Ustekinumab

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Identification

Summary

Ustekinumab is a targeted antibody therapy used to manage inflammatory conditions such as plaque psoriasis, psoriatic arthritis, Crohn's Disease, and ulcerative colitis.

Brand Names

Stelara

Generic Name

Ustekinumab

DrugBank Accession Number

DB05679

Background

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.⁷ 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.

Ustekinumab biosimilars are available in some markets, including Wezlana (ustekinumab-auub) in the US¹¹ and Jamteki (AVT04) in Canada.¹²

Type

Biotech

Groups

Approved, Investigational

Biologic Classification

Protein Based Therapies
Monoclonal antibody (mAb)

Protein Structure

Protein Chemical Formula: Not Available
Protein Average Weight: 148600.0 Da (approximate)

Sequences

>Ustekinumab heavy chain
EVQLVQSGAEVKKPGESLKISCKGSGYSFTTYWLGWVRQMPGKGLDWIGIMSPVDSDIRY
SPSFQGQVTMSVDKSITTAYLQWNSLKASDTAMYYCARRRPGQGYFDFWGQGTLVTVSSS
STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH

References:

USTEKINUMAB FAB HEAVY CHAIN in PDB entry 3hmx [Link]

>Ustekinumab light chain
DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPS
RFSGSGSGTDFTLTISSLQPEDFATYYCQQYNIYPYTFGQGTKLEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

References:

USTEKINUMAB FAB LIGHT CHAIN in PDB entry 3hmx [Link]

Download FASTA Format

Synonyms

Stelera
Ustekinumab
Ustekinumab-auub

External IDs

AVT04
CNTO 1275
CNTO-1275
CNTO1275
L04AC05
TT 20
TT-20
TT20

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Pharmacology

Indication

Ustekinumab is indicated for the management of moderate to severe plaque psoriasis in patients 6 years of age and older who are candidates for phototherapy or systemic therapy.⁶ In adult patients, it is also indicated for the management of active psoriatic arthritis (PsA) alone or in combination with methotrexate, moderately to severely active Crohn’s disease (CD) and moderately to severely active ulcerative colitis.¹⁰

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Management of	Moderate, active ulcerative colitis		••••••••••••	•••••		•••••••••
Management of	Severe plaque psoriasis		••••••••••••	•••••• •••••••••	•••••••••• ••• •••••••• ••••••• ••• •••••••••• •••••••••• ••• ••••••••••••	•••••••••
Management of	Severe, active ulcerative colitis		••••••••••••	•••••		•••••••••
Management of	Active psoriatic arthritis		••••••••••••	•••••		•••••••••
Used in combination to manage	Active psoriatic arthritis	Regimen in combination with: Methotrexate (DB00563)	••••••••••••	•••••		•••••••••

Contraindications & Blackbox Warnings

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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.⁶ It downregulates the gene expression of inflammatory cytokines and chemokines such as MCP-1, TNF-alpha, IP-10, and IL-8.⁸ 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.⁶ The steady-state was achieved by 28 weeks after multiple subcutaneous dose administration in adult patients with psoriasis.⁶

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 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-12Rβ1,⁸ 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

Target	Actions	Organism
AInterleukin-23	inhibitor	Humans
AInterleukin-12 subunit beta	inhibitor	Humans

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.⁸ 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.⁶

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%.⁸

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.⁶ 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.⁸

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

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.⁸ The estimated median terminal half-life of approximately 19 days in patients with Crohn’s disease or ulcerative colitis.⁶

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.⁸ In patients with Crohn’s disease, the clearance was 0.19 L/day in patients with Crohn’s disease or ulcerative colitis.⁶

Adverse Effects

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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

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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Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Ustekinumab.
Adalimumab	The risk or severity of adverse effects can be increased when Adalimumab is combined with Ustekinumab.
Aducanumab	The risk or severity of adverse effects can be increased when Ustekinumab is combined with Aducanumab.
Alemtuzumab	The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Ustekinumab.
Alirocumab	The risk or severity of adverse effects can be increased when Ustekinumab is combined with Alirocumab.

