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,
,,,
*
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; Departments of
Pediatrics and
Medicine,
Division of Oncology, University of Washington, Seattle, WA 98109; and
¶ Protein Design Laboratories, Inc., Fremont, CA 94555
Human trials in organ allografts have demonstrated that murine
anti-CD3 mAbs are immunosuppressive. By mimicking Ag, anti-CD3
can produce T cell activation, anergy, or death. Activation of resting
T cells in vivo results in dose-limiting cytokine release and is caused
by Ab-mediated cross-linking of T cells and Fc
receptor
(FcR)-bearing cells. With the goal of minimizing cytokine-induced
toxicity, anti-CD3 have been engineered to lower Fc binding
avidity. Preclinical murine studies have indicated that non-FcR-binding
anti-CD3 can induce apoptosis of Ag-activated T cells. Since
induction of T cell apoptosis may be an important mechanism of
immunosuppression by anti-CD3, we tested whether Fc mutations
affect the ability of anti-human CD3 to induce apoptosis of
activated T cells. We compared wild-type murine anti-CD3, M291, and
OKT3 and their humanized, FcR- and non-FcR-binding structural variants
in quantitative assays of T cell apoptosis. Non-FcR-binding variants
produced more sustainable phosphorylation of extracellular
signal-regulated kinase-2, greater release of IFN-, and more
effectively caused activation-dependent T cell apoptosis.
Non-FcR-binding variants dissociated more quickly from the T cell
surface and caused less internalization of the TCR, which then remained
available in greater abundance on the cell surface for signaling.
Cross-linking of non-FcR-binding variants by antiglobulin enhanced TCR
internalization and minimized induction of T cell apoptosis. We
conclude that non-FcR-binding, humanized anti-CD3 have improved
ability to induce apoptosis of activated T cells, presumably by
allowing durable expression of the TCR and sustained
signaling.
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