Abatacept Chemische Eigenschaften,Einsatz,Produktion Methoden
Beschreibung
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.
History
Abatacept (trade name: Orencia) is a selective T-cell co-stimulatory modulator developed by Bristol-Myers Squibb Company. It was first approved by the FDA on December 23, 2005, for the treatment of rheumatoid arthritis. Following further research, Orencia was approved on July 31, 2011, for adult patients with moderate to severe rheumatoid arthritis. It is a proven non-anti-TNF biologic. Six years later, Orencia expanded its indications and was approved by the FDA (July 6, 2017) for the treatment of active psoriatic arthritis in adults. As of December 15, 2021, Orencia, in combination with a calcineurin inhibitor and methotrexate, was approved for the prevention of acute graft-versus-host disease (aGvHD).
Verwenden
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)).
Biologische Funktion
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.
Nebenwirkungen
Side effects may include headache, nausea, and mild
infections, such as upper respiratory tract infections.
Abatacept Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
