A cytokine receptor-masked IL2 prodrug selectively activates tumor-infiltrating lymphocytes for potent antitumor therapy

As a potent lymphocyte activator, interleukin-2 (IL-2) is an FDA-approved treatment for multiple metastatic cancers. However, its clinical use is limited by short half-life, low potency, and severe in vivo toxicity. Current IL-2 engineering strategies exhibit evidence of peripheral cytotoxicity. Here, we address these issues by engineering an IL-2 prodrug (ProIL2). We mask the activity of a CD8 T cell-preferential 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 expands antigen-specific CD8 T cells. This significantly reduces IL-2 toxicity and mortality without compromising antitumor efficacy. ProIL2 also overcomes resistance of cancers to immune checkpoint blockade. Lastly, neoadjuvant ProIL2 treatment can eliminate metastatic cancer through an abscopal effect. Taken together, our approach presents an effective tumor targeting therapy with reduced toxicity. While recognized as the first effective immunotherapy for human cancer, IL-2 based immunotherapy still encounters several limitations in the clinic. Here, the authors design a cytokine receptor-masked IL-2 mutein prodrug that is selectively activated by matrix metalloproteinases in the tumor microenvironment, promoting anti-tumor immune response while minimizing systemic toxicity.

Automated summary

This study introduces an IL-2 prodrug, ProIL2, which is selectively activated inside tumors by tumor-associated enzymes. By specifically targeting the tumor microenvironment, ProIL2 effectively promotes anti-tumor immune response while minimizing systemic toxicity, overcoming limitations of traditional IL-2 based immunotherapy.