Platelet surface IgG in patients receiving infusions of Fab fragments of a chimaeric monoclonal antibody to glycoprotein IIb-IIIa

Abstract

SUMMARYPlatelet surface immunoglobulin G (PSIgG) was measured ex vivo in nine patients with stable angina pectoris receiving continuous (48-96 h) infusions of Fab fragments of a chimaeric MoAb (human IgG with murine variable regions) to platelet glycoprotein Ilb-IIIa. PSIgG was measured using flow cytometry (FC) and an Fc-specific anti-IgG polyclonal antibody, which did not crossreact with the chimaeric Fab fragment (c7E3-Fab). A variable but statistically significant (P < 0 05) elevation of PSIgG was present within 24 h after the onset of the infusion, and was more marked (P < 0 01) several days after the end of the infusion despite an exponential fall in platelet surface c7E3-Fab post-infusion. PSIgG returned to normal within 2 weeks after the end of the infusion. The timing of IgG recruitment to the platelet surface suggested the pre-existence in the patients' plasma of IgG binding to c7E3-Fab-bearing platelets. None of the patients developed thrombocytopenia. In order to assess the incidence of IgG bindable to c7E3-Fab-bearing platelets in controls clinically comparable to the c7E3-Fab infusion patients, normal platelets coated with either chimaeric (c) or murine (m) 7E3-Fab were incubated with plasmas from 21 patients with ischaemic heart disease, and recruitment of IgG to the platelet surface was measured by FC. Fourteen of the 21 plasmas contained IgG bindable to c7E3-Fab-coated platelets, whereas only one of the 21 plasmas contained IgG bindable to m7E3-Fab-coated platelets (a highly significant difference, P < 0-001). These findings indicate that infusions of Fab fragments of the chimaeric anti-platelet antibody 7E3 are often associated with elevations in PSIgG, which are probably due to pre-existing 'naturally occurring' antibodies to the Fab fragments of chimaeric (but not murine) 7E3, and most probably other chimaeric MoAbs. The possible clinical significance of such ex vivo measured activities is at present a matter for speculation, and requires further study.

Preclinical Safety Assessment of 2 Inhaled Single-Domain Antibodies in the Cynomolgus Monkey

“…33 These observations parallel findings of naturally occurring/preexisting autoantibodies to Fab or F(ab′)2 fragments of immunoglobulins in humans. 35,36 The absence of preexisting antibodies in the cynomolgus monkey to GSK3191812 probably reflects differences in epitopes arising from critical regions of the framework of the 2 dAbs.…”

Drug-induced immune thrombocytopenia: incidence, clinical features, laboratory testing, and pathogenic mechanisms

“…65,66 Like DIIT induced by fibans, some patients affected with abcixmab-induced immune thrombocytopenia also have preexisting antibodies in their serum. 66 Many normal, healthy people never exposed to abciximab also have IgG antibodies that react with abciximabcoated platelets 65,67 ; however, these antibodies recognize the cleaved end of the Fab fragment that is created when the drug is treated with papain. It is unknown whether Fab-reactive antibodies seen in healthy people can cause DIIT should these individuals ever be exposed to the drug.…”