Protein factor VIII fused or conjugated to a toxin for the prevention of the formation of inhibitory antibodies to factor VIII in hemophilic patients.
- Could be used as prophylactic and prevent the formation of factor VIII inhibitors in hemophilia A patients prior to initial dosing with factor VIII.
- Potentially eliminates inhibitors in patients who have received factor VIII therapy.
Factor VIII (FVIII) is a protein that functions in blood coagulation. Mutations in the FVIII result in decreased or defective FVIII protein and give rise to the bleeding disorder hemophilia A. As such, patients with hemophilia A are treated with FVIII via intravenous infusion. Unfortunately, approximately 30% of patients with hemophilia A develop inhibitory antibodies to FVIII in response to these infusions. Most inhibitors occur early in life following initial treatment with FVIII. Generally, the more treatments a person has without developing inhibitors, the less likely they are to appear. Bleeds in individuals who have developed inhibitors are more difficult to manage because they do not always respond to standard treatment. Therefore, these patients have an increased risk of developing complications such as joint damage from internal bleeds.
B cells that recognize factor VIII (FVIII) can either differentiate into plasma cells or become memory B cells. Memory and naÃ¯ve B cells contain surface immunoglobulin that binds FVIII. When a patient with hemophilia and inhibitor anti-FVIII antibodies is treated with factor VIII, memory B cells are stimulated which helps to maintain the immune response. Emory researchers have fused or conjugated FVIII protein to a known cell toxin. Generally, the FVIII-toxin conjugate binds to the surface immunoglobulin on naive and memory B cells. The toxin then kills the B cell and decreases the formation of anti-FVIII antibodies. By eliminating FVIII-specific naÃ¯ve and memory B cells, the formation of FVIII inhibitors could be prevented in hemophilic patients who have either not been treated with FVIII therapy yet or eliminate existing inhibitor antibodies in patients who have already developed them.
In vivo proof of principle in a hemophilia A mouse model has been demonstrated.