1. Novel Arginase Inhibitor, AZD0011, Demonstrates Immune Cell Stimulation and Antitumor Efficacy with Diverse Combination Partners
- Author
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Aatman S. Doshi, Susan Cantin, Marylens Hernandez, Srimathi Srinivasan, Sharon Tentarelli, Matthew Griffin, Yanjun Wang, Petar Pop-Damkov, Laura B. Prickett, Cecilia Kankkonen, Minhui Shen, Maryann San Martin, Song Wu, M. Paola Castaldi, Hormas Ghadially, Jeffrey Varnes, Sonya Gales, David Henry, Clare Hoover, Deanna A. Mele, Iain Simpson, Eric T. Gangl, Scott N. Mlynarski, M. Raymond V. Finlay, Lisa Drew, Stephen E. Fawell, Wenlin Shao, and Alwin G. Schuller
- Subjects
Cancer Research ,Oncology - 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.
- Published
- 2023
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