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

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.FcRn antagonist ͉ protein-protein interactions ͉ phage display ͉ autoimmune disease

Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration

“…In separate experiments, treatment of cynomolgus monkeys with rozanolixizumab did not affect IgM or IgA concentrations (data not shown), consistent with these molecules not being salvaged and recycled by FcRn, and with data reported by others on elimination of FcRn function (by a peptide antagonist; 19 in FcRn knockout mice 14 ). Generation of anti-drug antibodies (ADA) was detected in the majority of animals during the dosing period; however, no impact to PK or PD was observed.…”

X-ray Crystal Structures of Monomeric and Dimeric Peptide Inhibitors in Complex with the Human Neonatal Fc Receptor, FcRn

“…Our group has focused on studying the effect of anti-FcRn peptides on IgG:FcRn interaction in vitro and their effects on IgG catabolism in vivo. Using peptide phage display screening, we discovered a consensus motif, Gly-His-Phe-Gly-Gly-X-Tyr, where X is preferably a hydrophobic amino acid (10). The motif is enclosed by a cysteine disulfide loop forming an 11-amino acid loop including the cysteines.…”

“…The peptide was optimized (11,12) for inhibition of IgG binding to FcRn and stability in plasma, resulting in monomeric peptide SYN1327 (1) and dimeric peptide SYN1436 (2). Remarkably, peptide 2 was able to reduce the IgG concentrations in cynomolgus monkeys by up to 80% with repeated administration, and therefore may be a candidate for the treatment of humorally mediated autoimmune diseases (10).…”

Neonatal Fc Receptor Promotes Immune Complex–Mediated Glomerular Disease

“…To inhibit human FcRn, we used a lysine analog of SYN1436 ( Figure 4A), 29 a peptide that binds with subnanomolar affinity to human FcRn, thus preventing IgG binding. 30 In vivo, SYN1436 reduces IgG levels in cynomolgus monkeys by 80%. 30 Serum anti-a3NC1 autoantibodies in FCRN-humanized mice treated with anti-FcRn peptide, but not with control peptide, sharply decreased to the same levels as in Fcrn 2/2 mice ( Figure 4B), and were no longer detected after 4 days.…”

“…30 In vivo, SYN1436 reduces IgG levels in cynomolgus monkeys by 80%. 30 Serum anti-a3NC1 autoantibodies in FCRN-humanized mice treated with anti-FcRn peptide, but not with control peptide, sharply decreased to the same levels as in Fcrn 2/2 mice ( Figure 4B), and were no longer detected after 4 days. In mice, human IgG elicits murine antihuman IgG antibodies, forming ICs that …”