Abstract 1833: Novel IL-12 Partial Agonist For Cancer Immunotherapy Avoids NK-cell Mediated Toxicity

Here we report on a novel human IL-12 partial agonist (hIL-12v) that has diminished binding to IL-12Rb1. IL-12v is designed to more selectively engage antigen activated T-cells, which strongly upregulate IL-12Rb1 upon activation, and to reduce stimulation of NK cells or resting T cells, which express modest levels of IL-12Rb1. To explore anti-tumor efficacy and toxicity in mouse syngeneic tumor models, we generated a half-life extended mouse surrogate of the IL-12 partial agonist (mIL-12v Fc) and compared it to a similarly engineered half-life extended version of wild type mouse IL-12 (mIL-12wt Fc). At efficacious doses, systemic administration of mIL-12wt Fc induced significant weight loss and lethality characterized by early proinflammatory cytokine release and systemic NK cell activation. Conversely, mIL-12v Fc was well tolerated and avoided the robust and rapid NK cell activation and peripheral NK count decreases seen with mIL-12v Fc, suggestive of extravasation to tissues. Both mIL-12v Fc and mIL-12 WT Fc showed similar robust single-agent anti-tumor efficacy in syngeneic tumor models. Depletion of NK cells did not diminish anti-tumor efficacy. Efficacy for both molecules was characterized by CD8 T cell activation, myeloid cell reprograming and antigen presentation. Moreover, combination of mIL-12v Fc with systemic immunotherapies further enhanced anti-tumor activity without compromising tolerability. Overall, mIL-12v Fc retained anti-tumor efficacy without induction of severe toxicities compared to mIL-12wt Fc. These data suggest IL-12 partial agonists may represent a novel immunotherapy approach to maintain efficacy while avoiding classical toxicity associated with IL-12 therapy.1 Atkins, et al.; (1997) Clinical Cancer Research 3(3):409-172 Carson, et al. (1999) J Immunology 162 (8): 4943-4951. Citation Format: Ievgen Koliesnik, Jan Emmerich, Kim Q. Tran, Michele Bauer, Michael Totagrande, Bhargavi Jayaraman, Cindy Buffone, Priyanka Balasubrahmanyam, Deepti Rokkam, Rene de Waal Malefyt, Luis Zuniga, Heiko Greb, Navneet Ratti, Sandro Vivona, Martin Oft, Patrick J. Lupardus, Robert A. Kastelein. Novel IL-12 Partial Agonist For Cancer Immunotherapy Avoids NK-cell Mediated Toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1833.