| Version |
2.5 |
| Creation Date |
2007-05-16 22:55:57 |
| Update Date |
2009-04-28 19:23:56 |
| Primary Accession Number |
DB01281 |
| Secondary Accession Number |
Not Available |
| Name |
Abatacept |
| Drug Type |
|
| 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). |
| Synonyms |
- CTLA4-Ig
- CTLA4-IgG4m
- CTLA4Ig
- CTLA4IgG4m
- RG-1046
- RG-2077
- RG1046
- RG2077
- abatacept
|
| Brand Names |
- Orencia
- Orencia (Bristol-Myers Squibb)
|
| Brand Mixtures |
Not Available |
| Chemical IUPAC Name |
Not Available |
| Chemical Formula |
Not Available |
| Chemical Structure |
 |
| Protein Sequence(s) |
Not Available |
| CAS Registry Number |
332348-12-6 |
| InChI Identifier |
Not Available |
| InChI Key |
Not Available |
| KEGG Drug |
D03203  |
| KEGG Compound |
Not Available |
| PubChem Compound |
Not Available |
| PubChem Substance |
Not Available |
| ChEBI ID |
Not Available |
| PharmGKB ID |
Not Available |
| HET ID |
Not Available |
| GenBank ID |
Not Available |
| Drug ID Number [DIN] |
02282097 |
| RxList Link |
http://www.rxlist.com/cgi/generic/orencia.htm |
| PDRhealth Link |
Not Available |
| Wikipedia Link |
http://en.wikipedia.org/wiki/Abatacept |
| FDA Label |
|
| Material Safety Data Sheet (MSDS) |
Not Available |
| Synthesis Reference |
Not Available |
| Average Molecular Weight |
92000.0000 |
| Monoisotopic Molecular Weight |
Not Available |
| State |
Solid |
| Melting Point |
Not Available |
| Experimental Water Solubility |
Not Available
Source: PhysProp
|
| Predicted Water Solubility |
Not Available
Calculated using ALOGPS
|
| Experimental LogP/Hydrophobicity |
Not Available
Source: PhysProp
|
| Predicted LogP |
Not Available
Calculated using ALOGPS
|
| Experimental LogS |
Not Available |
| Predicted LogS |
Not Available
Calculated using ALOGPS
|
| Experimental Caco2 Permeability |
Not Available |
| pKa/Isoelectric Point |
Not Available |
| Mass Spectrum |
Not Available
|
| MOL File |
Not Available |
| SDF File |
Not Available |
| PDB File |
Not Available |
| Experimental PDB ID |
Not Available |
| Isomeric SMILES |
Not Available |
| Canonical SMILES |
Not Available |
| Drug Category |
|
| ATC Codes |
|
| AHFS Codes |
|
| Indication |
For the second line reduction of the signs and symptoms of moderate-to-severe active rheumatoid arthritis, inducing inducing major clinical response, slowing the progression of structural damage, and improving physical function in adult patients who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate or TNF antagonists. It is indicated both as a monotherapy and for use in combination with a continued regimen of DMARDs (not including TNF antagonists). |
| Pharmacology |
Abatacept is the first in a new class of drugs known as Selective Co-stimulation Modulators. 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, shown to inhibit Tcell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Blockade of this interaction has been shown to inhibit the autoimmune T-Cell activation that has been implcated in the pathogenesis of rheumatoid arthritis. |
| Absorption |
Not Available |
| Toxicity |
