Alloimmune responses to hemophilia therapeutics

About This Grant

PROJECT SUMMARY Anti-drug antibodies against protein-based therapeutics can significantly impair treatment effectiveness and cause severe adverse events. Coagulation factor VIII (FVIII) is one of the most immunogenic therapies, with around 30% of severe hemophilia A (HA) patients developing neutralizing anti-FVIII antibodies (inhibitors), compared to 3-5% of severe hemophilia B (HB) patients with factor IX (FIX) deficiency. Factor replacement therapy is the main option for managing bleeding, but inhibitor development complicates treatment, and immune tolerance induction (ITI) is not always successful and carries risks. Patients with inhibitors are often excluded from gene therapy, limiting curative treatment options. Current research lacks sufficient understanding of what drives inhibitor development and how to predict response to ITI. As inhibitors are the terminal outcome of an upstream immune response, earlier markers of immune response to FVIII or FIX may be more sensitive predictors especially in an era where factor exposures are more protracted due to the increasing use of non- factor therapies. Further, as HA is more common than HB and the rate of inhibitors is higher, there is a critically unmet need in understanding the pathogenesis of antibodies to FIX which has limited immune tolerance approaches for these patients. Studies on FVIII immunogenicity have linked levels or genetic polymorphisms in T-helper cytokines with inhibitor development, but the downstream cellular consequences of these associations remain unclear. We have shown that B cell activating factor (BAFF), a cytokine implicated in autoimmune diseases, is associated with inhibitors in HA. BAFF levels are regulated by cis-genetic variants and influence B cell responses in autoimmune diseases. In HA mouse models, anti-BAFF therapy prevented FVIII inhibitors, but its ability to mediate tolerance to FIX is unknown. Our recent data suggest associations between BAFF and FIX antibody development, suggesting a more global role for BAFF in alloantibody responses to hemophilia therapeutics. This study aims to investigate the relationship between altered B/T-cell subsets, cytokine levels, and genetic variants, especially BAFF, in the development of FVIII and FIX antibodies. Aim 1 will focus on associating changes in cytokine expression, cellular profiles, and genetic variants with anti-FVIII IgG, using samples from HA patients with and without inhibitors. Aim 2 will explore the effects of proinflammatory cytokines and BAFF on FVIII-specific B cell development, using a novel B-cell tracking mouse model on a hemophilia A background. Aim 3 will investigate the impact of FIX dose response and BAFF on immune responses in HB, testing whether BAFF neutralization can prevent FIX IgG responses and the effect of FIX dose on B and T cell responses. This study represents the first exploration of BAFF’s general contribution to alloantibody responses to protein replacement therapy in hemophilia. It will provide valuable insights into the interactions between genetic variants, lymphocyte subsets, and cytokines in FVIII immunogenicity and could lead to new therapeutic approaches for FIX inhibitors in HB management.