Dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. The Fc component of etanercept contains the CH2 domain, the CH3 domain and hinge region, but not the CH1 domain of IgG1. Etanercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids.

Protein structure

Protein chemical formula

C₂₂₂₄H₃₄₇₅N₆₂₁O₆₉₈S₃₆

Protein average weight

51234.9 Da

Sequences

> Etanercept Sequence
LPAQVAFTPYAPEPGSTCRLREYYDQTAQMCCSKCSPGQHAKVFCTKTSDTVCDSCEDST
YTQLWNWVPECLSCGSRCSSDQVETQACTREQNRICTCRPGWYCALSKQEGCRLCAPLRK
CRPGFGVARPGTETSDVVCKPCAPGTFSNTTSSTDICRPHQICNVVAIPGNASMDAVCTS
TSPTRSMAPGAVHLPQPVSTRSQHTQPTPEPSTAPSTSFLLPMGPSPPAEGSTGDEPKSC
DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD
GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK
GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS
DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Download FASTA Format

Synonyms

Etanercept
etanercept-szzs
etanercept-ykro
Recombinant human TNF
rhu TNFR:Fc
rhu-TNFR:Fc
TNFR-Immunoadhesin

External IDs

CHS-0214 / DWP-422 / ENIA-11 / GP-2015 / GP2015 / GP2015C / HD-203 / HD203 / LBEC-0101 / LBEC0101 / SB-4 / SB4

Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Unlock Additional Data
Brenzys	Solution	50 mg	Subcutaneous	Samsung Bioepis Co., Ltd.	2016-09-13	Not applicable
Brenzys	Solution	50 mg	Subcutaneous	Samsung Bioepis Co., Ltd.	2016-09-23	Not applicable
Enbrel	Solution	50 mg/1mL	Subcutaneous	Immunex Corporation	2005-10-06	Not applicable
Enbrel	Solution	50 mg/1mL	Subcutaneous	Immunex Corporation	2017-09-29	Not applicable
Enbrel	Injection, powder, for solution	25 mg	Subcutaneous	Pfizer	2000-02-03	Not applicable
Enbrel	Injection, powder, for solution	50 mg	Subcutaneous	Pfizer	2000-02-03	Not applicable
Enbrel	Injection, powder, for solution	50 mg	Subcutaneous	Pfizer	2000-02-03	Not applicable
Enbrel	Injection, solution	25 mg	Subcutaneous	Pfizer	2000-02-03	Not applicable
Enbrel	Injection, solution	50 mg	Subcutaneous	Pfizer	2000-02-03	Not applicable
Enbrel	Solution	50 mg/1mL	Subcutaneous	Physicians Total Care, Inc.	2005-10-06	2012-06-30

Additional Data Available

Application Number

A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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Product Code

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

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Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End
Enbrel	Etanercept (25 mg/1mL) + Benzyl alcohol (9.93 mg/1mL)	Kit		Physicians Total Care, Inc.	2003-04-30	2012-06-30
Enbrel	Etanercept (25 mg) + Water (1 ml)	Kit; Liquid; Powder, for solution	Subcutaneous	Immunex Corporation	2001-03-14	Not applicable

International/Other Brands

Davictrel / Tunex

Categories

UNII

OP401G7OJC

CAS number

185243-69-0

Pharmacology

Indication

Etanercept is indicated for the treatment of moderately to severely active rheumatoid arthritis in adults and chronic moderate to severe plaque psoriasis in adults. It is also used to manage signs and symptoms of polyarticular idiopathic arthritis in those aged 4 to 17 after insufficient response to one or more disease-modifying anti-rheumatic drugs. Etanercept is also used to improve psoriatic arthritis and ankylosing spondylitis.

Associated Conditions

Pharmacodynamics

Etanercept binds specifically to tumor necrosis factor (TNF) and thereby modulates biological processes that are induced or regulated by TNF. Such processes or molecules affected include the level of adhesion molecules expressed, as well as serum levels of cytokines and matrix metalloproteinase-3, also known as stromelysin. In animal models, etanarcept has been demonstrated to affect inflammation, such as in murine collagen-induced arthritis.

Mechanism of action

There are two distinct receptors for TNF (TNFRs), a 55 kilodalton protein (p55) and a 75 kilodalton protein (p75). The biological activity of TNF is dependent upon binding to either cell surface receptor (p75 or p55). Etanercept is a dimeric soluble form of the p75 TNF receptor that can bind to two TNF molecules, thereby effectively removing them from circulation.

TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Increased levels of TNF are found in tissues and fluids of those with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis (AS), and plaque psoriasis.

Target	Actions	Organism
ATumor necrosis factor	antibody	Humans
UTumor necrosis factor receptor superfamily member 1B	Not Available	Humans
UHigh affinity immunoglobulin gamma Fc receptor I	Not Available	Humans
ULow affinity immunoglobulin gamma Fc region receptor III-A	Not Available	Humans
ULow affinity immunoglobulin gamma Fc region receptor II-a	Not Available	Humans
ULow affinity immunoglobulin gamma Fc region receptor II-b	Not Available	Humans
ULow affinity immunoglobulin gamma Fc region receptor II-c	Not Available	Humans
ULymphotoxin-alpha	Not Available	Humans
ULow affinity immunoglobulin gamma Fc region receptor III-B	Not Available	Humans
UComplement C1s subcomponent	Not Available	Humans
UComplement C1r subcomponent	Not Available	Humans
UComplement C1q subcomponent subunit A	Not Available	Humans
UComplement C1q subcomponent subunit B	Not Available	Humans
UComplement C1q subcomponent subunit C	Not Available	Humans

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Additional Data Available

Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Additional Data Available

Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available

Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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Absorption

Bioavailability following sub-Q administration is approximately 60%. Peak plasma concentrations achieved within 69 hours.

