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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-TNFα therapy.

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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 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.

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

^ ABATACEPT & BELATACEPT: the CTLA-4-Igs. Healthvalue.net. Retrieved on 2007-05-25.
^ Dall'Era M, Davis J (2004). "CTLA4Ig: a novel inhibitor of co-stimulation". Lupus 13 (5): 372–376. PMID 15230295.
^ Bristol-Myers Squibb (March 13 2007). ORENCIA labelPDF (110 KiB). United States Food and Drug Administration. Retrieved on 2007-05-25.
^ ^a ^b Moreland L, Bate G, Kirkpatrick P (2006). "Abatacept". Nature Reviews Drug Discovery 5: 185–186. PMID 16557658.
^ A Study of Abatacept in Patients With Active Ulcerative Colitis. ClinicalTrials.gov. United States National Institutes of Health (May 11 2007). Retrieved on 2007-05-25. ClinicalTrials.gov Identifier NCT00410410.

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Categories: Monoclonal antibodies | Engineered proteins

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Abatacept". A list of authors is available in Wikipedia.