1092 The CD8+ T cell selectivity of AB248 is essential for optimal anti-tumor activity and safety in nonclinical models

Abstract

Background AB248 is a fusion of an affinity-attenuated IL-2 mutein and an antibody targeting CD8+ T cells designed to overcome the limitations of wild-type IL-2 and second-genera-tion IL-2R bg agonists, “ not- a ” IL-2 and IL-15 variants. Like “ not- a ” IL-2, AB248 ’ s IL-2 mutein does not bind IL-2R a and thus avoids IL-2R a -associated vascular leak syndrome (VLS) and preferential Treg activation in nonclinical models. Further, the IL-2 mutein in AB248 has reduced IL-2R b affinity, and its cis-targeting to CD8+ T cells enables AB248 to avoid the biased expansion of IL-2R b high NK cells and IL2R bg -mediated activation of Tregs associated with untargeted IL2R bg agonists. Thus, AB248 ’ s design enables robust IL-2 pharmacology on CD8+ T cells, key effectors with IL-2-based therapy 1-2 , while avoiding cell types that may promote toxicity or oppose antitumor activity. Here, the mechanisms by which AB248 achieves enhanced nonclinical activity and safety profiles over untargeted IL-2-based therapies are elucidated. sorted PBMC subsets interrogated this and necessity of dual IL-2R a and IL-2R bg affinity reduction as well as CD8+ T cell cis-targeting to avoid antigen-independent cytokine release. Strong anti-tumor activity elicited by muAB248 multiple murine