De novo design of potent and selective mimics of IL-2 and IL-15.
Ulge, Umut Y
Spangler, Jamie B
Crowley, Stephanie J
Walkey, Carl D
Weitzner, Brian D
Riddell, Stanley R
Garcia, K Christopher
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Silva, D., Yu, S., Ulge, U. Y., Spangler, J. B., Jude, K. M., Labão-Almeida, C., Ali, L. R., et al. (2019). De novo design of potent and selective mimics of IL-2 and IL-15.. Nature, 565 (7738), 186-191. https://doi.org/10.1038/s41586-018-0830-7
The considerable potential of the central immune cytokine interleukin-2 (IL-2) for cancer treatment 1–4 has sparked numerous efforts to improve its therapeutic properties by mutation and/or chemical modification 5–14. However, because these approaches are closely tied to native IL-2, they cannot eliminate undesirable properties such as low stability and binding to the IL-2 receptor α subunit (IL-2Rα) 9,13. Here, we describe a computational approach for designing de novo cytokine mimics that recapitulate the functional sites of natural cytokines, but otherwise are unrelated in topology or amino acid sequence. We use this strategy to design de novo mimics of IL-2 and interleukin-15 (IL-15) 15 that bind to the IL-2 receptor βƔc heterodimer (IL-2RβƔc) 16,17, but have no binding site for IL-2Rα or IL-15Rα. The designs are hyper-stable, bind to human and mouse IL-2RβƔc with higher affinity than the natural cytokines, and elicit downstream cell signaling independent of IL-2Rα and IL-15Rα. Crystal structures of an experimentally optimized mimic, Neoleukin-2/15 (Neo-2/15), are very close to the design model and provide the first structural information on the murine IL-2RβƔc complex. Neo-2/15 has highly efficacious therapeutic activity compared to IL-2 in murine models of melanoma and colon cancer, with reduced toxicity and no signs of immunogenicity. This strategy for building hyper-stable de novo mimetics can be readily applied to a multitude of natural cytokines and other signaling proteins, enabling the creation of superior therapeutic candidates with enhanced clinical profiles.
Animals, Humans, Mice, Melanoma, Colonic Neoplasms, Disease Models, Animal, Receptors, Interleukin-2, Interleukin-2, Interleukin-15, Crystallography, X-Ray, Signal Transduction, Binding Sites, Molecular Mimicry, Amino Acid Sequence, Drug Design, Models, Molecular, Computer Simulation, Interleukin-2 Receptor alpha Subunit, Protein Stability
Royal Society (RGF/EA/180007)
European Commission Horizon 2020 (H2020) ERC (676832)
External DOI: https://doi.org/10.1038/s41586-018-0830-7
This record's URL: https://www.repository.cam.ac.uk/handle/1810/288536