Identification

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Name
Ustekinumab
Accession Number
DB05679
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

Ustekinumab is a human immunoglobulin (Ig) G1 kappa monoclonal antibody directed against interleukin(IL)-12 and IL-23, which are cytokines that are involved in immune and inflammatory responses.2 It was generated via recombinant human IL-12 immunization of human Ig (hu-Ig) transgenic mice.2 It is a targeted biologic disease-modifying anti-rheumatic drug (bDMARDs) that is used in the management of various inflammatory conditions that involve the activation of IL-12 and IL-23 signalling pathways.1

The therapeutic use of the drug started in Canada, the US, and Europe since 2009 when it was first approved for the treatment of adult patients with moderate to severe plaque psoriasis and active psoriatic arthritis, alone or in combination with methotrexate. In September 2016, ustekinumab was additionally approved for the management of moderate to severe Crohn's disease in selected adult patients. In October 2019, it was also approved by the FDA for use to manage moderately to severely active ulcerative colitis in adults. Ustekinumab is currently the first and only approved biologic therapy for ulcerative colitis that targets the interleukin (IL)-12 and IL-23 cytokines.8 The dosing regimen for ustekinumab is based on the patient's weight and there are intravenous and subcutaneous formulations of the drug based on the dosing schedule and condition being treated. Ustekinumab is commonly marketed under the trade name STELARA®.

Protein structure
Db05679
Protein chemical formula
Not Available
Protein average weight
148600.0 Da (approximate)
Sequences
>Ustekinumab heavy chain
EVQLVQSGAEVKKPGESLKISCKGSGYSFTTYWLGWVRQMPGKGLDWIGIMSPVDSDIRY
SPSFQGQVTMSVDKSITTAYLQWNSLKASDTAMYYCARRRPGQGYFDFWGQGTLVTVSSS
STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH
References:
  1. USTEKINUMAB FAB HEAVY CHAIN in PDB entry 3hmx [Link]
>Ustekinumab light chain
DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPS
RFSGSGSGTDFTLTISSLQPEDFATYYCQQYNIYPYTFGQGTKLEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. USTEKINUMAB FAB LIGHT CHAIN in PDB entry 3hmx [Link]
Download FASTA Format
Synonyms
  • Stelera
External IDs
CNTO 1275 / CNTO-1275 / CNTO1275 / L04AC05 / TT 20 / TT-20 / TT20
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
StelaraInjection, solution90 mgSubcutaneousJanssen Cilag International Nv2009-01-16Not applicableEu
StelaraSolution45 mgSubcutaneousJanssen Pharmaceuticals2009-01-05Not applicableCanada
StelaraInjection, solution90 mg/1mLSubcutaneousJanssen Biotech, Inc.2009-09-25Not applicableUs
StelaraInjection, solution45 mgSubcutaneousJanssen Cilag International Nv2009-01-16Not applicableEu
StelaraSolution130 mg/26mLIntravenousJanssen Biotech, Inc.2016-09-23Not applicableUs
StelaraInjection, solution45 mg/0.5mLSubcutaneousJanssen Biotech, Inc.2009-09-25Not applicableUs
StelaraSolution5 mgIntravenousJanssen Pharmaceuticals2016-12-21Not applicableCanada
StelaraInjection, solution90 mgSubcutaneousJanssen Cilag International Nv2009-01-16Not applicableEu
StelaraInjection, solution45 mgSubcutaneousJanssen Cilag International Nv2009-01-16Not applicableEu
StelaraSolution90 mgSubcutaneousJanssen Pharmaceuticals2013-01-07Not applicableCanada
Additional Data Available
  • Application Number
    Application Number

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  • Product Code
    Product Code

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Categories
UNII
FU77B4U5Z0
CAS number
815610-63-0

Pharmacology

Indication

Ustekinumab is indicated for the management of moderate to severe plaque psoriasis in adolescent (over 12 years of age) and adult patients who are candidates for phototherapy or systemic therapy.6,7

It is indicated for the management of active psoriatic arthritis in adults, alone or in combination with methotrexate.6

It is indicated for the management of moderately to severely active Crohn’s disease in adults who were clinically unresponsive or intolerant to immunomodulator or corticosteroid therapy (but never failed a tutor necrosis factor (TNF) blocker) or treatment with one or more TNF blockers.6

It is indicated for the management of moderately to severely active ulcerative colitis in adults.7