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Not Available

Route of elimination

Not Available

Half life

102 +/- 30 hrs in individuals with rheumatoid arthritis and 68 hours in healthy adults.

Clearance

160 +/- 80 mL/hr [RA patients]

Toxicity

Not Available

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

Drug	Interaction
Unlock Additional Data
(R)-warfarin	The metabolism of (R)-warfarin can be increased when combined with Etanercept.
(S)-Warfarin	The metabolism of (S)-Warfarin can be increased when combined with Etanercept.
2-Methoxyethanol	The risk or severity of adverse effects can be increased when Etanercept is combined with 2-Methoxyethanol.
3,5-diiodothyropropionic acid	The metabolism of 3,5-diiodothyropropionic acid can be increased when combined with Etanercept.
4-hydroxycoumarin	The metabolism of 4-hydroxycoumarin can be increased when combined with Etanercept.
4-Methoxyamphetamine	The metabolism of 4-Methoxyamphetamine can be increased when combined with Etanercept.
5-androstenedione	The metabolism of 5-androstenedione can be increased when combined with Etanercept.
6-O-benzylguanine	The metabolism of 6-O-benzylguanine can be increased when combined with Etanercept.
7-ethyl-10-hydroxycamptothecin	The metabolism of 7-ethyl-10-hydroxycamptothecin can be increased when combined with Etanercept.
8-azaguanine	The metabolism of 8-azaguanine can be increased when combined with Etanercept.

Additional Data Available

Extended Description

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

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Severity

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

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Evidence Level

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

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Action

Evidence Level

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

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Food Interactions

Not Available

References

Synthesis Reference

Timothy D. Osslund, Christi L. Clogston, Shon Lee Crampton, Randal B. Bass, "Crystals of etanercept and methods of making thereof." U.S. Patent US07276477, issued October 02, 2007.

US07276477

General References

Link [Link]
Link [Link]

External Links

UniProt: P20333
Genbank: M32315
KEGG Drug: D00742
KEGG Compound: C07897
PubChem Substance: 46506732
ChEMBL: CHEMBL1201572
Therapeutic Targets Database: DNC000605
PharmGKB: PA449515
Wikipedia: Etanercept

