Evaluation of the Antigenicity of Black Restricted FVIII Haplotypes and Haplotype

Evaluation of the Antigenicity of Black-Restricted Haplotypes of Factor VIII ABSTRACT About 30% of congenital Hemophilia A (HA) patients develop alloantibodies that neutralize the activity of replacement Factor (F) VIII proteins. Such patients, who are termed inhibitor patients, are typically treated with so called bypassing agents such as recombinant (r) FVIIa and FEIBA. Bypassing agents are more expensive and in general less effective than FVIII in fully controlling bleeding. Older HA inhibitor patientsfrequently have reduced mobility in comparison to patients who can be managed with FVIII. Although rare, acquired HA, caused by the sudden development of autoantibodies to the patient's own endogenous FVIII, is a life threatening condition. Acquired HA istreated with immune-response modulators, often in combination with bypassing agents. A FVIII therapeutic that possessed low reactivity with an inhibitor patient's extant antibodies and did not elicit an adverse immune response would be a significant advance over current therapies. We have identified several human FVIII haplotypes that we believe could represent low antigenic FVIII for some inhibitors patients. More importantly, we believe that using such haplotypes as starting templates may represent a fruitful approach to prepare a universal low antigenicity FVIII construct that would offer efficacy for most inhibitor patients. HA patients of Black African ancestry develop FVIII inhibitors twice as frequently as White HA patients. Resequencing studies of the FVIII gene (F8) have revealed four common nonsynonymous- single-nucleotide polymorphisms (ns-SNPs) that, together with two infrequent ns-SNPs, encode eight distinct wild-type FVIII proteins referred to as haplotype (H)1, H2, ..., H8. Individuals of BlackAfrican descent express all FVIII haplotypes except H6, which, to date, has only been identified in Asians. H3 and H4 FVIII occur only in the Black population. The ns-SNPs that define the H3 and H4 haplotypes reside within immunodominant epitopes of FVIII. This is intriguing as it suggests that these variations may impart differing reactivity with FVIII inhibitors. In collaboration with Dr. James Lillard, of the Morehouse School of Medicine, we plan to test the antigenicity of the naturally occurring Blackrestricted H3 and H4 FVIII protein haplotypes and a hybrid H3/H4 FVIII in this Phase 1 project. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Patients with hemophilia A suffer from uncontrolled bleeding due to a lack of a fully functional protein called FVIII. Replacement FVIII works well in some patients; but others experience an adverse immune response to infused FVIII rendering it ineffective. There is a need for a FVIII product that can work in this group of patients. We are doing research to identify one.