Reduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRn.
The neonatal Fc receptor FcRn provides IgG molecules with their characteristically long half-lives in vivo by protecting them from intracellular catabolism and then returning them to the extracellular space. Other investigators have demonstrated that mice lacking FcRn are protected from induction of various autoimmune diseases, presumably because of the accelerated catabolism of pathogenic IgGs in the animals. Therefore, targeting FcRn with a specific inhibitor may represent a unique approach for the treatment of autoimmune disease or other diseases where the reduction of pathogenic IgG will have a therapeutic benefit. Using phage display peptide libraries, we screened for ligands that bound to human FcRn (hFcRn) and discovered a consensus peptide sequence that binds to hFcRn and inhibits the binding of human IgG (hIgG) in vitro. Chemical optimization of the phage-identified sequences yielded the 26-amino acid peptide dimer SYN1436, which is capable of potent in vitro inhibition of the hIgG-hFcRn interaction. Administration of SYN1436 to mice transgenic for hFcRn induced an increase in the rate of catabolism of hIgG in a dose-dependent manner. Treatment of cynomolgus monkeys with SYN1436 led to a reduction of IgG by up to 80% without reducing serum albumin levels that also binds to FcRn. SYN1436 and related peptides thus represent a previously uncharacterized family of potential therapeutic agents for the treatment of humorally mediated autoimmune and other diseases.
Mezo
Adam R
AR
Syntonix Pharmaceuticals, Inc., 9 Fourth Avenue, Waltham, MA 02451, USA. amezo@syntnx.com
McDonnell
Kevin A
KA
Hehir
Cristina A Tan
CA
Low
Susan C
SC
Palombella
Vito J
VJ
Stattel
James M
JM
Kamphaus
George D
GD
Fraley
Cara
C
Zhang
Yixia
Y
Dumont
Jennifer A
JA
Bitonti
Alan J
AJ
D000418:Albumins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology; D007141:Immunoglobulin Fc Fragments / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D007075:Immunoglobulin M / Q000276:immunology; D008252:Macaca fascicularis / Q000276:immunology* / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D011485:Protein Binding; D011961:Receptors, Fc / Q000037:antagonists & inhibitors* / Q000276:immunology*; D012995:Solubility; D020349:Surface Plasmon Resonance
D000418:Albumins; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D007070:Immunoglobulin A; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D010455:Peptides; D011961:Receptors, Fc; C100688:Fc receptor, neonatal