ATC Codes

L04AB01 — Etanercept

AHFS Codes

92:36.00 — Disease-modifying Antirheumatic Agents

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
0	Completed	Treatment	Inclusion Body Myositis (IBM)	1
1	Completed	Not Available	Healthy Volunteers	2
1	Completed	Basic Science	Bioequivalence / Phase 1	1
1	Completed	Basic Science	Healthy Volunteers	2
1	Completed	Health Services Research	Alzheimer's Disease (AD)	1
1	Completed	Other	Healthy Volunteers	1
1	Completed	Treatment	Acute and Chronic Inflammation / Autoimmune Diseases / Disorder of Pleura and Pleural Cavity / Disorder of Synovium / Felty's Syndrome / Rheumatoid Arthritis / Rheumatoid Nodules / Sjögren's Syndrome	1
1	Completed	Treatment	Dermatomyositis	1
1	Completed	Treatment	Healthy Men and Women	1
1	Completed	Treatment	Healthy Volunteers	4
1	Completed	Treatment	Human Immunodeficiency Virus (HIV) Infections	1
1	Completed	Treatment	Psoriasis	1
1	Completed	Treatment	Rheumatoid Arthritis	1
1	Completed	Treatment	Tumors	1
1	Not Yet Recruiting	Prevention	Subarachnoid Hemorrhage, Aneurysmal	1
1	Recruiting	Treatment	Psoriatic plaque	1
1	Terminated	Treatment	One to five years postmenopausal / Osteopenia / Osteoporosis / Rheumatoid Arthritis	1
1	Terminated	Treatment	Rheumatoid Arthritis	1
1	Unknown Status	Not Available	Rheumatoid Arthritis	1
1, 2	Active Not Recruiting	Treatment	Diabetes, Diabetes Mellitus Type 1	1
1, 2	Completed	Other	Rheumatoid Arthritis	1
1, 2	Completed	Treatment	Adenocarcinomas / Neoplasms, Pancreatic	1
1, 2	Completed	Treatment	Chronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma (SLL)	1
1, 2	Completed	Treatment	De Novo Myelodysplastic Syndromes / Previously Treated Myelodysplastic Syndromes / Secondary Myelodysplastic Syndromes	1
1, 2	Completed	Treatment	Diabetes, Diabetes Mellitus Type 1	2
1, 2	Completed	Treatment	Leukemias / Myelodysplastic Syndromes / Myelodysplastic/Myeloproliferative Diseases	1
1, 2	Completed	Treatment	Obliterative Bronchiolitis / Pneumonia / Respiratory Distress Syndrome, Adult	1
1, 2	Completed	Treatment	Psoriasis	1
1, 2	Not Yet Recruiting	Treatment	Autoimmune Diseases / Diabetes Mellitus (DM) / Diabetes, Diabetes Mellitus Type 1 / Hypoglycemia	1
1, 2	Not Yet Recruiting	Treatment	Psoriasis Vulgaris (Plaque Psoriasis)	1
1, 2	Recruiting	Treatment	Diabetes, Diabetes Mellitus Type 1	1
1, 2	Withdrawn	Treatment	Diabetes, Diabetes Mellitus Type 1	1
2	Active Not Recruiting	Prevention	Graft Versus Host Disease (GVHD)	1
2	Active Not Recruiting	Treatment	Diabetes, Diabetes Mellitus Type 1	1
2	Active Not Recruiting	Treatment	Lichen Planus (LP)	1
2	Active Not Recruiting	Treatment	Mucocutaneous Lymph Node Syndrome	1
2	Completed	Other	Rheumatoid Arthritis	1
2	Completed	Treatment	Accelerated Phase Chronic Myelogenous Leukemia / Blastic Phase Chronic Myelogenous Leukemia / Childhood Acute Lymphoblastic Leukemia in Remission / Childhood Acute Myeloid Leukemia in Remission / Childhood Chronic Myelogenous Leukemia / Childhood Myelodysplastic Syndromes / Chronic Phase Chronic Myelogenous Leukemia / De Novo Myelodysplastic Syndromes / Disseminated Neuroblastoma / Juvenile Myelomonocytic Leukemia / Previously Treated Childhood Rhabdomyosarcoma / Previously Treated Myelodysplastic Syndromes / Pulmonary Complications / Recurrent Childhood Acute Lymphoblastic Leukemia / Recurrent Childhood Acute Myeloid Leukemia / Recurrent Childhood Large Cell Lymphoma / Recurrent Childhood Lymphoblastic Lymphoma / Recurrent Childhood Rhabdomyosarcoma / Recurrent Childhood Small Noncleaved Cell Lymphoma / Recurrent Neuroblastoma / Recurrent Wilms Tumor and Other Childhood Kidney Tumors / Recurrent/Refractory Childhood Hodgkin Lymphoma / Relapsing Chronic Myelogenous Leukemia / Secondary Acute Myeloid Leukemia (Secondary AML, sAML) / Secondary Myelodysplastic Syndromes	1
2	Completed	Treatment	Acute Lung Injury (ALI) / Obliterative Bronchiolitis / Respiratory Distress Syndrome, Adult	1
2	Completed	Treatment	Alzheimer's Disease (AD)	1
2	Completed	Treatment	Asthma Bronchial	1
2	Completed	Treatment	Diabetes, Diabetes Mellitus Type 1	2
2	Completed	Treatment	Graft Versus Host Disease (GVHD)	2
2	Completed	Treatment	Graft Versus Host Disease (GVHD) / Immune System Disorders	1
2	Completed	Treatment	Granulomatosis With Polyangiitis / Vasculitis	1
2	Completed	Treatment	Healthy Volunteers / Inflammatory Reaction	1
2	Completed	Treatment	Healthy Volunteers / Rheumatoid Arthritis	1
2	Completed	Treatment	Hidradenitis Suppurativa (HS)	1
2	Completed	Treatment	Histiocytosis, Langerhans-Cell	1
2	Completed	Treatment	Leukemias / Myelodysplastic Syndromes	1
2	Completed	Treatment	Leukemias / Myelodysplastic Syndromes / Myelodysplastic/Myeloproliferative Diseases	1
2	Completed	Treatment	Lupus Erythematosus, Chronic Cutaneous / Lupus Erythematosus, Cutaneous / Lupus Erythematosus, Discoid	1
2	Completed	Treatment	Pemphigus Vulgaris (PV)	1
2	Completed	Treatment	Persistent Knee Joint Synovitis	1
2	Completed	Treatment	Psoriasis	1
2	Completed	Treatment	Pulmonary Fibrosis	1
2	Completed	Treatment	Rheumatoid Arthritis	2
2	Completed	Treatment	Rheumatoid Arthritis, Juvenile / Uveitis	1
2	Completed	Treatment	Sjögren's Syndrome	1
2	Completed	Treatment	Temporomandibular Joint Disorders	1
2	Completed	Treatment	Transplanted Kidney Ischemia Reperfusion Injury	1
2	Completed	Treatment	Vitiligo	1
