disclosed in PCT Publication Number WO2023159087.
[0057] In an embodiment, the KRAS inhibitor is an inhibitor disclosed in PCT Publication Number WO2023159086.
[0058] In an embodiment, the KRAS inhibitor is an inhibitor disclosed in PCT Publication Number WO2024076672.
[0059] In an embodiment, the KRAS inhibitor is an inhibitor disclosed in PCT Publication Number WO2024076674.
[0060] In an embodiment, the KRAS inhibitor is an inhibitor disclosed in PCT Publication Number W02024076670.
[0061] In an embodiment, the KRAS inhibitor is an inhibitor disclosed in PCT Application Number PCT/US2024/027587, filed May 3, 2024.
[0062] In an embodiment, the KRAS inhibitor is an inhibitor disclosed in United States Provisional Application Number 63/632,091, filed April 10, 2024.
[0063] In an embodiment, the KRAS inhibitor is an inhibitor disclosed in PCT Application Number PCT/US2023/074842, filed December 19, 2023.
[0064] In an embodiment, the KRAS inhibitor is adagrasib (MRTX840).
[0065] In an embodiment, the KRAS inhibitor is glecirasib (JAB-21822).
[0066] In an embodiment, the KRAS inhibitor is divarasib (GDC-6036).
[0067] In an embodiment, the KRAS inhibitor is garsorasib (D-1553).
[0068] In an embodiment, the KRAS inhibitor is opnurasib (JDQ443).
[0069] In an embodiment, the KRAS inhibitor is fulzerasib (IBI351, GFH925).
[0070] In an embodiment, the KRAS inhibitor is GH35.
[0071] In an embodiment, the KRAS inhibitor is BI1823911.
[0072] In an embodiment, the KRAS inhibitor is ZG1077.
[0073] In an embodiment, the KRAS inhibitor is ZG19018.
[0074] In an embodiment, the KRAS inhibitor is AZD4747.
[0075] In an embodiment, the KRAS inhibitor is AZD4625.
[0076] In an embodiment, the KRAS inhibitor is APG4625.
[0077] In an embodiment, the KRAS inhibitor is LY3537982.
[0078] In an embodiment, the KRAS inhibitor is MK-1084. [0079] In an embodiment, the KRAS inhibitor is JNJ-74699157.
[0080] In an embodiment, the KRAS inhibitor is YL-15293.
[0081] In an embodiment, the KRAS inhibitor is MRTX-1133.
[0082] In an embodiment, the KRAS inhibitor is JDQ443.
[0083] In an embodiment, the KRAS inhibitor is ARS-853.
[0084] In an embodiment, the KRAS inhibitor is ARS-1620.
[0085] In an embodiment, the KRAS inhibitor is MRTX-EX185.
[0086] In an embodiment, the KRAS inhibitor is MRTX-1133.
[0087] In an embodiment, the KRAS inhibitor is ASP2453.
[0088] In an embodiment, the KRAS inhibitor is RMC-6291.
[0089] In an embodiment, the KRAS inhibitor is RMC-6236.
[0090] In an embodiment, the KRAS inhibitor is RMC-036.
[0091] In an embodiment, the KRAS inhibitor is RMC-037.
[0092] In an embodiment, the KRAS inhibitor is BBO-8520.
[0093] In an embodiment, the KRAS inhibitor is ERAS-3490.
[0094] In an embodiment, the KRAS inhibitor is LY3499446.
[0095] In an embodiment, the cancer patient has a solid tumor. In an embodiment, 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. In an embodiment, the cancer patient has pancreatic cancer. In an embodiment, the cancer patient has colorectal cancer. In an embodiment, the cancer patient has lung cancer. In an embodiment, the cancer patient has non-small cell lung cancer.
[0096] In an embodiment, 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. In an embodiment, 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. In an embodiment, LCDR1 comprises SEQ ID NO: 4. In an embodiment, LCDR1 comprises SEQ ID NO: 11. In an embodiment, 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. 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. In an embodiment, the lung cancer is non-small cell lung cancer. In an embodiment, the inhibitor of KRAS is sotorasib. In embodiment, 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. In an embodiment, 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.
