Background: Neonatal Fc receptor (FcRn) antagonism is a clinically validated strategy for treating autoantibody diseases such as generalized myasthenia gravis (gMG), chronic inflammatory demyelinating polyneuropathy (CIDP), and systemic lupus erythematosus (SLE). However, current FcRn blockers typically require frequent dosing to maintain clinically meaningful activity. To address this limitation, we have engineered a novel bispecific antibody targeting human FcRn and albumin to extend systemic half-life and enable sustained IgG reduction.

Objectives: To characterize the preclinical pharmacologic profile of the FcRn × albumin bispecific antibody in non-human primates (NHPs).

Methods: Parental anti-FcRn IgG and FcRn × albumin bispecific antibody were generated and engineered as previously described (Hang, S. et al. 2025). The bispecific antibody was evaluated for FcRn binding affinity, inhibition of FcRn-mediated IgG recycling, and FcRn degradation in vitro. In vivo pharmacokinetic and pharmacodynamic studies were conducted in cynomolgus monkeys to assess drug exposure, endogenous IgG reduction and albumin/LDL homeostasis.

Results: In addition to potent FcRn binding and blocking activity, the bispecific antibody showed minimal FcRn degradation in vitro, which is important for maintaining albumin recycling. Structural analysis of the antibody–antigen complex suggested a favorable FcRn binding orientation that may limit FcRn crosslinking and subsequent lysosomal degradation. Following a single intravenous dose in cynomolgus monkeys, the bispecific antibody induced rapid and profound reductions in circulating IgG levels. Compared with nipocalimab, the bispecific antibody exhibited more sustained IgG reduction and higher systemic exposure (C _max and AUC). Serum albumin and LDL-cholesterol levels were also comparable to nipocalimab.

Conclusions: The FcRn × albumin bispecific antibody potently inhibits FcRn-mediated IgG recycling while maintaining albumin recycling with limited FcRn degradation. The deep and more sustained IgG reduction in NHPs supports its potential as a long-acting FcRn blocker with the potential for less frequent dosing for the treatment of a broad spectrum of autoantibody-driven diseases.

REFERENCES: [1] Su H, Li L, Pei Z, Duplantis B, Wang Y, Li Y, Yu Q. A Novel FcRn × Albumin Bispecific Antibody Demonstrates Extended Half-life and Deep IgG Reduction in Preclinical [2] Mouse Models [abstract]. Arthritis Rheumatol. 2025; 77 (suppl 9). https://acrabstracts.org/abstract/a-novel-fcrn-x-albumin-bispecific-antibody-demonstrates-extended-half-life-and-deep-igg-reduction-in-preclinical-mouse-models/ . Accessed January 12, 2026.

Acknowledgments: NIL.

Disclosure of Interests: None declared.