Protein therapies and antiproliferatives: a new paradigm in immunosuppression

The development of immunosuppressive therapies has focused on inhibiting effects of the activated T cell. The introduction of powerful immunosuppressive agents that interrupt the effects of T-cell activation, such as the calcineurin inhibitors (CNIs), has revolutionized solid organ transplantation. However, the ubiquitous location of their targets causes a number of side effects, which can compromise recipient health and long-term allograft survival. Therefore, a common goal in the development of emerging immunosuppressive strategies is to maintain efficacy and minimize toxicities related to these immunosuppressant compounds. The rationale for CNI-free regimens that exploit combinations of antiproliferative and protein therapeutic agents is attractive. Recently, studies employing these agents in CNI-free regimens have begun to offer additional insight into both the potential benefits and limitations of currently available strategies. The currently available biologic agents provide either too potent immunosuppression (eg, T-cell depletion) or inhibit an aspect of T-cell activation too limited to provide adequate rejection prophylaxis (eg, interleukin 2 receptor [IL-2R] blockade). Growing evidence suggests that costimulation blockade, particularly those protein therapeutics targeting CD28 and CD40, provides the correct balance between immunosuppressive and low toxicity, with a more specific, nondepleting, and timely targeting of the immune response. Already, results from a phase 2 trial suggests that combination with a costimulation blockade using belatacept with mycophenolate mofetil as a maintenance therapy after induction with an IL-2R blocker is closest to fulfill this promise. Belatacept represents an emerging immunosuppression paradigm with maintenance protein therapy that fulfills the need of more selective immunosuppression with reduced toxicities, which offers the potential of improving long-term outcomes in renal transplant.