Tacrolimus vs. Cyclosporine

Tacrolimus and Cyclosporine are drugs that are both considered Calcineurine Inhibitors. Both drugs work to inhibit the cystolic protien Calcineurine by different pathways, and thus ulitmately have the same immunosuppressive effect. Because of the separate pathways, however, the drugs both have a distinct degree of effectiveness. Tacrolimus has proved to be more clinically successful in enlongating graft survival in patients. This can be confirmed in the accompanying chart. Another favorable aspect of Tacrolimus is that it has a less significant side-effect profile.

Definitive reasons for the discrepancies in patient outcomes are not completely clear to researchers. In fact, results are skewed from patient to patient. The overall trend confirms that Tacrolimus is the favored Calcineurine Inhibitor of Immunosuppressant Therapy. This can be confirmed in the table above. Tacrolimus is, in fact, the more favored in use in Triple Therapy.

Monoclonal vs. Polyclonal

Results from a randomized control trial of a Monoclonal Antibody (against the IL-2R) as compared with RATG for prophylaxis against rejection against renal allographs (New England Journal of Medicine)

Monoclonal and Polyclonal antibodies work simularly to block such elements such a costimulatory signals, cytokines and their receptors, and portions of the TCR. Polyclonal antibodies are more complex and comprehensive, and correspondingly are more recent developments in immunotherapy. The difference between the two can be summed up by the fact that monoclonal antibodies are specific for only one target, while polyclonal antibodies have multiple specificities.

In terms of efficacy, polyclonal and monoclonal antibodies have proven to be simular in the prevention of graft rejection. Polyclonal antibodies demonstrate less acute rejection episodes early in postoperative treatment. In the long term, however, monoclonal antibodies have the same, if not better, graft survival. This is evident in statistics of graft loss at 12 months of a representative New England Journal of Medicine trial (shown at the left). In the first 3 months, episodes of acute rejection occured for 31% of patients receiving the monoclonal antibody, while only 26% of patients being administered the rat polyclonal antibody experienced acute rejection. In contrast, the results reverse themselves at 12 months, with a smaller percentage of graft loss of patients in the monoclonal subgoup (14%) was observed as compared to that in the polyclonal subgroup (16%). These differences in percents are admittedly small but speak well of polyclonal antibodies. It is important to realize that polyclonal antibody therapy is very new and experimental. It is impressive for this type of new therapy to compete effectively against a more established monoclonal therapy. However, at this point, there are more drawbacks to polyclonal antibody use. One such drawback is the increased incidence of side effects, such as opportunistic infections and serum sickness (see statistics in the figure above). These can be accounted for by the less humanized quality of the current polyclonal antibodies. It can be expected that future research will work towards chimerizing these drugs.

Options within Monoclonal Therapies

One of the major problems affecting monoclonal thearpy is the side effects associated with the HAMA response and serum sickness. These are both directly caused by the structure and manufacturing techniques currently used. In creating antibodies, laboratories routinely use murine antibodies as a starting point. This poses a problem because the human immune system is able to identify the murine antibody as non-self and eliminate the treatment from circulation. This renders the monoclonal therapy ineffective.

A counteractive measure includes humanizing (or chimerizing) the antibody. Because the only immunologically offensive portion of the antibody is the constant region (the stem of the Y shape), recominant techniques can be used to splice and replace the constant region of the murine antibody with that of a characteristic human antibody. Current drugs have been developed that are more favorably humanized. They are also shown to be more effective with less adverse side effects. This evolution towards chimerization can be demonstrated through the replacement of Orthoclone (70% human/30% murine; shown to the left) with the newer generation of monoclonal antibodies, a group which includes Basiliximab and Daclizumab (90% human/10% murine). Further chimerization and other improvements in antibody therapy are active fronts of research today.

Another promising attribute of monoclonal therapies is the fact that therapeutic addition of this medication has the potential to eliminate need for either corticosteriods or calcineurine inhibitors within standard immunotherapy.