Modulation of the human T cell response by a novel non-mitogenic anti-CD3 antibody

The agonistic anti-human CD3ε antibody (Ab), OKT3, has been used to control acute transplant rejection. The in vivo administration of OKT3 was previously shown to induce the partial depletion of T cells and unresponsiveness (anergy) in the remaining CD4+ T cells. However, this therapy is also associated with the systemic release of several cytokines, which leads to a series of adverse side effects. We established a novel anti-human CD3ε Ab, 20-2b2, which recognized a close, but different determinant on the CD3ε molecule from that recognized by OKT3. 20-2b2 was non-mitogenic for human CD4+ T cells, could inhibit the activation of T cells in vitro, and induced T cell anergy in in vivo experiments using humanized mice. Cytokine release in humanized mice induced by the administration of 20-2b2 was significantly less than that induced by OKT3. Our results indicated that the CD3ε molecule is still an attractive, effective, and useful target for the modulation of T cell responses. The establishment of other Abs that recognize CD3ε, even though the determinant recognized by those Abs may be close to or different from that recognized by OKT3, may represent a novel approach for the development of safer Ab therapies using anti-CD3 Abs, in addition to the modification of OKT3 in terms of the induction of cytokine production.