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

Yang, Wei, Hicks, Derrick R., Ghosh, Agnidipta, Schwartze, Tristin A., Conventry, Brian, Goreshnik, Inna, Allen, Aza, Halabiya, Samer F., Kim, Chan Johng, Hinck, Cynthia S., Lee, David S., Bera, Asim K., Li, Zhe, Wang, Yujia, Schlichthaerle, Thomas, Cao, Longxing, Huang, Buwei, Garrett, Sarah, Gerben, Stacey R., Rettie, Stephen, Heine, Piper, Murray, Analisa, Edman, Natasha, Carter, Lauren, Stewart, Lance, Almo, Steven C., Hinck, Andrew P., Baker, David·2025·Nature Communications
DOI 10.1038/s41467-025-57192-zPMC PMC11865580
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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.

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Metadata

Authors
Yang, W., Hicks, D. R., Ghosh, A., Schwartze, T. A., Conventry, B., Goreshnik, I., Allen, A., Halabiya, S. F., Kim, C. J., Hinck, C. S., Lee, D. S., Bera, A. K., Li, Z., Wang, Y., Schlichthaerle, T., Cao, L., Huang, B., Garrett, S., Gerben, S. R., Rettie, S., Heine, P., Murray, A., Edman, N., Carter, L., Stewart, L., Almo, S. C., Hinck, A. P., & Baker, D.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-02-26
Volume
16
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-025-57192-z
PMC
PMC11865580
Cited by
40
References
11
Language
en
Licence
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (R01AG063845, U19AG065156)
  • United States Department of Defense | Defense Advanced Research Projects Agency (HR001120S0052, HR001117S0003)
  • Gates Ventures;Audacious Project;Open Philanthropy Project Improving Protein Design Fund;Howard Hughes Medical Institute

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