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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. In order for a T cell to be activated and produce an immune response, an antigen presenting cell must present two signals to the T cell. One of those signals is the major histocompatibility complex (MHC), combined with the antigen, and the other signal is the CD80 or CD86 molecule (also known as B7-1 and B7-2). Abatacept binds to the CD80 and CD86 molecule, and prevents the second signal. Without the second signal, the T cell can't be activated. Abatacept 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
A team led by researchers at Harvard-affiliated Massachusetts General Hospital (MGH) has reported that treatment with abatacept (Orencia) appeared to halt the course of focal segmental glomerulosclerosis (FSGS) in five patients, preventing four from losing transplanted kidneys and achieving disease remission in the fifth.
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.
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.
Abatacept 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. This prevents the T cells from being fully activated, and even downregulates them. 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.
In order for T cells to be activated and attack an antigen, that antigen must be presented to the T cell by an antigen-presenting cell (APC).
That activation requires two co-stimulatory signals:
For signal 1, the APC must bind the antigen to a major histocompatibility complex (MHC) molecule, bring that complex to its surface, and present it to the T cell receptor on the surface of the T cell.
For signal 2, the APC must present a B7 protein on its cell surface to a CD28 protein on the surface of the T cell. These two signals activate the T cell. Without signal 2, the T cell will not be activated, and will become anergic.
Abatacept consists of a fusion protein of the extracellular domain of CTLA-4 and human IgG1, binds to the B7 protein on the APC and prevents it from delivering the co-stimulatory signal to the T cell.
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).
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