DOMINANT C2 DOMAIN EPITOPE SPECIFICITY OF INHIBITOR ANTIBODIES ELICITED BY A HEAT PASTEURIZED PRODUCT, FACTOR-VIII CPS-P, IN PREVIOUSLY TREATED HEMOPHILIA-A PATIENTS WITHOUT INHIBITORS

From June, 1990, to November, 1991, in The Netherlands and Belgium, 16 previously treated severe hemophilia A patients (PTP) developed inhib itors after exposure to factor Vm CPS-P, a new heat pasteurized produc t. A previously untreated patient (PUP) also developed an inhibitor to CPS-P, In inhibitor neutralization assays with recombinant fVIII C2 a nd A2 domain polypeptides, plasmas from 14 PTPs were greater than or e qual to 79% neutralized by C2 and <10% by A2, but the PUP plasma was p artially neutralized by C2 (48%) and A2 (28%). Immunoprecipitation ass ays of the PTP and PUP plasmas with the MII heavy chain and with recom binant C2 and A3-C1 polypeptides confirmed that the C2 dominant immune response to CPS-P was found only in the PTPs. Competition of the bind ing of 2 inhibitors to I-125-CPS-P by unlabeled CPS-P and another plas ma fVIII was similar, demonstrating that the antibody response was not directed to epitopes only present in CPS-P. We propose that the immun ogenicity of the CPS-P C2 domain was altered by heat pasteurization.