A cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy
Abstract Interleukin-2 (IL-2) is an FDA approved treatment for multiple metastatic cancers. However, while IL-2 is a potent activator of CD8 and NK cells, its clinical use is limited by short in vivo half-life, low potency, and severe in vivo toxicity. Current strategies of reducing IL-2 receptor alpha binding and increasing IL-2 receptor beta binding reduce efficacy or increase toxicity. Here, we address these issues by engineering a novel IL-2 prodrug (ProIL2). We mask the activity of a CD8 T cell-preferred IL-2 mutein/Fc fusion protein with IL2 receptor beta linked to a tumor-associated protease substrate. ProIL2 restores activity after cleavage by tumor-associated enzymes, and preferentially activates inside tumors, where it is efficiently cleaved and expands CD8 T cells. This significantly reduces IL-2 associated cytokine storm, body weight loss, and mortality without compromising antitumor efficacy. ProIL2 also overcomes resistance of cancers to immune checkpoint blockade. Lastly, neoadjuvant ProIL2 treatment can effectively eliminate metastatic cancer by inducing an abscopal effect. Taken together, our approach presents an effective tumor targeting therapy with reduced toxicity.