Research Grade Belatacept

Belatacept is an immunosuppressive that was approved by the U.S. FDA for prophylactic prevention of rejection in kidney transplant recipients. Belatacept, which selectively blocks T cell costimulation, provides an alternative to the calcineurin inhibitors, which are associated with adverse effects on renal function as well as cardiovascular and metabolic parameters. T-cell activation by antigen-presenting cells (APCs) requires a costimulatory signal in addition to the signal mediated by interaction of the T-cell receptor and MHC-bound peptide antigen. Belatacept can block that second signal by binding to APC costimulatory surface proteins CD80 and CD86 to inhibit their interaction with the T-cell signaling molecule CD28. Belatacept is a recombinant protein comprising a hinge-region modified (to reduce Fc receptor binding) carboxylterminal human IgG1 Fc domain fused to a modified extracellular domain of human CTLA-4 that includes two amino acid substitutions in the ligand-binding site. As a result of this modification, belatacept binds more tightly to CD80 and CD86 than the parent molecule abatacept (Orencia, FDA approved for treatment of adult RA and juvenile idiopathic arthritis), from which its structure is derived. CTLA-4 is a T-cell negative signaling molecule that is structurally related to CD28 and shares its two ligands. While belatacept incorporates CTLA-4 sequences to bind CD80 and CD86, the immunosuppressive activity of the drug suggests that its principal mechanism of action is blockade of CD28-mediated T-cell activation.