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Identification
Name Abatacept
Accession Number DB01281
Type biotech
Groups approved
Description

Abatacept is a soluble fusion protein, which links the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgG1). It is produced through recombinant DNA technology in mammalian cells. The drug has activity as a selective costimulation modulator with inhibitory activity on T lymphocytes. Although approved for the treatment of rheumatoid arthritis, Repligen has entered a slightly different formulation of CTLA4-Ig into clinical trials (RG2077).
Protein structure
Protein chemical formula Not Available
Protein average weight 92000.0000
Sequences
Synonyms
  • abatacept
  • CTLA4-Ig
  • CTLA4-IgG4m
  • CTLA4Ig
  • CTLA4IgG4m
  • RG-1046
  • RG-2077
  • RG1046
  • RG2077
Brand names
  • Orencia
  • Orencia (Bristol-Myers Squibb)
Brand name mixtures Not Available
Categories
  • Antirheumatic Agents
CAS number 332348-12-6
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
Pharmacology
Indication For the management of the signs and symptoms of moderate-to-severe active rheumatoid arthritis, inducing major clinical response, slowing the progression of structural damage, and improving physical function in adult patients. It is indicated both as a monotherapy and for use in combination with a continued regimen of DMARDs (not including TNF antagonists). Also used for the management of the signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in children.
Pharmacodynamics Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. Known as a recombinant fusion protein, the drug consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G1 (IgG1. The Fc portion of the drug consists of the hinge region, the CH2 domain, and the CH3 domain of IgG1. Although there are multiple pathways and cell types involved in the pathogenesis of rheumatoid arthritis, evidence suggests that T-cell activation may play an important role in the immunopathology of the disease. Ordinarily, full T-cell activation requires binding of the T-cell receptor to an antigen-MHC complex on the antigen-presenting cell as well as a co-stimulatory signal provided by the binding of the CD28 protein on the surface of the T-cell with the CD80/86 proteins on the surface of the antigen-presenting cell. CTLA4 is a naturally occurring protein which is expressed on the surface of T-cells some hours or days after full T-cell activation and is capable of binding to CD80/86 on antigen-presenting cells with much greater affinity than CD28. Binding of CTLA4-Ig to CD80/86 provides a negative feedback mechanism which results in T-cell deactivation. Abatacept was developed by Bristol-Myers-Squibb and is licensed in the US for the treatment of Rheumatoid Arthritis in the case of inadequate response to anti-TNF-alpha therapy.
Mechanism of action Abatacept is a selective costimulation modulator, like CTLA-4, the drug has shown to inhibit T-cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the delivery of the second co-stimulatory signal required for optimal activation of T-cells. This results in the inhibition of autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis.
Absorption Not Available
Volume of distribution
  • 0.02-0.13 L/kg [RA Patients]
  • 0.06-0.13 L/kg [Healthy Subjects]
Protein binding Not Available
Metabolism
Route of elimination Not Available
Half life 16.7 (12-23) days in healthy subjects, 13.1 (8-25) days in RA subjects.
Clearance
  • 0.23 mL/h/kg [Healthy Subjects after 10 mg/kg Intravenous Infusion]
  • 0.22 mL/h/kg [RA Patients after multiple 10 mg/kg Intravenous Infusions]
  • 0.4 mL/h/kg [juvenile idiopathic arthritis patients]
Toxicity Doses up to 50 mg/kg have been administered without apparent toxic effect.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers Not Available
Packagers
Dosage forms
Form Route Strength
Powder, for solution Intravenous
Prices Not Available
Patents
Country Patent Number Approved Expires
Canada 2110518 2007-05-22 2012-06-16
Properties
State solid
Melting point Not Available
Experimental Properties Not Available
References
Synthesis Reference Not Available
General Reference
  1. Dall’Era M, Davis J: CTLA4Ig: a novel inhibitor of costimulation. Lupus. 2004;13(5):372-6. Pubmed
  2. Moreland L, Bate G, Kirkpatrick P: Abatacept. Nat Rev Drug Discov. 2006 Mar;5(3):185-6. Pubmed
  3. Weisman MH, Durez P, Hallegua D, Aranda R, Becker JC, Nuamah I, Vratsanos G, Zhou Y, Moreland LW: Reduction of inflammatory biomarker response by abatacept in treatment of rheumatoid arthritis. J Rheumatol. 2006 Nov;33(11):2162-6. Epub 2006 Oct 1. Pubmed
  4. Weyand CM, Goronzy JJ: T-cell-targeted therapies in rheumatoid arthritis. Nat Clin Pract Rheumatol. 2006 Apr;2(4):201-10. Pubmed
  5. Scheinfeld N: Abatacept: A review of a new biologic agent for refractory rheumatoid arthritis for dermatologists. J Dermatolog Treat. 2006;17(4):229-34. Pubmed
  6. Maxwell LJ, Singh JA: Abatacept for rheumatoid arthritis: a Cochrane systematic review. J Rheumatol. 2010 Feb;37(2):234-45. Epub 2010 Jan 15. Pubmed
  7. Maxwell L, Singh JA: Abatacept for rheumatoid arthritis. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD007277. Pubmed
  8. Nogid A, Pham DQ: Role of abatacept in the management of rheumatoid arthritis. Clin Ther. 2006 Nov;28(11):1764-78. Pubmed
  9. Hervey PS, Keam SJ: Abatacept. BioDrugs. 2006;20(1):53-61; discussion 62. Pubmed
  10. Reynolds J, Shojania K, Marra CA: Abatacept: a novel treatment for moderate-to-severe rheumatoid arthritis. Pharmacotherapy. 2007 Dec;27(12):1693-701. Pubmed
External Links
Resource Link
Drug Product Database 2282097 Link_out
RxList http://www.rxlist.com/cgi/generic/orencia.htm Link_out
Drugs.com http://www.drugs.com/cdi/abatacept.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Abatacept Link_out
ATC Codes
  • L04AA24
AHFS Codes
  • 92:00.00
PDB Entries Not Available
FDA label show (108.2 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. T-lymphocyte activation antigen CD80

