학술논문
Novel Arginase Inhibitor, AZD0011, Demonstrates Immune Cell Stimulation and Antitumor Efficacy with Diverse Combination Partners.
Document Type
Academic Journal
Author
Doshi AS; Bioscience, Oncology R&D, AstraZeneca, Waltham, Massachusetts.; Cantin S; Bioscience, Oncology R&D, AstraZeneca, Waltham, Massachusetts.; Hernandez M; Translational Medicine, Oncology R&D, AstraZeneca, Waltham, Massachusetts.; Srinivasan S; Translational Medicine, Oncology R&D, AstraZeneca, Waltham, Massachusetts.; Tentarelli S; Chemistry, Oncology R&D, AstraZeneca, Waltham, Massachusetts.; Griffin M; Bioscience, Oncology R&D, AstraZeneca, Waltham, Massachusetts.; Wang Y; Bioscience, Oncology R&D, AstraZeneca, Waltham, Massachusetts.; Pop-Damkov P; Drug Metabolism and Pharmacokinetics, Oncology R&D, Waltham, Massachusetts.; Prickett LB; Bioscience, Oncology R&D, AstraZeneca, Waltham, Massachusetts.; Kankkonen C; Discovery Sciences, R&D, AstraZeneca, Mölndal, Sweden.; Shen M; Bioscience, Oncology R&D, AstraZeneca, Waltham, Massachusetts.; Martin MS; Bioscience, Oncology R&D, AstraZeneca, Waltham, Massachusetts.; Wu S; Translational Medicine, Oncology R&D, AstraZeneca, Gaithersburg, Maryland.; Castaldi MP; Discovery Sciences, R&D, AstraZeneca, Waltham, Massachusetts.; Ghadially H; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.; Varnes J; Global Portfolio and Project Management, Waltham, Massachusetts.; Gales S; Toxicology, Oncology R&D, AstraZeneca, Cambridge, United Kingdom.; Toxicology, Oncology R&D, AstraZeneca, Boston, Massachusetts.; Henry D; Toxicology, Oncology R&D, AstraZeneca, Cambridge, United Kingdom.; Toxicology, Oncology R&D, AstraZeneca, Boston, Massachusetts.; Hoover C; Safety Pathology, Oncology R&D, AstraZeneca, Boston, Massachusetts.; Mele DA; Bioscience, Oncology R&D, AstraZeneca, Waltham, Massachusetts.; Simpson I; Chemistry, Oncology R&D, AstraZeneca, Cambridge, United Kingdom.; Gangl ET; Drug Metabolism and Pharmacokinetics, Oncology R&D, Waltham, Massachusetts.; Mlynarski SN; Chemistry, Oncology R&D, AstraZeneca, Waltham, Massachusetts.; Finlay MRV; Chemistry, Oncology R&D, AstraZeneca, Cambridge, United Kingdom.; Drew L; Bioscience, Oncology R&D, AstraZeneca, Waltham, Massachusetts.; Fawell SE; Bioscience, Oncology R&D, AstraZeneca, Waltham, Massachusetts.; Shao W; Projects, Oncology R&D, AstraZeneca, Boston, Massachusetts.; Schuller AG; Bioscience, Oncology R&D, AstraZeneca, Waltham, Massachusetts.
Source
Publisher: American Association for Cancer Research, Inc Country of Publication: United States NLM ID: 101132535 Publication Model: Print Cited Medium: Internet ISSN: 1538-8514 (Electronic) Linking ISSN: 15357163 NLM ISO Abbreviation: Mol Cancer Ther Subsets: MEDLINE
Subject
Language
English
Abstract
Antitumor immunity can be hampered by immunosuppressive mechanisms in the tumor microenvironment, including recruitment of arginase (ARG) expressing myeloid cells that deplete l-arginine essential for optimal T-cell and natural killer cell function. Hence, ARG inhibition can reverse immunosuppression enhancing antitumor immunity. We describe AZD0011, a novel peptidic boronic acid prodrug to deliver an orally available, highly potent, ARG inhibitor payload (AZD0011-PL). We demonstrate that AZD0011-PL is unable to permeate cells, suggesting that this compound will only inhibit extracellular ARG. In vivo, AZD0011 monotherapy leads to arginine increases, immune cell activation, and tumor growth inhibition in various syngeneic models. Antitumor responses increase when AZD0011 is combined with anti-PD-L1 treatment, correlating with increases in multiple tumor immune cell populations. We demonstrate a novel triple combination of AZD0011, anti-PD-L1, and anti-NKG2A, and combination benefits with type I IFN inducers, including polyI:C and radiotherapy. Our preclinical data demonstrate AZD0011's ability to reverse tumor immunosuppression and enhance immune stimulation and antitumor responses with diverse combination partners providing potential strategies to increase immuno-oncology therapies clinically.
(©2023 American Association for Cancer Research.)
(©2023 American Association for Cancer Research.)