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De Novo Design of Potent and Selective Mimics of IL-2 and IL-15

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, etc.

Nature. 2019 Jan;565(7738):186-191.

PMID: 30626941

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42413353	IL-15 from mouse			Price

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