The role of newer monoclonal antibodies in renal transplantation

Abstract

BIOLOGIC agents have been used in transplantation in the prophylaxis of rejection, in the induction phase of therapy, and in the reversal of acute rejection, especially steroid-resistant or vascular-type rejection. Historically, two biologic agents have been used: the polyclonal antilymphocyte agents and the murine monoclonal antibody (MAb) anti-CD3, OKT3. Although effective, these agents are associated with many side effects. The newer generation of humanized antibodies (also chimeric) have many advantages over the traditional polyclonal agents and OKT3. These humanized MAbs tend to lack drug-specific side effects, have no immunogenicity, can be used for longer periods of time, and can be reused. They have a prolonged half-life, and the specific epitope target of the MAbs can be readily saturated. The humanized antibodies can be administered anytime perioperatively, and they are easy to infuse in the outpatient setting or even at home. Their prolonged biologic effects may decrease dependence on calcineurin inhibitors and corticosteroids. The evolving role of the newer MAbs in transplantation is to improve tolerance to the graft in the induction and postinduction periods, to provide effective immunosuppression in delayed graft function, and to reduce dependence on calcineurin inhibitors and corticosteroids. Several MAbs are either approved for use or are in clinical trials. The anti-interleukin-2 receptor (IL-2R) MAbs, daclizumab and basiliximab, approved in the late 1990s, are the prototype of the new generation of humanized antibodies. The humanized anti-LFA1 antibody, hu1124, is currently in phase I trial. A number of antibodies that block the co-stimulatory pathway are also currently in clinical trials. The humanized anti-CD40 ligand was in phase I, but its clinical development is currently on hold because of thromboembolic complications. Currently, the combination of anti-B7.1 and B7.2 is in phase I clinical trial, and the second-generation CTL4Ig (BMS-224818) will be entering phase I trials very soon.