A Non-immunogenic Bivalent <scp>d</scp>-Protein Potently Inhibits Retinal Vascularization and Tumor Growth
Paul S. Marinec, Kyle E. Landgraf, Maruti Uppalapati, Gang Chen, Daniel Xie, Qiyang Jiang, Yanlong Zhao, Annalise Petriello, Kurt Deshayes, Stephen B. H. Kent, Dana Ault-Riché, Sachdev S. Sidhu
Abstract
. Mirror-image phage display and structure-guided design were utilized to create a d-protein that uses receptor mimicry to antagonize vascular endothelial growth factor A (VEGF-A). Selections against the d-protein form of VEGF-A using phage-displayed libraries of two different domain scaffolds yielded two proteins that bound distinct receptor interaction sites on VEGF-A. X-ray crystal structures of the d-protein/VEGF-A complexes were used to guide affinity maturation and to construct a heterodimeric d-protein VEGF-A antagonist with picomolar activity. The d-protein VEGF-A antagonist prevented vascular leakage in a rabbit eye model of wet age-related macular degeneration and slowed tumor growth in the MC38 syngeneic mouse tumor model with efficacies comparable to those of approved antibody drugs, and in contrast with antibodies, the d-protein was non-immunogenic during treatment and following subcutaneous immunizations.