Variations in Antigenicity of Factor VIII Concentrates: Preclinical Evaluation

Treating haemophilia A patients with factor VIII (FVIII) concentrates carries the risk of inducing an immune response against FVIII, which is nowadays considered as a frequent (20-50% according to the authors) and major complication of such treatment. It remains a most challenging problem insofar as very little information has been gained on factors defining host susceptibility on the one hand, or on alterations of FVlIl itself on the other hand. The capacity to mount an immune response toward FVIll obviously varies from one individual to an other. Earlier attempts to identify an association with certain MHC class I1 determinants have failed [l], probably because the number of antigenic determinants that can be recognised on a molecule as large as FVlIl (250 kD) is too high: such an association might be detected whenever it becomes possible to analyse the anti-FVIII immune response at the level of single epitopes (see below). In the meantime, we are left with epidemiological data showing that there is indeed a good but not absolute concordance in the occurrence of inhibitors between pairs of siblings [2, 31 or comparing the incidence of inhibitors induced by different FVIII concentrates. Methods by which one could anticipate an immune response to FVIII are clearly required, if on considers how difficult it may be to treat a patient who has developed an antiFV 1 I I immune response. If defining the factors that render an individual susceptible to develop an anti-FVIII immune response is no easy task for the time being, the second factor that condition such an immune response, namely, the FVIII concentrate itself, may be more amenable to analysis. This option was chosen by our laboratory a few years ago and led us to first develop a series of immunoassays, which allow studying the antigenicity of FVIII concentrates on a comparative basis. The present paper summarizes our current views on this matter. Importance of FVlll Antigenicity