TREATMENT OF RENAL-ALLOGRAFT REJECTION WITH T10B9.1A31 OR OKT3 - FINAL ANALYSIS OF A PHASE-II CLINICAL-TRIAL

Background. Treatment of acute renal allograft rejection with the mono clonal antibody (mAb) OKT3 has been shown to be superior to treatment with polyclonal antisera. To date, only OKT3 has demonstrated consiste nt efficacy in reversing rejection crisis. Methods. From 1989 to 1993, a phase II trial comparing the mAb T10B9.1A31 (T10B9) with OKT3 for t reatment of acute cellular rejection in renal allograft recipients was done at the University of Kentucky. We collected data from 178 patien ts potentially eligible to enter the study; 48 never rejected, 9 refus ed, 13 could not be biopsied, 16 received methylprednisolone, and 11 r eceived antithymocyte globulin or OKT3. Altogether, 81 patients entere d the study, 76 of whom were able to be evaluated. Patients with biops y-confirmed acute rejection were randomly assigned to T10B9 or OKT3 fo r at least 10 days. Results. Demographically, there was no difference between the T10B9 or OKT3 cohorts. Actuarial graft survival at 4 years was 87% for patients receiving T10B9, 79% for those receiving OKT3, a nd 89% for those receiving both mAbs (P=0.55). Patient survival at 4 y ears was 94% for T10B9, 100% for OKT3, and 89% for both mAbs (P=0.45). Mean creatinines of the cohorts were no different at 1, 6, 12, 24, an d 36 months. There was less cytokine nephropathy (P<0.001) observed in patients receiving T10B9. Untoward gastrointestinal, neurological, re spiratory, and febrile effects were significantly more frequent in the OKT3 cohort after the first dose (day 0) and with later (day 1-9) adm inistration. Cytokine levels (tumor necrosis factor alpha and interfer on gamma) measured 2 hr after the first dose were three to six times h igher in patients treated with OKT3 than in those treated with T10B9 ( P<0.005). Infectious complications were not significantly different, a lthough serious infections occurred only in patients receiving OKT3. N o cases of posttransplant lymphoproliferative disorder were seen in ei ther cohort. Human anti-mouse antibody development was as follows: tit er 1:100, 30% T10B9, 42% OKT3; titer 1:1000, 3% T10B9, 3% OKT3. There was no cross-reactivity with OKT3 in patients treated with T10B9, and there was only 9.7% cross-reactivity to T10B9 in patients treated with OKT3. Conclusions. T10B9 provides treatment for renal allograft acute cellular rejection as effective as that of OKT3 with fewer untoward e ffects, less cytokine release and nephropathy, fewer serious infection s, and without increased development of human anti-mouse antibody. The lack of cross-reactivity offers an alternative therapy should the fir st mAb fail or re-rejection occur. A phase III trial should be initiat ed in renal allograft recipients, and phase I and phase II trials shou ld be initiated in other solid-organ transplantations.