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JP-7856566-B2 - Combination of DGK inhibitor and checkpoint antagonist

JP7856566B2JP 7856566 B2JP7856566 B2JP 7856566B2JP-7856566-B2

Inventors

  • ウィー，スーザン
  • マーティン，スコット ダブリュー
  • マクドナルド，アイバー エム
  • オルソン，リチャード イー
  • ジェン，シャオファン
  • トカルスキー，ジョン エス
  • ダスグプタ，ビレシュワル
  • カンブレ，マンジュナタ ナラヤナ ラオ
  • マヌーリ，ラジュ
  • ラーマン，ハシブル
  • ジャラガム，プラサダ ラオ
  • ベンチ，ジョセフ エル
  • ロイ，ソーミャ
  • トヌクヌル，ゴピキシャン
  • ヴェライアー，シヴァスダル
  • ウォリアー，ジャヤクマール サンカラ
  • レディ，コタ ラトナカル
  • ラジャ，ティルベンカダム
  • グリューネンフェルダー，デニース
  • ウィクロスキー，マイケル ジェイ
  • ワン，シンユー
  • ベラパルチ，アッペンダー
  • チュパック，ルイス エス
  • ダルネ，チェタン ピー
  • ディン，ミン
  • ジェントルズ，ロバート ジー
  • フアン，ヤジョン

Assignees

  • ブリストル－マイヤーズ スクイブ カンパニー

Dates

Publication Date
20260511
Application Date
20201218
Priority Date
20191219

Claims (14)

  1. A pharmaceutical composition for treating cancer in a subject, comprising a DGKα and/or DGKζ inhibitor, a PD1/PD-L1-binding antagonist, and a CTLA4 antagonist, wherein the PD1/PD-L1-binding antagonist is an antibody that binds to human PD1 or PD-L1, the CTLA4 antagonist is an antibody that binds to human CTLA4, and the DGKα and/or DGKζ inhibitor has the following structure: A pharmaceutical composition which is a compound or a salt thereof having [a certain property].
  2. A pharmaceutical composition for treating cancer in a subject, comprising a DGKα and/or DGKζ inhibitor, a PD1/PD-L1-binding antagonist, and a CTLA4 antagonist, wherein the PD1/PD-L1-binding antagonist is an antibody that binds to human PD1 or PD-L1, the CTLA4 antagonist is an antibody that binds to human CTLA4, and the DGKα and/or DGKζ inhibitor is 4-((2S,5R)-2,5-diethyl-4-((S)-1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile, 4-((2S,5R)-2,5-diethyl-4-((R)-1-(4-(trifluoromethyl)phenyl)propyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile, 4-((2S,5R)-2,5-diethyl-4-((S)-1-(4-(trifluoromethyl)phenyl)butyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile, or 4-((2S,5R)-2,5-diethyl-4-((R)-1-(4-(trifluoromethyl)phenyl)butyl)piperazin-1-yl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidine-6-carbonitrile, A pharmaceutical composition selected from the pharmaceutically acceptable salts thereof.
  3. The pharmaceutical composition according to claim 1 or 2 , wherein the antibody that binds to human PD1 is nivolumab or pembrolizumab.
  4. The pharmaceutical composition according to any one of claims 1 to 3 , wherein the antibody that binds to human PD-L1 is atezolizumab.
  5. The pharmaceutical composition according to any one of claims 1 to 4 , wherein the antibody that binds to human CTLA4 is ipilimumab.
  6. The pharmaceutical composition according to any one of claims 1 to 5 , wherein the cancer is a solid tumor or a hematological (liquid) tumor.
  7. The pharmaceutical composition according to any one of claims 1 to 5, wherein the cancer is selected from the group consisting of squamous cell carcinoma, small cell lung cancer, pituitary cancer, esophageal cancer, astrocytoma, soft tissue sarcoma, non-small cell lung cancer (including squamous non-small cell lung cancer), lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, renal cell carcinoma, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, brain tumor, endometrial cancer, testicular cancer, bile duct cancer, gallbladder cancer, stomach cancer , melanoma , and various types of head and neck cancer (including head and neck squamous cell carcinoma).
  8. A pharmaceutical composition according to any one of claims 1 to 7 , characterized in that it is used in combination with one or more other cancer treatments.
  9. The pharmaceutical composition according to claim 8 , wherein one or more other cancer treatments include radiation therapy, surgery, chemotherapy, or administration of a biopharmaceutical.
  10. The pharmaceutical composition according to claim 8 , wherein one or more other cancer treatments are the administration of a biopharmaceutical, the biopharmaceutical being an agent that stimulates the immune system.
  11. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that the subject is not being treated with other cancer treatments while being treated with a DGKα and/or DGKζ inhibitor, a PD1/PD- L1 -binding antagonist, and/or a CTLA4 antagonist.
  12. The pharmaceutical composition according to any one of claims 1 to 11, characterized in that the subject has not been treated with a PD1/PD-L1 antagonist or a CTLA4 antagonist prior to administration of a DGKα and/or DGKζ inhibitor, a PD1/PD-L1 antagonist, and/or a CTLA4 antagonist.
  13. A pharmaceutical composition according to any one of claims 1 to 11 , wherein the subject is resistant to or refractory to treatment with checkpoint inhibitor antagonists (e.g., PD1/PD-L1 binding antagonists and/or CTLA4 antagonists).
  14. The pharmaceutical composition according to any one of claims 1 to 2 and 6 to 13 , wherein the PD1/PD-L1 binding antagonist is nivolumab or a variant thereof, and the CTLA4 antagonist is ipilimumab or a variant thereof.

