Abatacept
Encyclopedia
Abatacept 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 cell
s. 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.
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.
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
).
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.
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.
composed of the extracellular domain of CTLA-4
with the hinge, CH2, and CH3 domains of IgG1.
Fusion protein
Fusion proteins or chimeric proteins are proteins created through the joining of two or more genes which originally coded for separate proteins. Translation of this fusion gene results in a single polypeptide with functional properties derived from each of the original proteins...
composed of an immunoglobulin fused to the extracellular domain of CTLA-4
CTLA-4
CTLA4 also known as CD152 is a protein that plays an important regulatory role in the immune system...
, a molecule capable of binding B7
B7 (protein)
B7 is a type of peripheral membrane protein found on activated antigen presenting cells that, when paired with either a CD28 or CD152 surface protein on a T cell, can produce a costimulatory signal to enhance or decrease the activity of a MHC-TCR signal between the APC and the T cell, respectively...
. Abatacept is a selective costimulation modulator as it inhibits the costimulation of T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s. It was developed by Bristol-Myers Squibb
Bristol-Myers Squibb
Bristol-Myers Squibb , often referred to as BMS, is a pharmaceutical company, headquartered in New York City. The company was formed in 1989, following the merger of its predecessors Bristol-Myers and the Squibb Corporation...
and is licensed in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
for the treatment of rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
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
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
to the antigen-MHC
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
complex on the antigen presenting cell (APC) and 2) a costimulatory signal provided by the binding of the T cell's CD28
CD28
CD28 is one of the molecules expressed on T cells that provide co-stimulatory signals, which are required for T cell activation. CD28 is the receptor for CD80 and CD86 . When activated by Toll-like receptor ligands, the CD80 expression is upregulated in antigen presenting cells...
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 belataceptBelatacept
Belatacept 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 for T-cell costimulation, selectively blocking the process of T-cell activation...
currently being tested in clinical trials. They differ by only 2 amino acids. In organ transplantation, belatacept is intended to provide extended graft
Medical grafting
Grafting refers to a surgical procedure to move tissue from one site to another on the body, or from another person, without bringing its own blood supply with it. Instead, a new blood supply grows in after it is placed. A similar technique where tissue is transferred with the blood supply intact...
survival while limiting the toxicity generated by standard immune-suppressing regimens such as calcineurin
Calcineurin
Calcineurin is a protein phosphatase also known as protein phosphatase 3, PPP3CA, and calcium-dependent serine-threonine phosphatase, and formerly known as protein phosphatase 2B . It activates the T cells of the immune system and can be blocked by drugs...
inhibitors (for example ciclosporin
Ciclosporin
Ciclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
).
Indications
Abatacept is currently approved for use in rheumatoid arthritisRheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
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
Anakinra
Anakinra is a drug used to treat rheumatoid arthritis.-Mechanism:Anakinra is an interleukin-1 receptor antagonist...
or TNF antagonists. It is also likely to be beneficial in the treatment of psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
and in organ transplantation.
Clinical trials for additional indications
Abatacept had a phase III trialfor the treatment of patients suffering moderate to severe active ulcerative colitis
Ulcerative colitis
Ulcerative colitis is a form of inflammatory bowel disease . Ulcerative colitis is a form of colitis, a disease of the colon , that includes characteristic ulcers, or open sores. The main symptom of active disease is usually constant diarrhea mixed with blood, of gradual onset...
, 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
Honeymoon period (diabetes)
The honeymoon period for patients with Diabetes mellitus type 1 is the period that often follows diagnosis and initiation of insulin treatment. It is often suggestive of remission, but it is important to note that the two are unrelated - it is not a cure for type 1 diabetes...
" 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
National Institute of Allergy and Infectious Diseases
The National Institute of Allergy and Infectious Diseases is one of the 27 institutes and centers that make up the National Institutes of Health , an agency of the United States Department of Health and Human Services...
is studying abatacept treatment in lupus nephritis
Lupus nephritis
Lupus nephritis is an inflammation of the kidney caused by systemic lupus erythematosus , a disease of the immune system. Apart from the kidneys, SLE can also damage the skin, joints, nervous system and virtually any organ or system in the body....
when used in combination with cyclophosphamide
Cyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
therapy.
Abetacept in a subcutaneous administration form has been approved by USFDA, for self administration by the patient.
Structure
Abatacept is a fusion proteinFusion protein
Fusion proteins or chimeric proteins are proteins created through the joining of two or more genes which originally coded for separate proteins. Translation of this fusion gene results in a single polypeptide with functional properties derived from each of the original proteins...
composed of the extracellular domain of CTLA-4
CTLA-4
CTLA4 also known as CD152 is a protein that plays an important regulatory role in the immune system...
with the hinge, CH2, and CH3 domains of IgG1.