[0097] In an embodiment, the cancer patient has gastric cancer and is treated with an effective amount of an anti-CCR8 antibody and an effective amount of an inhibitor of KRAS. In an embodiment, 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. In an embodiment, LCDR1 comprises SEQ ID NO: 4. In an embodiment, LCDR1 comprises SEQ ID NO: 11. In an embodiment, 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. 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. In an embodiment, the inhibitor of KRAS is sotorasib. In embodiment, 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. In an embodiment, 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. [0098] In an embodiment, the cancer patient has head and neck squamous cell carcinoma and is treated with an effective amount of an anti-CCR8 antibody and an effective amount of an inhibitor of KRAS. In an embodiment, 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. In an embodiment, LCDR1 comprises SEQ ID NO: 4. In an embodiment, LCDR1 comprises SEQ ID NO: 11. In an embodiment, 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. 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. In an embodiment, the inhibitor of KRAS is sotorasib. In embodiment, 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. In an embodiment, 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. [0099] In an embodiment, 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. In an embodiment, 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. In an embodiment, LCDR1 comprises SEQ ID NO: 4. In an embodiment, LCDR1 comprises SEQ ID NO: 11. In an embodiment, 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. 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. In an embodiment, the inhibitor of KRAS is sotorasib. In embodiment, 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. In an embodiment, 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. [00100] In an embodiment, the cancer patient has triple-negative breast cancer and is treated with an effective amount of an anti-CCR8 antibody and an effective amount of an inhibitor of KRAS. In an embodiment, 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. In an embodiment, LCDR1 comprises SEQ ID NO: 4. In an embodiment, LCDR1 comprises SEQ ID NO: 11. In an embodiment, 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. 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. In an embodiment, the inhibitor of KRAS is sotorasib. In embodiment, 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. In an embodiment, 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. [00101] In an embodiment, the cancer patient has colorectal cancer and is treated with an effective amount of an anti-CCR8 antibody and an effective amount of an inhibitor of KRAS. In an embodiment, 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. In an embodiment, LCDR1 comprises SEQ ID NO: 4. In an embodiment, LCDR1 comprises SEQ ID NO: 11. In an embodiment, 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. 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. In an embodiment, the inhibitor of KRAS is sotorasib. In embodiment, 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. In an embodiment, 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. [00102] In an embodiment, the cancer patient has pancreatic cancer and is treated with an effective amount of an anti-CCR8 antibody and an effective amount of an inhibitor of KRAS. In an embodiment, 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. In an embodiment, LCDR1 comprises SEQ ID NO: 4. In an embodiment, LCDR1 comprises SEQ ID NO: 11. In an embodiment, 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. 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. In an embodiment, the inhibitor of KRAS is sotorasib. In embodiment, 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. In an embodiment, 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. [00103] In an embodiment, 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. In an embodiment, 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. In an embodiment, LCDR1 comprises SEQ ID NO: 4. In an embodiment, LCDR1 comprises SEQ ID NO: 11. In an embodiment, 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. 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. In an embodiment, the inhibitor of KRAS is sotorasib. In embodiment, 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. In an embodiment, 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. [00104] In an embodiment, the cancer patient’s tumor is reduced by at least 30%. In an embodiment, 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.
[00105] In embodiment, 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.
[00106] In an embodiment, the inhibitor of KRAS is sotorasib.
BRIEF DESCRIPTION OF THE DRAWINGS
[00107] Figure 1 depicts Treg numbers following treatment with 100 mg/kg sotorasib (“AMG 510”), an anti-PD-1 antibody (100 pg/ml), sotorasib 100 mg/kg in combination with an anti-PD-1 antibody, or 10 mg/kg of a MEK inhibitor in CT-26 KRAS p.G12C tumors.
[00108] 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.
[00109] 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).
[00110] Figures 4A-4B depict mean tumor volume from the results shown in Figure 3 when all mice were on study. Fig. 4A depicts mean tumor volume following treatment with vehicle control and Isotype (mIgG2a) control, vehicle and CCR8 Antibody 1 (300 pg), sotorasib (30 mg/kg) and Isotype (mIgG2a) control, or 30 mg/kg sotorasib and 300 pg CCR8 Antibody 1. Fig. 4B depicts mean tumor volume following treatment with vehicle control and Isotype (mIgG2a) control, vehicle and CCR8 Antibody 1 (300 pg), sotorasib (100 mg/kg) and Isotype (mIgG2a) control, or 100 mg/kg sotorasib and 300 pg CCR8 Antibody 1.
[00111] 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.
[00112] Figures 6A-6D depict pharmacodynamic changes in the CT-26 KRAS p.G12C tumor microenvironment following treatment of mice with CCR8 Antibody 1 (300 pg), sotorasib (30 mg/kg), or both CCR8 Antibody 1 (300 pg) and sotorasib (30 mg/kg).
[00113] Figures 7A-7F depict individual tumor volume of animals bearing CT-26 KRAS p.G12C tumors during treatment with (A) vehicle control and Isotype (mIgG2a) control, (B) vehicle and anti-CCR8 afucosylated antibody (“CCR8 Antibody 2”; 300 pg), (C) sotorasib (30 mg/kg) and and Isotype (mIgG2a) control , (D) sotorasib (100 mg/kg) and Isotype (mIgG2a) control, (E) 30 mg/kg sotorasib and 300 pg CCR8 Antibody 2, or (F) 100 mg/kg sotorasib and 300 pg CCR8 Antibody 2.
[00114] Figures 8A-8B depict the mean tumor volumes of the tumor volumes shown in Figure 7.
[00115] Figures 9A-9B depict survival of CT-26 KRAS p.G12C tumor-bearing animals following treatment with CCR8 Antibody 2, sotorasib (30 mg/kg - Fig. 9A; or 100 mg/kg - Fig. 9B), or combination of CCR8 Antibody 2 and sotorasib.
DETAILED DESCRIPTION
[00116] Data in multiple tumor types have demonstrated 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.
