Background/Purpose: Autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome are characterized by elevated levels of pathogenic autoantibodies that drive inflammation. The neonatal Fc receptor (FcRn) prolongs the half-life of IgG by mediating its recycling, and FcRn blockade has emerged as a promising strategy to reduce pathogenic autoantibodies. However, the inhibition of IgG recycling also leads to a shortened half-life of FcRn blockers, necessitating frequent dosing. Here, we report a novel bispecific antibody, based on an effector-silent human IgG1 backbone, that targets both human FcRn (hFcRn) and human serum albumin (HSA). The optimized bispecific design enables potent FcRn inhibition while leveraging albumin binding to prolong half-life without compromising pharmacologic activity.

Methods: Parental anti-FcRn IgG and anti-HSA VHH were generated through epitope-focusing antibody discovery and NGS-powered phage display screening, followed by bispecific format optimization and affinity tuning. Binding properties and FcRn-blocking activity were evaluated in vitro using biochemical and cell-based assays. In vivo functional and pharmacokinetic studies were performed in hFcRn/HSA/Rag1⁻/⁻ transgenic mice.

Results: The bispecific antibody demonstrated sub-nanomolar binding affinity to hFcRn, cross-reactivity with cynomolgus FcRn, and potent inhibition of IgG-FcRn interaction. Structural modeling and in vitro experiments confirmed that HSA binding to hFcRn was maintained in the presence of anti-FcRn or HSA antibody. A single intravenous dose of the bispecific antibody in transgenic mice led to rapid and profound clearance of exogenous administrated circulating human IgG. The bispecific antibody exhibited a prolonged serum half-life compared to the parental anti-FcRn antibody and other FcRn blockers, and did not meaningfully affect circulating HSA levels.

Conclusion: The rationally designed FcRn × HSA bispecific antibody effectively blocks FcRn-mediated IgG recycling while achieving extended systemic exposure and a favorable preclinical safety profile. These findings support its potential as a long-acting therapeutic candidate for the treatment of autoantibody-driven diseases with reduced dosing frequency.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-fcrn-x-albumin-bispecific-antibody-demonstrates-extended-half-life-and-deep-igg-reduction-in-preclinical-mouse-models/