2	Recruiting	Treatment	Ankylosing Spondylitis (AS)	1
2	Recruiting	Treatment	Diabetes, Diabetes Mellitus Type 1 / Transplant, Kidney	1
2	Suspended	Treatment	Primary Systemic Amyloidosis	1
2	Terminated	Treatment	End Stage Renal Disease (ESRD)	1
2	Terminated	Treatment	Leukemias	1
2	Terminated	Treatment	Lichen Planus (LP)	1
2	Terminated	Treatment	Myalgic Encephalomyelitis (ME)	1
2	Terminated	Treatment	Nephritis, Lupus	1
2	Terminated	Treatment	Rheumatoid Arthritis	1
2	Terminated	Treatment	Vesicular Stomatitis	1
2	Unknown Status	Treatment	Ankylosing Spondylitis (AS)	1
2	Unknown Status	Treatment	Discoid Lupus Erythematosus (DLE)	1
2	Unknown Status	Treatment	Moderate to Severe Active Axial Spondyloarthritis	1
2	Unknown Status	Treatment	Spondyloarthritis	1
2, 3	Completed	Treatment	Acute Exacerbation of Chronic Obstructive Pulmonary Disease	1
2, 3	Completed	Treatment	Granulomatosis With Polyangiitis	1
2, 3	Completed	Treatment	Lumbosacral Radiculopathy	1
2, 3	Completed	Treatment	Metabolic Syndromes	1
2, 3	Completed	Treatment	Rheumatoid Arthritis, Juvenile	1
2, 3	Recruiting	Treatment	Ankylosing Spondylitis (AS) / Arthritis / Bone Diseases / Joint ankylosis / Musculoskeletal Disorders / Spinal Diseases / Spondylarthritis / Spondylarthropathy / Spondylitis	1
2, 3	Terminated	Diagnostic	Bone Cancer / Lung Cancers / Neoplasms Metastasis / Prostate Cancer	1
2, 3	Terminated	Treatment	Dermatomyositis	1
2, 3	Withdrawn	Treatment	Chronic Idiopathic Urticaria	1
3	Active Not Recruiting	Treatment	Chronic Severe Plaque-type Psoriasis	1
3	Active Not Recruiting	Treatment	Diabetes, Diabetes Mellitus Type 1	1
3	Active Not Recruiting	Treatment	Juvenile Idiopahtic Arthritis	1
3	Active Not Recruiting	Treatment	Psoriasis	2
3	Active Not Recruiting	Treatment	Psoriasis Vulgaris (Plaque Psoriasis)	2
3	Active Not Recruiting	Treatment	Rheumatoid Arthritis	3
3	Completed	Prevention	Psoriasis / Psoriatic Arthritis	1
3	Completed	Supportive Care	Anorexic / Cachexia / Unspecified Adult Solid Tumor, Protocol Specific	1
3	Completed	Supportive Care	Arthritis, Rheumatoid; Arthritis, Psoriatic	1
3	Completed	Treatment	Active Rheumatoid Arthritis	1
3	Completed	Treatment	Ankylosing Spondylitis (AS)	6
3	Completed	Treatment	Chronic Plaque Psoriasis	1
3	Completed	Treatment	Diabetes, Diabetes Mellitus Type 1	2
3	Completed	Treatment	Graft Versus Host Disease, Acute	1
3	Completed	Treatment	Idiopathic Pneumonia Syndrome / Pneumonia	1
3	Completed	Treatment	Inflammatory Reaction / Psoriasis	1
3	Completed	Treatment	Juvenile Idiopathic Arthritis (JIA)	1
3	Completed	Treatment	Moderate to Severe Plaque Psoriasis	1
3	Completed	Treatment	Palmoplantaris Pustulosis	1
3	Completed	Treatment	Pediatric Plaque Psoriasis	1
3	Completed	Treatment	Polymyalgia Rheumatica	1
3	Completed	Treatment	Psoriasis	11
3	Completed	Treatment	Psoriasis Vulgaris (Plaque Psoriasis)	2
3	Completed	Treatment	Psoriasis Vulgaris (Plaque Psoriasis) / Rheumatoid Arthritis	1
3	Completed	Treatment	Psoriasis / Psoriasis Vulgaris (Plaque Psoriasis)	1
3	Completed	Treatment	Psoriasis / Psoriatic Arthritis	1
3	Completed	Treatment	Psoriatic Arthritis	1
3	Completed	Treatment	Psoriatic Arthritis / Rheumatoid Arthritis	1
3	Completed	Treatment	Prophylaxis of Rheumatic fever / Psoriatic Arthritis / Rheumatoid Arthritis	1
3	Completed	Treatment	Rheumatoid Arthritis	17
3	Not Yet Recruiting	Treatment	Oligoarthritis, Juvenile / Polyarthritis, Juvenile, Rheumatoid Factor Negative	1
3	Not Yet Recruiting	Treatment	Stevens Johnson Syndrome / Toxic Epidermal Necrolyses	1
3	Recruiting	Treatment	Juvenile Idiopathic Arthritis (JIA)	1
3	Recruiting	Treatment	Psoriasis	1
3	Recruiting	Treatment	Psoriasis / Psoriasis Vulgaris (Plaque Psoriasis)	1
3	Suspended	Treatment	Rheumatoid Arthritis	1
3	Terminated	Treatment	Rheumatoid Arthritis	1
3	Terminated	Treatment	Rheumatoid Arthritis, Juvenile	2
3	Withdrawn	Treatment	Psoriasis Vulgaris (Plaque Psoriasis)	1
4	Active Not Recruiting	Treatment	Ankylosing Spondylitis (AS)	2
4	Active Not Recruiting	Treatment	Spondyloarthritis	1
4	Completed	Not Available	Ankylosing Spondylitis (AS)	3
4	Completed	Not Available	Arthritis / Rheumatoid	1
4	Completed	Not Available	Inflammatory Reaction / Rheumatoid Arthritis	1
4	Completed	Not Available	Psoriasis	1
4	Completed	Not Available	Psoriatic Arthritis / Rheumatoid Arthritis	1
4	Completed	Not Available	Rheumatoid Arthritis	2
4	Completed	Prevention	Ankylosing Spondylitis (AS) / Recurrences	1
4	Completed	Treatment	Active Rheumatoid Arthritis / Rheumatoid Arthritis	1
4	Completed	Treatment	Ankylosing Spondylitis (AS)	6
4	Completed	Treatment	Ankylosing Spondylitis (AS) / Inflammatory Reaction	1
4	Completed	Treatment	Ankylosing Spondylitis (AS) / Psoriatic Arthritis / Spondylarthropathy	1
4	Completed	Treatment	Cardiovascular Disease, Rheumatoid Arthritis / Rheumatoid Arthritis	1
4	Completed	Treatment	Juvenile Chronic Polyarthritis / Juvenile Idiopathic Arthritis (JIA) / Rheumatoid Arthritis, Juvenile	1
4	Completed	Treatment	Melanoma / Non-Melanoma Skin Cancer (NMSC) / Psoriasis	1
4	Completed	Treatment	Nail Psoriasis / Psoriasis Vulgaris (Plaque Psoriasis)	1
4	Completed	Treatment	Psoriasis	10
4	Completed	Treatment	Psoriasis Vulgaris (Plaque Psoriasis)	4
4	Completed	Treatment	Psoriasis Vulgaris (Plaque Psoriasis) / Rheumatoid Arthritis	1
