Monoclonal antibody treatment of human allograft recipients

Abstract

Antilymphocyte antibody immunosuppression has evolved to the use of therapeutic antibodies which are monoclonal in content. An antibody is termed monoclonal if each immunoglobulin molecule is produced by a single clone of cells and, thus, is identical in both the heavy and light chain structure to every other molecule in the preparation. Monoclonal preparations provide more consistent bioefficacy and predictable toxicity than do polyclonal products. Studies in nonhuman primate allograft recipients have established the immunosuppressive efficacy of several mAb. The results of pilot trial studies using a pan-T-cell mAb, OKT3, either prophylactically or at the time of acute rejection have revealed OKT3 to be remarkably immunosuppressive in man. OKT3 has subsequently been shown in multicenter, randomized trials to be more effective than conventional suppression in reversing renal and hepatic allograft rejection. In uncontrolled trial studies, similar efficacy in reversing cardiac rejection has been reported. Despite these impressive results, several limitations to OKT3 therapy persist. These include febrile and other systemic symptoms after the first or second infusion, a frequency of recurrent rejection episodes and the development of antibodies to the murine protein which may preclude subsequent treatment with the same mAb. Other murine mAb, such as CBL1 and anti-T12, have been noted to produce less side effects; however, these mAb have not been as effective. The next generation of mAb will be selected to minimize these limitations. It is anticipated that future mAb protocols will specifically suppress only selected subsets of T cells, and that these mAb may be chimeric or even human in structure to limit their immunogenicity.