Tyrosyl sulfamide derivatives as ligands for affinity adsorption of anti FVIII antibodies.

Abstract

Human anti factor VIII (anti FVIII) antibodies neutralize factor VIII procoagulant activity. These antibodies appear in about 5-10% of severely affected haemophiliac A patients treated with FVIII concentrates. In order to obtain non-thrombogenic materials able to interact specifically with anti FVIII, we have grafted amino acid residues which mimic part of the epitope of the FVIII molecule recognized by the anti FVIII. For this purpose, crosslinked polystyrenes functionalized with sulfonate and tyrosyl or methyl ester tyrosyl sulfamide groups have been synthesized and characterized. The in vitro removal of anti FVIII from haemophiliac patient plasma with antibodies, was performed on these different active supports. These polymers exhibit strong and selective affinity for the anti FVIII. The adsorption of the antibodies vary with the percentage of units bearing methyl ester tyrosyl sulfamide groups and present a maximum at 25% grafting rate. For the more efficient resin, the affinity constant, determined for the adsorption isotherm for the anti FVIII is about 10(9) M-1, whereas the affinity constant for the IgG in the same experimental conditions, is low (10(5) M-1). The influence of different chemical groups on the polymeric phase, on their affinity for the inhibitors was also studied. The most active resins can be selected and used in an extracorporeal circulation to reduce the concentration of anti FVIII in a blood epuration process.