26 April 2021

Researchers have discovered a potential route to prevent the development of ‘inhibitor’ antibodies to coagulation factor VIII therapy for haemophilia A.

Although factor VIII (FVIII) replacement therapy prevents bleeding-related illness and mortality, some patients develop anti-FVIII antibodies, also called inhibitors. However, the process of how these inhibitors develop is not well understood.

Dr Moanaro Biswas, of the Children's Hospital of Philadelphia, USA, and colleagues looked into the mechanisms that create these inhibitors. They examined the B cell activating factor (BAFF), high levels of which have previously been implicated in immune disorders.

Child and adult patient samples showed that high BAFF levels were correlated with FVIII inhibitors. In mouse models, the researchers tested whether altering BAFF levels before administering FVIII could prevent the development of inhibitors.

The researchers show that anti-BAFF antibody therapy prior to FVIII prevented inhibitor formation.

“Our data suggest that BAFF may regulate the generation and maintenance of FVIII inhibitors and/or anti-FVIII B cells,” they report. “Blocking BAFF is effective in the prevention of FVIII inhibitors in an animal model of haemophilia A. These findings may offer additional therapeutic targets for FVIII inhibitors.”

The team also gave mice a combination of an anti-BAFF antibody plus the CD20 antibody rituximab in mice with established FVIII inhibitors. They found that it was successful in reducing FVIII levels, due to its effects on memory B cells and plasma cells.

An anti-BAFF antibody, belimumab, is already available and in use for autoimmune diseases including lupus.


Source:

Doshi BS, Rana J, Castaman G, Shaheen MA, Kaczmarek R, Butterfield JS, Meeks SL, Leissinger C, Biswas M, Arruda VR. (2021) “B cell–activating factor modulates the factor VIII immune response in hemophilia A.” Journal of Clinical Investigation, doi: 10.1172/JCI142906

 

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