Fine specificity of drug-dependent antibodies reactive with a restricted domain of platelet GPIIIA

Abstract

Drug

Mechanism of quinine-dependent monoclonal antibody binding to platelet glycoprotein IIb/IIIa

“…18,40 We previously identified a relatively small region in the GPIIIa hybrid domain that is a favored target for antibodies from patients with quinine-induced thrombocytopenia but found that there was no sequence homology between this domain and regions similarly targeted on GPIX and GPIba by quinine-dependent antibodies, as might be expected if quinine initiated an antibodytarget interaction by binding to a structural motif common to these proteins. 41 In addition, SPR analysis failed to demonstrate binding of quinine to this region of GPIIIa. 41 The most convincing evidence that DDAb binding does not start with binding of quinine to the target protein was provided by Zhu et al who soaked 0.2 mM quinine into crystals of the GPIIb/IIIa headpiece and, in crystallographic studies, were unable to identify any density representing quinine in domains targeted by the "314" mAbs or by human DDAbs.…”

Antibodies causing thrombocytopenia in patients treated with RGD-mimetic platelet inhibitors recognize ligand-specific conformers of αIIb/β3 integrin

“…However, blocking studies with various mAbs (Table 4) indicate that the Ab footprints are distinctly different and that not all are overlapping despite being clustered about the 7E3-binding site. Finally, RGD and RGD-mimetic drugs are known to induce significant structural changes in ␣ IIb /␤ 3 that can be immunogenic, 21,24,29 whereas drugs like quinine appear to have no preferred binding site 15,20,44 and are not known to induce structural changes. These considerations favor the possibility that Abs causing thrombocytopenia in patients treated with ligand-mimetic drugs are distinctly different from those found in patients with quinine-associated thrombocytopenia, being specific for structural changes (neoepitopes, MIBS) created adjacent to the RGD recognition site when ligand binds.…”

Review of Continuing Education Course on Hemostasis

“…A small subset of patients treated with fibans develops acute, severe thrombocytopenia in every clinical trial (Aster 2005b). Serologic studies in some of these patients demonstrated the presence of preexisting, naturally occurring antibodies that recognize GPIIbIIIa in complex with a fiban and may cause acute DITP (Bougie et al 2002;Brassard et al 2002;Peterson et al 2008). DDAbs were also detected in one chimpanzee and one rhesus macaque with fiban-induced thrombocytopenia (Bednar et al 1999).…”