CTLA4-Ig: a novel immunosuppressive agent

Abstract

Activation of naive T-cells requires two signals: one is antigen-specific and based on T-cell receptor (TCR) recognition of a peptide-MHC complex and the second is antigen-nonspecific and delivered by specific T-cell receptors after ligation with their ligands (costimulatory molecules) expressed by antigen-presenting cells (APCs). Engagement of the B7 family of molecules on APCs with their T-cell associated ligands, CD28 and CTLA-4 (CD152), provides a pivotal costimulatoty signal in T-cell activation. The lack of costimulation after engagement of the T-cell receptor by antigen, results in a state of antigen-specific unresponsiveness, termed anergy. Manipulation of CD28/B7 pathway has therefore been envisioned as a potential strategy for achieving therapeutically useful immunosuppression or tolerance. CTLA4-Ig has been initially developed by Bristol-Myers Squibb as a competitive inhibitor of CD28/B7 pathway (BMS-188667). Thereafter, CTLA4-Ig was produced by Repligen and also in some individual laboratories. In various animal models, discussed in this paper, CTLA4-Ig has been shown to inhibit T-cell-dependent antibody responses, significantly prolong transplanted organ survival, induce long-term donor-specific tolerance in some models, slow progression of autoimmune disease and to have immunomodulatory function in several other immunological disease models. Recently, CTLA4-Ig has entered Phase I clinical trials for the treatment of psoriasis, a T-cell mediated skin disease and treatment of graft-versus-host disease in allogeneic bone marrow transplantation. Large clinical randomised trials on the use of CTLA4-Ig are missing, nevertheless, its immunosuppressive effects coupled with features such as specificity of interaction and low toxicity, make CTLA4-Ig a promising new therapeutic agent for induction of donor-specific immunological tolerance, the ultimate goal of clinical immunosuppression.