Food Interactions

No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Finlius	Solution	45 mg / 0.5 mL	Subcutaneous	Janssen Pharmaceuticals	2024-07-02	Not applicable
Finlius	Solution	90 mg / 1 mL	Subcutaneous	Janssen Pharmaceuticals	2024-07-02	Not applicable
Finlius I.V.	Solution	5 mg / mL	Intravenous	Janssen Pharmaceuticals	2024-07-02	Not applicable
Jamteki	Solution	45 mg / 0.5 mL	Subcutaneous	Jamp Pharma Corporation	2024-03-01	Not applicable
Jamteki	Solution	90 mg / 1 mL	Subcutaneous	Jamp Pharma Corporation	2024-03-01	Not applicable

Chemical Identifiers

UNII: FU77B4U5Z0
CAS number: 815610-63-0

References

General References

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. [Article]
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. [Article]
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. [Article]
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. [Article]
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. [Article]
FDA Approved Drug Products: Stelara (ustekinumab) injection for subcutaneous or intravenous use [Link]
Janssen Announces FDA Approval of Stelara (ustekinumab) for the Treatment of Adults with Moderately to Severely Active Ulcerative Colitis [Link]
Health Canada Approved Drug Products: STELARA (ustekinumab) subcutaneous or intravenous injection [Link]
FDA Approved Drug Products: STELARA (ustekinumab) injection, for subcutaneous or intravenous use (July 2022) [Link]
FDA Approved Drug Products: STELARA (ustekinumab) injection, for subcutaneous or intravenous use (March 2023) [Link]
FDA Approved Drug Products: Wezlana (ustekinumab-auub) injection for subcutaneous or intravenous administration [Link]
BioSpace: Alvotech and JAMP Pharma Announce Receipt of Marketing Authorization for Jamteki™ (AVT04), the First Biosimilar of Stelara® (ustekinumab) [Link]

External Links

KEGG Drug: D09214
PubChem Substance: 347910190
RxNav: 847083
ChEMBL: CHEMBL1201835
Drugs.com: Drugs.com Drug Page
Wikipedia: Ustekinumab

Clinical Trials

Clinical Trials Clinical Trial & Rare Diseases Add-on Data Package Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package

Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
Unlock 175K+ rows when you subscribe.View sample data
Not Available	Active Not Recruiting	Not Available	Ulcerative Colitis	1	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Atherosclerosis / Atopic Dermatitis / Psoriasis	1	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Crohn's Disease (CD)	5	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Crohn's Disease (CD) / Ulcerative Colitis	1	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Generalized Pustular Psoriasis (GPP)	1	somestatus	stop reason	just information to hide

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Solution	Subcutaneous	90 mg / 1 mL
Injection	Subcutaneous	45 mg/0.5ml
Injection	Subcutaneous	90 MG/ML
Injection, solution	Intravenous; Subcutaneous	45 MG
Injection, solution	Intravenous; Subcutaneous	90 MG
Injection, solution	Subcutaneous	45 mg/0.5mL
Injection, solution	Subcutaneous	90 mg/1mL
Injection, solution, concentrate	Intravenous	130 mg
Injection, solution, concentrate	Intravenous; Parenteral	130 MG
Solution	Intravenous	130 mg/26mL
Solution	Subcutaneous	45 mg / 0.5 mL
Solution	Subcutaneous	45.000 mg
Solution	Subcutaneous	90 mg / 1.0 mL
Injection, solution, concentrate	Intravenous	130 mg/26ml
Injection, solution, concentrate		130 mg/26ml
Injection, solution		45 mg
Solution		45 mg/0.5mL
Injection, solution		90 mg
Injection, solution	Subcutaneous	90 mg/mL
Solution	Intravenous	130 mg
Solution	Intravenous	5 mg / mL
Solution	Intravenous	135.000 mg
Injection, solution	Subcutaneous	45 mg
Injection, solution	Subcutaneous	90 mg
Solution	Subcutaneous	45 mg
Solution	Subcutaneous	4500000 mg
Solution	Subcutaneous	90 mg
Injection, solution		90 mg/1ml

Prices

Not Available

Patents

Not Available

Properties

State: Liquid
Experimental Properties: Not Available

Targets

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Details1. Interleukin-23 (Protein Group)

Kind: Protein group
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General 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
Specific Function: cytokine activity

Components:

Name	UniProt ID
Interleukin-12 subunit beta	P29460
Interleukin-23 subunit alpha	Q9NPF7

References

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. [Article]
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. [Article]

Details2. Interleukin-12 subunit beta

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

General 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
Specific Function: cytokine activity
Gene Name: IL12B
Uniprot ID: P29460
Uniprot Name: Interleukin-12 subunit beta
Molecular Weight: 37168.645 Da

References

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. [Article]
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. [Article]

Drug created at November 18, 2007 18:26 / Updated at December 08, 2023 12:54

Ustekinumab

Identification

References:

References:

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Clinical Trial & Rare Diseases Add-on Data Package

Pharmacoeconomics

Properties

Targets

Components:

References

References