AN ANTIMURINE CD3 MONOCLONAL-ANTIBODY WITH A LOW-AFFINITY FOR FC-GAMMA RECEPTORS SUPPRESSES TRANSPLANTATION RESPONSES WHILE MINIMIZING ACUTE TOXICITY AND IMMUNOGENICITY

145-2C11, a hamster mAb directed against the mouse CD3 complex, is a p otent immunosuppressive agent. Upon initial treatment, 145-2C11 trigge rs a systemic release of multiple cytokines that is responsible for th e acute toxicity of the mAb. This cellular activation is a consequence of the cross-linking between T lymphocytes and Fc gamma R-bearing cel ls, mediated by the high affinity of the hamster mAb for murine Fc gam ma Rs. Repeated mAb injections result in the onset of a neutralizing h umoral response. Therefore, there has been an increased interest in de veloping nonmitogenic forms of anti-CD3 mAbs, although it is not clear whether these Abs will retain immunosuppressive properties. To determ ine whether the initial cytokine production is necessary for the immun osuppressive properties and the immunogenicity of anti-CD3 mAbs in viv o, we have generated chimeric (hamster 145-2C11 F(ab')(2) region/mouse Fc gamma portion) mAbs using murine isotypes with different affinitie s for Fc gamma Rs. The 145-2C11 and a chimeric IgG2a isotype, both of which bind murine Fc gamma Rs avidly, had similar activating, immunoge nic, and immunosuppressive properties in mice. The administration of a chimeric IgG3 isotype with a very low affinity for murine Fc gamma Rs did not result in cytokine production, a humoral response against the mAb, or TCR desensitization. Nevertheless, prolongation of skin graft survival was similar in the IgG3, IgG2a, and 145-2C11-treated mice, i ndicating that Fc gamma R nonbinding anti-CD3 mAbs retain potent immun osuppressive properties in vivo while not being immunogenic. This enha nced therapeutic to toxic profile may be beneficial in clinical transp lantation.