OC 50.2 - Low dose FVIII injections as a potential treatment to prevent Inhibitor development in Hemophilia A - an in vivo study

Background: Hemophilia A (HA) is a hemorrhagic disorder caused by a decrease/absence of Factor VIII (FVIII). Management involves administration of FVIII to prevent bleeding. A serious complication of replacement therapy is the development of anti-FVIII antibodies which neutralize the infused FVIII. Low zone tolerance (LZT) is a state where the immune system is unresponsive to an antigen induced by repeated exposure to low doses of said antigen. Previous animal studies exploring LZT demonstrated successful T-cell tolerance induction by this mechanism.

Aims: Investigate whether the administration of low-dose FVIII can induce immune tolerance to FVIII in HA mice.

Methods: HA mice received FVIII intravenously at doses ranging from 0.01 IU/kg - 5 IU/kg to determine the most promising doses (0.25 IU/kg, 2.5 IU/Kg) to further investigate. Naïve mice were treated with 0.25 IU/kg or 2.5 IU/kg weekly for 6 weeks, then immunized with 25 IU/kg FVIII weekly for 4 weeks. Two weeks later (week 12), mice received a 25 IU/Kg booster. Blood was collected on weeks 7, 11 and 13 and anti-FVIII antibody concentrations were measured by ELISA. Control mice were injected with phosphate buffered saline (PBS) during weeks 1-6 and another group received only 25 IU/kg.

Results: 89% of mice receiving 2.5 IU/kg and 100% of mice receiving 25 IU/kg FVIII developed high anti-FVIII antibody titers. 73% of mice injected with PBS followed by 25 IU/kg FVIII developed antibodies. 46% of mice treated with 0.25 IU/kg had no detectable antibodies, and the remaining mice had significantly reduced titers. Upon booster injection, 100% of 0.25 IU/kg mice retained tolerance, suggesting that tolerance through low-dose injections is maintained upon FVIII re-exposure.

Conclusion(s): The LZT experiments conducted shine light on a new approach to preventing FVIII inhibitors. This study suggests that frequently administering low doses of FVIII may be effective in inducing tolerance to FVIII in HA mice.