Anti-CD4 monoclonal antibody therapy.

Because they can be selected to target only cells which are crucial for rejection, monoclonal antibodies (mAbs) offer enormous potential for specific manipulation of the immune response. Interest in the clinical potential of anti-CD4 mAbs has been heightened by the demonstration, in experimental models, that such therapy can produce long-term donor-specific non-responsiveness. Early clinical trials using two murine anti-CD4 mAbs (BL4 and mT-151) were discouraging, with over 50% of recipients suffering early rejection episodes. Another murine preparation, OKT4A, was initially found to prolong allograft survival in non-human primates. Limited clinical trials revealed that this mAb was well tolerated, that most recipients produced an antimurine response, and that only 26% of patients suffered rejection episodes during the first 3 post-operative months. Another murine preparation, Max. 16H5, has been reported to reverse late onset acute rejection episodes as effectively as, but more safely than, conventional immunosuppression. More recent interest has focused upon humanized recombinants of these earlier murine anti-CD4 preparations. cMT-412, has been studied in recipients of heart or heart-lung allografts. These patients were observed to have less frequent and markedly delayed rejection episodes, fewer infectious complications, and better overall survival than that observed in an ATG-treated control group. Further studies are thus being undertaken. A CDR grafted IgG4 preparation of OKT4A has also been studied. This molecule (OKTcdr4a) contains only 8% of the parent murine sequence while retaining the binding affinity of OKT4A for the human CD4 antigen. In a pilot trial, biopsy-proven reversible rejection episodes were observed in 2/11 (18%) of renal allograft recipients. There were no allograft failures and no antibody response to the mAb. These and other trials emphasize the intense interest in immunosuppressive regimens incorporating anti-CD4 mAbs as well as the difficulties encountered in defining optimal protocols. Nevertheless, the impressive results observed in rodent and non-human primate models suggest that these agents are likely to play an important role in future immunosuppressive protocols, particularly those designed to induce tolerance.