Abatacept

Description

Rheumatoid arthritis (RA) is a debilitating autoimmune disease causing joint destruction and pain via the infiltration of inflammatory mediators. While some patients find relief using traditional disease-modifying antirheumatic drugs (DMARDs), such as methotrexate or tumor necrosis factor-blocking agents, a large proportion of individuals fail to respond adequately to existing therapy. For those that may initially benefit, issues with side effects may lead to the termination of treatment. Abatacept attempts to address the unmet need as a new class of DMARD that targets T-cell function. With the recognition that Tcells play a central role in the pathogenesis of RA, abatacept has been developed as a novel, rational approach to interfere with the upstream effector of the inflammation. As a recombinant protein consisting of a fusion between the extracellular domain of human cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and the modified heavy chain constant segment of human immunoglobulin G1, abatacept acts as a costimulatory modulator of the CD80/86:CD28 pathway. In addition to the antigen-specific signal elicited by recognition of an immunogenic peptide bound to the major histocompatibility complex on an antigen-presenting cell, T cells also require the engagement of CD28 on T cells with CD80/86 on antigen-presenting cells for full activation. Abatacept acts as a downregulator by binding to CD80/86 with higher affinity than CD28, thereby, mimicking endogenous CTLA-4 in its inhibition of T cell costimulation. The immunoglobulin portion of the protein serves as a handle to facilitate purification of the protein that is produced by recombinant DNA technology in a mammalian cell expression system. It also enhances the solubility and serum half-life of the fusion protein.

Originator

Bristol–Myers Squibb (US)

The Uses of Abatacept

Treatment of autoimmune diseases such as rheumatoid arthritis (selective co-stimulation modulator; binds to the B7 family of molecules expressed on antigen-presenting cells (APC)).

brand name

Orencia

Biological Functions

Abatacept, therefore, acts like an antibody that binds with great affinity to B7 ligands, preventing these ligands from interacting with CD28 on activated Tcells. In patients with rheumatoid arthritis, blocking this response by abatacept prevents the generation of positive costimulation signals and stimulation of T-cell activation, suppressing the proliferation of reactive T-cells and the release of more cytokines that destroy tissue, causing the symptoms and signs of arthritis. The extracellular CTLA-4 portion of abatacept is responsible for the affinity of B7. Thus, abatacept slows the damage to bones and cartilage and relieves the symptoms and signs of arthritis.

Clinical Use

Abatacept, the first in a new class of immunosuppressant agents, known as costimulation modulators, acts by down-regulating T-cell activation for the treatment of rheumatoid arthritis. Abatacept is a novel chimeric CTLA-4–IgG1 fused protein created from the fusion of the extracellular domain of the mouse CT LA-4 with the modified heavy-chain constant region of human IgG1.

Side Effects

Side effects may include headache, nausea, and mild infections, such as upper respiratory tract infections.

Drug interactions

Potentially hazardous interactions with other drugs
Avoid with certolizumab, etanercept, golimumab and infliximab.
Vaccines: avoid concomitant use with live vaccines.

Metabolism

Abatacept is cleared via Fc-mediated phagocytosis.