Abatacept

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A relatively new immunosuppressant agent–originally approved for treatment of refractory rheumatoid arthritis but now gaining steam as an anti-rejection medication for kidney transplant recipients–is abatacept (marketed under the trade name Orencia by Bristol-Myers-Squibb. Its mechanism of action is based on the idea of T-cell costimulation, a pathway which will likely be the target of further immunosuppressive drugs of the future.

Under normal conditions, full T-cell activation requires (a) binding of the T-cell receptor to the antigen-MHC complex on the antigen-presenting cell, and (b) a costimulatory signal–with two of the important molecules responsible for this signal being CD28 (expressed on T-cells) and B7 protein (expressed on antigen-presenting cells). Abatacept is a fusion protein comprised of an IgG fused to the extracellular domain of CTLA-4 (essentially a subtype of CD28, which binds to B7). The addition of this soluble B7 binder outcompetes the endogenous costimulatory interaction, and as a result, T-cell activation is prevented.

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