IMMUNOSUPPRESSIVE AGENTS IN CLINICAL-TRIALS IN TRANSPLANTATION

Many new agents are in or near clinical trials in organ transplantatio n. The small molecule antibioticlike drugs are inhibitors of key enzym es in T-cell signal transduction (calcineurin target of rapamycin [TOR ], and inosine monophosphate dehydrogenase). Calcineurin inhibitors in clude cyclosporine microemulsion formulation generic cyclosporine prep arations, and tacrolimus. Rapamycin (also known as sirolimus) acts on target of rapamycin to abrogate signals necessary for clonal expansion and is now in phase III. Recent trials of mycophenolate mofetil, an i nhibitor of inosine monophosphate dehydrogenase, have shown that it re duces acute renal graft rejection when used with steroids and cyclospo rine. New protein reagents in trials include polyclonal antilymphocyte antibodies, mouse monoclonal antibodies, ''humanized'' mouse monoclon als, and engineered proteins based on naturally occurring signalling m olecules, Humanized antibodies against the interleukin-2 receptor are promising because humanized antibodies should combine low toxicity wit h the potential for long-term use. Engineered human proteins designed to block costimulatory molecules on antigen-presenting cells could hav e similar potential for low toxicity and extended use. These agents ar e designed to reduce acute rejection and the toxicity of the existing drugs and eventually improve long-term patient and graft survival. Org an transplant practice will probably change considerably as these agen ts become available.