Recombinant factor VIII: past, present and future of treatment of hemophilia A

摘要

The development of recombinant factor VIII (rFVIII) was initially driven by the necessity to treat hemophilia A (HA) patients with FVIII concentrates without the risk of transmitting infectious agents. Over the last three decades the safety of rFVIII has been further improved by completely removing animal or human proteins from the manufacturing process, so that patients would not be exposed to known or emerging pathogens. Recent efforts have concentrated on improving the expression of rFVIII, reducing its immunogenicity and enhancing its pharmacokinetic (PK) behavior. These new goals have been possible thanks to the development of biotechnology and a better knowledge of the function and structure of FVIII. Several approaches such as deletion of the B-domain, expression of FVIII by human cell lines, sequence modification, structural modification, coexpression with other proteins, fusion with the Fc fragment of immunoglobulins and PEGylation have been utilized. As a result of these efforts, different rFVIII products have been validated in terms of efficacy, immunogenicity and PK profile. Other technologies are currently being explored to improve the PK of FVIII and allow its subcutaneous administration. Although nonreplacement therapies and HA gene therapy appear to be promising alternatives for HA, rFVIII will very likely remain as a critical component for the treatment of HA because of its physiological activity and mode of action, as well as its unique ability to induce or restore tolerance to exogenous FVIII. This review summarizes the principal features of past, current and emerging rFVIII products for HA.