[00117] Regulatory T cell (Treg) suppression of the immune response in the tumor can be reduced by blocking CCR8 function, thereby promoting an inflammatory response and reduced tumor volume. Another therapeutic strategy is to deplete tumor Treg cells via anti-CCR8 antibody dependent cell killing (such as ADCC). For ADCC, anti-CCR8 antibodies may induce redirected T cell lysis of tumor-resident CCR8+ Tregs while sparing normal tissue Tregs that have little to no CCR8 expression by preferentially binding to CCR8 on tumor-resident Tregs and depleting these tumor-resident Tregs via ADCC (e.g., Tanaka et al. (2019) “Targeting Treg cells in cancer immunotherapy” European J. of Immun.; 49(8)1140-1146).
[00118] Sotorasib (LUMAKRAS®), a KRASG12C 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). [00119] Sotorasib, also referred to as “AMG 510,” is a specific, irreversible inhibitor of the GTPase protein, KRAS G12C, and has been shown to have clinical efficacy, e.g., when used to treat adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), who have received at least one prior systemic therapy. A recent analysis with over 2-year follow-up data from the CodeBreaK 100 clinical trial (ClinicalTrials.gov identifier: NCT03600883) demonstrated that nearly a quarter of previously treated advanced stage KRAS G12C-mutated NSCLC patients who were treated with sotorasib derived long-term benefit, with few late-onset treatment-related toxi cities (Dy et al., J Clin Oncol. 2023 Jun 20;41(18):3311-3317). Despite these promising results, there is still a need for optimal therapies to increase survival of cancer patients.
[00120] Remarkably, as described herein, treatment of CT-26 KRAS G12C tumor bearing animals with an inhibitor of KRAS G12C resulted in an increase in the number of Tregs in tumor-bearing animals, and the combination treatment of an inhibitor of KRAS and an anti- CCR8 antibody led to a synergistic reduction in tumor growth and increased survival in vivo compared to vehicle control or either sotorasib or anti-CCR8 antibody alone. The data demonstrate an enhanced survival effect of combining a KRAS inhibitor (such as sotorasib) with an anti-CCR8 antibody for the treatment of cancer.
[00121] In an embodiment, 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. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, realtime PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays and microarray analyses. In some embodiments, samples are evaluated for G12C KRAS, HRAS or NRAS mutations by real-time PCR. In real-time PCR, fluorescent probes specific for the KRAS, HRAS or NRAS G12C mutation are used. When a mutation is present, the probe binds and fluorescence is detected. In some embodiments, the KRAS, HRAS or NRAS G12C mutation is identified using a direct sequencing method of specific regions (e.g., exon 2 and/or exon 3) in the KRAS, HRAS or NRAS gene. This technique will identify all possible mutations in the region sequenced. Methods for detecting a mutation in a KRAS, HRAS or NRAS protein are known by those of skill in the art. These methods include, but are not limited to, detection of a KRAS, HRAS or NRAS mutant using a binding agent (e.g., an antibody) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.
[00122] Methods for determining whether a tumor or cancer comprises a G12C KRAS, HRAS or NRAS mutation can use a variety of samples. In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is a fresh tumor/cancer sample. In some embodiments, the sample is a frozen tumor/cancer sample. In some embodiments, the sample is a formalin-fixed paraffin- embedded sample. In some embodiments, the sample is a circulating tumor cell (CTC) sample. In some embodiments, the sample is processed to a cell lysate. In some embodiments, the sample is processed to DNA or RNA.
[00123] 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.
[00124] Methods of making KRAS inhibitors are known in the art (see, e.g., PCT Publication Number WO 2018217651).
[00125] In an embodiment, 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.
[00126] Methods of making anti-CCR8 antibodies are known in the art (see, e.g., PCT Publication Number WO 2022256563).
[00127] As used herein, an “antibody” is an immunoglobulin molecule comprising 2 heavy chains (HCs) and 2 light chains (LCs) interconnected by disulfide bonds. The amino terminal portion of each LC and HC includes a variable region of about 100-120 amino acids primarily responsible for antigen recognition via the CDRs contained therein. The CDRs are interspersed with regions that are more conserved, termed framework regions (“FR”). Each light chain variable region (LCVR) and heavy chain variable region (HCVR) is composed of 3 CDRs and 4 FRs, arranged from amino-terminus to carboxy -terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. 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. 190:382-93 (1971); Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 (1991)). It is understood that other numbering conventions may also be used, such as, for example, Chothia (Chothia et al., “Canonical structures for the hypervariable regions of immunoglobulins”, Journal of Molecular Biology, 196, 901-917 (1987); Al-Lazikani et al., “Standard conformations for the canonical structures of immunoglobulins”, Journal of Molecular Biology, 273, 927-948 (1997)), and/or North (North et al., “A New Clustering of Antibody CDR Loop Conformations”, Journal of Molecular Biology, 406, 228-256 (2011)).
[00128] 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.