Associated Conditions
Pharmacodynamics

Ustekinumab is a targeted antibody therapy that suppresses immune responses. It acts by reducing the signaling pathways of pro-inflammatory cytokines IL-12 and IL-23, which play a role in various inflammatory conditions.7 It downregulates the gene expression of inflammatory cytokines and chemokines such as MCP-1, TNF-alpha, IP-10, and IL-8.9 The formation of cytochrome P-450 enzymes may be altered by elevated levels of certain cytokines during chronic inflammation.6 Research shows that there is an inverse relationship between plasma levels of inflammatory cytokines and CYP450 enzyme formation and activity. While ustekinumab may potentially normalize the formation of CYP enzymes and enhance the CYP-mediated metabolism of drugs,5 there were no clinically significant effects on human CYP enzyme activities.7 The steady-state was achieved by 28 weeks after multiple subcutaneous dose administration in adult patients with psoriasis.7

Mechanism of action

Interleukin (IL)-12 and IL-23 are heterodimeric cytokines that evoke immune and inflammatory responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation.6,7 The role of IL-12 and IL-23 were implicated in a variety of chronic inflammatory conditions, such as psoriasis and inflammatory bowel diseases. They modulate lymphocyte function, including T-helper (Th) 1 and Th17 cell subsets,2 as CD4+ T cells can differentiate into T-helper (Th) effector lineages based on the environment. Th cells can further activate the downstream pro-inflammatory mediators and transcription factors such as TNFα and IFNγ that drive innate and adaptive immunity.4

IL-12 and IL-23 share a common p40 subunit, paired with p35 and p19 subunits of IL-12 and IL-23, respectively. 4 The antigen-binding fragment (Fab) of ustekinumab binds the D1 domain of the p40 subunit of IL-12 and IL-23 in a 1:1 ratio.4 This prevents IL-12 and IL-23 from binding to the IL-12Rβ1 receptor chain of IL-12 (IL-12Rβ1/β2) and IL-23 (IL-12Rβ1/23R) receptor complexes on the surface of NK and T cells.2 Ustekinumab only binds to IL-12 and IL-23 that are unbound to IL-12Rβ1,9 so it is unlikely to initiate Fc effector functions, such as ADCC or CDC.2 Inhibition of the IL-12/23 signalling pathway leads to profound suppression of both the Th1 and Th17 cell lineage of cytokines and chemokines and their inflammatory pathways.3

TargetActionsOrganism
AInterleukin-12 subunit beta
inhibitor
Humans
AInterleukin-23
inhibitor
Humans
Additional Data Available
Adverse Effects

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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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Blackbox Warnings

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Absorption

The median Tmax following a single subcutaneous dose administration of 45mg and 90mg in adults with psoriasis was 13.5 days and 7 days, respectively. The median Cmax in the same group of patients was 2.4 μg/mL and 5.3 μg/mL at doses of 45mg and 90mg, respectively. The median AUC was 84.9 μg·day/mL and 226.9 μg·day/mL, respectively.9 Following an intravenous induction dose administration, the mean ± SD Cmax was 125.2 ± 33.6 mcg/mL in patients with Crohn’s disease and 129.1 ± 27.6 mcg/mL in patients with ulcerative colitis.7

The systemic exposure of ustekinumab (Cmax and AUC) increases in a linear or dose-proportional manner following a single subcutaneous administration at doses ranging from approximately 24 mg to 240 mg in patients with psoriasis. The estimated absolute bioavailability (F) of ustekinumab following a single subcutaneous dose administration in patients with psoriasis is 57.2%.9

Volume of distribution

The total volume of distribution at steady-state was 4.62 L in patients with Crohn’s disease and 4.4 L in patients with ulcerative colitis.7 The median apparent volume of distribution during the terminal phase (Vz/F) ranged from 76 to 161 mL/kg in patients with psoriasis receiving a single subcutaneous dose.9

Protein binding

There is no information on plasma protein binding of ustekinumab.

Metabolism

The metabolic pathway of ustekinumab has not been fully characterized; it is expected to undergo nonspecific protein degradation via catabolic pathways in the same manner as endogenous IgG.6,7

Route of elimination

There is limited information on the main route of elimination of ustekinumab; it is expected to undergo renal excretion following degradation.

