Abatacept is a drug used to treat autoimmune diseases like rheumatoid arthritis, by interfering with the immune activity of T cells. It is a modified antibody. Abatacept is a fusion proteincomposed of the Fc region of the immunoglobulinIgG1 fused to the extracellular domain of CTLA-4. In order for a T cell to be activated and produce an immune response, an Antigen-presenting cell must present two signals to the T cell. One of those signals is the major histocompatibility complex, combined with the antigen, and the other signal is the CD80 or CD86 molecule. Abatacept binds to the CD80 and CD86 molecule, and prevents the second signal. Without the second signal, the T cell can't be activated. Abatacept was developed by Bristol-Myers Squibb and is licensed in the United States for the treatment of rheumatoid arthritis in the case of inadequate response to anti-TNFα therapy. Some doctors criticize its cost and its promotional marketing.
Medical uses
Abatacept is used to treat adults with moderate to severe rheumatoid arthritis as a second line agent, and as a first line agent for people whose RA is severe and rapidly progressing. It also used to treat psoriatic arthritis and juvenile idiopathic arthritis.
Contraindications
Abatacept has not been tested in pregnant women and it is not known if it is secreted in breast milk; it causes birth defects in rodents when given in very high doses, and is transmitted in rodent breast milk. People should be tested for tuberculosis and any infection cleared before starting abatacept; vaccines should be updated prior to starting abatacept as well. Abacept will likely interfere with any vaccine given while people are taking it. It should not be used in combination with anakinra or TNF antagonists. Because abatacept, anakinra, and TNF antagonists suppress the immune system, using them in combination may significantly increase the risk for severe infections.
Abatacept prevents antigen-presenting cells from delivering the co-stimulatory signal. This prevents the T cells from being fully activated, and even downregulates them. Simple signaling without co-stimulation allows the cell to recognize the primary signal as "self" and not ramp-up responses for future responses as well. In order for T cells to be activated and attack an antigen, that antigen must be presented to the T cell by an antigen-presenting cell. That activation requires two signals : For signal 1, the APC must bind the antigen to a major histocompatibility complex molecule, bring that complex to its surface, and present it to the T cell receptor on the surface of the T cell. For signal 2, the APC must present a B7 protein on its cell surface to a CD28 protein on the surface of the T cell. These two signals activate the T cell. Without signal 2, the T cell will not be activated, and will become anergic. Abatacept consists of a fusion protein of the extracellular domain of CTLA-4 and human IgG1, binds to the B7 protein on the APC and prevents it from delivering the co-stimulatory signal to the T cell.
Chemistry
Abatacept is a fusion protein composed of the extracellular domain of CTLA-4 with the hinge, CH2, and CH3 domains of IgG1.
Research
Abatacept is the basis for the second-generation belatacept currently being tested in clinical trials. They differ by only 2 amino acids. In organ transplantation, belatacept is intended to provide extended graft survival while limiting the toxicity generated by standard immune-suppressing regimens such as calcineurin inhibitors.
