De novo design of potent and selective mimics of IL-2 and IL-15

Daniel-Adriano Silva (), Shawn Yu, Umut Y. Ulge, Jamie B. Spangler, Kevin M. Jude, Carlos Labão-Almeida, Lestat R. Ali, Alfredo Quijano-Rubio, Mikel Ruterbusch, Isabel Leung, Tamara Biary, Stephanie J. Crowley, Enrique Marcos, Carl D. Walkey, Brian D. Weitzner, Fátima Pardo-Avila, Javier Castellanos, Lauren Carter, Lance Stewart, Stanley R. Riddell, Marion Pepper, Gonçalo J. L. Bernardes, Michael Dougan, K. Christopher Garcia () and David Baker ()
Additional contact information
Daniel-Adriano Silva: University of Washington
Shawn Yu: University of Washington
Umut Y. Ulge: University of Washington
Jamie B. Spangler: Johns Hopkins University
Kevin M. Jude: Stanford University School of Medicine
Carlos Labão-Almeida: Universidade de Lisboa
Lestat R. Ali: Massachusetts General Hospital, Harvard Medical School
Alfredo Quijano-Rubio: University of Washington
Mikel Ruterbusch: University of Washington School of Medicine
Isabel Leung: Clinical Research Division
Tamara Biary: Massachusetts General Hospital, Harvard Medical School
Stephanie J. Crowley: Massachusetts General Hospital, Harvard Medical School
Enrique Marcos: University of Washington
Carl D. Walkey: University of Washington
Brian D. Weitzner: University of Washington
Fátima Pardo-Avila: Stanford University School of Medicine
Javier Castellanos: University of Washington
Lauren Carter: University of Washington
Lance Stewart: University of Washington
Stanley R. Riddell: Clinical Research Division
Marion Pepper: University of Washington School of Medicine
Gonçalo J. L. Bernardes: Universidade de Lisboa
Michael Dougan: Massachusetts General Hospital, Harvard Medical School
K. Christopher Garcia: Stanford University School of Medicine
David Baker: University of Washington

Nature, 2019, vol. 565, issue 7738, 186-191

Abstract: Abstract We describe a de novo computational approach for designing proteins that recapitulate the binding sites of natural cytokines, but are otherwise unrelated in topology or amino acid sequence. We use this strategy to design mimics of the central immune cytokine interleukin-2 (IL-2) that bind to the IL-2 receptor βγc heterodimer (IL-2Rβγc) but have no binding site for IL-2Rα (also called CD25) or IL-15Rα (also known as CD215). The designs are hyper-stable, bind human and mouse IL-2Rβγc with higher affinity than the natural cytokines, and elicit downstream cell signalling independently of IL-2Rα and IL-15Rα. Crystal structures of the optimized design neoleukin-2/15 (Neo-2/15), both alone and in complex with IL-2Rβγc, are very similar to the designed model. Neo-2/15 has superior therapeutic activity to IL-2 in mouse models of melanoma and colon cancer, with reduced toxicity and undetectable immunogenicity. Our strategy for building hyper-stable de novo mimetics could be applied generally to signalling proteins, enabling the creation of superior therapeutic candidates.

Date: 2019
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Citations: View citations in EconPapers (11)

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DOI: 10.1038/s41586-018-0830-7

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