Abatacept
| Clinical data | |
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| Pregnancy category |
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| Routes of administration | Intravenous |
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| Pharmacokinetic data | |
| Metabolism | unknown |
| Elimination half-life | 13.1 days |
| Excretion | unknown |
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| DrugBank | |
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.
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
References
- ^ "ABATACEPT & BELATACEPT: the CTLA-4-Igs". Healthvalue.net. Retrieved 2007-05-25.
- ^ Dall'Era M, Davis J (2004). "CTLA4Ig: a novel inhibitor of co-stimulation". Lupus. 13 (5): 372–376. doi:10.1191/0961203303lu1029oa. PMID 15230295.
- ^ Bristol-Myers Squibb (March 13 2007). Template:PDFlink. 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. doi:10.1038/nrd1989. PMID 16557658.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ "A Study of Abatacept in Patients With Active Ulcerative Colitis". ClinicalTrials.gov. United States National Institutes of Health. May 11 2007. Retrieved 2007-05-25.
{{cite web}}: Check date values in:|date=(help) ClinicalTrials.gov Identifier NCT00410410. - ^ "CTLA-4 Ig (Abatacept) in Recent Onset Diabetes". diabetestrialnet.org. TrialNet. Retrieved 2008-08-08. diabetestrialnet.org.
- ^ "ACCESS clinical trial for lupus nephritis". www.lupusnephritis.org. Immune Tolerance Network. Retrieved 2009-09-14. ClinicalTrials.gov Identifier NCT00774852