Doses up to 50 mg/kg have been administered without apparent toxic effect. |
| Protein Binding |
Not Available |
| Biotransformation |
Not Available |
| Half Life |
16.7 (12-23) days in healthy subjects, 13.1 (8-25) days in RA subjects. |
| Dosage Forms |
| Form |
Route |
| Powder, for solution |
Intravenous |
|
| Patient Information |
Show |
| Contraindications |
Show |
| Interactions |
Show |
| Drug Interactions |
Not Available
|
| Food Interactions |
Not Available
|
| Pathways |
Not Available
|
| General References |
- Dall'Era M, Davis J: CTLA4Ig: a novel inhibitor of costimulation. Lupus. 2004;13(5):372-6. [PubMed ]
- Moreland L, Bate G, Kirkpatrick P: Abatacept. Nat Rev Drug Discov. 2006 Mar;5(3):185-6. [PubMed ]
- Wikipedia
- RxList
|
| Organisms Affected |
|
| Targets |
- T-lymphocyte activation antigen CD86
- T-lymphocyte activation antigen CD80
|
|
Drug Target 1
[top]
|
| Target 1 ID |
942 |
| Target 1 Name |
T-lymphocyte activation antigen CD86 |
| Target 1 Synonyms |
- Activation B7-2 antigen
- B70
- BU63
- CTLA-4 counter-receptor B7.2
- FUN-1
- T-lymphocyte activation antigen CD86 precursor
|
| Target 1 Gene Name |
CD86 |
| Target 1 Protein Sequence |
>T-lymphocyte activation antigen CD86 precursor
MDPQCTMGLSNILFVMAFLLSGAAPLKIQAYFNETADLPCQFANSQNQSLSELVVFWQDQ
ENLVLNEVYLGKEKFDSVHSKYMGRTSFDSDSWTLRLHNLQIKDKGLYQCIIHHKKPTGM
IRIHQMNSELSVLANFSQPEIVPISNITENVYINLTCSSIHGYPEPKKMSVLLRTKNSTI
EYDGIMQKSQDNVTELYDVSISLSVSFPDVTSNMTIFCILETDKTRLLSSPFSIELEDPQ
PPPDHIPWITAVLPTVIICVMVFCLILWKWKKKKRPRNSYKCGTNTMEREESEQTKKREK
IHIPERSDEAQRVFKSSKTSSCDKSDTCF
|
| Target 1 Number of Residues |
334 |
| Target 1 Molecular Weight |
37697 |
| Target 1 Theoretical pI |
6.91 |
| Target 1 GO Classification |
Not Available |
| Target 1 General Function |
Involved in coreceptor activity |
| Target 1 Specific Function |
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 |
| Target 1 Pathways |
Not Available
|
| Target 1 Reactions |
Not Available |
| Target 1 Pfam Domain Function |
|
| Target 1 Signals |
|
| Target 1 Transmembrane Regions |
|
| Target 1 Essentiality |
Non-Essential |
| Target 1 GenBank ID Protein |
439839 |
| Target 1 UniProtKB/Swiss-Prot ID |
P42081 |
| Target 1 UniProtKB/Swiss-Prot Entry Name |
CD86_HUMAN |
| Target 1 PDB ID |
1NCN |
| Target 1 PDB File |
Show |
| Target 1 3D Structure |
|
| Target 1 Cellular Location |
- Membrane
- single-pass type I membrane protein
|
| Target 1 Gene Sequence |
>972 bp
ATGGGACTGAGTAACATTCTCTTTGTGATGGCCTTCCTGCTCTCTGGTGCTGCTCCTCTG
AAGATTCAAGCTTATTTCAATGAGACTGCAGACCTGCCATGCCAATTTGCAAACTCTCAA
AACCAAAGCCTGAGTGAGCTAGTAGTATTTTGGCAGGACCAGGAAAACTTGGTTCTGAAT
GAGGTATACTTAGGCAAAGAGAAATTTGACAGTGTTCATTCCAAGTATATGGGCCGCACA
AGTTTTGATTCGGACAGTTGGACCCTGAGACTTCACAATCTTCAGATCAAGGACAAGGGC
TTGTATCAATGTATCATCCATCACAAAAAGCCCACAGGAATGATTCGCATCCACCAGATG
AATTCTGAACTGTCAGTGCTTGCTAACTTCAGTCAACCTGAAATAGTACCAATTTCTAAT
ATAACAGAAAATGTGTACATAAATTTGACCTGCTCATCTATACACGGTTACCCAGAACCT
AAGAAGATGAGTGTTTTGCTAAGAACCAAGAATTCAACTATCGAGTATGATGGTATTATG
CAGAAATCTCAAGATAATGTCACAGAACTGTACGACGTTTCCATCAGCTTGTCTGTTTCA
TTCCCTGATGTTACGAGCAATATGACCATCTTCTGTATTCTGGAAACTGACAAGACGCGG
CTTTTATCTTCACCTTTCTCTATAGAGCTTGAGGACCCTCAGCCTCCCCCAGACCACATT
