Design of high-affinity binders to immune modulating receptors for cancer immunotherapy

Wei Yang, Derrick R. Hicks, 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 and David Baker ()
Additional contact information
Wei Yang: University of Washington
Derrick R. Hicks: University of Washington
Agnidipta Ghosh: Bronx
Tristin A. Schwartze: University of Pittsburgh
Brian Conventry: University of Washington
Inna Goreshnik: University of Washington
Aza Allen: University of Washington
Samer F. Halabiya: University of Washington
Chan Johng Kim: University of Washington
Cynthia S. Hinck: University of Pittsburgh
David S. Lee: University of Washington
Asim K. Bera: University of Washington
Zhe Li: University of Washington
Yujia Wang: University of Washington
Thomas Schlichthaerle: University of Washington
Longxing Cao: University of Washington
Buwei Huang: University of Washington
Sarah Garrett: Bronx
Stacey R. Gerben: University of Washington
Stephen Rettie: University of Washington
Piper Heine: University of Washington
Analisa Murray: University of Washington
Natasha Edman: University of Washington
Lauren Carter: University of Washington
Lance Stewart: University of Washington
Steven C. Almo: Bronx
Andrew P. Hinck: University of Pittsburgh
David Baker: University of Washington

Nature Communications, 2025, vol. 16, issue 1, 1-12

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.

Date: 2025
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DOI: 10.1038/s41467-025-57192-z

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