Engineering neonatal Fc receptor-mediated recycling and transcytosis in recombinant proteins by short terminal peptide extensions
- 18 September 2012
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (40), 16095-16100
- https://doi.org/10.1073/pnas.1208857109
Abstract
The importance of therapeutic recombinant proteins in medicine has led to a variety of tactics to increase their circulation time or to enable routes of administration other than injection. One clinically successful tactic to improve both protein circulation and delivery is to fuse the Fc domain of IgG to therapeutic proteins so that the resulting fusion proteins interact with the human neonatal Fc receptor (FcRn). As an alternative to grafting the high molecular weight Fc domain to therapeutic proteins, we have modified their N and/or C termini with a short peptide sequence that interacts with FcRn. Our strategy was motivated by results [Mezo AR, et al. (2008) Proc Natl Acad Sci USA 105:2337-2342] that identified peptides that compete with human IgG for FcRn. The small size and simple structure of the FcRn-binding peptide (FcBP) allows for expression of FcBP fusion proteins in Escherichia coli and results in their pH-dependent binding to FcRn with an affinity comparable to that of IgG. The FcBP fusion proteins are internalized, recycled, and transcytosed across cell monolayers that express FcRn. This strategy has the potential to improve protein transport across epithelial barriers, which could lead to noninvasive administration and also enable longer half-lives of therapeutic proteins.Keywords
This publication has 30 references indexed in Scilit:
- Soluble Monomeric IgG1 FcPublished by Elsevier BV ,2012
- Shortened Engineered Human Antibody CH2 Domains: INCREASED STABILITY AND BINDING TO THE HUMAN NEONATAL Fc RECEPTOR*Journal of Biological Chemistry, 2011
- Extending Half-life by Indirect Targeting of the Neonatal Fc Receptor (FcRn) Using a Minimal Albumin Binding DomainJournal of Biological Chemistry, 2011
- In situ growth of a PEG-like polymer from the C terminus of an intein fusion protein improves pharmacokinetics and tumor accumulationProceedings of the National Academy of Sciences of the United States of America, 2010
- X-ray Crystal Structures of Monomeric and Dimeric Peptide Inhibitors in Complex with the Human Neonatal Fc Receptor, FcRnPublished by Elsevier BV ,2010
- An intracellular traffic jam: Fc receptor-mediated transport of immunoglobulin GCurrent Opinion in Structural Biology, 2010
- Human growth hormone–transferrin fusion protein for oral delivery in hypophysectomized ratsJournal of Controlled Release, 2010
- Analyses of the Recycling Receptor, FcRn, in Live Cells Reveal Novel Pathways for Lysosomal DeliveryTraffic, 2009
- Reduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRnProceedings of the National Academy of Sciences of the United States of America, 2008
- Elucidation of intracellular recycling pathways leading to exocytosis of the Fc receptor, FcRn, by using multifocal plane microscopyProceedings of the National Academy of Sciences of the United States of America, 2007