Relevant targets for therapy with monoclonal antibodies in allograft transplantation

Abstract

A 45-year-old woman had been dialyzed for 3 years for end-stage renal disease secondary to polycystic kidney disease. She had received two transfusions and had developed antibodies reacting with 20% of the local screening panel. The patient was offered renal transplantation and agreed to enroll in a randomized study to evaluate the efficacy of a monoclonal antibody (mAb), directed against an adhesion/co-stimulatory molecule, CDIIa, in improving graft survival. In this study, the antibody, which had yielded encouraging results in a recent pilot study, was compared (in an induction protocol) with anti-thymocyte polyclonal globulins. The protocol called for the monoclonal antibody to be administered at 20 mg/day for 10 days, along with 1 mg/kg of steroids (tapered every week, until complete withdrawal at day 45) and 2.5 mg/kg of azathioprine; cyclosporine A (C5A) was begun at the end of the mAb administration. At day 2 post transplantation, the patient excreted 2 liters of urine; her serum creatinine level decreased progressively to levels below 150 j.M (1.6 mg/dl) at day 9. No adverse effect of the mAb was noted. Circulating trough levels reached 7 jsg/ml at day 6 and peaked at 11 jig/mI at day 11. No changes in white blood cell counts were noted after an initial decline of 20% in lymphocyte count. As early as day 3, LFA-1 site occupancy of the patient's lymphocytes by the antibody was saturated. In addition, patient-activated T-cells had lost their capacity to bind a B-cell line bearing ICAM-1, the ligand of LFA-1. An almost total modulation of the patient's CD11a molecule at the lymphocyte surface membrane was found at the end of the treatment. All these biologic effects disappeared by day 30. The patient did not have any rejection episodes during the first 3 months after transplantation; her serum creatinine concentration was 130 jiM (1.4 mg/dl) at that time.