Prevention of the anti-factor VIII memory B-cell response by inhibition of Bruton tyrosine kinase in experimental hemophilia A.

Abstract

Hemophilia A is a rare hemorrhagic disorder caused by the lack of functional pro-coagulant factor VIII. Factor VIII replacement therapy in patients with severe hemophilia A results in the development of inhibitory anti-factor VIII IgG in up to 30% of cases. To date, immune tolerance induction, with daily injection of large amounts of factor VIII, is the only strategy to eradicate factor VIII inhibitors. This strategy is, however, efficient in only 60-80% of patients. We investigated whether blocking B-cell receptor signaling upon inhibition of Bruton tyrosine kinase prevents anti-factor VIII immune responses in a mouse model of severe hemophilia A. Factor VIII-naïve and factor VIII-sensitized factor VIII-deficient mice were fed with the selective inhibitor of Bruton tyrosine kinase, (R)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-[2,4-difluorophenoxyl] phenyl)-1H pyrazole-4-carboxamide (PF-06250112), to inhibit B-cell receptor signaling prior to challenge with exogenous factor VIII. The consequences on the anti-factor VIII immune response were studied. Inhibition of Bruton tyrosine kinase during the primary anti-factor VIII immune response in factor VIII-naïve mice did not prevent the development of inhibitory anti-factor VIII IgG. In contrast, the anti-factor VIII memory B-cell response was consistently reduced upon treatment of factor VIII-sensitized mice with the Bruton tyrosine kinase inhibitor. The Bruton tyrosine kinase inhibitor reduced the differentiation of memory B cells ex vivo and in vivo following adoptive transfer to factor VIII-naïve animals. Taken together, our data identify inhibition of Bruton tyrosine kinase using PF-06250112 as a strategy to limit the reactivation of factor VIII-specific memory B cells upon re-challenge with therapeutic factor VIII.

• Authors: Sandrine Delignat, Jules Russick, Bagirath Gangadharan, Julie Rayes, Mathieu Ing, Jan Voorberg, Srinivas V Kaveri, Sébastien Lacroix-Desmazes
• Journal: Haematologica (Haematologica) Vol. 104 Issue 5 Pg. 1046-1054 (05 2019) ISSN: 1592-8721 [Electronic] Italy
• PMID: 30545924 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© 2019 Ferrata Storti Foundation.

Chemical References

• 5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-(2,4-difluorophenoxy)phenyl)-1H-pyrazole-4-carboxamide
• Immunoglobulin G
• Piperidines
• Pyrazoles
• Factor VIII
• Agammaglobulinaemia Tyrosine Kinase
• Btk protein, mouse

Topics

• Agammaglobulinaemia Tyrosine Kinase (antagonists & inhibitors)
• Animals
• Antibody Formation
• B-Lymphocytes (drug effects, immunology, metabolism)
• Disease Models, Animal
• Factor VIII (administration & dosage, antagonists & inhibitors, physiology)
• Hemophilia A (drug therapy, immunology, metabolism)
• Immune Tolerance (drug effects, immunology)
• Immunoglobulin G (drug effects, immunology)
• Immunologic Memory (drug effects, immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Piperidines (pharmacology)
• Pyrazoles (pharmacology)