Phase I trial of a humanized, fc receptor nonbinding OKT3 antibody, huOKT3gamma(1)(Ala-Ala) in the treatment of acute renal allograft rejection

Background. HuOKT3 gamma(1)(Ala-Ala) is a genetically-engineered derivative of the parental murine OKT3 monoclonal antibody, in which the six compleme ntarity-determining regions have been grafted within a human IgG1 mAb, and whose C(H)2 region has been altered by site-directed mutagenesis to alter F cR-binding activity, thereby eliminating T cell activation properties. This report describes the results of a phase I trial of huOKT3 gamma(1)(Ala-Ala ) treatment of acute renal allograft rejection. Methods. Acute renal allograft rejection in kidney and kidney-pancreas tran splant recipients was treated with huOKT3 gamma(1)(Ala-Ala). huOKT3 gamma(1 )(Ala-Ala) dosing consisted of daily 5- or 10-mg doses adjusted initially t o achieve target levels of 1000 ng/ml. Results. A total of seven patients, five kidney transplant and two kidney-p ancreas transplant recipients, were treated with the monoclonal antibody fo r first rejection episodes. Corticosteroids (500 mg i.v. Solumedrol) were g iven 2 hr before the first huOKT3 gamma(1)(Ala-Ala) dose only. Banff classi fication of treated rejections were the following: grade I, 1 patient, grad e IIA, 1 patient, grade IIB, 4 patients, and grade III, 1 patient. Median t ime from transplant to rejection was 15 days, and median follow up 12 month s (range 10-17 months). HuOKT3 gamma(1)(Ala-Ala) therapy was given for 10.1 +/-2.5 days, and mean total dose was 76+/-27 mg. Rejection was reversed in five of seven patients, and recurrent rejection was observed in one patient . Serum creatinine values peaked on day 1 of huOKT3 gamma(1)(Ala-Ala) thera py, and thereafter demonstrated a progressive decline. Rejection reversal ( return of creatinine to baseline) occurred at a median of 4 days and a mean of 4.1+/-2 days. Renal allograft biopsies obtained during huOKT3 gamma(1)( Ala-Ala) therapy provided evidence of rapid rejection reversal. Patient and graft survival were both 100%. First dose reactions were minimal, and anti OKT3 antibodies were not detected. Elevations in serum IL-10, but not IL 2 levels were observed after the first huOKT3 gamma(1)(Ala-Ala) dose. Marked reductions in circulating CD2(+), CD4(+), and CD8(+) T cells were observed after the first huOKT3 gamma(1)(Ala-Ala) dose, followed by a slow progress ive return of cell counts toward pretreatment values. Pharmacokinetic analy sis revealed a half-life of 142+/-32 hr. Conclusions. HuOKT3 gamma(1)(Ala-Ala) possesses the ability to reverse vigo rous rejection episodes in kidney and kidney-pancreas transplant recipients , and in comparison to murine OKT3, possesses minimal first dose reactions and does not seem to induce antibodies that bind the OKT3 idiotype. These r esults support the conduct of additional clinical trials with the huOKT3 ga mma(1)(Ala-Ala) antibody.