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Protein Catalyzed Capture Agents with Tailored Performance for In Vitro and In Vivo Applications

Coppock, Matthew B. and Warner, Candice R. and Dorsey, Brandi and Orlicki, Joshua A. and Sarkes, Deborah A. and Lai, Bert T. and Pitram, Suresh M. and Rohde, Rosemary D. and Malette, Jacquie and Wilson, Jeré A. and Kearney, Paul and Fang, Kenneth C. and Law, Scott M. and Candelario, Sherri L. and Farrow, Blake and Finch, Amethist S. and Agnew, Heather D. and Heath, James R. and Stratis-Cullum, Dimitra N. (2017) Protein Catalyzed Capture Agents with Tailored Performance for In Vitro and In Vivo Applications. Biopolymers, 108 (2). Art. No. e22934. ISSN 0006-3525. PMCID PMC6585716.

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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 sensing/diagnostics 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 (T_(1/2)) 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°C, and  > 81% binding activity for PA after heating at 90°C for 1 h. We discuss the potential of the PCC agent screening process for the discovery and enrichment of next generation antibody alternatives.

Item Type:Article
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URLURL TypeDescription CentralArticle
Heath, James R.0000-0001-5356-4385
Additional Information:© 2016 The Authors Peptide Science Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Issue online: 25 March 2017; Version of record online: 25 March 2017; Accepted manuscript online: 19 August 2016; The authors would like to thank Jonathan Bohn from Enzo Life Sciences for technical support and Yue Li of the University of Maryland Mass Spectrometry Facility for performing mass spectrometry confirmations. This research was primarily supported by the Army Institute for Collaborative Biotechnologies through grant W911NF-09-0001 and B.F. was supported by an HHMI ISRF. The content of the information does not necessarily reflect the position or the policy of the United States Government, and no official endorsement should be inferred.
Funding AgencyGrant Number
Army Research Office (ARO)W911NF-09-0001
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:biological stability; protective antigen; protein catalyzed capture agent; synthetic antibody; thermal stability; peptide; vascular endothelial growth factor
Issue or Number:2
PubMed Central ID:PMC6585716
Record Number:CaltechAUTHORS:20160901-081827918
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Official Citation:Coppock MB, Warner CR, Dorsey B, et al. Protein catalyzed capture agents with tailored performance for in vitro and in vivo applications. Peptide Science 2017;108:e22934.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:70104
Deposited By: Tony Diaz
Deposited On:01 Sep 2016 16:23
Last Modified:03 Oct 2019 10:28

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