Alefacept

Identification

Name
Alefacept
Accession Number
DB00092  (BTD00055, BIOD00055)
Type
Biotech
Groups
Approved, Investigational, Withdrawn
Biologic Classification
Protein Based Therapies
Fusion proteins
Description

Immunosuppressive dimeric fusion protein that consists of the extracellular CD2-binding portion of the human leukocyte function antigen-3 (LFA-3) linked to the Fc (hinge, CH2 and CH3 domains) portion of human IgG1. Produced by CHO cells, mW is 91.4 kD.

Protein structure
Db00092
Protein chemical formula
C2306H3594N610O694S26
Protein average weight
51801.1 Da
Sequences
>Alefacept heavy chain 
CFSQQIYGVVYGNVTFHVPSNVPLKEVLWKKQKDKVAELENSEFRAFSSFKNRVYLDTVS
GSLTIYNLTSSDEDEYEMESPNITDTMKFFLYVLESLPSPTLTCALTNGSIEVQCMIPEH
YNSHRGLIMYSWDCPMEQCKRNSTSIYFKMENDLPQKIQCTLSNPLFNTTSSIILTTCIP
SSGHSRHRYALIPIPLAVITTCIVLYMNGILKCDRKPDRTNSNRVEPKSCDKTHTCPPCP
APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPQVKFNWYVDGVQVHNAKTK
PREQQYNSTYRVVSVLTVLHQNWLDGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL
TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>Alefacept light chain
MVAGSDAGRALGVLSVVCLLHCFGFISCFSQQIYGVVYGNVTFHVPSNVPLKEVLWKKQK
DKVAELENSEFRAFSSFKNRVYLDTVSGSLTIYNLTSSDEDEYEMESPNITDTMKFFLYV
LESLPSPTLTCALTNGSIEVQCMIPEHYNSHRGLIMYSWDCPMEQCKRNSTSIYFKMEND
LPQKIQCTLSNPLFNTTSSIILTTCIPSSGHSRHRYALIPIPLAVITTCIVLYMNGILKC
DRKPDRTNSN
Download FASTA Format
Synonyms
  • ASP0485
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AmevivePowder, for solution15 mgIntramuscularAstellas Pharma Inc2004-10-122012-12-01Canada
Categories
UNII
ELK3V90G6C
CAS number
222535-22-0

Pharmacology

Indication

As an immunosuppressive drug, Alefacept can be used for treatment of moderate to severe chronic plaque psoriasis

Structured Indications
Not Available
Pharmacodynamics

Interferes with lymphocyte activation by specifically binding to the lymphocyte antigen, CD2, and inhibiting LFA-3/CD2 interaction. Activation of T lymphocytes involving the interaction between LFA-3 on antigen-presenting cells and CD2 on T lymphocytes plays a role in the pathophysiology of chronic plaque psoriasis. Also causes a reduction in subsets of CD2+ T lymphocytes as well as CD4+ and CD8+ T lymphocytes.

Mechanism of action

Inhibits T-lymphocyte activation and production by binding to the CD2 lymphocyte antigen.

TargetActionsOrganism
AT-cell surface antigen CD2
inhibitor
Human
UComplement C1r subcomponentNot AvailableHuman
UComplement C1q subcomponent subunit ANot AvailableHuman
UComplement C1q subcomponent subunit BNot AvailableHuman
UComplement C1q subcomponent subunit CNot AvailableHuman
ULow affinity immunoglobulin gamma Fc region receptor III-ANot AvailableHuman
UHigh affinity immunoglobulin gamma Fc receptor INot AvailableHuman
ULow affinity immunoglobulin gamma Fc region receptor II-aNot AvailableHuman
ULow affinity immunoglobulin gamma Fc region receptor II-bNot AvailableHuman
ULow affinity immunoglobulin gamma Fc region receptor II-cNot AvailableHuman
ULow affinity immunoglobulin gamma Fc region receptor III-BNot AvailableHuman
Absorption

Bioavailability after IM administration is 63%.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