4	Completed	Treatment	Psoriasis, Moderate to Severe	1
4	Completed	Treatment	Psoriasis / Psoriasis Vulgaris (Plaque Psoriasis)	1
4	Completed	Treatment	Psoriasis / Psoriatic Arthritis	1
4	Completed	Treatment	Psoriatic Arthritis	3
4	Completed	Treatment	Rheumatoid Arthritis	20
4	Completed	Treatment	Spondylarthropathies, Enthesitis	1
4	Completed	Treatment	Spondyloarthritis, Axial	1
4	Completed	Treatment	Spondyloarthropathies	1
4	Enrolling by Invitation	Basic Science	Rheumatoid Arthritis	1
4	Not Yet Recruiting	Treatment	Acute Gouty Arthritis	1
4	Not Yet Recruiting	Treatment	Ankylosing Spondylitis (AS)	1
4	Not Yet Recruiting	Treatment	Rheumatoid Arthritis	2
4	Recruiting	Basic Science	Rheumatoid Arthritis	1
4	Recruiting	Prevention	Spondyloarthritis	1
4	Recruiting	Treatment	Pancreatitis, Chronic; Diabetes; Transplant	1
4	Recruiting	Treatment	Psoriasis	1
4	Recruiting	Treatment	Rheumatoid Arthritis	8
4	Terminated	Treatment	Ankylosing Spondylitis (AS)	1
4	Terminated	Treatment	Moderate to Severe Rheumatoid Arthritis	1
4	Terminated	Treatment	Psoriasis	1
4	Terminated	Treatment	Rheumatoid Arthritis	3
4	Terminated	Treatment	Rheumatoid Arthritis / Vascular Inflammation	1
4	Unknown Status	Basic Science	Absolute Number, Density of Immune Infiltrate and Dendritic Cells and Inflammatory Cytokines Expression Pattern / Psoriasis, Moderate to Severe	1
4	Unknown Status	Screening	Ankylosing Spondylitis (AS) / Rheumatoid Arthritis	1
4	Unknown Status	Treatment	Ankylosing Spondylitis (AS) / High Blood Pressure (Hypertension) / Psoriatic Arthritis / Rheumatoid Arthritis	1
4	Unknown Status	Treatment	Arthritis / Rheumatoid Arthritis	1
4	Unknown Status	Treatment	Juvenile Idiopathic Arthritis (JIA)	1
4	Unknown Status	Treatment	Myocardial Infarction	1
4	Unknown Status	Treatment	Psoriasis	1
4	Unknown Status	Treatment	Rheumatoid Arthritis	2
4	Withdrawn	Not Available	Pediatric Psoriasis	1
4	Withdrawn	Basic Science	Rheumatoid Arthritis	1
4	Withdrawn	Treatment	Psoriasis Vulgaris (Plaque Psoriasis)	1
4	Withdrawn	Treatment	Rheumatoid Arthritis	1
Not Available	Active Not Recruiting	Treatment	Psoriasis	1
Not Available	Completed	Not Available	Ankylosing Spondylitis (AS)	3
Not Available	Completed	Not Available	Ankylosing Spondylitis (AS) / Psoriatic Arthritis / Rheumatoid Arthritis	1
Not Available	Completed	Not Available	Atherosclerosis / Atopic Dermatitis (AD) / Psoriasis	1
Not Available	Completed	Not Available	Hidradenitis Suppurativa (HS)	1
Not Available	Completed	Not Available	Inflammatory Bowel Diseases (IBD) / Psoriasis	1
Not Available	Completed	Not Available	Inflammatory Reaction / Psoriasis	1
Not Available	Completed	Not Available	Juvenile Idiopathic Arthritis (JIA)	1
Not Available	Completed	Not Available	Pregnancy	1
Not Available	Completed	Not Available	Psoriasis	4
Not Available	Completed	Not Available	Psoriasis Arthritis / Rheumatoid Arthritis	1
Not Available	Completed	Not Available	Psoriasis Vulgaris (Plaque Psoriasis) / Psoriatic Arthritis / Rheumatoid Arthritis / Spondyloarthritis, Axial	1
Not Available	Completed	Not Available	Psoriasis / Psoriatic Arthritis / Skin Diseases, Papulosquamous	2
Not Available	Completed	Not Available	Psoriatic Arthritis	1
Not Available	Completed	Not Available	Psoriatic Arthritis / Rheumatoid Arthritis / Spondyloarthritis	1
Not Available	Completed	Not Available	Rheumatoid Arthritis	12
Not Available	Completed	Not Available	Rheumatoid Arthritis, Juvenile	1
Not Available	Completed	Not Available	Rheumatoid Arthritis / Spondyloarthropathies	1
Not Available	Completed	Not Available	Rhupus Syndrome, Etanercept	1
Not Available	Completed	Not Available	Spondyloarthritis / Ultrasonography	1
Not Available	Completed	Basic Science	Psoriasis	1
Not Available	Completed	Health Services Research	Congenital Hypoplastic Anemia	1
Not Available	Completed	Prevention	Inguinal Hernias / Postoperative pain	1
Not Available	Completed	Screening	Ankylosing Spondylitis (AS)	1
Not Available	Completed	Treatment	Asthma Bronchial	1
Not Available	Completed	Treatment	Drug hypersensitivity reaction	1
Not Available	Completed	Treatment	Human Immunodeficiency Virus (HIV) Infections	1
Not Available	Completed	Treatment	Metabolic Syndromes	2
Not Available	Completed	Treatment	Psoriasis	1
Not Available	Completed	Treatment	Rheumatoid Arthritis	1
Not Available	Recruiting	Not Available	Ankylosing Spondylitis (AS) / Psoriatic Arthritis / Rheumatoid Arthritis	2
Not Available	Recruiting	Not Available	Enthesitis / Psoriasis / Psoriatic Arthritis	1
Not Available	Recruiting	Not Available	Psoriasis	1
Not Available	Recruiting	Not Available	Rheumatoid Arthritis	4
Not Available	Recruiting	Not Available	Rheumatoid Arthritis / Spondyloarthritis, Axial	1
Not Available	Recruiting	Treatment	Knee Osteoarthritis (Knee OA)	2
Not Available	Terminated	Not Available	Ankylosing Spondylitis (AS) / Rheumatoid Arthritis	1
Not Available	Terminated	Prevention	BMI >30 kg/m2 / High Blood Pressure (Hypertension) / Hyperlipidemias / Metabolic Syndromes / Psoriasis	1
Not Available	Unknown Status	Not Available	Scleritis / Uveitis	1
Not Available	Unknown Status	Treatment	Behcet's Syndrome / Uveal Disease	1
Not Available	Unknown Status	Treatment	Psoriasis	1
Not Available	Withdrawn	Not Available	Rheumatoid Arthritis	1
Not Available	Withdrawn	Treatment	Chronic Regional Pain Syndrome / CRP	1

