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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/12 23:53:52」(JST)

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Abatacept (marketed as Orencia) is a fusion protein composed of the Fc region of the immunoglobulin IgG1 fused to the extracellular domain of CTLA-4. In order for a T cell 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 or CD86 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 and is licensed in the United States for the treatment of rheumatoid arthritis in the case of inadequate response to anti-TNFα therapy.

Medical uses

Abatacept is currently approved for use in people with rheumatoid arthritis who have had an inadequate response to one or more DMARDs.^[1] 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.^[2]

Clinical trials for additional indications

A team led by researchers at Harvard-affiliated Massachusetts General Hospital (MGH) has reported that treatment with abatacept (Orencia) appeared to halt the course of focal segmental glomerulosclerosis (FSGS) in five patients, preventing four from losing transplanted kidneys and achieving disease remission in the fifth.^[3]

Abatacept had a phase III trial^[4] 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.^[5]

Abatacept is (As of 2008^[update]) in trial^[6] 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.^[7]

Abatacept is currently in a phase II trial for Multiple Sclerosis in a joint Bristol Meyers and NIAID program.

The ACCESS phase II clinical trial,^[8]^[9] sponsored by the National Institute of Allergy and Infectious Diseases is (As of 2009^[update]) studying abatacept treatment in lupus nephritis when used in combination with cyclophosphamide therapy.

Abatacept in a subcutaneous administration form has been approved by USFDA, for self-administration by the patient.

Mechanism of action

Abatacept prevents antigen-presenting cells (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 antigen-presenting cell (APC).

That activation requires two co-stimulatory signals:

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 on its cell surface to a CD28 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.

Abatacept 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.^[10]^[11]

Derivatives

Abatacept is the basis for the second-generation belatacept 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 cyclosporin).

Structure

Abatacept is a fusion protein composed of the extracellular domain of CTLA-4 with the hinge, CH2, and CH3 domains of IgG1.^[2]

Similar agents

Belatacept

References

^ Bristol-Myers Squibb (March 13, 2007).ORENCIA label PDF (110 KiB). United States Food and Drug Administration. Retrieved on 2007-05-25.
^ ^a ^b Moreland L, Bate G, Kirkpatrick P (2006). "Abatacept". Nature Reviews Drug Discovery 5 (3): 185–186. doi:10.1038/nrd1989. PMID 16557658.
^ "Researchers find drug that could halt kidney failure". The Harvard Gazette. Retrieved 2014-02-23. harvard.edu.
^ "A Study of Abatacept in Patients With Active Ulcerative Colitis". ClinicalTrials.gov. United States National Institutes of Health. May 11, 2007. Retrieved 2007-05-25. ClinicalTrials.gov Identifier NCT00410410.
^ http://clinicaltrials.gov/ct2/show/results/NCT00410410 Ulcerative Colitis Study results
^ "CTLA-4 Ig (Abatacept) in Recent Onset Diabetes DEAD URL". diabetestrialnet.org. TrialNet. Retrieved 2008-08-08. diabetestrialnet.org.
^ The Lancet, Volume 378, Issue 9789, pp. 412–419, 30 July 2011 doi:10.1016/S0140-6736(11)60886-6C
^ "ACCESS clinical trial for lupus nephritis". www.lupusnephritis.org. Immune Tolerance Network. Retrieved 2009-09-14. ClinicalTrials.gov Identifier NCT00774852
^ http://clinicaltrials.gov/ct/show/NCT00774852
^ "ABATACEPT & BELATACEPT: the CTLA-4-Igs". Healthvalue.net. Retrieved 2007-05-25.
^ Dall'Era M, Davis J (2004). "CTLA4Ig: a novel inhibitor of co-stimulation". Lupus 13 (5): 372–376. doi:10.1191/0961203303lu1029oa. PMID 15230295.

External links

Orencia Official Site

UpToDate Contents

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1. 初回の非生物学的DMARD療法に耐性を示す成人における関節リウマチの治療 treatment of rheumatoid arthritis in adults resistant to initial nonbiologic dmard therapy
2. リウマチ性疾患のマネージメントに用いる生物学的製剤とキナーゼ阻害薬の概要 overview of biologic agents and kinase inhibitors in the rheumatic diseases
3. 関節リウマチのためのT細胞標的療法 t cell targeted therapies for rheumatoid arthritis
4. びまん性または巣状増殖性ループス腎炎の治療 therapy of diffuse or focal proliferative lupus nephritis
5. 初回の生物学的DMARD療法に耐性を示す成人における関節リウマチの治療 treatment of rheumatoid arthritis in adults resistant to initial biologic dmard therapy

English Journal

The Use of Biologic Therapies in Uveitis.

