Abatacept - Drugbank

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10/3/2018 Abatacept - DrugBank

Abatacept

Targets (2) Biointeractions (2)

IDENTIFICATION

Name Abatacept

Accession Number DB01281

Type Biotech

Groups Approved

Biologic Classiﬁcation Protein Based Therapies Fusion proteins

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). Structurally, abatacept is a glycosylated fusion protein with a MALDI-MS molecular weight of 92,300 Da and it is a homodimer of two homologous polypeptide chains of 357 amino acids each. It is produced through recombinant DNA technology in mammalian CHO cells. The drug has activity as a selective co-stimulation 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 chemical formula

C3498H5458N922O1090S32 https://www.drugbank.ca/drugs/DB01281 1/14 10/3/2018 Abatacept - DrugBank

Protein average weight 92300.0 Da (with glycosylation)

Sequences

>Abatacept monomer sequence MHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTF LDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEPC PDSDQEPKSSDKTHTSPPSPAPELLGGSSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Download FASTA Format

Synonyms

Abatacept recombinant

External IDs

BMS-188667 / CTLA4-IGG4M / RG-1046 / RG-2077 / RG1046 / RG2077

Prescription Products

MARKETING MARKETING NAME ↑↓ DOSAGE ↑↓ STRENGTH ↑↓ ROUTE ↑↓ LABELLER ↑↓ START ↑↓ END ↑↓ ↑↓ ↑↓

Orencia Injection, 250 mg/15mL Intravenous E.R. Squibb & 2009-01-01 Not applicable powder, Sons, L.L.C. lyophilized, for solution

Orencia Powder, for 250 mg Intravenous Bristol Myers 2006-08-08 Not applicable solution Squibb

Orencia Injection, 50 mg/0.4mL Subcutaneous E.R. Squibb & 2011-07-29 Not applicable solution Sons, L.L.C.

Orencia Solution 125 mg Subcutaneous Bristol Myers Not applicable Not applicable Squibb

Orencia Injection, 125 mg/1mL Subcutaneous E.R. Squibb & 2011-07-29 Not applicable solution Sons, L.L.C.

Orencia Solution 125 mg Subcutaneous Bristol Myers 2013-05-09 Not applicable https://www.drugbank.ca/drugs/DB01281 2/14 10/3/2018 Abatacept - DrugBank Orencia Solution 125 mg Subcutaneous Bristol Myers 2013 05 09 Not applicable Squibb MARKETING MARKETING NAME ↑↓ DOSAGE ↑↓ STRENGTH ↑↓ ROUTE ↑↓ LABELLER ↑↓ START ↑↓ END ↑↓ ↑↓ ↑↓ Orencia Injection, 87.5 Subcutaneous E.R. Squibb & 2011-07-29 Not applicable solution mg/0.7mL Sons, L.L.C.

Showing 1 to 7 of 7 entries ‹ ›

Categories

Amino Acids, Peptides, and Proteins

Antibodies

Antineoplastic and Immunomodulating Agents

Biologics for Rheumatoid Arthritis Treatment

Blood Proteins

Decreased Cytokine Activity

Disease-modifying Antirheumatic Agents

Globulins

Immunoconjugates

Immunologic Factors

Immunoproteins

Immunosuppressive Agents

Proteins

Recombinant Fusion Proteins

Selective Immunosuppressants

Selective T Cell Costimulation Modulator

Serum Globulins

UNII

7D0YB67S97

CAS number

332348-12-6

PHARMACOLOGY

https://www.drugbank.ca/drugs/DB01281 3/14 10/3/2018 Abatacept - DrugBank 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.

Associated Conditions

Moderate Juvenile idiopathic arthritis

Moderate Rheumatoid arthritis

Severe Juvenile idiopathic arthritis

Severe Rheumatoid arthritis

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 aer 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.

A T-lymphocyte activation antigen CD80 https://www.drugbank.ca/drugs/DB01281 4/14 10/3/2018 Abatacept - DrugBank A T lymphocyte activation antigen CD80

antagonist

Human

A T-lymphocyte activation antigen CD86

antagonist

Human

Absorption When a single 10 mg/kg intravenous infusion of abatacept is administered in healthy subjects, the peak plasma concentration (Cmax) was 292 mcg/mL. When multiple doses of 10 mg/kg was given to rheumatoid arthritis (RA) patients, the Cmax was 295 mcg/mL. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%.

