SYNT001: A Humanized IgG4 Monoclonal Antibody That Disrupts the Interaction of FcRn and IgG for the Treatment of IgG-Mediated Autoimmune Diseases

Introduction

The neonatal crystallizable fragment receptor (FcRn) contributes in a variety of ways to pathogenic processes associated with many autoimmune diseases that are mediated by IgG and IgG immune complexes, including warm autoimmune hemolytic anemia (WAIHA). FcRn does so by protecting IgG, presumably including pathogenic autoantibodies, from catabolism. In addition, FcRn regulates innate and adaptive responses initiated by IgG immune complexes. These properties make FcRn a potential target for immune therapy. SYNT001 is a humanized, de-immunized IgG4 monoclonal antibody with a stabilizing hinge mutation designed to block the interaction between FcRn and the Fc portion of IgG molecules, at both acidic and neutral pH, in order to disrupt the associated pathways related to IgG homeostasis and innate and adaptive immunity. This first-in-human, proof-of-concept study evaluated the safety, tolerability, and biological effects of SYNT001 in healthy volunteers.

Methods

We performed a single-ascending-dose, randomized, double-blind, placebo-controlled, phase 1a trial at a single site in the US. Healthy male subjects aged 18 to 55 years were to receive 1, 3, 10, 30, or 60 mg/kg SYNT001 intravenously (IV) or placebo in a 6:2 ratio per dose cohort. To avoid exposure of healthy subjects to low levels of IgG, the study included a stopping rule if ≥1 subject exhibited serum total IgG (tIgG) levels below the lower limit of normal following SYNT001 dosing. To provide an appropriate pharmacodynamic range in order to observe responses, eligible subjects were required to have tIgG levels greater than or equal to the midpoint of the normal range (≥1200 mg/dL). The primary objective was evaluation of safety. The pharmacokinetics and pharmacodynamics of SYNT001 were also assessed. The study was reviewed and approved by the site's Institutional Review Board and all subjects provided written informed consent.

Results

SYNT001 was administered to 23 subjects (6 subjects in each of the 1, 3, or 10 mg/kg dose groups and 5 in the 30 mg/kg dose group) and 8 subjects received placebo. The tIgG stopping rule was reached before the final subject in the 30 mg/kg cohort was enrolled; thus, dose escalation to 60 mg/kg was halted. Exposure (AUC_0-inf and C_max) increased with ascending SYNT001 doses in a greater than dose-proportional manner, t_1/2 increased with dose, and the V_d for SYNT001 was less than the estimated plasma volume at all doses. Semilog plots suggested that elimination from serum occurred by target-mediated drug disposition via FcRn at lower serum concentrations. Treatment-emergent adverse events (TEAEs) were reported in 9 subjects, including 8 treated with SYNT001 and 1 treated with placebo. Headache was the most commonly reported TEAE, occurring in all 8 SYNT001-treated subjects who reported a TEAE. No other TEAE was reported by more than one SYNT001-treated subject. One TEAE of severity grade 2 (moderate), a headache in the 10 mg/kg cohort, was reported; all other TEAEs were severity grade 1 (mild). There were no grade 3 or 4 TEAEs or serious AEs. No significant changes in urinalysis, hematology, or blood chemistries, including albumin, IgA, and IgM, were reported. The nadir of an approximately 50% reduction in tIgG levels in the 30 mg/kg dose group occurred 5 days post-dosing. The tIgG effect was durable; on Day 28, the mean percent change of total IgG from baseline was −8.9%, 4.3%, −4.4%, and −27.9% in the 1, 3, 10, and 30 mg/kg dose groups, respectively. The magnitude, but not the duration, of the nadir differed for each IgG subclass with IgG3 (70% decrease from baseline) > IgG1 (55%) > IgG4 (45%) > IgG2 (35%) at the 30 mg/kg dose. SYNT001 administration also resulted in a dose-dependent decrease in circulating immune complexes (CIC), with up to a 50% decrease from baseline in the 30 mg/kg group and an effect lasting more than a week.

Conclusions

SYNT001 was well tolerated and produced rapid, durable, and clinically significant reductions in all IgG subclasses and CIC in healthy volunteers. Both the level and duration of the pharmacodynamic effect provide strong support for the potential efficacy of SYNT001 as a therapeutic agent in the treatment of IgG-mediated autoimmune diseases such as WAIHA. Accordingly, a phase 1b study of SYNT001 in WAIHA patients is underway (www.clinicaltrials.gov ID: NCT03075878).