Half life

Following administration of a single subcutaneous dose of 45 mg or 90 mg in patients with psoriasis, the median half-life was 19.8 days and 21.2, respectively.9 The estimated median terminal half-life of approximately 19 days in patients with Crohn’s disease or ulcerative colitis.6,7

Clearance

The median apparent clearance (CL/F) following a single subcutaneous administration to patients with psoriasis ranged from 2.7 to 5.3 mL/day/kg.9 In patients with Crohn’s disease, the clearance was 0.19 L/day in patients with Crohn’s disease or ulcerative colitis.6,7

Toxicity

Signs of dose-limiting toxicity were not observed with intravenous administration of single doses up to 6 mg/kg in clinical trials. Information on overdose of ustekinumab is limited: in the event of overdose, patients should be monitored for any signs and symptoms of drug-related adverse events and appropriate symptomatic treatment should be initiated.6,7

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.
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Ustekinumab.
AbituzumabThe risk or severity of adverse effects can be increased when Ustekinumab is combined with Abituzumab.
AbrilumabThe risk or severity of adverse effects can be increased when Ustekinumab is combined with Abrilumab.
AdecatumumabThe risk or severity of adverse effects can be increased when Adecatumumab is combined with Ustekinumab.
AducanumabThe risk or severity of adverse effects can be increased when Ustekinumab is combined with Aducanumab.
AlirocumabThe risk or severity of adverse effects can be increased when Ustekinumab is combined with Alirocumab.
AmatuximabThe risk or severity of adverse effects can be increased when Ustekinumab is combined with Amatuximab.
AMG 108The risk or severity of adverse effects can be increased when AMG 108 is combined with Ustekinumab.
Anetumab ravtansineThe risk or severity of adverse effects can be increased when Ustekinumab is combined with Anetumab ravtansine.
AnifrolumabThe risk or severity of adverse effects can be increased when Ustekinumab is combined with Anifrolumab.
Additional Data Available
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    Extended Description

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  • Severity
    Severity

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  • Action
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Food Interactions
No interactions found.

References

General References
  1. Thibodaux RJ, Triche MW, Espinoza LR: Ustekinumab for the treatment of psoriasis and psoriatic arthritis: a drug evaluation and literature review. Expert Opin Biol Ther. 2018 Jul;18(7):821-827. doi: 10.1080/14712598.2018.1492545. Epub 2018 Jul 9. [PubMed:29949399]
  2. Benson JM, Peritt D, Scallon BJ, Heavner GA, Shealy DJ, Giles-Komar JM, Mascelli MA: Discovery and mechanism of ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders. MAbs. 2011 Nov-Dec;3(6):535-45. doi: 10.4161/mabs.3.6.17815. Epub 2011 Nov 1. [PubMed:22123062]
  3. Koutruba N, Emer J, Lebwohl M: Review of ustekinumab, an interleukin-12 and interleukin-23 inhibitor used for the treatment of plaque psoriasis. Ther Clin Risk Manag. 2010 Apr 15;6:123-41. doi: 10.2147/tcrm.s5599. [PubMed:20421912]
  4. Luo J, Wu SJ, Lacy ER, Orlovsky Y, Baker A, Teplyakov A, Obmolova G, Heavner GA, Richter HT, Benson J: Structural basis for the dual recognition of IL-12 and IL-23 by ustekinumab. J Mol Biol. 2010 Oct 8;402(5):797-812. doi: 10.1016/j.jmb.2010.07.046. Epub 2010 Aug 4. [PubMed:20691190]
  5. Frye RF, Schneider VM, Frye CS, Feldman AM: Plasma levels of TNF-alpha and IL-6 are inversely related to cytochrome P450-dependent drug metabolism in patients with congestive heart failure. J Card Fail. 2002 Oct;8(5):315-9. [PubMed:12411982]
  6. STELARA® (ustekinumab) injection - FDA Label [Link]
  7. STELARA® (ustekinumab) injection -Janssen Full Prescribing Information [Link]
  8. Janssen Announces FDA Approval of Stelara (ustekinumab) for the Treatment of Adults with Moderately to Severely Active Ulcerative Colitis [Link]
  9. STELARA® (ustekinumab) Product Monograph - Janssen Inc. [Link]
External Links
KEGG Drug
D09214
PubChem Substance
347910190
ChEMBL
CHEMBL1201835
Drugs.com
Drugs.com Drug Page
Wikipedia
Ustekinumab
ATC Codes
L04AC05 — Ustekinumab
AHFS Codes
  • 92:20.00 — Immunomodulatory Agents
  • 84:92.00 — Misc. Skin and Mucous Membrane Agents