[00129] An “anti-CCR8 antibody” is an antibody that specifically binds CCR8. An antibody is said to “specifically bind” to its antigen (CCR8) when the antibody binds its antigen with a dissociation constant (KD) of <10'7 M as measured via a surface plasma resonance technique (e.g., BIACore, GE-Healthcare Uppsala, Sweden) or Kinetic Exclusion Assay (KinExA, Sapidyne, Boise, Idaho).
[00130] 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. In an in vitro ADCC assay to detect cell killing of murine cells, Antibody 1 had an ECso of 215 pm and Antibody 2 had an ECso value of 2.5 nM. [00131] 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. In an embodiment, 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. 9, 2022) or by the methods described herein (e.g., Example 1 and Example 5). [00132] Enhanced survival and/or reduced tumor growth upon treatment with an anti- CCR8 antibody and a KRAS inhibitor (vs. control, or either anti-CCR8 antibody or KRAS inhibitor alone) may occur if, for example, greater than about 80% of CCR8-positive Tregs are depleted.
[00133] Also included are Fabs, scFabs, and scFvs comprising the CDRs and/or the variable regions of the anti-CCR8 antibodies disclosed herein.
[00134] An “inhibitor of KRAS” (also referred to as a “KRAS inhibitor”) is a compound that is capable of inhibiting RAS-mediated cell signaling. Inhibition of RAS-mediated signal transduction can be assessed and demonstrated by a wide variety of ways known in the art. Nonlimiting examples include a showing of (a) a decrease in GTPase activity of RAS; (b) a decrease in GTP binding affinity or an increase in GDP binding affinity; (c) an increase in K off of GTP or a decrease in K off of GDP; (d) a decrease in the levels of signaling transduction molecules downstream in the RAS pathway, such as a decrease in pMEK, pERK, or pAKT levels; and/or (e) a decrease in binding of RAS complex to downstream signaling molecules including but not limited to Raf. Kits and commercially available assays can be utilized for determining one or more of the above.
[00135] 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.
[00136] Additional efforts are also underway to develop compounds that inhibit KRAS with a G12 mutation wherein the 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 (see, e.g., Tria et al., Cancers (Basel). 2023 Apr 19; 15(8):2375 for a review of KRAS inhibitors). Such inhibitor is part of the present invention, in combination with an anti- CCR8 antibody.
[00137] An anti-CCR8 antibody, or a pharmaceutical composition comprising the same, may be administered by parenteral routes, non-limiting examples of which are subcutaneous administration and intravenous administration. Intramuscular, intraarterial, intralesional, and peritoneal bolus injection are other possible routes of administration. An anti-CCR8 antibody can also be administered via infusion or injection, for example intravenous or subcutaneous infusion or injection. An anti-CCR8 antibody may be administered to a cancer patient with pharmaceutically acceptable carriers, diluents, or excipients in single or multiple doses. Optionally, the composition additionally comprises one or more physiologically active agents. Pharmaceutical compositions can be prepared by methods well known in the art (e.g., Remington: The Science and Practice of Pharmacy, 22nd ed. (2012), A. Loyd et al., Pharmaceutical Press) and comprise an antibody, as disclosed herein, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
[00138] In an embodiment, the anti-CCR8 antibody binds human CCR8 and 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.
[00139] Pharmaceutical compositions that include an inhibitor of KRAS, together with a pharmaceutically acceptable excipient, such as, for example, a diluent or carrier, are also included. Compounds and pharmaceutical compositions suitable for use in the present invention include those wherein the compound can be administered in an effective amount to achieve its intended purpose.
[00140] Suitable pharmaceutical formulations can be determined by the skilled artisan depending on the route of administration and the desired dosage. See, e.g., Remington’s Pharmaceutical Sciences, 1435-712 (18th ed., Mack Publishing Co, Easton, Pennsylvania, 1990). Formulations may influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of the administered agents. Depending on the route of administration, a suitable dose may be calculated according to body weight, body surface areas or organ size.
[00141] A “cancer patient” refers to a human with cancer.
[00142] As used herein, an “effective amount” refers to the amount of an anti-CCR8 antibody or inhibitor of KRAS (or pharmaceutical composition comprising such an antibody or inhibitor of KRAS) that will elicit the biological or medical response of or desired therapeutic effect on a tissue, system, or human that is being sought by the researcher, medical doctor, or other clinician. An effective amount of the antibody or inhibitor may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effect of the antibody is outweighed by the therapeutically beneficial effects. Such benefit includes improving signs or symptoms of cancer. An effective amount of an anti-CCR8 antibody or inhibitor of KRAS may be administered in a single dose or in multiple doses. In determining the effective amount for a cancer patient, 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. [00143] As used interchangeably herein, “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. In an embodiment, the cancer patient’s tumor size is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In an embodiment, the cancer patient’s tumor is reduced by 10%. In an embodiment, the cancer patient’s tumor is reduced by 20%. In an embodiment, the cancer patient’s tumor is reduced by 30%. In an embodiment, the cancer patient’s tumor is reduced by 40%. In an embodiment, the cancer patient’s tumor is reduced by 50%. In an embodiment, the cancer patient’s tumor is reduced by 60%. In an embodiment, the cancer patient’s tumor is reduced by 70%. In an embodiment, the cancer patient’s tumor is reduced by 80%. In an embodiment, the cancer patient’s tumor is reduced by 90%. In an embodiment, the cancer patient’s tumor is no longer detectable. In an embodiment, the cancer patient’s spread of cancer cells to another part(s) of the body is slowed or stopped.