~270 hours

Clearance
Not Available
Toxicity

While it has been found to cross the placenta in monkeys, it is not yet known if it also diffuses into breast milk.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with Alefacept.Investigational
Clostridium tetani toxoid antigen (formaldehyde inactivated)The therapeutic efficacy of Clostridium tetani toxoid antigen (formaldehyde inactivated) can be decreased when used in combination with Alefacept.Approved
Corynebacterium diphtheriae toxoid antigen (formaldehyde inactivated)The therapeutic efficacy of Corynebacterium diphtheriae toxoid antigen (formaldehyde inactivated) can be decreased when used in combination with Alefacept.Approved
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Alefacept.Approved
FingolimodAlefacept may increase the immunosuppressive activities of Fingolimod.Approved, Investigational
G17DTThe therapeutic efficacy of G17DT can be decreased when used in combination with Alefacept.Investigational
GI-5005The therapeutic efficacy of GI-5005 can be decreased when used in combination with Alefacept.Investigational
Hepatitis A VaccineThe therapeutic efficacy of Hepatitis A Vaccine can be decreased when used in combination with Alefacept.Approved
Hepatitis B Vaccine (Recombinant)The therapeutic efficacy of Hepatitis B Vaccine (Recombinant) can be decreased when used in combination with Alefacept.Approved, Withdrawn
INGN 201The therapeutic efficacy of INGN 201 can be decreased when used in combination with Alefacept.Investigational
INGN 225The therapeutic efficacy of INGN 225 can be decreased when used in combination with Alefacept.Investigational
LeflunomideThe risk or severity of adverse effects can be increased when Alefacept is combined with Leflunomide.Approved, Investigational
NatalizumabThe risk or severity of adverse effects can be increased when Alefacept is combined with Natalizumab.Approved, Investigational
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Alefacept.Approved, Investigational
Rabies virus inactivated antigen, AThe risk or severity of adverse effects can be increased when Alefacept is combined with Rabies virus inactivated antigen, A.Approved
Rabies virus inactivated antigen, AThe therapeutic efficacy of Rabies virus inactivated antigen, A can be decreased when used in combination with Alefacept.Approved
RindopepimutThe therapeutic efficacy of Rindopepimut can be decreased when used in combination with Alefacept.Investigational
RoflumilastRoflumilast may increase the immunosuppressive activities of Alefacept.Approved
Rotavirus VaccineThe therapeutic efficacy of Rotavirus Vaccine can be decreased when used in combination with Alefacept.Approved
Rubella virus vaccineThe therapeutic efficacy of Rubella virus vaccine can be decreased when used in combination with Alefacept.Approved
Salmonella typhi ty21a live antigenThe therapeutic efficacy of Salmonella typhi ty21a live antigen can be decreased when used in combination with Alefacept.Approved
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Alefacept.Approved
SRP 299The therapeutic efficacy of SRP 299 can be decreased when used in combination with Alefacept.Investigational
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Alefacept.Approved, Investigational
TecemotideThe therapeutic efficacy of Tecemotide can be decreased when used in combination with Alefacept.Investigational
TG4010The therapeutic efficacy of TG4010 can be decreased when used in combination with Alefacept.Investigational
TofacitinibAlefacept may increase the immunosuppressive activities of Tofacitinib.Approved, Investigational
TrastuzumabTrastuzumab may increase the neutropenic activities of Alefacept.Approved, Investigational
Yellow fever vaccineThe therapeutic efficacy of Yellow fever vaccine can be decreased when used in combination with Alefacept.Approved
Zoster vaccineThe therapeutic efficacy of Zoster vaccine can be decreased when used in combination with Alefacept.Approved
Food Interactions
Not Available

