Abstract ND03: PD1-IL2v: A next generation, PD-1-targeted cytokine

High dose interleukin-2 (IL-2) has been the first effective cancer immunotherapy to treat metastatic melanoma and renal cell carcinoma, but its clinical use is limited due to toxicity and the detrimental expansion of regulatory T cells (Tregs). As both of these issues are compounded by binding to IL-2Ra (CD25), second generation IL-2 and IL-15 molecules ("IL2Rbg-biased agonists"), engineered to bind preferentially or exclusively to the intermediate-affinity IL-2R but not to CD25, are currently in clinical trials. However, reduced CD25 binding limits the ability of these 2nd generation cytokines for expansion of tumor antigen-specific T-cells. We have now generated a novel PD-1-targeted IL-2 variant (IL2v), by fusing a high-affinity anti-PD-1 antibody to an IL2v with abolished binding to CD25. High-affinity PD-1 binding allows IL2v to effectively expand tumor-antigen specific T-cells, and to differentiate those cells towards better, non-dysfunctional immune effectors, to much higher levels vs. anti-PD-1/-L1 antibodies alone or in combination with either tolerable doses of standard IL-2 or with a non-PD-1-targeted 2nd generation IL-2Rbg agonist currently in clinical development, and thus mediate significantly superior anti-tumor efficacy at well tolerated drug doses. PD1-IL2v is currently being tested in a Ph1 clinical trial. Citation Format: Pablo Umana. PD1-IL2v: A next generation, PD-1-targeted cytokine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr ND03.