[00144] In an embodiment, the cancer patient has a solid tumor. In an embodiment, 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. In an embodiment, the cancer patient has pancreatic cancer. In an embodiment, the cancer patient has colorectal cancer. In an embodiment, the cancer patient has lung cancer. In an embodiment, the cancer patient has non-small cell lung cancer. In an embodiment, the cancer patient has KRAS G12 and/or KRAS Q61 mutated. In an embodiment, the cancer patient has KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L. Q61R, or G12C mutated. In an embodiment, the cancer patient has KRAS G12C mutated. In an embodiment, the cancer is KRAS G12 and/or KRAS Q61 mutated. In an embodiment, the cancer is KRAS G12D, G12V, G12A, G12R, G12S, G13D, Q61H, Q61R, Q61L or G12C mutated. In an embodiment, the cancer is KRAS G12C mutated.
[00145] 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. For prostate cancer, prostate-specific antigen (PSA) can be determined by a blood test known in the art.
[00146] The terms “combination” and “combined” refer to administration of an inhibitor of KRAS and an anti-CCR8 antibody. In an embodiment, the inhibitor of KRAS is sotorasib, and 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. In an embodiment, the HCVR comprises SEQ ID NO: 7 and the LCVR comprises SEQ ID NO: 12. In an embodiment, the HC comprises SEQ ID NO: 9 and the LC comprises 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 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 patient has a G12C mutation. In an embodiment, the patient has lung cancer.
[00147] The term “about” refers to values that are within 10% above or below the referenced value.
[00148] In an embodiment, the disclosure provides a method of treating a cancer patient, wherein the method comprises determining if the cancer patient has a KRAS, HRAS or NRAS mutation and if the cancer patient is determined to have the KRAS, HRAS or NRAS mutation, then administering to the cancer patient an effective amount of an inhibitor of KRAS and an effective amount of an anti-CCR8 antibody. In an embodiment, the cancer patient has a G12C mutation. In an embodiment, the cancer patient has a G12D mutation. In an embodiment, the cancer patient has a G12V mutation. In an embodiment, the cancer patient has a G12A mutation. In an embodiment, the cancer patient has a G12R mutation. In an embodiment, the cancer patient has a G12S mutation. In an embodiment, the cancer patient has a G13D mutation. In an embodiment, the cancer patient has a Q61H mutation. In an embodiment, the cancer patient has a Q61R mutation. In an embodiment, the cancer patient has a Q61L mutation. In a preferred embodiment, the cancer patient has a G12C mutation.
EXAMPLES
EXAMPLE 1 : TUMOR TREG NUMBERS IN VIVO FOLLOWING TREATMENT WITH AN INHIBITOR OF KRAS G12C, PD-1, OR MEK
[00149] To determine if treatment with an inhibitor of KRAS G12C, PD-1, MEK, or combination of inhibition of KRAS G12C and PD-1 affect the number of regulatory T cells (Tregs) in vivo, CT-26 KRAS G12C tumor bearing animals were treated over four days with either vehicle, sotorasib 100 mg/kg (a KRAS G12C inhibitor), 100 g anti-PD-1 antibody (a PD- 1 inhibitor), sotorasib 100 mg/kg in combination with anti-PD-1 antibody, or 10 mg/kg of PD- 325901 (a MEK inhibitor). Vehicle, sotorasib, or MEKi was administered once daily orally (PO QD), anti-PD-1 antibody was administered intraperitoneally (IP) once every three days for two total doses (Q3Dx2). Two hours after the last sotorasib treatment (day 26), 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 tumor were prepared for flow cytometry analysis of T cell proportions and phenotypes. T cells were gated using TCRP+Thyl.2+ staining within the Live/CD45+ fraction. Absolute numbers of Treg cells depicted in Figure 1 were assessed within the CD4+ T cell compartment using CD25+Foxp3+ gating scheme. Each dot represents data obtained from individual mouse. Statistical analysis was performed using one-way ANOVA followed by Tukey’s post hoc test comparing treatment groups (* p < 0.05 compared to vehicle; $ p<0.05 sotorasib vs sotorasib and anti-PD-1; # p<0.05 sotorasib vs MEK inhibitor).
[00150] These data demonstrate that treatment of CT-26 KRAS p.G12C tumor-bearing animals with an inhibitor of KRAS G12C resulted in increased number of Tregs compared to animals treated with vehicle (control) or the MEK inhibitor. The treatment of animals with a combination of the inhibitor of KRAS G12C and an inhibitor of PD-1 similarly resulted in an increase in the number of Tregs compared to control animals. These data demonstrate that treatment with an inhibitor of KRAS G12C results in an increase in the number of Tregs in tumor-bearing animals.
