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Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging

2015; National Academy of Sciences; Volume: 112; Issue: 47 Linguagem: Inglês

10.1073/pnas.1519623112

1091-6490

Roy L. Maute, Sydney R. Gordon, Aaron T. Mayer, Melissa N. McCracken, Arutselvan Natarajan, Nan Ring, Richard H. Kimura, Jonathan M. Tsai, Aashish Manglik, Andrew C. Kruse, Sanjiv S. Gambhir, Irving L. Weissman, Aaron M. Ring,

Cancer Immunotherapy and Biomarkers

Significance Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) are key targets in the treatment of cancer, but current antibody-based drugs against this pathway have inherent drawbacks that may limit their effectiveness. We used directed evolution with yeast display to engineer a nonantibody biologic based on the ectodomain of PD-1. High-affinity PD-1 was more effective than anti–PD-L1 antibodies in the treatment of mouse tumor models and could additionally be used as a PET imaging tracer to noninvasively assess the PD-L1 expression status of tumors. This engineered protein thus represents an agent useful for clinical translation and highlights the paradigm of small protein biologics for future drug development.