Belatacept inhibits the activation of T-lymphocytes after antigen presentation by the antigen-presenting cell (APC) that plays an important role in transplant rejection. Activation of a T-cell requires two signals from the APC. The first signal is antigen specific and is given when antigenic peptides are presented to the T-cell through the Major Histocompatibility Complex (MHC). A second signal, the so-called co-stimulation develops from the interaction between the CD80 or CD 86 antigen on the APC and the CD28 antigen on the T-cell.
Belatacept (CTLA4-Ig) is a fusion protein of the extracellular domain of the human Cytotoxic T Lymphocyte associated antigen (CTLA-4) linked to a modified Fc of human immunoglobulin 1 (IGG1). Belatacept binds with the extracellular domain of CTLA-4 to the CD 80 or the CD 86 antigen on the APC with a higher affinity than CD28. Belatacept therefore prevents the essential second signal for T-cell activation and prevents rejection of transplants successfully.
Belatacept has been registered to prevent the body from rejecting a transplanted kidney. It is used with corticosteroids and a mycophenolic acid.
The occurrence of all kinds of infections as adverse effect of belatacept is explained by its mechanism of suppressing the immune response. Furthermore, headache, nausea, hypertension and gastrointestinal disorders are other often noticed adverse effects. A small percentage of the treated patients displays autoimmunity by developing anti-belatacept antibodies.
Belatacept carries a Boxed Warning from FDA for an increased risk of posttransplant lymphoproliferative disorder (PTLD). As the risk of PTLD is higher for transplant recipients who have never been exposed to Epstein-Barr virus (EBV), patients should be tested for EBV and should only receive belatacept if the test shows they have already been exposed to the virus.
Abatacept, a first generation CTLA4-Ig, has a similar molecular structure as belatacept and differs only in 2 amino acids. However, abatacept is characterized by a lower affinity and is registered for the indication of rheumatoid arthritis, read more in RA multiple-hit model.