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

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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Publication Details

Journal
Nature Communications
Published
2025-02-26
DOI
https://doi.org/10.1038/s41467-025-57192-z
Citations
20
Primary Topic
Immunotherapy and Immune Responses
Type
article
Field-Weighted Citation Impact
15.15

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

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20 citations
Nature Communications
Immunotherapy and Immune Responses
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Design of high-affinity binders to immune modulating receptors for cancer immunotherapy

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article en
20 citations

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.

Nature CommunicationsVol. 16(1)
Albert Einstein College of Medicine (US), Howard Hughes Medical Institute (US), University of Pittsburgh (US), University of Washington (US), PDL BioPharma (United States) (US)
Defense Advanced Research Projects Agency, National Institute on Aging
Good health and well-being
Openalex Percentile: Top 1%
Immunotherapy and Immune Responses
15.15
DOIOpen Access PDFOpenAlex
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