Volume of distribution 0.07 L/kg [RA Patients, IV administration] 0.09 L/kg [Healthy Subjects, IV administration] 0.11 L/kg [RA patients, subcutaneous administration]

Protein binding Not Available

Metabolism Not Available

Route of elimination kidney and liver

Half life

16.7 (12-23) days in healthy subjects; 13.1 (8-25) days in RA subjects; 14.3 days when subcutaneously administered to adult RA patients.

Clearance

0.23 mL/h/kg [Healthy Subjects aer 10 mg/kg Intravenous Infusion] 0.22 mL/h/kg [RA Patients aer multiple 10 mg/kg Intravenous Infusions] 0.4 mL/h/kg [juvenile idiopathic arthritis patients]. The mean systemic clearance is 0.28 mL/h/kg when a subcutaneously administered to adult RA patients. The clearance of abatacept increases with increasing body weight.

Toxicity

Most common adverse events (≥10%) are headache, upper respiratory tract infection, https://www.drugbank.ca/drugs/DB01281 5/14 10/3/2018 Abatacept - DrugBank Most common adverse events (≥10%) are headache, upper respiratory tract infection, nasopharyngitis, and nausea. Doses up to 50 mg/kg have been administered without apparent toxic eﬀect.

Aﬀected organisms

Humans and other mammals

Pathways Not Available

Pharmacogenomic Eﬀects/ADRs

Not Available

INTERACTIONS

Drug Interactions

ALL DRUGS APPROVED VET APPROVED NUTRACEUTICAL ILLICIT WITHDRAWN

INVESTIGATIONAL EXPERIMENTAL

DRUG ↑↓ INTERACTION ↑↓ Adalimumab The risk or severity of infection can be increased when Adalimumab is combined with Abatacept.

Afelimomab The risk or severity of infection can be increased when Afelimomab is combined with Abatacept.

Alclometasone The risk or severity of adverse eﬀects can be increased when Abatacept is combined with Alclometasone.

Aldesleukin The risk or severity of adverse eﬀects can be increased when Abatacept is combined with Aldesleukin.

Alemtuzumab The risk or severity of adverse eﬀects can be increased when Abatacept is combined with Alemtuzumab.

Altretamine The risk or severity of adverse eﬀects can be increased when Abatacept is combined with Altretamine.

Amcinonide The risk or severity of adverse eﬀects can be increased when Abatacept is combined with Amcinonide.

Amsacrine The risk or severity of adverse eﬀects can be increased when Abatacept is combined with Amsacrine. https://www.drugbank.ca/drugs/DB01281 6/14 10/3/2018 Abatacept - DrugBank

DRUG ↑↓ INTERACTION ↑↓

Anthrax immune globulin The risk or severity of adverse eﬀects can be increased when Abatacept is human combined with Anthrax immune globulin human.

Antithymocyte The risk or severity of adverse eﬀects can be increased when Abatacept is immunoglobulin (rabbit) combined with Antithymocyte immunoglobulin (rabbit).

Showing 1 to 10 of 149 entries ‹ ›

Food Interactions Not Available

REFERENCES

Synthesis Reference Sang-Lin Kim, Hyun-Kwang Tan, Sang-Min Lim, Wuk-Sang Ryu, Hahn-Sun Jung, Song-Jae Lee, Cheon- Ik Park, Seung-Hoon Kang, Dong Il Kim, "Plant Recombinant Human CTLA4IG and a Method for Producing the Same." U.S. Patent US20100189717, issued July 29, 2010. US20100189717

