Coadministration of either cyclosporine or steroids with humanized monoclonal antibodies against CD80 and CD86 successfully prolong allograft survival after life supporting renal transplantation in cynomolgus monkeys

Background. Recent studies have shown some efficacy using monotherapy with monoclonal antibodies (mAb) against CD80 and CD86 receptors after life-sup- porting renal transplantation in non-human primates. Our study was designed to evaluate the efficacy of combinations of the same mAbs with either micr oemulsion cyclosporine (CsA) or steroids. Methods. Unilateral renal transplantation was performed in 16 blood group-m atched and AMR-mismatched cynomolgus monkeys that were assigned to four dif ferent treatment groups. All monkeys in groups I, II, and IV were treated w ith the combination of a CD80 (h1F1) and CD86 (h3D1) mAb given at 20 mg/kg each preoperatively, then 5 mg/kg at weekly intervals starting postoperativ e (po) day 0 until poday 56 (9 doses). In group I the animals (n=4) were tr eated with mAbs only. In group II (n=4) mAbs were combined with a CsA regim en adjusted daily to maintain target 24 hr trough levels of 150-300 ng/ml C sA for poday 0 to poday 56. In group III (n=4) the animals received CsA mon otherapy according to the same regimen as group II. In group IV methylpredn isone was administered at 2 mg/kg TV on poday 0-2, then at 0.5 mg/kg/day pr ednisone per gavage that was and tapered to 0.2 mg/kg/day on which they wer e maintained until poday 56. All animals were off all immunosuppressive tre atment after poday 56 and were then followed until poday 119. Results. The mean survival of groups I-IV was 74 (range 9-119 days), 113 (9 6-119 days), 39 (22-71 days), and 79 days (6 to 119), respectively. All ani mals in group I showed clinical evidence of acute severe rejection (fever, creatinine increase, anuria) within the first week posttransplant, includin g those that retained renal function until poday 119. Only one animal in gr oup II had a moderate clinical rejection during the treatment period and th ree of four animals survived the intended follow-up period. All animals in group III had multiple biopsy proven or severe clinical rejection episodes within the first 21 days and only one animal survived beyond poday 40. Mode rate or severe acute rejection was diagnosed in three of four animals of gr oup IV within the first 28 days post transplant and only one animal survive d until poday 119. Conclusion. Our data show that combining a calcineurin inhibitor or prednis one with mAbs designed to block costimulatory signals does not antagonize t he immunosuppressive efficacy of these mAbs. In addition, combining CsA wit h mAbs directed against the CD80 and CD86 receptors significantly prolongs graft survival when compared to CsA monotherapy. Therefore clinical trials of humanized mAbs to CD80 and CD86 used in combination with conventional im munosuppression can be considered.