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentCrohn's Disease (CD)1
1CompletedTreatmentHealthy Volunteers2
1CompletedTreatmentPsoriasis2
1Not Yet RecruitingOtherHealthy Volunteers1
1Not Yet RecruitingTreatmentPrimary Sjögren's Syndrome1
1RecruitingOtherCrohn's Disease (CD)1
1, 2Active Not RecruitingTreatmentChronic Functional Diarrhea / CVID / CVID Enteropathy / Enteropathy / Gastrointestinal Inflammation Associated With CVID / Malabsorption / Maldigestion1
1, 2Active Not RecruitingTreatmentGiant Cells Arteritis / Temporal Arteritis1
1, 2Active Not RecruitingTreatmentType 1 Insulin-Dependent Diabetes Mellitus1
1, 2RecruitingTreatmentLAD1 / Leukocyte Adhesion Deficiency Type 11
1, 2WithdrawnTreatmentUveitis1
2Active Not RecruitingTreatmentBehçet's Disease1
2Active Not RecruitingTreatmentPsoriatic Arthritis1
2CompletedTreatmentAnkylosing Spondylitis (AS)1
2CompletedTreatmentAtopic Dermatitis (AD)2
2CompletedTreatmentCrohn's Disease (CD)2
2CompletedTreatmentDisseminated Sclerosis1
2CompletedTreatmentGraft Versus Host Disease (GVHD)1
2CompletedTreatmentHidradenitis Suppurativa (HS)1
2CompletedTreatmentPrimary Biliary Cholangitis1
2CompletedTreatmentPsoriasis3
2CompletedTreatmentPsoriatic Arthritis1
2CompletedTreatmentRheumatoid Arthritis1
2CompletedTreatmentSarcoidosis1
2CompletedTreatmentSystemic Lupus Erythematosus (SLE)1
2Not Yet RecruitingTreatmentAutoimmune Diseases / Inflammatory Diseases1
2Not Yet RecruitingTreatmentBullous Pemphigoid (BP)1
2RecruitingTreatmentCrohn's Disease (CD)1
2RecruitingTreatmentPatients Relapsing Refractory Giant Cell Arteritis1
2RecruitingTreatmentPatients With Newly Diagnosed Active NISU1
2RecruitingTreatmentPsoriatic arthritis aggravated1
2RecruitingTreatmentType 1 Insulin-Dependent Diabetes Mellitus1
2RecruitingTreatmentUveitis1
2, 3Not Yet RecruitingTreatmentType 1 Insulin-Dependent Diabetes Mellitus1
2, 3RecruitingTreatmentCrohn's Disease (CD)1
3Active Not RecruitingNot AvailableInflammatory Bowel Diseases (IBD) / Ulcerative Colitis1
3Active Not RecruitingTreatmentChronic Plaque Psoriasis / Moderate to Severe Chronic Plaque Psoriasis / Psoriatic Arthritis1
3Active Not RecruitingTreatmentColitis / Crohn's Disease (CD) / Inflammatory Bowel Diseases (IBD)1
3Active Not RecruitingTreatmentCrohn's Disease (CD)1
3Active Not RecruitingTreatmentPsoriasis1
3CompletedTreatmentChronic Plaque Type Psoriasis1
3CompletedTreatmentColitis / Crohn's Disease (CD) / Inflammatory Bowel Diseases (IBD)2
3CompletedTreatmentPsoriasis11
3CompletedTreatmentPsoriasis Vulgaris (Plaque Psoriasis)2
3CompletedTreatmentPsoriatic Arthritis2
3Not Yet RecruitingTreatmentPouchitis1
3Not Yet RecruitingTreatmentSystemic Lupus Erythematosus (SLE)1
3RecruitingTreatmentCrohn's Disease (CD)3
3RecruitingTreatmentDermatomyositis / Polymyositis1
3RecruitingTreatmentPsoriatic Arthritis1
3RecruitingTreatmentSystemic Lupus Erythematosus (SLE)1
3TerminatedTreatmentModerate to Severe Plaque Psoriasis2
3TerminatedTreatmentNonradiographic Axial Spondylitis, Ankylosing1
3TerminatedTreatmentPalmo-Plantar Pustular Psoriasis / Palmo-Plantar Pustulosis1
3TerminatedTreatmentPsoriasis1
3TerminatedTreatmentSpondyloarthritis, Axial2
4CompletedNot AvailablePsoriasis Vulgaris (Plaque Psoriasis)1
4CompletedTreatmentCardiovascular Disease (CVD) / Psoriasis1
4CompletedTreatmentPsoriasis2
4Not Yet RecruitingBasic ScienceInflammatory Bowel Diseases (IBD) / Psoriasis1
4RecruitingTreatmentCrohn's Disease (CD) / Inflammatory Bowel Diseases (IBD) / Ulcerative Colitis1
4RecruitingTreatmentPsoriasis1
4RecruitingTreatmentPsoriasis With Cell-derived Microparticles1
4Unknown StatusTreatmentPsoriasis Vulgaris (Plaque Psoriasis) / Scalp Psoriasis1
Not AvailableActive Not RecruitingNot AvailableCrohn's Disease (CD)1
Not AvailableActive Not RecruitingNot AvailablePsoriatic Arthritis1
Not AvailableAvailableNot AvailableCrohn's Disease (CD)1
Not AvailableCompletedNot AvailableAtherosclerosis / Atopic Dermatitis (AD) / Psoriasis1
Not AvailableCompletedNot AvailableInflammatory Bowel Diseases (IBD)1
Not AvailableCompletedNot AvailableInflammatory Reaction / Psoriasis1
Not AvailableCompletedNot AvailablePsoriasis2
Not AvailableCompletedNot AvailablePsoriatic Arthritis / Rheumatoid Arthritis / Spondyloarthritis1
Not AvailableCompletedTreatmentModerate to Severe Palmar Plantar Psoriasis1
Not AvailableRecruitingNot AvailableAlzheimer's Disease (AD)1
Not AvailableRecruitingNot AvailableAnkylosing Spondylitis (AS) / Psoriatic Arthritis / Rheumatoid Arthritis1
Not AvailableRecruitingNot AvailableAtopic Dermatitis (AD) / Psoriasis1
Not AvailableRecruitingNot AvailableCrohn's Disease (CD)4
Not AvailableRecruitingNot AvailablePsoriasis2
Not AvailableRecruitingNot AvailablePsoriasis / Psoriatic Arthritis1
Not AvailableRecruitingPreventionCrohn's Disease (CD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionSubcutaneous45 mg/0.5mL
Injection, solutionSubcutaneous45 mg
Injection, solutionSubcutaneous90 mg/1mL
Injection, solutionSubcutaneous90 mg
SolutionIntravenous130 mg/26mL
SolutionIntravenous5 mg
SolutionSubcutaneous45 mg
SolutionSubcutaneous90 mg
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
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

