A split, conditionally active mimetic of IL-2 reduces the toxicity of systemic cytokine therapy

Alfredo Quijano-Rubio, Aladdin M. Bhuiyan, Huilin Yang, Isabel Leung, Elisa Bello, Lestat R. Ali, Kevin Zhangxu, Jilliane Perkins, Jung Ho Chun, Wentao Wang, Marc J. Lajoie, Rashmi Ravichandran, Yun Huai Kuo, Stephanie K. Dougan, Stanley R. Riddell, Jamie B. Spangler, Michael Dougan, Daniel Adriano Silva, David Baker

Research output: Contribution to journalArticlepeer-review

Abstract

The therapeutic potential of recombinant cytokines has been limited by the severe side effects of systemic administration. We describe a strategy to reduce the dose-limiting toxicities of monomeric cytokines by designing two components that require colocalization for activity and that can be independently targeted to restrict activity to cells expressing two surface markers. We demonstrate the approach with a previously designed mimetic of cytokines interleukin-2 and interleukin-15—Neoleukin-2/15 (Neo-2/15)—both for trans-activating immune cells surrounding targeted tumor cells and for cis-activating directly targeted immune cells. In trans-activation mode, tumor antigen targeting of the two components enhanced antitumor activity and attenuated toxicity compared with systemic treatment in syngeneic mouse melanoma models. In cis-activation mode, immune cell targeting of the two components selectively expanded CD8+ T cells in a syngeneic mouse melanoma model and promoted chimeric antigen receptor T cell activation in a lymphoma xenograft model, enhancing antitumor efficacy in both cases.

Original languageEnglish (US)
Pages (from-to)532-540
Number of pages9
JournalNature biotechnology
Volume41
Issue number4
DOIs
StatePublished - Apr 2023

ASJC Scopus subject areas

  • Applied Microbiology and Biotechnology
  • Bioengineering
  • Molecular Medicine
  • Biotechnology
  • Biomedical Engineering

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