IL-2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, while others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting of IL-2 to CD8+ T cells, which are key anti-tumor effectors, could enhance its therapeutic index. To this aim, we developed AB248, CD8 cis-targeted IL-2 that demonstrates over 500-fold preference for CD8+ T cells over NK and Treg cells, which may contribute to toxicity and immunosuppression, respectively. AB248 recapitulated IL-2's effects on CD8+ T cells in vitro and induced selective expansion of CD8+ T cells in primates. In mice, an AB248 surrogate demonstrated superior anti-tumor activity and enhanced tolerability as compared to an untargeted IL-2RBy agonist. Efficacy was associated with expansion and phenotypic enhancement of tumor-infiltrating CD8+ T cells, including the emergence of a "better effector" population. These data support the potential utility of AB248 in clinical settings.
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