References

General References
  1. Koo JY, Bagel J, Sweetser MT, Ticho BS: Alefacept in combination with ultraviolet B phototherapy for the treatment of chronic plaque psoriasis: results from an open-label, multicenter study. J Drugs Dermatol. 2006 Jul-Aug;5(7):623-8. [PubMed:16865867]
  2. Krell JM: Use of alefacept and etanercept in 3 patients whose psoriasis failed to respond to etanercept. J Am Acad Dermatol. 2006 Jun;54(6):1099-101. [PubMed:16713481]
  3. Parrish CA, Sobera JO, Robbins CM, Cantrell WC, Desmond RA, Elewski BE: Alefacept in the treatment of psoriatic nail disease: a proof of concept study. J Drugs Dermatol. 2006 Apr;5(4):339-40. [PubMed:16673801]
  4. Link [Link]
External Links
PubChem Substance
46505772
ChEMBL
CHEMBL1201571
Therapeutic Targets Database
DAP000540
PharmGKB
PA164748040
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Alefacept
ATC Codes
L04AA15 — Alefacept

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailablePharmacokinetics of Alefacept1
1CompletedTreatmentMalignant Lymphomas1
1SuspendedTreatmentAplastic Anaemia (AA)1
1TerminatedTreatmentTransplant; Failure, Kidney1
1, 2CompletedTreatmentResistant Chronic GVHD1
2CompletedDiagnosticAtopic Dermatitis (AD)1
2CompletedPreventionDe Novo Kidney Transplantation1
2CompletedTreatmentPalmoplantaris Pustulosis / Psoriasis / Pustular Psoriasis of Palms and Soles / Pustulosis of Palms and Soles / Pustulosis Palmaris et Plantaris1
2CompletedTreatmentPsoriasis1
2CompletedTreatmentPsoriatic Arthritis1
2CompletedTreatmentTransplantation, Kidney1
2TerminatedTreatmentChronic Graft Versus Host Disease1
2TerminatedTreatmentLichen Planus (LP)1
2TerminatedTreatmentNew-onset Type 1 Diabetes Mellitus1
3CompletedTreatmentChronic Plaque Psoriasis3
3CompletedTreatmentPsoriasis1
3TerminatedPreventionGraft Versus Host Disease (GVHD)1
4CompletedPreventionChronic Plaque Psoriasis1
4CompletedTreatmentAtopic Dermatitis (AD)1
4CompletedTreatmentChronic Plaque Psoriasis1
4CompletedTreatmentModerate to Severe Chronic Plaque Psoriasis1
4CompletedTreatmentPlaque Psoriasis1
4CompletedTreatmentPsoriasis1
4TerminatedNot AvailablePsoriasis1
4TerminatedTreatmentChronic Plaque Psoriasis1
4TerminatedTreatmentPityriasis Rubra Pilaris1
Not AvailableCompletedNot AvailableAlopecia Areata (AA)1
Not AvailableCompletedEducational/Counseling/TrainingChronic Plaque Psoriasis1
Not AvailableCompletedTreatmentPsoriasis1
Not AvailableCompletedTreatmentPsoriasis, Moderate to Severe1
Not AvailableTerminatedNot AvailableChronic Plaque Psoriasis1
Not AvailableTerminatedNot AvailablePregnancy1
Not AvailableTerminatedTreatmentChediak-Higashi Syndrome / Chronic-granulomatous Disease / Congenital Hypoplastic Anemia / Dyskeratosis-congenita / Glanzmann Thrombasthenia / Leukocyte Adhesion Deficiency / Schwachman-Diamond Syndrome / Severe Aplastic Anemia (SAA) / Severe Congenital Neutropenia / Sickle Cell Disorders / Thalassaemic disorders / Wiskott-Aldrich Syndrome (WAS)1
Not AvailableWithdrawnNot AvailableTransplantation, Kidney1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Dosage forms
FormRouteStrength
Powder, for solutionIntramuscular15 mg
Prices
Unit descriptionCostUnit
Amevive 15 mg vial1190.4USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
hydrophobicity-0.432Not Available
isoelectric point7.86Not 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

