Comparison of in vivo efficacy and mechanism of action of antimurine monoclonal antibodies directed against TCR alpha beta (H57-597) and CD3 (145-2C11).
Monoclonal antibodies (mAbs) directed against the T cell receptor (TCR)-associated CD3 chains and against the TCR-alpha beta heterodimer can inhibit allograft rejection in humans and in experimental animals. Since the effects of stimulation through these cell surface structures may differ, it has been suggested that there could be advantages to targeting one structure versus the other. In order to directly compare two such mAbs for in vivo immunosuppressive properties and mechanisms of action, C57BL/10 mice were treated with mAbs H57-597 (H57, anti-alpha beta) or 145-2C11 (2C11, anti-CD3), either as intact mAb or as F(ab')2 fragments. F(ab')2 fragments of both mAbs had similar effects. Both prolonged skin allograft survival, preferentially depleted CD4+ T cells, downregulated IL-2 secretion, and failed to inhibit CTL. In contrast, the effects of the intact form of the two mAbs differed significantly. Intact H57 was far more effective than 2C11 in prolonging skin allograft survival and in inhibiting cytokine secretion and CTL function. This increased immunosuppressive effect was associated with a significantly more complete and prolonged depletion of both CD4+ and CD8+ T cells and down-modulation of TCR expression on remaining T cells. A markedly greater half-life was observed for H57, associated with reduced immunogenicity. These data suggest that the increased immunosuppressive properties of H57 are due to its reduced immunogenicity, rather than to differences in signal transduction, and support the argument that reducing the immunogenicity of mAbs in the clinical setting by "humanization" may result in improved efficacy.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017252:CD3 Complex / Q000276:immunology*; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use; D007165:Immunosuppression Therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D007140:Immunoglobulin Fab Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta