Abatacept, sold under the brand name Orencia, is a medication used to treat autoimmune diseases like
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
, by interfering with the immune activity of
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s.
It is a modified antibody.
Abatacept is a
fusion protein composed of the Fc region of the
immunoglobulin
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
IgG1 fused to the extracellular domain of
CTLA-4
CTLA-4 or CTLA4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 ( cluster of differentiation 152), is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA-4 is constitutively exp ...
. In order for a
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
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
The Cluster of differentiation 80 (also CD80 and B7-1) is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is cl ...
or
CD86
Cluster of Differentiation 86 (also known as CD86 and B7-2) is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells (including memory B-cells), and on other antigen-presenting cells. Along with CD80, CD8 ...
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
The Bristol Myers Squibb Company (BMS) is an American multinational pharmaceutical company. Headquartered in New York City, BMS is one of the world's largest pharmaceutical companies and consistently ranks on the ''Fortune'' 500 list of the lar ...
and is licensed in the United States for the treatment of rheumatoid arthritis in the case of inadequate response to anti-
TNFα
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
therapy. Abatacept received approval from the FDA in 2005.
Medical uses
Abatacept is used to treat adults with moderate to severe
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
(RA) as a second-line agent, and as a first-line agent for people whose RA is severe and rapidly progressing. It also used to treat
psoriatic arthritis
Psoriatic arthritis is a long-term inflammatory arthritis that occurs in people affected by the autoimmune disease psoriasis. The classic feature of psoriatic arthritis is swelling of entire fingers and toes with a sausage-like appearance. Th ...
and
juvenile idiopathic arthritis
Juvenile idiopathic arthritis (JIA) is the most common, chronic rheumatic disease of childhood, affecting approximately one per 1,000 children. ''Juvenile'', in this context, refers to disease onset before 16 years of age, while ''idiopathic'' r ...
.
Contraindications
Abatacept has not been tested in pregnant women and it is not known if it is secreted in breast milk; it causes birth defects in rodents when given in very high doses, and is transmitted in rodent breast milk.
[
Abatacept will likely interfere with any vaccine given while people are taking it.][
It should not be used in combination with ]anakinra
Anakinra, sold under the brand name Kineret, is a biopharmaceutical medication used to treat rheumatoid arthritis, cryopyrin-associated periodic syndromes, familial Mediterranean fever, and Still's disease. It is a recombinant and slightly modif ...
or TNF antagonist
A TNF inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis ...
s. Because abatacept, anakinra, and TNF antagonists suppress the immune system, using them in combination may significantly increase the risk for severe infections.
Adverse effects
People have experienced serious infections due to abatacept's suppression of the immune system; some of these infections have been fatal. People with COPD
Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce mu ...
are likely to get lung infections more often than usual. Some people have had anaphylactic
Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follow ...
reactions to the drug. Abatacept may cause otherwise slow-growing cancers
Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Poss ...
to proliferate and spread
Spread may refer to:
Places
* Spread, West Virginia
Arts, entertainment, and media
* ''Spread'' (film), a 2009 film.
* ''$pread'', a quarterly magazine by and for sex workers
* "Spread", a song by OutKast from their 2003 album ''Speakerboxxx/T ...
, due to suppression of the immune system.[
Very common adverse effects (occurring in more than 10% of people) include upper respiratory tract infections. Common adverse effects (occurring in between 1% and 10% of people) include lower respiratory tract infections, urinary tract infections, herpes infections, pneumonia, flu, cough, high blood pressure, stomach pain, diarrhea, nausea, vomiting, upset stomach, mouth sores, ]elevated transaminases
In medicine, the presence of elevated transaminases, commonly the transaminases alanine transaminase (ALT) and aspartate transaminase (AST), may be an indicator of liver dysfunction. Other terms include transaminasemia, transaminitis, and elevated ...
, rashes, fatigue, weakness, local injection site reactions, and systemic injection reactions.[
]
Chemistry
Abatacept is a fusion protein composed of the extracellular domain of CTLA-4
CTLA-4 or CTLA4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 ( cluster of differentiation 152), is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA-4 is constitutively exp ...
with the hinge, CH2, and CH3 domains of IgG1
Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG a ...
.
Mechanism of action
Abatacept is a soluble CTLA-4 analog that prevents antigen-presenting cells
An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using ...
(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 APC.
That activation requires two signals (one of which is called co-stimulatory signal or signal 2):
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 (CD80
The Cluster of differentiation 80 (also CD80 and B7-1) is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is cl ...
or CD86
Cluster of Differentiation 86 (also known as CD86 and B7-2) is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells (including memory B-cells), and on other antigen-presenting cells. Along with CD80, CD8 ...
) on its cell surface to a CD28
CD28 (Cluster of Differentiation 28) is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival. T cell stimulation through CD28 in addition to the T-cell receptor ( TCR) can provid ...
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
In immunology, anergy is a lack of reaction by the body's defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance. An individual in a state of anergy often indicates that the immune system ...
.
Abatacept, which 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.
Research
Abatacept is the basis for the second-generation belatacept
Belatacept, sold under the brand name Nulojix, is a fusion protein composed of the Fc fragment of a human IgG1 immunoglobulin linked to the extracellular domain of CTLA-4, which is a molecule crucial in the regulation of T cell costimulation, s ...
, which was approved by the FDA in 2012. The drugs differ by only 2 amino acids. In organ transplantation
Organ transplantation is a medical procedure in which an organ (anatomy), organ is removed from one body and placed in the body of a recipient, to replace a damaged or missing organ. The donor and recipient may be at the same location, or organ ...
, belatacept is intended to provide extended graft
Graft or grafting may refer to:
*Graft (politics), a form of political corruption
* Graft, Netherlands, a village in the municipality of Graft-De Rijp
Science and technology
*Graft (surgery), a surgical procedure
*Grafting, the joining of plant t ...
survival while limiting the toxicity generated by standard immune-suppressing regimens such as calcineurin
Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine protein phosphatase (also known as protein phosphatase 3, and calcium-dependent serine-threonine phosphatase). It activates the T cells of the immune system and can be bloc ...
inhibitors (for example cyclosporin
Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease ...
).
References
External links
*
{{Portal bar , Medicine
Engineered proteins
Bristol Myers Squibb
Immunosuppressants
Disease-modifying antirheumatic drugs