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Catalytic IgG from Patients with Hemophilia A Inactivate Therapeutic Factor VIII¹

Sébastien Lacroix-Desmazes^2,*, Bharath Wootla^*,, Suryasarathi Dasgupta^*, Sandrine Delignat^*, Jagadeesh Bayry^*, Joseph Reinbolt, Johan Hoebeke, Evgueni Saenko, Michel D. Kazatchkine^*, Alain Friboulet, Olivier Christophe^¶, Valakunja Nagaraja^|| and Srini V. Kaveri^*

^* Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 681 and Université Pierre et Marie Curie (UPMC)-Paris 6, Institut des Cordeliers, Paris, France; Unité Mixte de Recherche 6022 Centre National de la Recherche Scientifique (CNRS), Universite de Technologie de Compiegne, France; Unité Propre de Recherche 9021 CNRS, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France; University of Maryland School of Medicine, Baltimore, MD 21201; ^¶ INSERM Unité 770, Hôpital de Bicêtre, Université Paris-Sud, Faculté de Médecine Paris-Sud, Bicêtre, France; and ^|| Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India

Factor VIII (FVIII) inhibitors are anti-FVIII IgG that arise in up to 50% of the patients with hemophilia A, upon therapeutic administration of exogenous FVIII. Factor VIII inhibitors neutralize the activity of the administered FVIII by sterically hindering its interaction with molecules of the coagulation cascade, or by forming immune complexes with FVIII and accelerating its clearance from the circulation. We have shown previously that a subset of anti-factor VIII IgG hydrolyzes FVIII. FVIII-hydrolyzing IgG are detected in over 50% of inhibitor-positive patients with severe hemophilia A, and are not found in inhibitor-negative patients. Although human proficient catalytic Abs have been described in a number of inflammatory and autoimmune disorders, their pathological relevance remains elusive. We demonstrate here that the kinetics of FVIII degradation by FVIII-hydrolyzing IgG are compatible with a pathogenic role for IgG catalysts. We also report that FVIII-hydrolyzing IgG from each patient exhibit multiple cleavage sites on FVIII and that, while the specificity of cleavage varies from one patient to another, catalytic IgG preferentially hydrolyze peptide bonds containing basic amino acids.

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