Mechanism of Action of Stelara (Ustekinumab)

Introduction

Stelara (ustekinumab) is a fully human IgG1κ monoclonal antibody designed to target key cytokines involved in immune-mediated diseases. It selectively binds to the p40 subunit common to interleukin-12 (IL-12) and interleukin-23 (IL-23), blocking their interaction with cell surface receptors. Stelara is approved for several chronic inflammatory conditions including plaque psoriasis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis.

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Step-by-Step Mechanism of Action

1. Binding to p40 Subunit
   Ustekinumab binds with high affinity to the p40 protein subunit that is shared by IL-12 and IL-23 cytokines.
2. Prevention of Receptor Binding
   This binding inhibits the interaction of IL-12 and IL-23 with their receptor (IL-12Rβ1) on the surface of immune cells.
3. Inhibition of Th1 and Th17 Pathways
   IL-12 is essential for Th1 differentiation, while IL-23 is crucial for the maintenance and activation of Th17 cells. Blocking these pathways reduces downstream inflammatory cytokines like IFN-γ, IL-17, and TNF-α.
4. Suppression of Inflammatory Response
   By inhibiting Th1 and Th17 mediated pathways, ustekinumab reduces chronic inflammation in autoimmune and inflammatory conditions.
5. No Fc-Mediated Cytotoxicity
   As an IgG1κ antibody, ustekinumab does not mediate antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC), contributing to its safety profile.

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Pharmacokinetic Parameters

Parameter	Value
Route	Subcutaneous or Intravenous
Bioavailability	~57% (subcutaneous)
Time to Peak	7 to 14 days
Half-life	~20 days (range: 15–32 days)
Metabolism	Proteolytic degradation
Excretion	Non-renal, non-biliary

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Clinical Uses

• Moderate to severe plaque psoriasis (≥6 years old)
• Active psoriatic arthritis
• Moderate to severe Crohn’s disease
• Moderate to severe ulcerative colitis

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Adverse Effects

• Upper respiratory tract infections
• Headache and fatigue
• Injection site reactions
• Gastrointestinal discomfort
• Rare risk of serious infections and malignancies

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Comparative Analysis

Biologic	Target	Dosing Interval	Approved Indications
Ustekinumab	IL-12/IL-23 p40	Every 8–12 weeks	Psoriasis, PsA, Crohn’s, UC
Secukinumab	IL-17A	Monthly	Psoriasis, PsA
Adalimumab	TNF-α	Every 2 weeks	Psoriasis, PsA, RA, Crohn’s, UC

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MCQs

1. Ustekinumab inhibits which cytokines?
a) IL-6 and IL-1β
b) IL-12 and IL-23
c) IL-17A and IL-4
d) TNF-α and IL-10
Answer: b) IL-12 and IL-23

2. The shared subunit targeted by Stelara is:
a) p28
b) p19
c) p40
d) p65
Answer: c) p40

3. Which T-cell pathways are downregulated by ustekinumab?
a) Th2 and Treg
b) Th1 and Th17
c) Th9 and Th2
d) Treg and Th22
Answer: b) Th1 and Th17

4. Ustekinumab is classified as:
a) Chimeric monoclonal antibody
b) Fully human monoclonal antibody
c) Humanized monoclonal antibody
d) Murine monoclonal antibody
Answer: b) Fully human monoclonal antibody

5. One of the serious adverse effects is:
a) Pancreatitis
b) Cardiac arrhythmia
c) Serious infection
d) Cataracts
Answer: c) Serious infection

6. Which condition is NOT an approved indication?
a) Psoriasis
b) Rheumatoid arthritis
c) Crohn’s disease
d) Ulcerative colitis
Answer: b) Rheumatoid arthritis

7. Time to reach peak concentration after SC injection is:
a) 24 hours
b) 3 days
c) 7–14 days
d) 30 minutes
Answer: c) 7–14 days

8. Primary mode of elimination of ustekinumab is:
a) Renal excretion
b) Hepatic metabolism
c) Proteolytic degradation
d) Fecal elimination
Answer: c) Proteolytic degradation

9. Th17 cells primarily secrete:
a) IL-4
b) IL-5
c) IL-17
d) IL-10
Answer: c) IL-17

10. Mechanism of action includes inhibition of:
a) B-cell activity
b) T-cell proliferation
c) IL-12/IL-23 signaling
d) TNF-α production directly
Answer: c) IL-12/IL-23 signaling

11. The antibody isotype of ustekinumab is:
a) IgA
b) IgG1κ
c) IgM
d) IgE
Answer: b) IgG1κ

12. Ustekinumab dosing frequency is typically:
a) Weekly
b) Every 4 weeks
c) Every 8–12 weeks
d) Daily
Answer: c) Every 8–12 weeks

13. Major cytokine involved in Th1 activation is:
a) IL-17
b) IL-10
c) IL-12
d) IL-5
Answer: c) IL-12

14. Fc-mediated cytotoxicity with Stelara is:
a) Common
b) Absent
c) Dose-dependent
d) Inhibitory only
Answer: b) Absent

15. The receptor involved in IL-12/IL-23 signaling is:
a) IL-17R
b) IL-2R
c) IL-12Rβ1
d) TNFR1
Answer: c) IL-12Rβ1

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FAQs

1. What is Stelara used for?
It is used to treat psoriasis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis.

2. How does Stelara differ from anti-TNF drugs?
It targets upstream cytokines (IL-12 and IL-23), while anti-TNF drugs neutralize TNF-α directly.

3. Is Stelara safe in children?
It is approved for children ≥6 years with moderate-to-severe plaque psoriasis.

4. Can Stelara be self-injected?
Yes, the subcutaneous formulation allows for self-administration.

5. Is routine lab monitoring required?
Routine monitoring is not mandatory but assess for infections and TB before initiation.

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References

• Stelara Prescribing Information – Janssen Pharmaceuticals
• DrugBank: Ustekinumab
• StatPearls: Ustekinumab
• FDA Stelara Label – DailyMed
• PubMed Review on IL-12/23 Inhibition

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