THU0057 Targeting the Neonatal FC Receptor (FCRN) to Mediate Autoantibody Clearance in IgG-Driven Autoimmune Disease

Background

IgG autoantibodies mediate autoimmune pathology in a number of autoimmune diseases including rheumatoid arthritis, myasthenia gravis, idiopathic thrombocytopenia purpura, autoimmune skin blistering diseases, neuromyelitis optica, channelopathies, CIDP and SLE. Acute exacerbations and recurrent disease symptoms may benefit from rapid, reversible clearance of these pathogenic autoantibodies.

Objectives

Potent monoclonal antibodies (mAbs) which specifically inhibit IgG-FcRn interaction, but not albumin-FcRn interaction were developed to determine the potential of FcRn blockade to clear IgG and pathogenic autoantibodies to ameliorate autoimmune disease pathology.

Methods

Anti-FcRn blocking mAbs were discovered through a unique somatic hypermutation-based technology, SHM-XEL^tm. These mAbs displayed affinity subpicomolar binding to human and cynomolgus monkey FcRn and were tested for inhibition of IgG and albumin binding, induction of IgG clearance and optimized for pharmaceutical properties.

Results

High affinity (<100 pM) mAbs were identified which specifically inhibit IgG binding and IgG accumulation in endocytic vesicles in monocytic and endothelial cells. These mAbs demonstrated potent, rapid and reversible induction of IgG clearance in human transgenic FcRn, mouse FcRn null mice and in cynomolgus monkey. FcRn blockade by these antibodies also demonstrated potent efficacy when dosed therapeutically in mouse collagen-induced arthritis. A novel anti-FcRn IgG1, Fc effectorless mAb was chosen for further development preclinical and clinical development.

Conclusions

High potency anti-FcRn blocking monoclonal antibodies can induce rapid clearance of autoantibodies and ameliorate disease activity providing a promising therapeutic approach in IgG-dependent severe rheumatoid arthritis and other IgG autoantibody-driven diseases.

Disclosure of Interest

L. Ling Shareholder of: Momenta, Employee of: Momenta, S. Roy Shareholder of: Momenta, Employee of: Momenta, J. Meador Shareholder of: Momenta, Employee of: Momenta, M. Kehry Employee of: AnaptysBio, D. Mekala Shareholder of: Momenta, Employee of: Momenta, S. Tyler Shareholder of: Momenta, Employee of: Momenta, D. Bulik Shareholder of: Momenta, Employee of: Momenta, A. Choudhury Shareholder of: Momenta, Employee of: Momenta, L. Markowitz Shareholder of: Momenta, Employee of: Momenta, B. Schultes Shareholder of: Momenta, Employee of: Momenta, W. Avery Shareholder of: Momenta, Employee of: Momenta, V. Parge: None declared, E. Cochran Shareholder of: Momenta, Consultant for: Momenta, D. King Employee of: AnaptysBio, G. Kaundinya Shareholder of: Momenta, Employee of: Momenta, A. Manning Shareholder of: Momenta, Employee of: Momenta