Indication
Abatacept is licensed for the treatment of rheumatoid arthritis (RA) in combination with methotrexate. The indication includes moderate to severe RA unresponsive to other disease-modifying antirheumatic drugs including at least one tumour necrosis factor (TNF)- α blocker, or where patients have been intolerant of such drugs.
Mechanism
Abatacept (CTLA4Ig) is a fusion protein of the extracellular domain of the human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc of human immunoglobulin 1 (IgG1). Abatacept inhibits the activation of T lymphocytes that play an important role in the early stages of pathogenesis of RA.
Activation of a T cell requires two signals from the antigen-presenting cell (APC). The first signal is antigen specific and arises when antigenic peptides are presented to the T cell through the Major Histocompatibility Complex.
A second signal, so-called co-stimulation, develops from the interaction between CD80 or CD86 antigen on the APC and CD28 antigen on the T cell. Abatacept binds with the extracellular domain of CTLA-4 to CD80 or CD86 antigen on the APC with a higher affinity than CD28, preventing the essential second signal for T-cell activation. T-cell activation and the production of inflammatory mediators and cytokines (TNF-α, interferon-gamma and interleukin-2) are consequently reduced. Trials in patients with RA have shown that abatacept slows progression of joint damage and improves function.
Adverse effects
An increased incidence of all kinds of infections caused by abatacept is explained by its mechanism of suppressing the immune response. Headache, hypertension, dizziness, gastrointestinal disorders and rash are other common adverse effects. A small percentage of treated patients develop anti-abatacept antibodies.
(A) Activation of the T cell via two interactions with the antigen-presenting cell (APC). (B) Abatacept prohibits binding to CD80 or CD86 of the APC with CD28 of the T cell. Thereby it inhibits the realization of the second signal required for activation of the T cell
Literature
- 1. Available at http://www.emea.europa.eu/humandocs/Humans/EPAR/orencia/orencia.htm.
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