ROLE OF FC-GAMMA-RIIA GENE POLYMORPHISM IN HUMAN PLATELET ACTIVATION BY MONOCLONAL-ANTIBODIES

The aim of this study was to determine if there is a correlation betwe en the activity of a MoAb as an agonist and its ability to bind to the Fc platelet receptor, Fc gamma RIIa. A polymorphism at amino acid 131 [arginine (Arg) or histidine (His)] of Fc gamma RIIa was first shown to be determinant for MoAb-IgG(1) binding on monocytes. To clarify the role of this polymorphism in platelet activation by MoAb-IgG(1) we (i ) established the Fc gamma RIIA polymorphism at the gene level by adap ting the denaturating gradient gel electrophoresis method, (ii) analyz ed the binding affinity of the MoAbs to Fc gamma RIIa on platelets fro m homozygous Arg, homozygous His, and heterozygous Arg/His donors, and (iii) characterized the different reactivities of platelets according to the Fc gamma RIIA polymorphism. Among 167 caucasian donors we foun d 46% heterozygous Arg/His, 36% homozygous His and 18% homozygous Arg. ALB6, an anti CD9, P256 an anti GPIIb-IIIa, and AP3 an anti-GPIIIa we re chosen according to their ability (ALB6, P256) or not (AP3) to acti vate platelets. These 3 MoAbs-IgG(1) bind to Fc gamma RIIa with a stro nger affinity for the Arg-form of Fc gamma RIIa, a result which was co nfirmed with the use of diverse MoAbs directed against various antigen s. The different abilities of MoAbs to bind to the two Fc gamma RIIa f orms were well correlated to the different platelet responses induced by ALB6 and P256. However, low concentrations of ALB6, which allow ful l activation of platelets from homozygous Arg donors, as did P256, did not induce any activation of platelets from homozygous His donors, wh ereas P256 is able to induce a low aggregation. The results further de fine the respective roles of the antigen and the Fc receptor, dependin g on the MoAb, and the role of the Fc gamma RIIa polymorphism in plate let activation induced by MoAbs. In addition, the results obtained wit h MoAbs unable to induce platelet activation provide evidence that the binding of a MoAb on Fc gamma RIIa does not predict its ability to ac tivate platelets.