PEGylation enhances the therapeutic potential of peptide antagonists of the neonatal Fc receptor, FcRn

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 21; pp. 6332 - 6335
• Main Authors: Mezo, Adam R., Low, Susan C., Hoehn, Todd, Palmieri, Holly
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.11.2011; Elsevier
• Subjects: aldehydes; alkylation; Animals; antagonists; Autoimmune disease; Biological and medical sciences; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; FcRn inhibitor; Humans; immunoglobulin G; Immunoglobulin G - metabolism; Immunomodulators; Medical sciences; metabolism; Mice; Mice, Transgenic; Neonatal Fc receptor; PEGylation; peptides; Peptides - antagonists & inhibitors; Peptides - pharmacology; Pharmacology. Drug treatments; polyethylene glycol; Polyethylene Glycols - chemistry; protein-protein interactions; Receptors, Fc - antagonists & inhibitors; Receptors, Fc - metabolism; therapeutics; transgenic animals; Autoimmune disease; PEGylation; Neonatal Fc receptor; FcRn inhibitor; Immunopathology; Peptides; Gel electrophoresis; Rodentia; Immunoglobulin receptor; IgG; Biological activity; Ethylene oxide polymer; Vertebrata; Mammalia; Fc receptor; Mouse; Polypeptide; Animal; Dimer; Antagonist; Conjugated compound; Pegylated form; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.08.111

Peptides targeting the human neonatal Fc receptor (FcRn) were conjugated to poly(ethylene glycol) (PEG) polymers to study their effect on inhibition of the IgG:FcRn protein–protein interaction both in vitro and in mice. Both linear (5–40 kDa) and branched (20, 40 kDa) PEG aldehydes were conjugated to an amine-containing linker of a homodimeric anti-FcRn peptide using reductive alkylation chemistry. It was found that conjugation of PEG to the peptide compromised the in vitro activity, with larger and branched PEGs causing the most dramatic losses in activity. The conjugates were evaluated in transgenic mice for their ability to accelerate the catabolism of human IgG. Optimal pharmacodynamic properties were observed with PEG–peptide conjugates that contained 20–40 kDa linear PEGs and a 20 kDa branched PEG. The optimal PEG–peptide conjugates were more effective in vivo than the unconjugated peptide control on a mole:mole and mg/kg basis, and represent potential new longer-acting peptide therapeutics for the treatment of humorally-mediated autoimmune disease.