title: Engineering neonatal Fc receptor-mediated recycling and transcytosis in recombinant proteins by short terminal peptide extensions.
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.
authors.affiliation: Pharmaceutical Sciences and Pharmacogenomics Graduate Program, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143, USA.
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Sockolosky
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Tiffany
authors.forename: Francis C
authors.initials: FC
authors.lastname: Szoka
mesh_terms: D000818:Animals; D004285:Dogs; D016503:Drug Delivery Systems / Q000379:methods*; D004926:Escherichia coli; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000235:genetics; D007700:Kinetics; D061985:Madin Darby Canine Kidney Cells; D053758:Nanoparticles; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D015202:Protein Engineering / Q000379:methods*; D011961:Receptors, Fc / Q000235:genetics* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D057900:Transcytosis / Q000235:genetics / Q000502:physiology*
chemical_list: D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D010455:Peptides; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; C100688:Fc receptor, neonatal