EXAMPLE 2: CCL8 MRNA IN TUMOR MACROPHAGES
[00151] CD45-positive immune cells from mice injected with CT-26KRAS.pG12C neoplastic cells were isolated by FACS and profiled using 5’ droplet-based single-cell RNA- sequencing. Animals were randomized into different treatment groups on day 19 after implantation (n=3/group) and animals were treated for four days before tumors were harvested. Variable feature selection, dimension reduction, and clustering were applied to single-cell RNA- sequencing count matrices to classify cell types. Differential expression analyses were used to identify cell-specific marker genes and treatment-specific gene signatures.
[00152] UMAP projection in two dimensions of twelve major cell types classified by single-cell RNA-seq is shown in Figure 2A. Cell type identification was performed using unbiased clustering of cell barcodes and identification of canonical marker genes. Violin plots showing macrophage multi-gene signature scores combining top genes differentially expressed by MAST in macrophages compared to all other cell types (signature consists of Adgrel, Lyz2, Lgmn, Mrcl, Folr2, and Clqa/b/c) are shown in Figure 2B. All signature genes used were statistically significant (FDR<0.05, log-fold-change>2, specificity>75%) and have been previously reported for the identification of tumor macrophages. Horizontal lines depict mean expression scores per cell type. Violin plots showing CCL8 mRNA log-normalized expression values in tumor macrophages across pairs of treatment groups are shown in Figure 2C. Horizontal lines depict mean expression levels per cell type. Differential expression was performed using MAST. *** = FDR<0.001, n.s. = FDR>0.05
[00153] These data demonstrate an increase in the CCR8 ligand, CCL8, mRNA in tumor macrophages upon treatment with an inhibitor of KRAS G12C compared to treatment with an anti-PD-1 antibody.
EXAMPLE 3: TUMOR GROWTH INHIBITION
[00154] Anti -turn or activity of the afucosylated CCR8 mIgG2a depleting mAb (CCR8
Antibody 1) alone and in combination with sotorasib was assessed in the CRC CT-26 KRAS p.G12C syngeneic tumor model. CT-26 KRAS p.G12C tumor cells were implanted subcutaneously in the right flank of female Balb/c mice on study day 0. Tumors were randomized on day 14 into different treatment groups (n=10/group) with an average tumor volume of ~115 mm3. Animals were dosed intra-peritoneally with 300 pg of either control isotype mIgG2a or CCR8 Antibody 1 on study days 14, 17 and 20). An inhibitor of KRAS G12C was administered at doses of either 30 mg/kg or 100 mg/kg PO QD starting on day 14 until day 42.
[00155] 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. **** p<0.0001 treated groups versus vehicle control; t = p<0.0001 30 mg/kg sotorasib dose combination versus sotorasib or CCR8 Antibody 1 single agent; or t = p<0.0001 100 mg/kg sotorasib dose combination group versus CCR8 Antibody 1 single agent; # = p<0.0001 regression by Paired T-test. Animals with no measurable tumors defined as Complete Responders (CRs) have been assessed until the end of the study (day 137). 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).
[00156] These data demonstrate that CT-26 KRAS p.G12C tumor-bearing animals had a significant reduction in tumor volume following treatment with a combination of sotorasib and CCR8 Antibody 1 compared to vehicle control animals.
EXAMPLE 4: SURVIVAL OF KRAS G12C TUMOR-BEARING ANIMALS
[00157] CT-26 KRAS p.G12C tumor cells were implanted subcutaneously in the right flank of female Balb/c mice on study day 0. Tumors were assigned on day 14 into different treatment groups (n=10/group) with an average tumor volume of ~115 mm3. Animals were dosed intra-peritoneally with 300 pg of either control isotype mIgG2a or 300 pg CCR8 Antibody 1 (CCR8 afuco mIgG2a) on study days 14, 17 and 20. Sotorasib was administered at doses of either 30 mg/kg or 100 mg/kg orally once daily starting on day 14 until day 42. All animals were kept on study until their tumors reached 800 mm3 or according to IACUC standards of animal welfare. Survival data are shown in Figure 5. Tumor size of > 800 mm3 was considered as a death/event. Statistical analysis was performed using the Log-rank (Mantel-Cox) test comparing vehicle group to all other treatment groups and each relevant combination group to either monotherapy group. * p<0.05, ****p<0.0001 vs control group; # p<0.01 combination group versus single agent. Undefined means more than fifty percent of mice survived at the end of the study. The median survival time (days) is shown in Table 1.
[00158] These data demonstrate that combination treatment with CCR8 Antibody 1 and an inhibitor of KRAS G12C extends the median survival of tumor-bearing mice.
Table 1. Survival of CT-26 KRAS P.G12C tumor-bearing animals with or without treatment.
Figure imgf000027_0001
Figure imgf000028_0001
EXAMPLE 5: PHARMACODYNAMIC CHANGES IN TREATED ANIMALS
[00159] 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.
