The presence of circulating inhibitors is the result of a complex interaction between many immune partners providing positive or negative signals driving the production of such inhibitors [4]. Considering FVIII interactions with innate immunity, the question as to whether or not it might be possible to reduce FVIII immunogenicity by modifying its sequence and/or structure should be re-examined. Eliminating such interaction GSK-3 signaling pathway might be all that is required to prevent an adaptive response, and thereby the production of inhibitory antibodies. This is the matter of intense ongoing investigation.

One, but not least of the questions raised is to understand the molecular reasons as to why FVIII (and not FIX) interacts with innate immunity and, consequently, if eliminating this interaction would provide a viable way to reduce immunogenicity without affecting functional properties. Another issue which

learn more deserves attention is related to our capacity to prevent and/or suppress an adaptive immune response when it is already present, which is by definition the case when inhibitors are detected in a clinical setting. The recent development of methods by which an antigen-specific immune responses can be switched off by exposure to MHC-class II-restricted T-cell epitopes, modified to contain an oxido-reductase activity, likely provides a suitable treatment for patients with such inhibitors [5]. Switching off antigen-specific CD4 +  T lymphocytes prevents the formation of antibodies. Strikingly, FIX concentrates immunogenicity poses less difficulty, both in the clinic

and on experimental grounds. There are a number of reasons for this, including the much higher concentration of FIX in plasma as compared to FVIII, the size of the molecule and the fact that it does not or only marginally, activates the innate immune system. Interfering with a ‘mere’ adaptive response under such circumstances is conceptually much simpler. Current activities in the development of new clotting factor products focus on the extension of half-life and reduction of immunogenicity. A variety of potential new product candidates with molecular or chemical modifications are entering check details preclinical and clinical development. All chemical or molecular modifications bear the risk of creating neoepitopes for T cells or B cells and of creating structural alterations that stimulate innate immune cells. Consequently, such alterations could trigger the development of antibodies associated with unwanted clinical sequelae such as reduced efficacy, altered pharmacokinetics, hypersensitivity reactions or breakage of immune tolerance to the endogenous counterpart. Therefore, it is important to assess the potential immunogenicity risk of each modified protein before it enters clinical development.