This week we reported in Nature Biotechnology the design of a conditionally active mimetic of IL-2 that reduces the toxicity of systemic cytokine therapy. This work builds on our prior efforts to create functional interleukin mimics with reduced toxicity.

We first described Neoleukin-2/15 (Neo-2/15) in 2019. This compact protein reproduces the immunostimulatory function of IL-2 and IL-15 by activation of IL-2Rβ and IL-2Rγ but is fully independent of the CD25 and CD215 receptors. To further improve Neo-2/15, a team led by former UW Bioengineering graduate student Alfredo Quijano-Rubio recently dissected the molecule. When chopped up in just the right way, the resulting drug fragments displayed neither beneficial activity nor unwanted side effects. But when the fragments were each targeted to the surface of cancer cells, the drug’s activity could be restored.

The team tested the new split-drug approach in cancerous mice. As expected, individual drug fragments did not show any antitumor activity. But when both fragments were given in the right dosage, some animals achieved complete tumor remission with no toxic effects. This was not the case for mice treated with IL-2 or intact Neo-2/15, which while efficacious can show systemic toxicity at high doses.

“By controlling when and where drugs become active in the body, we may be able to create safer and more effective cancer treatments,” said Quijano-Rubio.

This research was performed at the University of Washington School of Medicine, the Dana-Farber Cancer Institute, Massachusetts General Hospital, Harvard Medical School, Johns Hopkins University, and the Fred Hutchinson Cancer Research Center. 

This research was supported by the National Institutes of Health (R01-AI 158488-01, R01-CA240339-01, 1K08DK114563–01), Washington Research Foundation, Howard Hughes Medical Institute, The Audacious Project at the Institute for Protein Design, Fariborz Maseeh Award for Innovative Medical Education, Peter and Ann Lambertus Family Foundation, ‘la Caixa’ Foundation (LCF/BQ/ AN15/10380003), Emerson Collective, Maryland Innovation Initiative, National Science Foundation, Melanoma Research Alliance, Ludwig Center at Harvard, and Claudia Adams Barr Foundation.