HuM291, a humanized anti-CD3 antibody, is immunosuppressive to T cells while exhibiting reduced mitogenicity in vitro
Cole, M.S.; Stellrecht, K.E.; Shi, J.D.; Homola, M.; Hsu, D.H.; Anasetti, C.; Vasquez, M.; Tso, J.Y.
Transplantation 68(4): 563-571
1999
ISSN/ISBN: 0041-1337 PMID: 10480417 Document Number: 1659
Background: OKT3, a mouse monoclonal antibody (Ab) specific for the human CD3 complex on T cells, is a potent immunosuppressive agent used for the treatment of acute allograft rejection. The utility of the drug has been limited by a neutralizing anti-mouse Ab response and adverse side effects resulting from T cell activation and systemic cytokine release. T cell activation is caused by OKT3-mediated cross-linking of T cells and Fc receptor-bearing cells. Studies in the mouse model have shown that global T cell activation is not necessary for immunosuppression, as Fc receptor-nonbinding anti-CD3 Abs can suppress graft rejection in the absence of the activation effects seen with Fc receptor-binding Abs. Thus, a humanized anti-CD3 antibody with 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-grafted versions of M291 featuring various Fc were engineered, including a previously 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 interleukin-10. Despite this reduction in T cell activation, HuM291 retained the ability to modulate the CD3 complex and inhibit the mixed lymphocyte reaction. Conclusions: When evaluated in vivo, HuM291 may be an immunosuppressive agent associated with less of the acute toxicity and immunogenicity seen with OKT3 therapy.
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