Pharmacological action: yes
Actions: antagonist

Involved in the costimulatory signal essential for T- lymphocyte activation. T-cell proliferation and cytokine production is induced by the binding of CD28 or CTLA-4 to this receptor

Organism class: human
UniProt ID: P33681 Link_out
Gene: CD80 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kremer JM: Selective costimulation modulators: a novel approach for the treatment of rheumatoid arthritis. J Clin Rheumatol. 2005 Jun;11(3 Suppl):S55-62. Pubmed
  2. Weyand CM, Goronzy JJ: T-cell-targeted therapies in rheumatoid arthritis. Nat Clin Pract Rheumatol. 2006 Apr;2(4):201-10. Pubmed
  3. Scheinfeld N: Abatacept: A review of a new biologic agent for refractory rheumatoid arthritis for dermatologists. J Dermatolog Treat. 2006;17(4):229-34. Pubmed
  4. Vincenti F, Luggen M: T cell costimulation: a rational target in the therapeutic armamentarium for autoimmune diseases and transplantation. Annu Rev Med. 2007;58:347-58. Pubmed
  5. Maxwell LJ, Singh JA: Abatacept for rheumatoid arthritis: a Cochrane systematic review. J Rheumatol. 2010 Feb;37(2):234-45. Epub 2010 Jan 15. Pubmed
  6. Nogid A, Pham DQ: Role of abatacept in the management of rheumatoid arthritis. Clin Ther. 2006 Nov;28(11):1764-78. Pubmed
  7. Hervey PS, Keam SJ: Abatacept. BioDrugs. 2006;20(1):53-61; discussion 62. Pubmed
  8. Reynolds J, Shojania K, Marra CA: Abatacept: a novel treatment for moderate-to-severe rheumatoid arthritis. Pharmacotherapy. 2007 Dec;27(12):1693-701. Pubmed
  9. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. T-lymphocyte activation antigen CD86

Pharmacological action: yes
Actions: antagonist

Receptor involved in the costimulatory signal essential for T-lymphocyte proliferation and interleukin 2 production, by binding CD28 or CTLA-4. May play a critical role in the early events of T-cell activation and costimulation of naive T-cells, such as deciding between immunity and anergy that is made by T- cells within 24 hours after activation. Isoform 2 interferes with the formation of CD86 clusters, and thus acts as a negative regulator of T-cell activation

Organism class: human
UniProt ID: P42081 Link_out
Gene: CD86 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Scheinfeld N: Abatacept: A review of a new biologic agent for refractory rheumatoid arthritis for dermatologists. J Dermatolog Treat. 2006;17(4):229-34. Pubmed
  2. Vincenti F, Luggen M: T cell costimulation: a rational target in the therapeutic armamentarium for autoimmune diseases and transplantation. Annu Rev Med. 2007;58:347-58. Pubmed
  3. Kremer JM: Selective costimulation modulators: a novel approach for the treatment of rheumatoid arthritis. J Clin Rheumatol. 2005 Jun;11(3 Suppl):S55-62. Pubmed
  4. Weyand CM, Goronzy JJ: T-cell-targeted therapies in rheumatoid arthritis. Nat Clin Pract Rheumatol. 2006 Apr;2(4):201-10. Pubmed
  5. Maxwell LJ, Singh JA: Abatacept for rheumatoid arthritis: a Cochrane systematic review. J Rheumatol. 2010 Feb;37(2):234-45. Epub 2010 Jan 15. Pubmed
  6. Nogid A, Pham DQ: Role of abatacept in the management of rheumatoid arthritis. Clin Ther. 2006 Nov;28(11):1764-78. Pubmed
  7. Hervey PS, Keam SJ: Abatacept. BioDrugs. 2006;20(1):53-61; discussion 62. Pubmed
  8. Reynolds J, Shojania K, Marra CA: Abatacept: a novel treatment for moderate-to-severe rheumatoid arthritis. Pharmacotherapy. 2007 Dec;27(12):1693-701. Pubmed
  9. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Comments
Drug created on May 16, 2007 16:55 / Updated on September 29, 2010 14:35

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.