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Receptor binding
Specific Function
CD2 interacts with lymphocyte function-associated antigen (LFA-3) and CD48/BCM1 to mediate adhesion between T-cells and other cell types. CD2 is implicated in the triggering of T-cells, the cytopla...
Gene Name
CD2
Uniprot ID
P06729
Uniprot Name
T-cell surface antigen CD2
Molecular Weight
39447.96 Da
References
  1. Chamian F, Lin SL, Lee E, Kikuchi T, Gilleaudeau P, Sullivan-Whalen M, Cardinale I, Khatcherian A, Novitskaya I, Wittkowski KM, Krueger JG, Lowes MA: Alefacept (anti-CD2) causes a selective reduction in circulating effector memory T cells (Tem) and relative preservation of central memory T cells (Tcm) in psoriasis. J Transl Med. 2007 Jun 7;5:27. [PubMed:17555598]
  2. da Silva AJ, Brickelmaier M, Majeau GR, Li Z, Su L, Hsu YM, Hochman PS: Alefacept, an immunomodulatory recombinant LFA-3/IgG1 fusion protein, induces CD16 signaling and CD2/CD16-dependent apoptosis of CD2(+) cells. J Immunol. 2002 May 1;168(9):4462-71. [PubMed:11970990]
  3. Larsen R, Ryder LP, Svejgaard A, Gniadecki R: Changes in circulating lymphocyte subpopulations following administration of the leucocyte function-associated antigen-3 (LFA-3)/IgG1 fusion protein alefacept. Clin Exp Immunol. 2007 Jul;149(1):23-30. Epub 2007 Apr 2. [PubMed:17403057]
  4. Goedkoop AY, de Rie MA, Picavet DI, Kraan MC, Dinant HJ, van Kuijk AW, Tak PP, Bos JD, Teunissen MB: Alefacept therapy reduces the effector T-cell population in lesional psoriatic epidermis. Arch Dermatol Res. 2004 Apr;295(11):465-73. Epub 2004 Feb 14. [PubMed:14968366]
  5. Ortonne JP: Clinical response to alefacept: results of a phase 3 study of intramuscular administration of alefacept in patients with chronic plaque psoriasis. J Eur Acad Dermatol Venereol. 2003 Jul;17 Suppl 2:12-6. [PubMed:12795770]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Human
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
  1. 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]
  2. 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]
Kind
Protein
Organism
Human
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
  1. 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]
  2. 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]
Kind
Protein
Organism
Human
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
  1. 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]
  2. 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]
Kind
Protein
Organism
Human
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
  1. 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]
  2. 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]
Kind
Protein
Organism
Human
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
  1. 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]
  2. 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]
  3. da Silva AJ, Brickelmaier M, Majeau GR, Li Z, Su L, Hsu YM, Hochman PS: Alefacept, an immunomodulatory recombinant LFA-3/IgG1 fusion protein, induces CD16 signaling and CD2/CD16-dependent apoptosis of CD2(+) cells. J Immunol. 2002 May 1;168(9):4462-71. [PubMed:11970990]
  4. Vaishnaw AK, TenHoor CN: Pharmacokinetics, biologic activity, and tolerability of alefacept by intravenous and intramuscular administration. J Pharmacokinet Pharmacodyn. 2002 Dec;29(5-6):415-26. [PubMed:12795239]
Kind
Protein
Organism
Human
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
  1. 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]
  2. 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]
Kind
Protein
Organism
Human
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
  1. 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]
  2. 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]
Kind
Protein
Organism
Human
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
  1. 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]
  2. 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]
Kind
Protein
Organism
Human
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
  1. 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]
  2. 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]
Kind
Protein
Organism
Human
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
  1. da Silva AJ, Brickelmaier M, Majeau GR, Li Z, Su L, Hsu YM, Hochman PS: Alefacept, an immunomodulatory recombinant LFA-3/IgG1 fusion protein, induces CD16 signaling and CD2/CD16-dependent apoptosis of CD2(+) cells. J Immunol. 2002 May 1;168(9):4462-71. [PubMed:11970990]

Drug created on June 13, 2005 07:24 / Updated on November 06, 2017 06:43