Abatacept

Identification

Name

Abatacept

Accession Number

DB01281

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).

Type

Biotech

Groups

Approved

Biologic Classification

Protein Based Therapies
Fusion proteins

Protein Chemical Formula

C₃₄₉₈H₅₄₅₈N₉₂₂O₁₀₉₀S₃₂

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

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.

Associated Conditions

Contraindications & Blackbox Warnings

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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 C_H2 domain, and the C_H3 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.

Target	Actions	Organism
AT-lymphocyte activation antigen CD80	antagonist	Humans
AT-lymphocyte activation antigen CD86	antagonist	Humans

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 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]. 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.

Adverse Effects

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Toxicity

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

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Abiraterone	The metabolism of Abiraterone can be increased when combined with Abatacept.
Acalabrutinib	The metabolism of Acalabrutinib can be increased when combined with Abatacept.
Acebutolol	The metabolism of Acebutolol can be increased when combined with Abatacept.
Acenocoumarol	The metabolism of Acenocoumarol can be increased when combined with Abatacept.
Acetaminophen	The metabolism of Acetaminophen can be increased when combined with Abatacept.
Acetohexamide	The metabolism of Acetohexamide can be increased when combined with Abatacept.
Acetylsalicylic acid	The metabolism of Acetylsalicylic acid can be increased when combined with Abatacept.
Acyclovir	The metabolism of Acyclovir can be increased when combined with Abatacept.
Adalimumab	The risk or severity of infection can be increased when Adalimumab is combined with Abatacept.
Adenovirus type 7 vaccine live	The risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Abatacept.

Additional Data Available

Extended Description

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Extended description of the mechanism of action and particular properties of each drug interaction.

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Severity

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A severity rating for each drug interaction, from minor to major.

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Evidence Level

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A rating for the strength of the evidence supporting each drug interaction.

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Action

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An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions

Not Available

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
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Orencia	Solution	125 mg	Subcutaneous	Bristol Myers Squibb	Not applicable	Not applicable
Orencia	Injection, solution	87.5 mg/0.7mL	Subcutaneous	E.R. Squibb & Sons, L.L.C.	2011-07-29	Not applicable
Orencia	Injection, powder, lyophilized, for solution	250 mg/15mL	Intravenous	E.R. Squibb & Sons, L.L.C.	2009-01-01	Not applicable
Orencia	Solution	125 mg	Subcutaneous	Bristol Myers Squibb	2013-05-09	Not applicable
Orencia	Injection, solution	50 mg/0.4mL	Subcutaneous	E.R. Squibb & Sons, L.L.C.	2011-07-29	Not applicable
Orencia	Powder, for solution	250 mg	Intravenous	Bristol Myers Squibb	2006-08-08	Not applicable
Orencia	Injection, solution	125 mg/1mL	Subcutaneous	E.R. Squibb & Sons, L.L.C.	2011-07-29	Not applicable

Additional Data Available

Application Number

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Product Code

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A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Chemical Identifiers

UNII: 7D0YB67S97
CAS number: 332348-12-6

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

Dall'Era M, Davis J: CTLA4Ig: a novel inhibitor of costimulation. Lupus. 2004;13(5):372-6. [PubMed:15230295]
Moreland L, Bate G, Kirkpatrick P: Abatacept. Nat Rev Drug Discov. 2006 Mar;5(3):185-6. [PubMed:16557658]
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]
Weyand CM, Goronzy JJ: T-cell-targeted therapies in rheumatoid arthritis. Nat Clin Pract Rheumatol. 2006 Apr;2(4):201-10. [PubMed:16932686]
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]
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]
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]
Nogid A, Pham DQ: Role of abatacept in the management of rheumatoid arthritis. Clin Ther. 2006 Nov;28(11):1764-78. [PubMed:17212998]
Hervey PS, Keam SJ: Abatacept. BioDrugs. 2006;20(1):53-61; discussion 62. [PubMed:16573350]
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
PubChem Substance: 46509198
RxNav: 614391
ChEMBL: CHEMBL1201823
Therapeutic Targets Database: DAP000867
PharmGKB: PA164747080
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Abatacept

AHFS Codes

92:36.00 — Disease-modifying Antirheumatic Agents
92:44.00 — Immunosuppressive Agents

FDA label

Download (108 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Rheumatoid Arthritis	3
4	Completed	Basic Science	Rheumatoid Arthritis	1
4	Completed	Treatment	Primary Biliary Cholangitis	1
4	Completed	Treatment	Rheumatoid Arthritis	5
4	Enrolling by Invitation	Other	Rheumatoid Arthritis	1
4	Not Yet Recruiting	Treatment	Palindromic Rheumatism, Wrist	1
4	Not Yet Recruiting	Treatment	Rheumatoid Arthritis	2
4	Recruiting	Diagnostic	Evaluate Bone Changes in Patients With PsA	1
4	Recruiting	Treatment	Dermatomyositis	1
4	Recruiting	Treatment	Myocardial Inflammation / Rheumatoid Arthritis	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Bristol-Myers Squibb Co.
Celltrion Inc.
E.R. Squibb and Sons LLC

Dosage Forms

Form	Route	Strength
Injection, powder, for solution	Intravenous	250 MG
Injection, powder, lyophilized, for solution	Intravenous	250 mg/15mL
Injection, solution	Cutaneous; Parenteral	125 MG
Injection, solution	Cutaneous; Parenteral	50 MG
Injection, solution	Cutaneous; Parenteral	87.5 MG
Injection, solution	Subcutaneous	125 mg/1mL
Injection, solution	Subcutaneous	50 mg/0.4mL
Injection, solution	Subcutaneous	87.5 mg/0.7mL
Injection, solution, concentrate	Intravenous	250 mg
Injection, powder, lyophilized, for solution	Intravenous	262.5 mg
Powder, for solution	Intravenous	250 mg
Injection		125 mg
Solution	Subcutaneous	125 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
Unlock Additional Data
CA2110518	No	2007-05-22	2012-06-16

Additional Data Available

Filed On

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The date on which a patent was filed with the relevant government.

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Properties

State: Liquid
Experimental Properties: Not Available

Targets

Details1. T-lymphocyte activation antigen CD80

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Antagonist

General Function: 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

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]
Weyand CM, Goronzy JJ: T-cell-targeted therapies in rheumatoid arthritis. Nat Clin Pract Rheumatol. 2006 Apr;2(4):201-10. [PubMed:16932686]
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]
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]
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]
Nogid A, Pham DQ: Role of abatacept in the management of rheumatoid arthritis. Clin Ther. 2006 Nov;28(11):1764-78. [PubMed:17212998]
Hervey PS, Keam SJ: Abatacept. BioDrugs. 2006;20(1):53-61; discussion 62. [PubMed:16573350]
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]
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Details2. T-lymphocyte activation antigen CD86

Kind: Protein
Organism: Humans
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

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]
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]
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]
Weyand CM, Goronzy JJ: T-cell-targeted therapies in rheumatoid arthritis. Nat Clin Pract Rheumatol. 2006 Apr;2(4):201-10. [PubMed:16932686]
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]
Nogid A, Pham DQ: Role of abatacept in the management of rheumatoid arthritis. Clin Ther. 2006 Nov;28(11):1764-78. [PubMed:17212998]
Hervey PS, Keam SJ: Abatacept. BioDrugs. 2006;20(1):53-61; discussion 62. [PubMed:16573350]
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]
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]