Year: 2026
Type: preprint
Abstract: Cytokines can elicit potent antitumor immunity, but their clinical use is often limited by systemic immune activation and dose-limiting toxicity. Protease-responsive masking offers a way to improve selectivity by linking cytokine activity to disease-associated protease cleavage, but current approaches have faced several challenges. Here we describe a de novo protein design strategy for generating protease-activatable cytokine prodrugs that overcomes these challenges. We use this strategy to design and characterize cytokine prodrugs and well-behaved AND-gated split systems that require both target-dependent colocalization and proteolytic unmasking to generate active cytokines. In challenging syngeneic tumor models, our IL-21 prodrugs reduced treatment-associated toxicity while maintaining antitumor efficacy.
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: Design of de novo interleukin mimics for targeted immunotherapy, G2038951588, MATCHMAKERS, G4726734171, G8686771678, Signaling pathways in tumoricidal macrophages in pancreatic cancer, Stromal modulation of pancreatic cancer malignant cell state and therapeutic sensitivity, CDK4/6 inhibition during CD8 T cell priming potentiates memory formation in mice and humans, Molecular Pathways Regulating Tissue-resident Memory T cells in the Gut, De Novo Design of Minibinder Antagonists for COVID-19 and Future Pandemics
OpenAlex ID: W7214276776