Abstract 4434: A PD-1-targeted, receptor-masked IL-2 immunocytokine with maintained potential to engage endogenous IL-2Ra drives selective stimulation of PD-1+ T cells and robust anti-tumor efficacy

Abstract

Abstract Interleukin-2 (IL-2) is a key cytokine for T cell proliferation, differentiation, and effector function. Recombinant IL-2 has been used for the treatment of metastatic melanoma and renal cell carcinoma, and induced complete, durable tumor regression in some patients. ​However, its broader use in cancer immunotherapy has been limited by severe toxicity. A new generation of IL-2 therapies with decreased binding to IL-2 receptor α-chain (IL-2Rα) is being developed to reduce toxicity and Tregs expansion yet with limited clinical success so far. Here, we show that the ability to engage IL-2Rα is critical for maximal anti-tumor activity of a systemic IL-2 therapy, and an alternative approach to circumvent systemic toxicity is to deliver IL-2 specifically to tumor-reactive T cells. We developed REGN10597, a PD-1-targeted, receptor-masked IL-2 immunocytokine with attenuated systemic IL-2 activity but maintained capacity to engage endogenous IL-2Rα on PD-1+ T cells. Compared to WT IL-2, receptor masked IL-2 shows improved PK and diminished systemic toxicity in mice. REGN10597 shows PD1-targeting-dependent IL-2 activity in vitro and drives selective expansion of tumor-infiltrating PD-1+ CD8 T cells with vigorous effector functions in vivo. In preclinical syngeneic tumor models in PD-1 humanized mice, REGN10597 demonstrates robust anti-tumor efficacy both as a single agent and in combination with PD-1 or PD-L1 blocking antibodies. These findings highlight the therapeutic potential of REGN10597 as a novel targeted and receptor masked WT IL-2 therapy, supporting its clinical development for the treatment of cancer. Citation Format: Jiaxi Wu, Nicolin Bloch, Aaron Chang, Ramandeep Bhavsar, Supriya Patel, Qingqing Wang, Hassan Shakil Ahmed, Vidur Garg, Michael Amatulli, Yuetian Yan, Shunhai Wang, Drew Dudgeon, Willy Ramos, Pamela Krueger, Ashique Rafique, Tammy Huang, Erica Ullman, Aynur Hermann, William Olson, John Lin, Eric Smith, Tong Zhang. A PD-1-targeted, receptor-masked IL-2 immunocytokine with maintained potential to engage endogenous IL-2Ra drives selective stimulation of PD-1+ T cells and robust anti-tumor efficacy. [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 4434.