General References

1. Dall'Era M, Davis J: CTLA4Ig: a novel inhibitor of costimulation. Lupus. 2004;13(5):372-6. [PubMed:15230295] 2. Moreland L, Bate G, Kirkpatrick P: Abatacept. Nat Rev Drug Discov. 2006 Mar;5(3):185-6. [PubMed:16557658] 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:17014006] 4. Weyand CM, Goronzy JJ: T-cell-targeted therapies in rheumatoid arthritis. Nat Clin Pract Rheumatol. 2006 Apr;2(4):201-10. [PubMed:16932686] 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:16971318] 6. Maxwell LJ, Singh JA: Abatacept for rheumatoid arthritis: a Cochrane systematic review. J Rheumatol. 2010 Feb;37(2):234-45. doi: 10.3899/jrheum.091066. Epub 2010 Jan 15. [PubMed:20080922] 7. Maxwell L, Singh JA: Abatacept for rheumatoid arthritis. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD007277. doi: 10.1002/14651858.CD007277.pub2. [PubMed:19821401] 8. Nogid A, Pham DQ: Role of abatacept in the management of rheumatoid arthritis. Clin Ther. 2006 Nov;28(11):1764-78. [PubMed:17212998] 9. Hervey PS, Keam SJ: Abatacept. BioDrugs. 2006;20(1):53-61; discussion 62. [PubMed:16573350] 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:18041889]

External Links

KEGG Drug

D03203 https://www.drugbank.ca/drugs/DB01281 7/14 10/3/2018 Abatacept - DrugBank

PubChem Substance 46509198

ChEMBL CHEMBL1201823

Therapeutic Targets Database DAP000867

PharmGKB PA164747080

RxList RxList Drug Page

Drugs.com Drugs.com Drug Page

Wikipedia Abatacept

ATC Codes L04AA24 — Abatacept L04AA — Selective immunosuppressants L04A — IMMUNOSUPPRESSANTS L04 — IMMUNOSUPPRESSANTS L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

AHFS Codes

92:36.00 — Disease-modifying Antirheumatic Agents

92:44.00 — Immunosuppressive Agents

FDA label

Download (108 KB)

CLINICAL TRIALS

Clinical Trials

https://www.drugbank.ca/drugs/DB01281 8/14 10/3/2018 Abatacept - DrugBank

PHASE ↑↓ STATUS ↑↓ PURPOSE ↑↓ CONDITIONS ↑↓ COUNT ↑↓ 0 Active Not Treatment Female Patients With Behcet's Syndrome 1 Recruiting

0 Recruiting Treatment Myasthenia Gravis 1

1 Active Not Treatment Rheumatoid Arthritis 1 Recruiting

1 Active Not Treatment Vitiligo 1 Recruiting

1 Completed Not Available Rheumatoid Arthritis 1

1 Completed Basic Science Healthy Volunteers 1

1 Completed Treatment Disseminated Sclerosis / Relapsing Remitting Multiple 1 Sclerosis (RRMS)

1 Completed Treatment Healthy Volunteers 1

1 Completed Treatment Nephritis, Lupus 1

1 Completed Treatment Psoriasis Vulgaris (Plaque Psoriasis) 2

Showing 1 to 10 of 100 entries ‹ ›

PHARMACOECONOMICS

Manufacturers

Not Available

Packagers

Bristol-Myers Squibb Co.

Celltrion Inc.

E.R. Squibb and Sons LLC

Dosage forms

FORM ↑↓ ROUTE ↑↓ STRENGTH ↑↓ Injection, powder, lyophilized, for solution Intravenous 250 mg/15mL

Injection, solution Subcutaneous 125 mg/1mL

Injection, solution Subcutaneous 50 mg/0.4mL

Injection, solution Subcutaneous 87.5 mg/0.7mL https://www.drugbank.ca/drugs/DB01281 9/14 10/3/2018 Abatacept - DrugBank

FORM ↑↓ ROUTE ↑↓ STRENGTH ↑↓

Powder, for solution Intravenous 250 mg

Solution Subcutaneous 125 mg

Showing 1 to 6 of 6 entries ‹ ›

Prices Not Available

Patents

PATENT NUMBER ↑↓ PEDIATRIC EXTENSION ↑↓ APPROVED ↑↓ EXPIRES (ESTIMATED) ↑↓ ↑↓

CA2110518 No 2007-05-22 2012-06-16

Showing 1 to 1 of 1 entries ‹ ›

PROPERTIES

State Liquid

Experimental Properties Not Available

TAXONOMY

Description

Not Available

Kingdom

Organic Compounds

Super Class

Organic Acids

https://www.drugbank.ca/drugs/DB01281 10/14 10/3/2018 Abatacept - DrugBank Class Carboxylic Acids and Derivatives