Pharmacoeconomics

Manufacturers

Amgen Inc. + Wyeth + Takeda

Packagers

Amgen Inc.
Boehringer Ingelheim Ltd.
DSM Corp.
Immunex Corp.
Physicians Total Care Inc.
Vetter Pharma Fertigung GmbH and Co. KG

Dosage forms

Form	Route	Strength
Injection, powder, for solution	Subcutaneous	10 mg
Injection, powder, for solution	Subcutaneous	25 mg
Injection, powder, for solution	Subcutaneous	50 mg
Injection, solution	Subcutaneous	25 mg
Injection, solution	Subcutaneous	50 mg
Kit
Kit		25 mg/1mL
Kit; liquid; powder, for solution	Subcutaneous
Solution	Subcutaneous	25 mg/0.5mL
Solution	Subcutaneous	50 mg/1mL
Solution	Subcutaneous	50 mg
Solution	Subcutaneous	25 mg

Prices

Unit description	Cost	Unit
Enbrel (1 Box = 1 Kit = Four 50 mg Syringes) 3.92ml Box	2033.14USD	box
Enbrel SureClick (1 Box Contains Four 50 mg Prefilled Autoinjectors)	2033.14USD	box
Enbrel 4 25 mg Kit (1 Box = 1 Kit = Four 25 mg Vials)	1016.57USD	box
Enbrel 50 mg/ml sureclick syr	488.74USD	syringe
Enbrel 25 mg kit	250.37USD	each

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
Unlock Additional Data
CA2476934	No	2009-06-16	2023-02-27
CA2123593	No	2000-03-14	2013-09-14
US7276477	No	2007-10-02	2024-07-29

Additional Data Available

Filed On

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

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Properties

State

Liquid

Experimental Properties

Property	Value	Source
melting point (°C)	71 °C (whole mAb)	Vermeer, A.W.P. & Norde, W., Biophys. J. 78:394-404 (2000)
hydrophobicity	-0.529	Not Available
isoelectric point	7.89	Not Available

Taxonomy

Description: Not Available
Kingdom: Organic Compounds
Super Class: Organic Acids
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

Details1. Tumor necrosis factor

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

General Function: Tumor necrosis factor receptor binding
Specific Function: Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct ac...
Gene Name: TNF
Uniprot ID: P01375
Uniprot Name: Tumor necrosis factor
Molecular Weight: 25644.15 Da

References

Park YC, Burkitt V, Villa AR, Tong L, Wu H: Structural basis for self-association and receptor recognition of human TRAF2. Nature. 1999 Apr 8;398(6727):533-8. [PubMed:10206649]
Sandborn WJ, Hanauer SB: Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results, and safety. Inflamm Bowel Dis. 1999 May;5(2):119-33. [PubMed:10338381]
Grell M, Zimmermann G, Gottfried E, Chen CM, Grunwald U, Huang DC, Wu Lee YH, Durkop H, Engelmann H, Scheurich P, Wajant H, Strasser A: Induction of cell death by tumour necrosis factor (TNF) receptor 2, CD40 and CD30: a role for TNF-R1 activation by endogenous membrane-anchored TNF. EMBO J. 1999 Jun 1;18(11):3034-43. [PubMed:10357816]
Moreland LW: Inhibitors of tumor necrosis factor: new treatment options for rheumatoid arthritis. Cleve Clin J Med. 1999 Jun;66(6):367-74. [PubMed:10375846]
Calabrese LH: Rheumatoid arthritis and primary care: the case for early diagnosis and treatment. J Am Osteopath Assoc. 1999 Jun;99(6):313-21. [PubMed:10405518]
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Details2. Tumor necrosis factor receptor superfamily member 1B

