HuM291, a humanized anti-CD3 antibody, is immunosuppressive to T cells while exhibiting reduced mitogenicity in vitro

Background. OKT3, a mouse monoclonal antibody (Ab) specific for the human C D3 complex on T cells, is a potent immunosuppressive agent used for the tre atment of acute allograft rejection. The utility of the drug has been limit ed by a neutralizing anti-mouse Ab response and adverse side effects result ing from T cell activation and systemic cytokine release. T cell activation is caused by OKT3-mediatetl cross-linking of T cells and Fc receptor-beari ng cells. Studies in the mouse model have shown that global T cell activati on is not necessary for immunosuppression, as Fc receptor-nonbinding anti-C DS Abs can suppress graft rejection in the absence of the activation effect s seen with Fc receptor-binding Abs. Thus, a humanized anti-CD3 antibody wi th a low affinity for Fc receptors might improve immunosuppressive therapy by reducing the side effects associated with OKT3, Methods. We developed a mouse monoclonal Ab, M291, which competes with OKT3 for binding to T cells, Humanized, complementary-determining region-grafte d versions of M291 featuring various Fc were engineered, including a previo usly described IgG2 mutant deficient in Fc receptor binding (HuM291), Results. Compared with OKT3 and HuM291-IgG1, HuM291 was significantly less mitogenic to T cells in vitro and induced the release of much lower levels of the cytokines tumor necrosis factor-alpha, interferon-gamma, and interle ukin-10. Despite this reduction in T cell. activation, HuM291 retained the ability to modulate the CD3 complex and inhibit the mixed lymphocyte reacti on, Conclusions. When evaluated in vivo, HuM291 may be an immunosuppressive age nt associated with less of the acute toxicity and immunogenicity seen with OKT3 therapy.