Novel Immunomodulatory Proteins Generated via Directed Evolution of Variant IgSF Domains

Frontiers in Immunology

Susan Bort¹  Stanford L. Peng¹  Erika Rickel¹  Steven D. Levin¹  Katherine E. Lewis¹  Lawrence S. Evans¹  Martin F. Wolfson¹  Michael G. Kornacker¹  Stacey R. Dillon¹  Mark W. Rixon¹  Sean MacNeil¹  Ryan Swanson¹  Joseph Hoover¹  Rebecca P. Wu¹  David La² 

[1] Alpine Immune Sciences Inc., Seattle, WA, United States;Department of Biochemistry, University of Washington, Seattle, WA, United States;

关键词: costimulation;    protein engineering;    protein therapeutics;    anti-inflammatory;    IgSF;    ICOS ligand (ICOSL);   

DOI  :  10.3389/fimmu.2019.03086

来源: DOAJ

【 摘 要 】

Immunoglobulin superfamily member (IgSF) proteins play a significant role in regulating immune responses with surface expression on all immune cell subsets, making the IgSF an attractive family of proteins for therapeutic targeting in human diseases. We have developed a directed evolution platform capable of engineering IgSF domains to increase affinities for cognate ligands and/or introduce binding to non-cognate ligands. Using this scientific platform, ICOSL domains have been derived with enhanced binding to ICOS and with additional high-affinity binding to the non-cognate receptor, CD28. Fc-fusion proteins containing these engineered ICOSL domains significantly attenuate T cell activation in vitro and in vivo and can inhibit development of inflammatory diseases in mouse models. We also present evidence that engineered ICOSL domains can be formatted to selectively provide costimulatory signals to augment T cell responses. Our scientific platform thus provides a system for developing therapeutic protein candidates with selective biological impact for treatments of a wide array of human disorders including cancer and autoimmune/inflammatory diseases.

【 授权许可】

Unknown