Journal Article

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

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

2025

Overview

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. Immune receptors regulate immune responses and are key cancer immunotherapy targets. Here, the authors designed helical concave scaffolds to bind convex sites in immune receptors, creating high-affinity protein binders for TGFβRII, CTLA-4, and PD-L1. Co-crystal structures confirmed their therapeutic potential.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 49/23 / 631/114/469 / 631/45/612 / 631/67/1244 / 82/103 / 82/83 / 96/106 / 96/31 / Affinity / B7-H1 Antigen - chemistry / B7-H1 Antigen - immunology / B7-H1 Antigen - metabolism / Binders / Biological activity / Cancer / Cancer immunotherapy / Crystal structure / Crystallography, X-Ray / CTLA-4 Antigen - chemistry / CTLA-4 Antigen - immunology / CTLA-4 Antigen - metabolism / CTLA-4 protein / Design / Drug Design / Humanities and Social Sciences / Humans / Immune response / Immunotherapy / Immunotherapy - methods / Models, Molecular / Modularity / multidisciplinary / Neoplasms - immunology / Neoplasms - therapy / PD-L1 protein / Protein Binding / Proteins / Receptor, Transforming Growth Factor-beta Type II - chemistry / Receptor, Transforming Growth Factor-beta Type II - metabolism / Receptors / Scaffolds / Science / Science (multidisciplinary) / Therapeutic applications / Therapeutic targets