High-Throughput De Novo Protein Design Yields Novel Immunomodulatory Agonists
Abedi, M.; Exposit, M.; Coventry, B.; Mathew, D.; Jain, S.; Krishnakumar, A.; Goreshnik, I.; Gray-Gaillard, S.; Lunn-Halbert, M.; Yu, T.-Y.; Glögl, M.; Mitchell, U.; Keshri, R.; Chun, J. H.; Ruohola-Baker, H.; Wherry, E. J.; Baker, D.
Show abstract
Cytokines regulate cell behavior by bringing together specific receptor subunits to trigger downstream signaling. Designed molecules that bring together non-natural receptor pairs could have novel signaling responses and cell specificities. We present a high-throughput de-novo design approach to create novel cytokines by generating and fusing pairs of computationally designed binders. By combining 33 designed receptor-binding domains, we generated over a thousand potential de novo designed "Novokines", of which 75 activated pSTAT signaling in peripheral blood mononuclear cells. We characterized 18 of these, including new pairings of established common receptors, cross-family pairings such as TrkA-{gamma}common, and a series of pairings with interferon receptor-1 (IFNAR1), revealing that IFNAR1 can function as a versatile common receptor similar to {gamma}common or {beta}common. We identify novokines that drive monocyte proliferation, T cell survival and CD4+ T cell-specific proliferation. Our framework provides a blueprint for expanding the understanding of cytokine signaling and generating novel therapeutic proteins.
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