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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 monoclonal antibody (mAb) OKT3 has been shown to be superior to treatment with polyclonal antisera. To date, only OKT3 has demonstrated consistent efficacy in reversing rejection crisis.


METHODS
From 1989 to 1993, a phase II trial comparing the mAb T10B9.1A31 (T10B9) with OKT3 for treatment of acute cellular rejection in renal allograft recipients was done at the University of Kentucky. We collected data from 178 patients potentially eligible to enter the study; 48 never rejected, 9 refused, 13 could not be biopsied, 16 received methylprednisolone, and 11 received antithymocyte globulin or OKT3. Altogether, 81 patients entered the study, 76 of whom were able to be evaluated. Patients with biopsy-confirmed acute rejection were randomly assigned to T10B9 or OKT3 for 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, and 89% for those receiving both mAbs (P=0.55). Patient survival at 4 years 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, and 36 months. There was less cytokine nephropathy (P<0.001) observed in patients receiving T10B9. Untoward gastrointestinal, neurological, respiratory, and febrile effects were significantly more frequent in the OKT3 cohort after the first dose (day 0) and with later (day 1-9) administration. Cytokine levels (tumor necrosis factor alpha and interferon gamma) measured 2 hr after the first dose were three to six times higher in patients treated with OKT3 than in those treated with T10B9 (P<0.005). Infectious complications were not significantly different, although serious infections occurred only in patients receiving OKT3. No cases of posttransplant lymphoproliferative disorder were seen in either cohort. Human anti-mouse antibody development was as follows: titer 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 effects, less cytokine release and nephropathy, fewer serious infections, and without increased development of human anti-mouse antibody. The lack of cross-reactivity offers an alternative therapy should the first mAb fail or re-rejection occur. A phase III trial should be initiated in renal allograft recipients, and phase I and phase II trials should be initiated in other solid-organ transplantations.