CCTTGGATTACAGCTGTACTTCCAACAGTTATTATATGTGTGATGGTTTTCTGTCTAATT
CTATGGAAATGGAAGAAGAAGAAGCGGCCTCGCAACTCTTATAAATGTGGAACCAACACA
ATGGAGAGGGAAGAGAGTGAACAGACCAAGAAAAGAGAAAAAATCCATATACCTGAAAGA
TCTGATGAAGCCCAGCGTGTTTTTAAAAGTTCGAAGACATCTTCATGCGACAAAAGTGAT
ACATGTTTTTAA
|
| Target 1 GenBank Gene ID |
|
| Target 1 GeneCard ID |
CD86 |
| Target 1 GenAtlas ID |
CD86 |
| Target 1 HGNC ID |
HGNC:1705 |
| Target 1 Chromosome Location |
3 |
| Target 1 Locus |
3q21 |
| Target 1 SNPs |
SNPJam Report |
| Target 1 General References |
- Magistrelli G, Caron G, Gauchat JF, Jeannin P, Bonnefoy JY, Delneste Y: Identification of an alternatively spliced variant of human CD86 mRNA. Biochem Biophys Res Commun. 2001 Feb 9;280(5):1211-5. [PubMed ]
- Engel P, Gribben JG, Freeman GJ, Zhou LJ, Nozawa Y, Abe M, Nadler LM, Wakasa H, Tedder TF: The B7-2 (B70) costimulatory molecule expressed by monocytes and activated B lymphocytes is the CD86 differentiation antigen. Blood. 1994 Sep 1;84(5):1402-7. [PubMed ]
- Lanier LL, O'Fallon S, Somoza C, Phillips JH, Linsley PS, Okumura K, Ito D, Azuma M: CD80 (B7) and CD86 (B70) provide similar costimulatory signals for T cell proliferation, cytokine production, and generation of CTL. J Immunol. 1995 Jan 1;154(1):97-105. [PubMed ]
- Jellis CL, Wang SS, Rennert P, Borriello F, Sharpe AH, Green NR, Gray GS: Genomic organization of the gene coding for the costimulatory human B-lymphocyte antigen B7-2 (CD86). Immunogenetics. 1995;42(2):85-9. [PubMed ]
- Azuma M, Ito D, Yagita H, Okumura K, Phillips JH, Lanier LL, Somoza C: B70 antigen is a second ligand for CTLA-4 and CD28. Nature. 1993 Nov 4;366(6450):76-9. [PubMed ]
- Freeman GJ, Gribben JG, Boussiotis VA, Ng JW, Restivo VA Jr, Lombard LA, Gray GS, Nadler LM: Cloning of B7-2: a CTLA-4 counter-receptor that costimulates human T cell proliferation. Science. 1993 Nov 5;262(5135):909-11. [PubMed ]
|
| Target 1 Drug References |
- 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 ]
- 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 ]
|
|
Drug Target 2
[top]
|
| Target 2 ID |
944 |
| Target 2 Name |
T-lymphocyte activation antigen CD80 |
| Target 2 Synonyms |
- Activation B7-1 antigen
- B7
- BB1
- CTLA-4 counter-receptor B7.1
- T-lymphocyte activation antigen CD80 precursor
|
| Target 2 Gene Name |
CD80 |
| Target 2 Protein Sequence |
>T-lymphocyte activation antigen CD80 precursor
MGHTRRQGTSPSKCPYLNFFQLLVLAGLSHFCSGVIHVTKEVKEVATLSCGHNVSVEELA
QTRIYWQKEKKMVLTMMSGDMNIWPEYKNRTIFDITNNLSIVILALRPSDEGTYECVVLK
YEKDAFKREHLAEVTLSVKADFPTPSISDFEIPTSNIRRIICSTSGGFPEPHLSWLENGE
ELNAINTTVSQDPETELYAVSSKLDFNMTTNHSFMCLIKYGHLRVNQTFNWNTTKQEHFP
DNLLPSWAITLISVNGIFVICCLTYCFAPRCRERRRNERLRRESVRPV
|
| Target 2 Number of Residues |
292 |
| Target 2 Molecular Weight |
33048 |
| Target 2 Theoretical pI |
7.71 |
| Target 2 GO Classification |
Not Available |
| Target 2 General Function |
Involved in coreceptor activity |
| Target 2 Specific Function |
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 |
| Target 2 Pathways |
Not Available
|
| Target 2 Reactions |
Not Available |
| Target 2 Pfam Domain Function |
|
| Target 2 Signals |
|
