Abatacept  

Abatacept (marketed as Orencia) is a fusion protein composed of an immunoglobulin fused to the extracellular domain of CTLA-4, a molecule capable of binding B7. Abatacept is a selective costimulation modulator as it inhibits the costimulation of T cells. It 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-TNF therapy.

Mechanism of action

Ordinarily, full T cell activation requires 1) binding of the T cell receptor to the antigen-MHC complex on the antigen presenting cell (APC) and 2) a costimulatory signal provided by the binding of the T cell's CD28 protein to the B7 protein on the APC. Abatacept, which contains a high-affinity binding site for B7, works by binding to the B7 protein on APCs and preventing them from delivering the costimulatory signal to T cells, thus preventing the full activation of T cells.^[1][2]

Abatacept is the basis for the second-generation belatacept currently being tested in clinical trials. In organ transplantation, it is intended to provide extended graft survival while limiting the toxicity generated by standard immune-suppressing regimens such as calcineurin inhibitors (eg, ciclosporin).

Indications

Abatacept is currently approved for use in rheumatoid arthritis patients who have had an inadequate response to one or more DMARDs.^[3] It is useful in delaying the progression of structural damage and reducing symptoms of rheumatoid arthritis. However, it should not be used in combination with anakinra or TNF antagonists.^[4] It is also likely to be beneficial in the treatment of psoriasis and in organ transplantation.^{[citation needed]}

Abatacept is currently [2007] in trial^[5] for the treatment of patients suffering moderate to severe active ulcerative colitis, where response to standard treatment has failed to bring about remission.

Abatacept is also currently [2008] in trial^[6] for the treatment of Type 1 Diabetes. In diabetic patients in the "honeymoon phase" of the disease, Abatacept may protect surviving beta cells from autoimmune attack.

The ACCESS clinical trial^[7], sponsored by the National Institute of Allergy and Infectious Diseases is currently [2009] studying abatacept treatment in lupus nephritis when used in combination with cyclophosphamide therapy.

Structure

Abatacept is a fusion protein composed of the extracellular domain of CTLA-4 with the hinge, CH2, and CH3 domains of IgG1.^[4]

Similar agents

• Belatacept

References

External links

• Orencia Official Site