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Abatacept (marketed as Orencia) is a fusion protein composed of the Fc region of the immunoglobulin IgG1 fused to the extracellular domain of CTLA-4. It is a molecule capable of binding with more avidity to CD80 (B7-1) than to CD86 (B7-2). Abatacept is a selective co-stimulation 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.
Abatacept is currently approved for use in people with rheumatoid arthritis who have had an inadequate response to one or more DMARDs. 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.
Clinical trials for additional indications
Abatacept had a phase III trial for the treatment of patients suffering moderate to severe active ulcerative colitis, where response to standard treatment has failed to bring about remission. The trial was due to run until 2009 but after review of interim results was terminated early due to lack of efficacy.
Abatacept is (As of 2008[update]) in trial 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.Template:The Lancet, Volume 378, Issue 9789, Pages 412 - 419, 30 July 2011 doi:10.1016/S0140-6736(11)60886-6C
Abatacept is currently in a phase II trial for Multiple Sclerosis in a joint Bristol Meyers and NIAID program.
The ACCESS phase II clinical trial, sponsored by the National Institute of Allergy and Infectious Diseases is (As of 2009[update]) studying abatacept treatment in lupus nephritis when used in combination with cyclophosphamide therapy.
Abetacept in a subcutaneous administration form has been approved by USFDA, for self administration by the patient.
Mechanism of action
Abatacept prevents antigen-presenting cells (APCs) from delivering the co-stimulatory signal to T cells to fully activate them. Note that binding of the activation signal without its complementary co-stimulatory signal also helps to enable downregulation of T cells by way of T cell anergy. 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.
Ordinarily, full T cell activation requires 1) binding of the T cell receptor to the antigen-MHC complex on the APC and 2) a co-stimulatory signal provided by the binding of CD28, a T cell 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 co-stimulatory signal to T cells, thus preventing the full activation of T cells.
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 (for example cyclosporin).
- Bristol-Myers Squibb (March 13, 2007). PDF (110 KiB). United States Food and Drug Administration. Retrieved on 2007-05-25.
- Moreland L, Bate G, Kirkpatrick P (2006). "Abatacept". Nature Reviews Drug Discovery 5 (3): 185–186. doi:10.1038/nrd1989. PMID 16557658.
- "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. ClinicalTrials.gov Identifier NCT00410410.
- http://clinicaltrials.gov/ct2/show/results/NCT00410410 Ulcerative Colitis Study results
- "CTLA-4 Ig (Abatacept) in Recent Onset Diabetes DEAD URL". 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
- "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.