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Protein Catalyzed Capture Agents with Tailored Performance for in vitro and in vivo Applications

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Journal Article - Open Access

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United States Army Research Laboratory Adelphi United States

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We report on peptide-based ligands matured through the protein catalyzed capture PCC agent method to tailor molecular binders for in vitro sensingdiagnostics and in vivo pharmacokinetics parameters. A vascular endothelial growth factor VEGF binding peptide and a peptide against the protective antigen PA protein of Bacillus anthracis discovered through phage and bacterial display panning technologies, respectively, were modified with click handles and subjected to iterative in situ click chemistry screens using synthetic peptide libraries. Each azide-alkyne cycloaddition iteration, promoted by the respective target proteins, yielded improvements in metrics for the application of interest. The anti-VEGF PCC was explored as a stable in vivo imaging probe. It exhibited excellent stability against proteases and a mean elimination in vivo half-life T12 of 36 min. Intraperitoneal injection of the reagent results in slow clearance from the peritoneal cavity and kidney retention at extended times, while intravenous injection translates to rapid renal clearance. The ligand competed with the commercial antibody for binding to VEGF in vivo. The anti-PA ligand was developed for detection assays that perform in demanding physical environments. The matured anti-PA PCC exhibited no solution aggregation, no fragmentation when heated to 100 deg C, and 81 binding activity for PA after heating at 90 deg C for 1 h. We discuss the potential of the PCC agent screening process for the discovery and enrichment of next generation antibody alternatives.

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  • Biochemistry

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