[00160] Figure 6 demonstrates that pharmacodynamic changes in the CT-26 KRAS p.G12C tumor microenvironment are consistent with Treg depletion following CCR8 Antibody 1 treatment, increased Tregs post sotorasib monotherapy, and enhanced CD8+ T cell activity with the CCR8 Antibody 1 and sotorasib combination. Percentage and absolute numbers of Treg cells depicted in panel (A) were assessed within the CD4+ T cell compartment using both Foxp3+ and CD25+Foxp3+ gating scheme. Absolute numbers of CCR8+ Tregs were assessed within the CD4+ T cell compartment in panel (B). 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.
EXAMPLE 6: TUMOR GROWTH INHIBITION
[00161] Anti -turn or activity of 300 pg CCR8 Antibody 2 alone or in combination with either 30 mg/kg or 100 mg/kg sotorasib was determined in the CRC CT-26 KRAS p.G12C syngeneic tumor model. 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. [00162] CT-26 KRAS p.G12C tumor cells were implanted subcutaneously in the right flank of female Balb/c mice on study day 0. Tumors were randomized on day 17 into different treatment groups (n=10/group) with an average tumor volume of -130 mm3. Animals were dosed intra-peritoneally with 300 pg of either control isotype m!gG2a or CCR8 Antibody 2 (anti- mCCR8) on study days 17, 20 and 23. Sotorasib was administered at doses of either 30 mg/kg or 100 mg/kg orally once daily starting on day 17 until day 45.
[00163] 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). 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. **** p<0.0001 treated groups versus vehicle control; # = p<0.0001 regression by Paired T-test. Animals with no measurable tumors defined as Complete Responders (CRs) have been assessed until end of study (day 137). 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.
EXAMPLE 7: SURVIVAL OF KRAS G12C TUMOR-BEARING ANIMALS
[00165] CT-26 KRAS p.G12C tumor cells were implanted subcutaneously in the right flank of female Balb/c mice on study day 0. Tumors were assigned on day 17 into different treatment groups (n=10/group) with an average tumor volume of -130 mm3. Animals were dosed intra-peritoneally with 300 pg of either control isotype mIgG2a or 300 pg CCR8 Antibody 2 on study days 17, 20 and 23. Sotorasib was administered at doses of either 30 mg/kg or 100 mg/kg PO QD starting on day 17 until day 45.
[00166] All animals were kept on study until their tumors reached 800 mm3 or according to IACUC standards of animal welfare and the survival data is displayed in this figure. Tumor size of > 800 mm3 was considered as a death/event. Statistical analysis was performed using the Log-rank (Mantel-Cox) test comparing vehicle group to all other treatment groups and each relevant combination group to either monotherapy group. Median survival for Vehicle control group = 31 days, CCR8 Antibody 2 group = 34 days; sotorasib 30 mg/kg group = 34 days; sotorasib 100 mg/kg = 51 days; sotorasib 30 mg/kg + CCR8 Antibody 2 = 38 days; sotorasib 100 mg/kg + CCR8 Antibody 2 = undefined. ** p <0.01, *** p<0.001, **** p<0.0001 vs control group; # p<0.0001 100 mg/kg sotorasib dose combo group compared to CCR8 Antibody 2 and p<0.05 combo group compared to 100 mg/kg sotorasib.
[00167] Fig. 9A demonstrates that CCR8 Antibody 2 and sotorasib 30 mg/kg combination treatment extends median survival of CT-26 KRAS p.G12C tumor-bearing animals compared to vehicle control animals. Fig. 9B demonstrates that CCR8 depleting antibody CCR8 Antibody 2 and sotorasib 100 mg/kg combination treatment extends median survival of CT-26 KRAS p.G12C tumor-bearing animals compared to vehicle control animals or animals treated with either CCR8 Antibody 2 or 100 mg/kg sotorasib alone.
EXAMPLE 8: COMBINATION TREATMENT WITH SOTORASIB AND AN ANTI- CCR8 ANTIBODY
[00168] A phase 1 trial will be conducted in cancer patients. The patients will be administered sotorasib and an anti-CCR8 antibody that 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 their cancer will be monitored by a physician. It is expected that patients treated with sotorasib and the anti-CCR8 antibody will have a reduction in their tumor size and/or a reduction in metastatic lesions.
EMBODIMENTS
El . A method of treating a cancer patient, wherein said method comprises administering to the cancer patient an effective amount of an anti-CCR8 antibody and an effective amount of an inhibitor of KRAS.
E2. The method of El, wherein the inhibitor of KRAS is an inhibitor of KRAS G12C.
E3. The method of El or E2, wherein the inhibitor of KRAS is sotorasib.
E4. The method of any one of El-3, wherein 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: 11, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6.
E5. The method of any one of El -4, wherein the anti-CCR8 antibody HCVR comprises SEQ ID NO: 7, and the LCVR comprises SEQ ID NO: 12.
E6. The method of any one of El-6, wherein the anti-CCR8 antibody HC comprises SEQ ID NO: 9 or SEQ ID NO: 27, and the LC comprises SEQ ID NO: 13.
E7. The method of any one of El-3, wherein the anti-CCR8 antibody comprises a HC and a LC, wherein the HC comprises a HCVR and wherein the LC comprises a 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, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6.
E8. The method of any one of El-3, wherein the anti-CCR8 antibody HCVR comprises SEQ ID NO: 7, and the LCVR comprises SEQ ID NO: 8.