| Target 2 Transmembrane Regions |
|
| Target 2 Essentiality |
Non-Essential |
| Target 2 GenBank ID Protein |
306916 |
| Target 2 UniProtKB/Swiss-Prot ID |
P33681 |
| Target 2 UniProtKB/Swiss-Prot Entry Name |
CD80_HUMAN |
| Target 2 PDB ID |
1I8L |
| Target 2 PDB File |
Show |
| Target 2 3D Structure |
|
| Target 2 Cellular Location |
- Membrane
- single-pass type I membrane protein
|
| Target 2 Gene Sequence |
>867 bp
ATGGGCCACACACGGAGGCAGGGAACATCACCATCCAAGTGTCCATACCTCAATTTCTTT
CAGCTCTTGGTGCTGGCTGGTCTTTCTCACTTCTGTTCAGGTGTTATCCACGTGACCAAG
GAAGTGAAAGAAGTGGCAACGCTGTCCTGTGGTCACAATGTTTCTGTTGAAGAGCTGGCA
CAAACTCGCATCTACTGGCAAAAGGAGAAGAAAATGGTGCTGACTATGATGTCTGGGGAC
ATGAATATATGGCCCGAGTACAAGAACCGGACCATCTTTGATATCACTAATAACCTCTCC
ATTGTGATCCTGGCTCTGCGCCCATCTGACGAGGGCACATACGAGTGTGTTGTTCTGAAG
TATGAAAAAGACGCTTTCAAGCGGGAACACCTGGCTGAAGTGACGTTATCAGTCAAAGCT
GACTTCCCTACACCTAGTATATCTGACTTTGAAATTCCAACTTCTAATATTAGAAGGATA
ATTTGCTCAACCTCTGGAGGTTTTCCAGAGCCTCACCTCTCCTGGTTGGAAAATGGAGAA
GAATTAAATGCCATCAACACAACAGTTTCCCAAGATCCTGAAACTGAGCTCTATGCTGTT
AGCAGCAAACTGGATTTCAATATGACAACCAACCACAGCTTCATGTGTCTCATCAAGTAT
GGACATTTAAGAGTGAATCAGACCTTCAACTGGAATACAACCAAGCAAGAGCATTTTCCT
GATAACCTGCTCCCATCCTGGGCCATTACCTTAATCTCAGTAAATGGAATTTTTGTGATA
TGCTGCCTGACCTACTGCTTTGCCCCAAGATGCAGAGAGAGAAGGAGGAATGAGAGATTG
AGAAGGGAAAGTGTACGCCCTGTATAA
|
| Target 2 GenBank Gene ID |
|
| Target 2 GeneCard ID |
CD80 |
| Target 2 GenAtlas ID |
CD80 |
| Target 2 HGNC ID |
HGNC:1700 |
| Target 2 Chromosome Location |
3 |
| Target 2 Locus |
3q13.3-q21 |
| Target 2 SNPs |
SNPJam Report |
| Target 2 General References |
- Ikemizu S, Gilbert RJ, Fennelly JA, Collins AV, Harlos K, Jones EY, Stuart DI, Davis SJ: Structure and dimerization of a soluble form of B7-1. Immunity. 2000 Jan;12(1):51-60. [PubMed ]
- Selvakumar A, Mohanraj BK, Eddy RL, Shows TB, White PC, Dupont B: Genomic organization and chromosomal location of the human gene encoding the B-lymphocyte activation antigen B7. Immunogenetics. 1992;36(3):175-81. [PubMed ]
- Freeman GJ, Gray GS, Gimmi CD, Lombard DB, Zhou LJ, White M, Fingeroth JD, Gribben JG, Nadler LM: Structure, expression, and T cell costimulatory activity of the murine homologue of the human B lymphocyte activation antigen B7. J Exp Med. 1991 Sep 1;174(3):625-31. [PubMed ]
- Freeman GJ, Freedman AS, Segil JM, Lee G, Whitman JF, Nadler LM: B7, a new member of the Ig superfamily with unique expression on activated and neoplastic B cells. J Immunol. 1989 Oct 15;143(8):2714-22. [PubMed ]
- Lanier LL, O'Fallon S, Somoza C, Phillips JH, Linsley PS, Okumura K, Ito D, Azuma M: CD80 (B7) and CD86 (B70) provide similar costimulatory signals for T cell proliferation, cytokine production, and generation of CTL. J Immunol. 1995 Jan 1;154(1):97-105. [PubMed ]
|
| Target 2 Drug References |
- 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 ]
- Weyand CM, Goronzy JJ: T-cell-targeted therapies in rheumatoid arthritis. Nat Clin Pract Rheumatol. 2006 Apr;2(4):201-10. [PubMed ]
- 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 ]
- 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 ]
- 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 ]
|