Schwartzman S1, Schwartzman M2.
Clinical reviews in allergy & immunology.Clin Rev Allergy Immunol.2015 Dec;49(3):307-16. doi: 10.1007/s12016-014-8455-6.
Therapy for autoimmune ophthalmic disease is currently evolving. The improved understanding of the abnormal immune response in the various forms of uveitis has resulted in targeted therapy. The aberrations of the immune system have been characterized by atypical cell populations, cytokine expression
PMID 25431348

Ocular Involvement in Juvenile Idiopathic Arthritis: Classification and Treatment.

Foeldvari I1.
Clinical reviews in allergy & immunology.Clin Rev Allergy Immunol.2015 Dec;49(3):271-7. doi: 10.1007/s12016-014-8436-9.
Juvenile idiopathic arthritis (JIA) is one of the most common rheumatic diseases in childhood with a prevalence of 4 in 1,000 children. Anterior uveitis is a well-known threatening comorbid condition of JIA and affects around 10 % of the patients depending on JIA subtype. A large proportion of chil
PMID 25081063

Are All Biologics the Same? Optimal Treatment Strategies for Patients With Early Rheumatoid Arthritis: Systematic Review and Indirect Pairwise Meta-Analysis.

Albert DA1.
Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases.J Clin Rheumatol.2015 Dec;21(8):398-404. doi: 10.1097/RHU.0000000000000272.
BACKGROUND: The use of biologic agents has revolutionized the treatment of rheumatoid arthritis (RA). However, there is much uncertainty about whether any agent may be preferable.PURPOSE: The aim of the study was to evaluate the comparative efficacy of biologic agents with a disease-modifying antirh
PMID 26226612

Japanese Journal

T細胞を指標としたアバタセプト (特集整形外科医のためのRA講座) -- (整形外科医のための生物学的製剤講座)

松原司
Bone joint nerve : BJN 1(1), 127-133, 2011-04
NAID 40019206463

Related Pictures

Abatacept -- Orencia Some people receiving an abatacept Abatacept ist ein rekombinantes If taken early enough, abatacept (Orencia abatacept for the treatment of rheumatoid abatacept generic name abatacept a bat a Figure 8. (click image to zoom) Abatacept Figure 1 : Abatacept : Nature Reviews Drug

★リンクテーブル★

リンク元

「アバタセプト」

Abatacept
Clinical data
Trade names	Orencia
AHFS/Drugs.com	monograph
MedlinePlus	a606016
Pregnancy; category	C (U.S.);
Legal status	POM (UK), ℞-only (U.S.);
Routes of; administration	Intravenous
Pharmacokinetic data
Biological half-life	13.1 days
Identifiers
CAS Registry Number	213252-14-3
ATC code	L04AA24
DrugBank	DB01281
UNII	7D0YB67S97
KEGG	D03203
ChEMBL	CHEMBL1201823
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英: abatacept
商: オレンシア
関: 他に分類されない代謝性医薬品

[1] Bristol-Myers Squibb (March 13, 2007).ORENCIA label PDF (110 KiB). United States Food and Drug Administration. Retrieved on 2007-05-25.

[Moreland-2] Moreland L, Bate G, Kirkpatrick P (2006). "Abatacept". Nature Reviews Drug Discovery 5 (3): 185–186. doi:10.1038/nrd1989. PMID 16557658.

[3] "Researchers find drug that could halt kidney failure". The Harvard Gazette. Retrieved 2014-02-23. harvard.edu.

[4] "A Study of Abatacept in Patients With Active Ulcerative Colitis". ClinicalTrials.gov. United States National Institutes of Health. May 11, 2007. Retrieved 2007-05-25. ClinicalTrials.gov Identifier NCT00410410.

[5] ttp://clinicaltrials.gov/ct2/show/results/NCT00410410 Ulcerative Colitis Study results

[6] "CTLA-4 Ig (Abatacept) in Recent Onset Diabetes DEAD URL". diabetestrialnet.org. TrialNet. Retrieved 2008-08-08. diabetestrialnet.org.

[7] The Lancet, Volume 378, Issue 9789, pp. 412–419, 30 July 2011 doi:10.1016/S0140-6736(11)60886-6C

[8] "ACCESS clinical trial for lupus nephritis". www.lupusnephritis.org. Immune Tolerance Network. Retrieved 2009-09-14. ClinicalTrials.gov Identifier NCT00774852

[9] ttp://clinicaltrials.gov/ct/show/NCT00774852

[10] "ABATACEPT & BELATACEPT: the CTLA-4-Igs". Healthvalue.net. Retrieved 2007-05-25.

[11] Dall'Era M, Davis J (2004). "CTLA4Ig: a novel inhibitor of co-stimulation". Lupus 13 (5): 372–376. doi:10.1191/0961203303lu1029oa. PMID 15230295.

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abatacept