NONHUMAN PRIMATE RESPONSES TO MURINE AND HUMANIZED OKT4A

A nonhuman primate antimurine response (MAMA) has been observed in 17 cynomolgus renal allograft recipients of murine OKT 4A. Neither cyclos porine, nor total-lymphoid irradiation, nor donor bone marrow preparat ion inhibited this antixenogeneic response. In an attempt to alter the antimurine basis of the response, a humanized chimeric OKT4A (IgG4) c ontaining the entire variable portion of the murine OKT4A and a humani zed CDR grafted OKT4A mAb sharing only the Complementarity Determining Region from the murine OKT4A, were administered to 8 cynomolgus allog raft recipients. MAMA was detected in each recipient. In contrast to s era from recipients of murine OKT4A, sera from recipients of humanized OKT4A displayed no reactivity to other murine mAbs. MAMA specificity did not assay constant (C) region differences between the murine and h umanized mAb; however, C region homology in humans should preclude a h uman antimouse antibody (HAMA) to the Fe portion of a humanized mAb. F urthermore, cynomolgus recipient serum levels of the humanized OKT4A m Ab were maintained (>1 mug/ml) for a longer period than following trea tment with murine OKT4A (murine <12 days versus between 12 and 24 days for the humanized). If the HAMA response to humanized mAb in future c linical trials, were to be predictably anti-idiotypic, then the opport unity for treatment with sequential mAbs of differing idiotypes would be retained. Moreover, these current studies also suggest that humaniz ed construction may influence the duration of therapeutic mAb levels. Thus, anti-idiotypic reactivity may not be as consequential to the cli nical administration of humanized mAb to allograft recipients.