Affiliation:
1. Apitope International NV, Diepenbeek, Belgium
2. University of Bristol, United Kingdom
3. University of Birmingham, United Kingdom
Abstract
Haemophilia A (HA) is a blood clotting disorder caused by various genetic deficiencies in the factor VIII (FVIII) encoding F8 gene. Patients receiving FVIII replacement therapy are at risk of developing neutralizing antibodies (FVIII inhibitors) rendering the FVIII replacement therapy ineffective. Immunological tolerance towards FVIII can be achieved through immune tolerance induction (ITI) protocols in some patients but this is a lengthy and costly desensitization programme. Long-term eradication of inhibitors in HA patients could be achieved by antigen-specific immunotherapy targeting CD4+ T cells since formation of FVIII inhibitors is T cell dependent. Here, we report a peptide-based, antigen-specific immunotherapy designed to specifically re-establish immune tolerance to FVIII through the development of antigen-processing-independent epitopes (apitopes). We identified two FVIII immunodominant peptides in immunised human leukocyte antigen (HLA) DRA*0101/DRB1*1501 transgenic (HLA-DR2tg) mice that were optimised for tolerogenicity. These modified peptide analogues were initially screened for recognition using FVIII-specific T cell hybridoma clones from FVIII-immunised HLA-DR2tg mice. The FVIII apitopes were promiscuous and bound common human HLA-DRB1*haplotypes. The combination of these two FVIII apitopes (ATX-F8-117), administered according to a dose escalation protocol, promoted T cell tolerance towards FVIII in HLA-DR2tg mice. Furthermore, treatment with ATX-F8-117 significantly reduced FVIII inhibitor formation. ATX-F8-117 regulates both anti-FVIII T cell and B cell responses, specifically the generation of FVIII inhibitors, revealing peptide-based antigen-specific immunotherapy as a promising approach to both suppress and treat inhibitor formation in susceptible HA patients.
Publisher
American Society of Hematology
Cited by
4 articles.
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