Development of new diagnostic possibilities and therapeutic approaches for hemophilia A patients with inhibitors

Development of new diagnostic possibilities and therapeutic approaches for hemophilia A patients with inhibitors

The formation of inhibitory antibodies (inhibitors) to factor VIII (FVIII) is the most serious complication of the modern FVIII replacement therapy in hemophilia A and is associated with a significantly increased morbidity and mortality. Up to 30% of the young patients are affected. Patients with inhibitors are treated with high daily doses of FVIII in an attempt to induce tolerance (immune tolerance induction, ITI), at an enormous effort and cost. There is no established elimination therapy or adequate prophylaxis available for patients in whom tolerance cannot be achieved by ITI, putting them at risk of life-threatening, uncontrollable bleeds associated with high morbidity and mortality.

The aim of this project is to establish new, individual approaches for the diagnosis and elimination of inhibitors. For that, peptides and antibody fragments specifically binding to FVIII-antibodies are isolated from phage display libraries. Isolated peptide sequences are matched with the surface area of FVIII in order to identify inhibitor-epitopes. Epitope-representing peptides, so-called ‘mimotopes’, are used to establish an ELISA-based "epitope mapping” in order to be able to identify patients’ inhibitor-epitopes more rapidly in the future. The location of the epitopes may have an influence on the course and outcome of ITI and a rapid epitope mapping could enable individualized therapy in the future. Based on this, it is possible to exchange amino acids which are important for inhibitor binding, thereby generating FVIII-molecules for replacement therapy, which are less antigenic and have a pro-coagulative effect even in the presence of inhibitors.

Inhibitor-binding peptides or better antibody fragments might be used therapeutically to neutralize FVIII-inhibitors, thereby supporting current therapies. Hence, mimotopes and antibody fragments which block the binding of antibodies to FVIII in vitro, should be tested for their ability to neutralize inhibitors and thus to restore coagulation in vivo. Perspectively the selected ligands will be used for the antigen-specific identification and elimination of FVIII-specific B cells. Therefore, mimotopes and antibody fragments interacting with FVIII-specific B cells will be coupled to cytotoxins in order to deplete FVIII-specific B cells.

Keywords 

  • Hemophilia A
  • Immune tolerance induction
  • FVIII inhibitor
  • FVIII inhibitor ligands

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