Design of high-affinity binders to immune modulating receptors for cancer immunotherapy
Abstract
Abstract Immune receptors have emerged as critical therapeutic targets for cancer immunotherapy. Designed protein binders can have high affinity, modularity, and stability and hence could be attractive components of protein therapeutics directed against these receptors, but traditional Rosetta based protein binder methods using small globular scaffolds have difficulty achieving high affinity on convex targets. Here we describe the development of helical concave scaffolds tailored to the convex target sites typically involved in immune receptor interactions. We employed these scaffolds to design proteins that bind to TGFβRII, CTLA-4, and PD-L1, achieving low nanomolar to picomolar affinities and potent biological activity following experimental optimization. Co-crystal structures of the TGFβRII and CTLA-4 binders in complex with their respective receptors closely match the design models. These designs should have considerable utility for downstream therapeutic applications.
Article Details
Authors (28)
Wei Yang
Derrick R. Hicks
Department of Biochemistry
Agnidipta Ghosh
Tristin A. Schwartze
Brian Conventry
Inna Goreshnik
Aza Allen
Samer F. Halabiya
Chan Johng Kim
Cynthia S. Hinck
David S. Lee
Asim K. Bera
Zhe Li
Yujia Wang
Thomas Schlichthaerle
Longxing Cao
Buwei Huang
Sarah Garrett
Stacey R. Gerben
Stephen Rettie
Piper Heine
Analisa Murray
Natasha Edman
Lauren Carter
Lance Stewart
Steven C. Almo
Andrew P. Hinck
David Baker