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.

中文翻译：

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IL-2 靶向 CD8+ T 细胞可促进强大的效应 T 细胞反应和有效的抗肿瘤免疫

IL-2 在多种细胞类型上发出多效性信号，其中一些细胞有助于针对肿瘤的治疗活性，而另一些细胞则会产生不良活性，例如免疫抑制或毒性。我们探索了这样的理论：将 IL-2 靶向 CD8+ T 细胞（关键的抗肿瘤效应细胞）可以提高其治疗指数。为此，我们开发了 CD8 顺式靶向 IL-2 AB248，它对 CD8+ T 细胞的偏好比 NK 和 Treg 细胞高 500 倍，这可能分别导致毒性和免疫抑制。 AB248 在体外重现了 IL-2 对 CD8+ T 细胞的作用，并诱导灵长类动物选择性扩增 CD8+ T 细胞。在小鼠中，与非靶向 IL-2RBy 激动剂相比，AB248 替代物表现出优异的抗肿瘤活性和增强的耐受性。疗效与肿瘤浸润 CD8+ T 细胞的扩增和表型增强有关，包括“更好的效应细胞”群体的出现。这些数据支持 AB248 在临床环境中的潜在用途。