E9. The method of any one of El -3 and 8, wherein the anti-CCR8 antibody HC comprises SEQ ID NO: 9 or SEQ ID NO: 27, and the LC comprises SEQ ID NO: 10.
E10. The method of any one of El-9, wherein the cancer patient has pancreatic cancer, colorectal cancer, or lung cancer.
El l. The method of any one of El-10, wherein the cancer is KRAS G12 and/or KRAS Q61 mutated.
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.
E13. The method of any one of El-12, wherein the cancer is KRAS G12C mutated.
E14. The method of any one of El-13, wherein CCR8-positive Tregs are depleted in the patient.
El 5. The method of any one of El -13, wherein the cancer patient has a reduction in tumor size of at least 30%.
E16. The method of any one of El-13, wherein the cancer patient has a reduction in tumor size of at least 40%.
E17. The method of any one of El-13, wherein the cancer patient has a reduction in tumor size of at least 50%.
El 8. The method of any one of El -13, wherein the cancer patient has a reduction in tumor size of at least 60%. E19. The method of any one of El-13, wherein the cancer patient has a reduction in tumor size of at least 70%.
20. The method of any one of El-13, wherein the cancer patient has a reduction in tumor size of at least 80%.
E21. The method of any one of El -13, wherein the cancer patient has a reduction in tumor size of at least 90%.
E22. The method of any one of El-13, wherein the cancer patient has a reduction in size or number of metastatic lesions.
E23. The method of any one of El 5-22, wherein the cancer and/or metastatic lesions are measured by computer tomography (CT), magnetic resonance imagine (MRI), or bone scans.
E24. The method of any one of El-23, wherein the anti-CCR8 antibody binds to an epitope of human CCR8 comprising a threonine at position 4 of SEQ ID NO: 14 or of SEQ ID NO: 15.
E25. The method of any one of El -24, wherein the anti-CCR8 antibody binds to an epitope of cynomolgus CCR8 comprising a threonine at position 4 of SEQ ID NO: 16.
E26. The method of any one of El-25, wherein CCR8-positive Tregs are depleted by at least 30% in the patient.
E27. The method of E6 or E9, wherein the anti-CCR8 antibody HC comprises SEQ ID NO: 9.
E28. The method of E6 or E9, wherein the anti-CCR8 antibody HC comprises SEQ ID NO: 27.
SEQUENCES
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001

Claims

CLAIMS What is claimed:
1. A method of treating a cancer patient, wherein said method comprises administering to the cancer patient an effective amount of an anti-CCR8 antibody and an effective amount of an inhibitor of KRAS.
2. The method of Claim 1, wherein the inhibitor of KRAS is an inhibitor of KRAS G12C.
3. The method of Claim 1 or Claim 2, wherein the inhibitor of KRAS is sotorasib.
4. The method of any one of Claims 1-3, wherein 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: 11, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6.
5. The method of any one of Claims 1-4, wherein the anti-CCR8 antibody HCVR comprises SEQ ID NO: 7, and the LCVR comprises SEQ ID NO: 12.
6. The method of any one of Claims 1-6, wherein the anti-CCR8 antibody HC comprises SEQ ID NO: 9, and the LC comprises SEQ ID NO: 13.
7. The method of any one of Claims 1-3, wherein the anti-CCR8 antibody comprises a HC and a LC, wherein the HC comprises a HCVR and wherein the LC comprises a 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, LCDR2 comprises SEQ ID NO: 5, and LCDR3 comprises SEQ ID NO: 6.
8. The method of any one of Claims 1-3, wherein the anti-CCR8 antibody HCVR comprises SEQ ID NO: 7, and the LCVR comprises SEQ ID NO: 8.
9. The method of any one of Claims 1-3 and 8, wherein the anti-CCR8 antibody HC comprises SEQ ID NO: 9, and the LC comprises SEQ ID NO: 10.
10. The method of any one of Claims 1-9, wherein the cancer patient has pancreatic cancer, colorectal cancer, or lung cancer.
11. The method of any one of Claims 1-10, wherein the cancer is KRAS G12 and/or KRAS Q61 mutated.
12. The method of any one of Claims 1-11, wherein the cancer is KRAS G12D, G12V, G12A, G12R, G12S, G13D, Q61H, Q61R, Q61L or G12C mutated.
13. The method of any one of Claims 1-12, wherein the cancer is KRAS G12C mutated.
14. The method of any one of Claims 1-13, wherein the number of CCR8-positive Tregs is depleted by at least 30%.
15. The method of any one of Claims 1-13, wherein the cancer patient has a reduction in tumor size of at least 30%.
16. The method of any one of Claims 1-3, wherein the anti-CCR8 antibody binds to an epitope of human CCR8 comprising a threonine at position 4 of SEQ ID NO: 14 or of SEQ ID NO: 15.
17. The method of any one of Claims 1-3, wherein the anti-CCR8 antibody binds to an epitope of cynomolgus CCR8 comprising a threonine at position 4 of SEQ ID NO: 16.
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