ANTI-CD3 MONOCLONAL ANTIBODY THERAPY: AN APPROACH TOWARD... : Transplantation (original) (raw)

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AN APPROACH TOWARD OPTIMIZATION BY IN VITRO ANALYSIS OF NEW ANTI-CD3 ANTIBODIES

WOODLE, E. STEVE; THITLETHWAITE, J. RICHARD; JOLLIFFE, LINDA K.; FUCELLO, ANTHONY J.; STUART, FRANK P.; BLUESTONE, JEFFREY A.

Section of Organ Transplantation, Department of Surgery, University of Chicago Pritzker School of Medicine; R. W. Johnson Pharmaceutical Research Institute, Ortho Pharmaceutical Corporation, Raritan, New Jersey; and Ben May Institute, Committee on Immunology, Department of Pathology, University of Chicago Pritzker School of Medicine, Chicago, Illinois 60637

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Abstract

Several problems remain associated with anti-CD3 monoclonal antibody therapy, including first-dose reactions, recurrent rejection, and the host humoral response to the xenogeneic mAb. One approach toward optimization of anti-CD3 mAb therapy involves the use of anti-CD3 mAbs of defined idiotype, isotype, and epitope specificity, so that the desired T cell activation and suppression properties are obtained and neutralization by antiidiotypic antibody is avoided. The purpose of the present study was to define the contribution of mAb isotype and epitope specificity in determining T cell activation and suppression potencies and to evaluate the idiotypic relationships among ten anti-CD3 mAbs and one anti-TCRαβ mAb selected for this study. Epitope mapping by flow cytofluorometry indicated that one mAb, OKT3D, possesses an epitope specificity distinct from that of other anti-CD3 mAbs. Analysis of early T cell activation, proliferation, and lymphokine production (TNF-α, γ-IFN, and GM-CSF) indicated that mAb isotype exerted a profound effect on activation potency (IgG2a>IgGl>IgG2b), whereas epitope specificity exerted a minor effect. CTL inhibition studies demonstrated an epitope effect with highest inhibition potencies observed with OKT3D IgG1 and OKT3D IgG2b mAbs. Idiotypic analysis of nine mAbs indicated that all anti-CD3 mAbs except OKT3E possess idiotypes distinct from that of OKT3. Thus, two anti-CD3 mAbs, OKT3D IgGl and OKT3D IgG2b, possess high immune suppression potency, low activation potency, and idiotypes distinct from OKT3. In conclusion, selection of anti-CD3 mAbs of defined idiotype and appropriate T cell activation and suppression properties may provide a means for mitigating problems associated with OKT3 therapy.