De novo design of protease-activatable cytokine prodrugs

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.

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BibTeX RIS

BibTeX

@misc{shin2026novo,
  title = {{De novo design of protease-activatable cytokine prodrugs}},
  author = {H. Shin and J. G. Tello and C. J. Kim and J.-H. Chun and F. Peprah and B. D. Parent and T. Atajanova and R. A. I. Mahmud and L. Qiang and A. J. Aguirre and S. K. Dougan and M. Dougan and D. Baker},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.19.752834},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.19.752834v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - De novo design of protease-activatable cytokine prodrugs
AU  - H. Shin
AU  - J. G. Tello
AU  - C. J. Kim
AU  - J.-H. Chun
AU  - F. Peprah
AU  - B. D. Parent
AU  - T. Atajanova
AU  - R. A. I. Mahmud
AU  - L. Qiang
AU  - A. J. Aguirre
AU  - S. K. Dougan
AU  - M. Dougan
AU  - D. Baker
PY  - 2026
DA  - 2026/09/19
PB  - bioRxiv
DO  - 10.64898/2026.09.19.752834
UR  - https://www.biorxiv.org/content/10.64898/2026.09.19.752834v1
AB  - 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.
ER  -

Abstract

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