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein heterodimerization activity
Specific Function
Cytokine that can act as a growth factor for activated T and NK cells, enhance the lytic activity of NK/lymphokine-activated killer cells, and stimulate the production of IFN-gamma by resting PBMC....
Gene Name
IL12B
Uniprot ID
P29460
Uniprot Name
Interleukin-12 subunit beta
Molecular Weight
37168.645 Da
References
  1. Reddy M, Davis C, Wong J, Marsters P, Pendley C, Prabhakar U: Modulation of CLA, IL-12R, CD40L, and IL-2Ralpha expression and inhibition of IL-12- and IL-23-induced cytokine secretion by CNTO 1275. Cell Immunol. 2007 May;247(1):1-11. Epub 2007 Aug 29. [PubMed:17761156]
  2. Wittig BM: Drug evaluation: CNTO-1275, a mAb against IL-12/IL-23p40 for the potential treatment of inflammatory diseases. Curr Opin Investig Drugs. 2007 Nov;8(11):947-54. [PubMed:17979029]
Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein heterodimerization activity
Specific Function
Cytokine that can act as a growth factor for activated T and NK cells, enhance the lytic activity of NK/lymphokine-activated killer cells, and stimulate the production of IFN-gamma by resting PBMC....

Components:
References
  1. Engel T, Kopylov U: Ustekinumab in Crohn's disease: evidence to date and place in therapy. Ther Adv Chronic Dis. 2016 Jul;7(4):208-14. doi: 10.1177/2040622316653306. Epub 2016 Jul 6. [PubMed:27433311]
  2. Khanna R, Chande N, Vermeire S, Sandborn WJ, Parker CE, Feagan BG: The Next Wave of Biological Agents for the Treatment of IBD: Evidence from Cochrane Reviews. Inflamm Bowel Dis. 2016 Jul;22(7):1737-43. doi: 10.1097/MIB.0000000000000808. [PubMed:27306074]

Drug created on November 18, 2007 11:26 / Updated on November 16, 2019 10:39