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Ubiquitin protein ligase binding
Specific Function: Receptor with high affinity for TNFSF2/TNF-alpha and approximately 5-fold lower affinity for homotrimeric TNFSF1/lymphotoxin-alpha. The TRAF1/TRAF2 complex recruits the apoptotic suppressors BIRC2 ...
Gene Name: TNFRSF1B
Uniprot ID: P20333
Uniprot Name: Tumor necrosis factor receptor superfamily member 1B
Molecular Weight: 48290.85 Da

References

Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Details3. High affinity immunoglobulin gamma Fc receptor I

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Receptor signaling protein activity
Specific Function: High affinity receptor for the Fc region of immunoglobulins gamma. Functions in both innate and adaptive immune responses.
Gene Name: FCGR1A
Uniprot ID: P12314
Uniprot Name: High affinity immunoglobulin gamma Fc receptor I
Molecular Weight: 42631.525 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]

Details4. Low affinity immunoglobulin gamma Fc region receptor III-A

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Not Available
Specific Function: Receptor for the Fc region of IgG. Binds complexed or aggregated IgG and also monomeric IgG. Mediates antibody-dependent cellular cytotoxicity (ADCC) and other antibody-dependent responses, such as...
Gene Name: FCGR3A
Uniprot ID: P08637
Uniprot Name: Low affinity immunoglobulin gamma Fc region receptor III-A
Molecular Weight: 29088.895 Da

References

Criswell LA, Lum RF, Turner KN, Woehl B, Zhu Y, Wang J, Tiwari HK, Edberg JC, Kimberly RP, Moreland LW, Seldin MF, Bridges SL Jr: The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept. Arthritis Rheum. 2004 Sep;50(9):2750-6. [PubMed:15457442]
Hughes LB, Criswell LA, Beasley TM, Edberg JC, Kimberly RP, Moreland LW, Seldin MF, Bridges SL: Genetic risk factors for infection in patients with early rheumatoid arthritis. Genes Immun. 2004 Dec;5(8):641-7. [PubMed:15526004]

Details5. Low affinity immunoglobulin gamma Fc region receptor II-a

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Not Available
Specific Function: Binds to the Fc region of immunoglobulins gamma. Low affinity receptor. By binding to IgG it initiates cellular responses against pathogens and soluble antigens. Promotes phagocytosis of opsonized ...
Gene Name: FCGR2A
Uniprot ID: P12318
Uniprot Name: Low affinity immunoglobulin gamma Fc region receptor II-a
Molecular Weight: 35000.42 Da

References

Criswell LA, Lum RF, Turner KN, Woehl B, Zhu Y, Wang J, Tiwari HK, Edberg JC, Kimberly RP, Moreland LW, Seldin MF, Bridges SL Jr: The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept. Arthritis Rheum. 2004 Sep;50(9):2750-6. [PubMed:15457442]
Hughes LB, Criswell LA, Beasley TM, Edberg JC, Kimberly RP, Moreland LW, Seldin MF, Bridges SL: Genetic risk factors for infection in patients with early rheumatoid arthritis. Genes Immun. 2004 Dec;5(8):641-7. [PubMed:15526004]

Details6. Low affinity immunoglobulin gamma Fc region receptor II-b

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Not Available
Specific Function: Receptor for the Fc region of complexed or aggregated immunoglobulins gamma. Low affinity receptor. Involved in a variety of effector and regulatory functions such as phagocytosis of immune complex...
Gene Name: FCGR2B
Uniprot ID: P31994
Uniprot Name: Low affinity immunoglobulin gamma Fc region receptor II-b
Molecular Weight: 34043.355 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]

Details7. Low affinity immunoglobulin gamma Fc region receptor II-c

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Transmembrane signaling receptor activity
Specific Function: Receptor for the Fc region of complexed immunoglobulins gamma. Low affinity receptor. Involved in a variety of effector and regulatory functions such as phagocytosis of immune complexes and modulat...
Gene Name: FCGR2C
Uniprot ID: P31995
Uniprot Name: Low affinity immunoglobulin gamma Fc region receptor II-c
Molecular Weight: 35577.96 Da

References

Hart SP, Ross JA, Ross K, Haslett C, Dransfield I: Molecular characterization of the surface of apoptotic neutrophils: implications for functional downregulation and recognition by phagocytes. Cell Death Differ. 2000 May;7(5):493-503. [PubMed:10800083]
Ranheim EA, Kipps TJ: Tumor necrosis factor-alpha facilitates induction of CD80 (B7-1) and CD54 on human B cells by activated T cells: complex regulation by IL-4, IL-10, and CD40L. Cell Immunol. 1995 Apr 1;161(2):226-35. [PubMed:7535196]

Details8. Lymphotoxin-alpha

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Receptor binding
Specific Function: Cytokine that in its homotrimeric form binds to TNFRSF1A/TNFR1, TNFRSF1B/TNFBR and TNFRSF14/HVEM. In its heterotrimeric form with LTB binds to TNFRSF3/LTBR. Lymphotoxin is produced by lymphocytes a...
Gene Name: LTA
Uniprot ID: P01374
Uniprot Name: Lymphotoxin-alpha
Molecular Weight: 22296.57 Da

