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CTLA4 Ig fusion proteins: promise for improved therapy of transplant rejection and autoimmune diseases

Francis J Dumont

T-cell activation is critically involved in the pathogenesis of both transplant rejection and autoimmunity, making its modulation a promising approach for immunotherapy. One attractive target for that purpose is provided by the CD28/B7 costimulatory pathway which is composed of the T-cell-associated CD28 molecule and its B7 ligands (CD80 and CD86) on antigen-presenting cells. This pathway is pivotal in complementing, in a non-antigenspecific manner, the antigen-specific signals of T-cell activation that are delivered upon triggering of the T-cell receptor. In the absence of CD28-mediated costimulation, T-cells activated through their T-cell receptor may acquire a state of antigen-specific unresponsiveness or undergo apoptotic cell death, leading to an abortive immune response. A competitive inhibitor of the CD28/B7 pathway has therefore been designed for use as a selective immunosuppressant. This reagent, called CTLA4–immunoglobulin (Ig), is a soluble fusion protein that binds B7 molecules with greater affinity than CD28. Extensive studies in animal models of allograft rejection and autoimmune diseases demonstrated that CTLA4–Ig exerts immunosuppressive effects without major toxicity. Over the past few years, the development of CTLA4–Ig and several analogs further proceeded to enter clinical trials in kidney transplantation, psoriasis and rheumatoid arthritis, with encouraging results. The present article will discuss the therapeutic potential of CTLA4–Ig molecules in the light of these new data.