FVIII Co-administered with IVIG Mitigates Anti-FVIII Immune Response in Hemophilia A

Prophylactic coagulation factor VIII (FVIII) concentrate co-administered with intravenous immunoglobulin (IVIG) mitigated anti-FVIII antibody development in mice with hemophilia A in a study published in Scientific Reports.

Hemophilia A is a rare genetic condition characterized by FVIII deficiency. Prophylactic factor replacement therapy is the standard of care to reduce the risk of bleeding for affected patients. Although FVIII replacement is typically highly effective, the development of anti-FVIII antibodies that target infused factor concentrate is a serious adverse effect of FVIII therapy.

Administering factor therapy with other proteins is one potential strategy to mitigate the development of inhibitory antibodies during treatment. Past studies in mouse models of hemophilia A have shown this method to reduce the anti-FVIII immune response that can occur when FVIII is administered alone.

IVIG is a concentrated antibody solution made of plasma from thousands of donors. Its mechanism of action is not fully understood, but it has demonstrated immunomodulatory effects and is used in clinical settings to treat autoimmune and inflammatory disorders and immunodeficiency disorders. The same effects have been recorded in mice, but human IVIG has not been studied in mice with hemophilia A.

The new study explored the effects of human IVIG co-administered with recombinant human FVIII (rFVIII) in treatment-naïve mice with hemophilia A. The authors’ main goal was to determine whether the co-injecting method would suppress the anti-FVIII immune response in these mice.

One group of mice received weekly injections of rFVIII co-injected with IVIG for 12 weeks, while a control group of mice received weekly injections of rFVIII alone for 12 weeks. Anti-human FVIII antibodies in plasma were measured by an in-house enzyme linked immunosorbent assay (ELISA).

After 4 weeks, 83% of the mice injected with rFVIII alone had detectable anti-FVIII antibodies. By week 6, all control group mice had detectable anti-FVIII antibodies, with antibody titers increasing until the end of the initial 12-week experiment.

Mice that were co-injected with rFVIII and IVIG had significantly lower anti-FVIII antibody titers throughout the experiment compared with the control group (mean antibody titers of 0.65 µg/mL versus 205.2 µg/mL after 12 weeks). While all mice in the control group developed anti-FVIII antibodies, just 2 of 6 mice in the treatment group had detectable anti-FVIII antibodies, and they were not detectable until week 10.

Overall, hemophilia A mice receiving co-injections of rFVIII and IVIG had significantly reduced and delayed anti-FVIII immune responses versus mice who received rFVIII only in the initial 12-week study period.

In the second phase of the study, mice in the dual treatment group were randomized to 2 additional groups: the first group continued receiving co-injections for 4 additional weeks, while the second group received rFVIII alone for the same time frame. Phase 2 aimed to determine whether the effect of IVIG persists once it is removed from the regimen.

Mice that continued to receive co-injections of rFVIII and IVIG maintained lower antibody titers, while mice that were switched to rFVIII alone experienced increased antibody titers. Two mice continued to have undetectable levels of antibodies after IVIG discontinuation, while 1 developed significant amounts of anti-FVIII antibody. These responses correlated with the antibody levels seen in the initial 12-week treatment period—the only mouse with low but detectable antibodies while receiving co-injections of rFVIII and IVIG developed high levels upon IVIG cessation.

“The overall findings from this study support our initial hypothesis, that IVIG co-injected with FVIII reduces anti-FVIII antibody development in previously untreated hemophilia A mice, with the caveat that we were working with a small sample size,” the authors wrote. “A longer follow-up might also have allowed a clearer conclusion.”

While the exact mechanism of the immunoregulatory effect of this treatment method is still unclear, the findings suggest that co-administration of FVIII and IVIG may hold promise as a prophylactic strategy for hemophilia A patients at a high risk of FVIII inhibitor development.

Reference

Afraz S, Stevic I, Matino D, et al. Co-administration of FVIII with IVIG reduces immune response to FVIII in hemophilia A mice. Sci Rep. 2022;12(1):20074. doi:10.1038/s41598-022-19392-1. Accessed December 6, 2022.