Description

(Related applications) This application claims priority to U.S. Provisional Application No. 62/950,570, filed December 19, 2019, which is incorporated herein by reference in its entirety. Human cancers encompass numerous genetic and epigenetic alterations and produce neoantigens that the immune system may recognize (Sjoblom et al. (2006) Science 314:268-74). The adaptive immune system, composed of T and B lymphocytes, possesses the potential to exhibit potent anti-cancer activity, exhibiting broad capabilities and high specificity in responding to diverse tumor antigens. Furthermore, this immune system has considerable flexibility and memory components. By effectively utilizing all these characteristics of the adaptive immune system, immunotherapy becomes a distinctive approach among all cancer treatments. However, although an endogenous immune response to cancer has been observed in preclinical models and patients, this response is ineffective, and established cancers are recognized as "self," exhibiting resistance to the immune system. This acceptance allows tumors to actively overcome anti-tumor immunity by utilizing multiple different mechanisms. These mechanisms include signaling from dysfunctional T cells (Mizoguchi et al., (1992) Science 258:1795-98), suppressive regulatory cells (Facciabene et al., (2012) Cancer Res. 72:2162-71), and the utilization of endogenous "immune checkpoints," which reduce the intensity of the adaptive immune response, protecting normal tissue from secondary damage by tumors and thus escaping immune destruction (Topalian et al., (2012) Curr. Opin. Immunol. 24:1-6; Mellman et al. (2011) Nature 480:480-489). Diacylglycerol kinase (DGK) is a lipid kinase that mediates the conversion of diacylglycerol to phosphatidic acid, thereby halting the function of T cells that propagate through the TCR signaling pathway. Therefore, DGK is expected to function as an intracellular checkpoint, and inhibiting DGK is expected to enhance T cell signaling pathways and T cell activation. Supporting this is evidence that knockout mouse models of either DGKα or DGKζ exhibit hyperreactive T cell phenotypes and improved antitumor immune activity (Riese M.J. et al., Journal of Biological Chemistry, (2011) 7: 5254-5265; Zha Y et al., Nature Immunology, (2006) 12:1343; Olenchock B.A. et al., (2006) 11: 1174-81). Furthermore, tumor-infiltrating lymphocytes extracted from human renal cell carcinoma patients have been observed to overexpress DGKα, which inhibits T cell function (Prinz, P.U. et al., J Immunology (2012) 12:5990-6000). Therefore, DGKα and DGKζ are considered targets for cancer immunotherapy (Riese M.J. et al., Front Cell Dev Biol. (2016) 4: 108; Chen, S.S. et al., Front Cell Dev Biol. (2016) 4: 130; Avila-Flores, A. et al., Immunology and Cell Biology (2017) 95: 549-563; Noessner, E., Front Cell Dev Biol. (2017) 5: 16; Krishna, S., et al., Front Immunology (2013) 4:178; Jing, W. et al., Cancer Research (2017) 77: 5676-5686). This application provides a method for treating a disease or disorder, characterized by administering an inhibitor of DGKα, DGKζ, or both DGKα and DGKζ (e.g., a compound of formula (I) or (II), for example, a compound selected from compounds 1 to 34, or a pharmaceutically acceptable salt thereof) to a subject in combination with a PD1/PD-L1-binding antagonist and/or a CTLA4 antagonist. Examples of diseases or disorders for which effects can be obtained by stimulating the immune system include, for example, cancer and infectious diseases. The application also provides the use of an inhibitor of DGKα, DGKζ, or both DGKα and DGKζ (e.g., a compound of formula (I) or (II), for example, a compound selected from compounds 1 to 34, or a pharmaceutically acceptable salt thereof) for use in the manufacture of a pharmacopoeia for treating diseases or disorders for which effects can be obtained by stimulating the immune system (e.g., cancer and infectious diseases). Here, the inhibitor is administered in combination with a PD1/PD-L1-binding antagonist and/or a CTLA4 antagonist. This application relates to inhibitors of DGKα, DGKζ, or both DGKα and DGKζ (e.g., compounds of formula (I) or (II), for example, compounds selected from compounds 1 to 34 or pharmaceutically acceptable salts thereof) for the manufacture of pharmaceuticals for treating diseases or disorders (e.g., cancer and infectious diseases) in which the effect can be obtained by stimulating the immune system. Herein, the inhibitor is administered in combination with a PD1/PD-L1 antagonist and a CTLA4 antagonist. Furthermore, PD1/PD-L1 antagonists are used for the manufacture of pharmaceuticals for treating diseases or disorders (e.g., cancer and infections) in which the effects can be obtained by stimulating the immune system. Here, the antagonist is administered in combination with an inhibitor of DGKα, DGKζ, or both DGKα and DGKζ (e.g., a compound of formula (I) or (II), for example, a compound selected from compounds 1