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. 2008 Feb 19;105(7):2337-42.
doi: 10.1073/pnas.0708960105. Epub 2008 Feb 12.

Reduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRn

Adam R Mezo  1 , Kevin A McDonnell, Cristina A Tan Hehir, Susan C Low, Vito J Palombella, James M Stattel, George D Kamphaus, Cara Fraley, Yixia Zhang, Jennifer A Dumont, Alan J Bitonti
Affiliations

Reduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRn

Adam R Mezo et al. Proc Natl Acad Sci U S A. .

Abstract

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.

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Conflict of interest statement

Conflict of interest statement: Syntonix has filed a patent application covering the peptides described herein.

Figures

Fig. 1.
Fig. 1.
Amino acid sequence/chemical structure of SYN746, SYN1327, and SYN1436. One-letter code is used for the amino acids except for Pen, l-penicillamine; NMeLeu, l-N-methylleucine; Sar, sarcosine. Solid lines between Pen/Cys and Cys denote a disulfide bridge.
Fig. 2.
Fig. 2.
Inhibition of hIgG binding to hFcRn at pH 6 with SYN746 (filled circles), SYN1327 (open circles), SYN1436 (filled triangles), and Fc (open triangles). (A) ELISA-based format using immobilized shFcRn. (B) HEK293 cells transfected with hFcRn incubated with fluorescently labeled IgG measured by FACS.
Fig. 3.
Fig. 3.
SPR peptide binding experiments. (A–C) SPR data for binding of serial twofold dilutions of SYN746 (A, 50 × 103 nM to 400 nM), SYN1327 (B, 1,000 nM to 2 nM), and SYN1436 (C, 20 nM to 0.04 nM) to immobilized shFcRn at pH 6.0. (D) Relative equilibrium response for binding of shFcRn to immobilized HSA at pH 6.0 in the presence of 5 mM HSA or 10 mM SYN746, SYN1327, or SYN1436.
Fig. 4.
Fig. 4.
Catabolism of hIgG in TG32B mice. Human IgG was injected i.v. at t = 0, followed by i.v. injections of test article at t = 24, 28, 72, and 96 h. Test article: vehicle (diamonds), 10 mg/kg SYN1327 (filled circles), and SYN1436 at 0.5 mg/kg (open circles), 1 mg/kg (filled triangles), 2.5 mg/kg (open triangles), 5 mg/kg (filled squares), and 10 mg/kg (open squares). Note that the vehicle and SYN1327 groups are nearly superimposed.
Fig. 5.
Fig. 5.
Effect of SYN1436 on endogenous IgG levels in cynomolgus monkeys. (A) SYN1436 (1 mg/kg) dosed i.v. three times per week until day 25 (filled circles), s.c. three times per week until day 25 (triangles), and s.c. once per week (open circles) until day 21. (B) SYN1436 (5 mg/kg) dosed i.v. three times per week until day 16 (filled circles), s.c. three times per week until day 25 (triangles), and s.c. once per week (open circles) until day 21. M, W, and F denote days of the week for dosing purposes. Once per week dosing occurred on Monday.
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