References

Johnson CJ, Reilly KM, Murray KM: Etanercept in juvenile rheumatoid arthritis. Ann Pharmacother. 2001 Apr;35(4):464-71. [PubMed:11302411]
Pennica D, Lam VT, Mize NK, Weber RF, Lewis M, Fendly BM, Lipari MT, Goeddel DV: Biochemical properties of the 75-kDa tumor necrosis factor receptor. Characterization of ligand binding, internalization, and receptor phosphorylation. J Biol Chem. 1992 Oct 15;267(29):21172-8. [PubMed:1328224]
Gudbrandsdottir S, Larsen R, Sorensen LK, Nielsen S, Hansen MB, Svenson M, Bendtzen K, Muller K: TNF and LT binding capacities in the plasma of arthritis patients: effect of etanercept treatment in juvenile idiopathic arthritis. Clin Exp Rheumatol. 2004 Jan-Feb;22(1):118-24. [PubMed:15005015]
Buch MH, Conaghan PG, Quinn MA, Bingham SJ, Veale D, Emery P: True infliximab resistance in rheumatoid arthritis: a role for lymphotoxin alpha? Ann Rheum Dis. 2004 Oct;63(10):1344-6. Epub 2004 Mar 19. [PubMed:15033655]
Kang CP, Lee KW, Yoo DH, Kang C, Bae SC: The influence of a polymorphism at position -857 of the tumour necrosis factor alpha gene on clinical response to etanercept therapy in rheumatoid arthritis. Rheumatology (Oxford). 2005 Apr;44(4):547-52. Epub 2005 Feb 3. [PubMed:15695296]

Details9. Low affinity immunoglobulin gamma Fc region receptor III-B

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Not Available
Specific Function: Receptor for the Fc region of immunoglobulins gamma. Low affinity receptor. Binds complexed or aggregated IgG and also monomeric IgG. Contrary to III-A, is not capable to mediate antibody-dependent...
Gene Name: FCGR3B
Uniprot ID: O75015
Uniprot Name: Low affinity immunoglobulin gamma Fc region receptor III-B
Molecular Weight: 26215.64 Da

References

Hart SP, Ross JA, Ross K, Haslett C, Dransfield I: Molecular characterization of the surface of apoptotic neutrophils: implications for functional downregulation and recognition by phagocytes. Cell Death Differ. 2000 May;7(5):493-503. [PubMed:10800083]
Ozgocmen S, Godekmerdan A, Ozkurt-Zengin F: Acute-phase response, clinical measures and disease activity in ankylosing spondylitis. Joint Bone Spine. 2007 May;74(3):249-53. Epub 2007 Mar 5. [PubMed:17387033]
Criswell LA, Lum RF, Turner KN, Woehl B, Zhu Y, Wang J, Tiwari HK, Edberg JC, Kimberly RP, Moreland LW, Seldin MF, Bridges SL Jr: The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept. Arthritis Rheum. 2004 Sep;50(9):2750-6. [PubMed:15457442]
Hughes LB, Criswell LA, Beasley TM, Edberg JC, Kimberly RP, Moreland LW, Seldin MF, Bridges SL: Genetic risk factors for infection in patients with early rheumatoid arthritis. Genes Immun. 2004 Dec;5(8):641-7. [PubMed:15526004]

Details10. Complement C1s subcomponent

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Serine-type endopeptidase activity
Specific Function: C1s B chain is a serine protease that combines with C1q and C1r to form C1, the first component of the classical pathway of the complement system. C1r activates C1s so that it can, in turn, activat...
Gene Name: C1S
Uniprot ID: P09871
Uniprot Name: Complement C1s subcomponent
Molecular Weight: 76683.905 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]

Details11. Complement C1r subcomponent

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Serine-type peptidase activity
Specific Function: C1r B chain is a serine protease that combines with C1q and C1s to form C1, the first component of the classical pathway of the complement system.
Gene Name: C1R
Uniprot ID: P00736
Uniprot Name: Complement C1r subcomponent
Molecular Weight: 80118.04 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]

Details12. Complement C1q subcomponent subunit A

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Not Available
Specific Function: C1q associates with the proenzymes C1r and C1s to yield C1, the first component of the serum complement system. The collagen-like regions of C1q interact with the Ca(2+)-dependent C1r(2)C1s(2) proe...
Gene Name: C1QA
Uniprot ID: P02745
Uniprot Name: Complement C1q subcomponent subunit A
Molecular Weight: 26016.47 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]

Details13. Complement C1q subcomponent subunit B

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Not Available
Specific Function: C1q associates with the proenzymes C1r and C1s to yield C1, the first component of the serum complement system. The collagen-like regions of C1q interact with the Ca(2+)-dependent C1r(2)C1s(2) proe...
Gene Name: C1QB
Uniprot ID: P02746
Uniprot Name: Complement C1q subcomponent subunit B
Molecular Weight: 26721.62 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]

Details14. Complement C1q subcomponent subunit C

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Not Available
Specific Function: C1q associates with the proenzymes C1r and C1s to yield C1, the first component of the serum complement system. The collagen-like regions of C1q interact with the Ca(2+)-dependent C1r(2)C1s(2) proe...
Gene Name: C1QC
Uniprot ID: P02747
Uniprot Name: Complement C1q subcomponent subunit C
Molecular Weight: 25773.56 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]

Drug created on June 13, 2005 07:24 / Updated on May 21, 2019 12:01