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.

Mechanism of action
Abatacept prevents APCs from delivering the costimulatory signal to T cells to fully activate them.

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.

Derivatives
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 ciclosporin).

Indications
Abatacept is currently approved for use in rheumatoid arthritis patients 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. It is also likely to be beneficial in the treatment of psoriasis and in organ transplantation.

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 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.

The ACCESS phase II clinical trial , sponsored by the National Institute of Allergy and Infectious Diseases is 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.

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

Similar agents

 * Belatacept