Abstract

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.