Engineered FcRn Binding Fusion Peptides Significantly Enhance the Half‐Life of a Fab Domain in Cynomolgus Monkeys. Issue 3 (26th June 2018)

• Record Type: Journal Article
• Authors: Datta‐Mannan, Amita; Boyles, Jeffrey; Huang, Lihua; Jin, Zhaoyan Y.; Peariso, Amber; Murphy, Anthony T.; Ellis, Bernice; Douglass, Nicole; Norouziyan‐Cooper, Fariba; Witcher, Derrick R.
• Is Part Of: Biotechnology journal. Volume 14:Issue 3(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-06-26
• Subjects: fusion peptides -- neonatal Fc receptor (FcRn) -- pharmacokinetics -- time‐extension technology; Biotechnology -- Periodicals; 660.605
• DOI: 10.1002/biot.201800007
• Languages: English
• ISSNs: 1860-6768

Abstract

Abstract : There is a rapidly growing reinvigoration of the investigation of small proteins, cyclic peptides, and mAb derived domains as biotherapies. The drugability of these structures are challenged by fast peripheral clearance properties that can reduce their potential to be realized as medicines. Engineering strategies have been of limited value because mechanistically the half‐life benefit is manifested by increasing the molecular weight and/or the hydrodyanimc radius which slows the molecule's renal elimination, but can result in the inherent loss of activity and target accessibility. The present work evaluated an alternative approach using smaller peptide sequences which bind to the neonatal Fc receptor (FcRn). Results revealed, small linear and cyclic FcRn binding peptides (FcRnBPs) fused to a combination of the N‐ and C‐termini of a Fab can significantly improve the pharmacokinetics of the protein in cynomolgus monkeys relative to the parental Fab. The linear and cyclic conformations, as well as, the number of FcRnBPs fused to the Fab both influence the clearance and the extent of pharmacokinetic benefit. FcRnBP fusion protein kinetics were also affected by a combination of post‐translation modifications and non‐specific binding properties. The results in this report lay some foundation in fostering the advent of newer technologies toward successfully improving the pharmacokinetics of proteins, peptides, and mAb‐derived domains. Additional work in the integration of a variety of factors including the intended site of action, tissue disposition, metabolism, toxicity and pharmacokinetic, and pharmacodynamics relationship of the intended therapeutic modality are key areas for advancement of these approaches. Abstract : Neonatal Fc receptor binding peptides (FcRnBPc) represents a promising alternative for improving the pharmacokinetics of protiens, peptides and mAb derived domains. In this study, the authors revealed, small linear and cyclic FcRnBPs fused to a combination of the N‐ and C‐termini of a Fab can significantly improve the pharmacokinetics of the fusion protien in cynomolgus monkeys relative to the parental Fab. The results lay a foundation in fostering the advent of newer technologies towards successfully improving the pharmacokinetics of various biologics.