Sub Class Amino Acids, Peptides, and Analogues

Direct Parent Peptides

Alternative Parents Not Available

Substituents Not Available

Molecular Framework Not Available

External Descriptors Not Available

TARGETS

1. T-lymphocyte activation antigen CD80

Kind

Protein

Organism

Human

Pharmacological action

Yes

Actions

Antagonist General Function

Virus receptor activity https://www.drugbank.ca/drugs/DB01281 11/14 10/3/2018 Abatacept - DrugBank Virus receptor activity

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, binding to CTLA-4 has opposite eﬀects an...

Gene Name CD80

Uniprot ID

P33681

Uniprot Name T-lymphocyte activation antigen CD80

Molecular Weight 33047.625 Da

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:16357751] 2. Weyand CM, Goronzy JJ: T-cell-targeted therapies in rheumatoid arthritis. Nat Clin Pract Rheumatol. 2006 Apr;2(4):201-10. [PubMed:16932686] 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:16971318] 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:17020493] 5. Maxwell LJ, Singh JA: Abatacept for rheumatoid arthritis: a Cochrane systematic review. J Rheumatol. 2010 Feb;37(2):234-45. doi: 10.3899/jrheum.091066. Epub 2010 Jan 15. [PubMed:20080922] 6. Nogid A, Pham DQ: Role of abatacept in the management of rheumatoid arthritis. Clin Ther. 2006 Nov;28(11):1764-78. [PubMed:17212998] 7. Hervey PS, Keam SJ: Abatacept. BioDrugs. 2006;20(1):53-61; discussion 62. [PubMed:16573350] 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:18041889] 9. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

2. T-lymphocyte activation antigen CD86

Kind Protein

Organism

Human https://www.drugbank.ca/drugs/DB01281 12/14 10/3/2018 Abatacept - DrugBank Pharmacological action

Yes

Actions

Antagonist General Function Virus receptor activity

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-cel...

Gene Name

CD86

Uniprot ID P42081

Uniprot Name

T-lymphocyte activation antigen CD86

Molecular Weight

37681.97 Da

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:16971318] 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:17020493] 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:16357751] 4. Weyand CM, Goronzy JJ: T-cell-targeted therapies in rheumatoid arthritis. Nat Clin Pract Rheumatol. 2006 Apr;2(4):201-10. [PubMed:16932686] 5. Maxwell LJ, Singh JA: Abatacept for rheumatoid arthritis: a Cochrane systematic review. J Rheumatol. 2010 Feb;37(2):234-45. doi: 10.3899/jrheum.091066. Epub 2010 Jan 15. [PubMed:20080922] 6. Nogid A, Pham DQ: Role of abatacept in the management of rheumatoid arthritis. Clin Ther. 2006 Nov;28(11):1764-78. [PubMed:17212998] 7. Hervey PS, Keam SJ: Abatacept. BioDrugs. 2006;20(1):53-61; discussion 62. [PubMed:16573350] 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:18041889] 9. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

https://www.drugbank.ca/drugs/DB01281 13/14 10/3/2018 Abatacept - DrugBank Drug created on May 16, 2007 16:55 / Updated on October 02, 2018 10:18

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This project is supported by the Canadian Institutes of Health Research (award #111062), Alberta Innovates - Health Solutions, and by The Metabolomics Innovation Centre (TMIC), a nationally-funded research and core facility that supports a wide range of cutting-edge metabolomic studies. TMIC is funded by Genome Alberta, Genome British Columbia, and Genome Canada, a not-for-proﬁt organization that is leading Canada's national genomics strategy with funding from the federal government. Maintenance, support, and commercial licensing is provided by OMx Personal Health Analytics, Inc. Designed by Educe Design & Innovation Inc.

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