Mechanism of Action of Natalizumab (Tysabri)

Introduction

Natalizumab is a humanized IgG4 monoclonal antibody targeting the α4 integrin subunit. It’s approved for relapsing-remitting multiple sclerosis (RRMS) and moderate to severe Crohn’s disease. By blocking leukocyte adhesion, it prevents immune cell migration into the brain and gut.

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Step-by-Step Mechanism of Action

1. Binding to α4 integrin
   Natalizumab binds to the α4 subunit on leukocytes, including lymphocytes and monocytes.
2. Blocking α4β1 and α4β7 integrins
   It prevents α4β1 interactions with VCAM-1 (vascular cell adhesion molecule–1) in the CNS and α4β7 interactions with MAdCAM-1 in the GI tract.
3. Inhibition of leukocyte adhesion and migration
   Leukocytes are unable to cross endothelial barriers in the brain and gut, reducing inflammation in MS and Crohn’s disease.
4. Decreased inflammatory damage
   Preventing immune cell infiltration leads to decreased demyelination in MS and mucosal inflammation in the gut.
5. Modulation of immune activity
   Peripheral lymphocytes remain functional, maintaining overall immune system competence outside target tissues.

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Pharmacokinetic Parameters

Parameter	Value
Route	Intravenous infusion
Half-life	~11 days
Distribution	Primarily vascular and extracellular fluid
Metabolism	Proteolytic catabolism
Excretion	Catabolized into peptides and amino acids

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Clinical Uses

• Relapsing-remitting multiple sclerosis (RRMS)
• Moderate to severe Crohn’s disease (after conventional therapy failure)

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Adverse Effects

• Infusion-related reactions
• Increased risk of progressive multifocal leukoencephalopathy (PML)
• Infections (e.g., herpes, respiratory)
• Rare hepatotoxicity or hypersensitivity reactions

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Comparative Analysis

Agent	Target Integrins	PML Risk	Indications
Natalizumab	α4β1 & α4β7	High	MS, Crohn’s
Vedolizumab	α4β7 only	Low	Ulcerative colitis, Crohn’s
Etrolizumab	β7 integrins	Low	Under investigation

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MCQs

1. Natalizumab primarily binds to which integrin subunit?
   a) β2 b) α4 c) β7 d) αEβ7
   Answer: b) α4
2. In MS, blockade of α4β1/VCAM-1 prevents leukocyte migration into the:
   a) Liver b) Gut c) Brain d) Skin
   Answer: c) Brain
3. In Crohn’s disease, blocking α4β7 prevents leukocyte migration into the:
   a) Brain b) Lungs c) Gut d) Pancreas
   Answer: c) Gut
4. A concerning adverse effect is:
   a) Diabetes b) Progressive multifocal leukoencephalopathy c) Hypothyroidism d) Hyperlipidemia
   Answer: b) Progressive multifocal leukoencephalopathy
5. Natalizumab differs from vedolizumab in that it blocks:
   a) α4β7 only b) α4β1 and α4β7 c) TNF‑α d) IL‑6R
   Answer: b) α4β1 and α4β7
6. Its typical half-life is approximately:
   a) 3 days b) 11 days c) 30 days d) 1 day
   Answer: b) 11 days
7. Which route is used for administration?
   a) Oral b) Intravenous c) Subcutaneous d) Intramuscular
   Answer: b) Intravenous
8. Which infection risk is most associated with natalizumab?
   a) Tuberculosis b) PML (JC virus) c) CMV colitis d) Candida
   Answer: b) PML (JC virus)
9. Compared to etrolizumab, natalizumab blocks integrins:
   a) α4β1 & α4β7 b) Only β7 c) Only α4 d) αLβ2
   Answer: a) α4β1 & α4β7
10. Why does natalizumab preserve systemic immunity?
    a) It targets only B cells b) It blocks migration into specific tissues only c) It depletes leukocytes d) It’s short acting
    Answer: b) It blocks migration into specific tissues only

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FAQs

1. Why is there a PML risk with natalizumab?
Blocking immune cell entry into the CNS reduces surveillance for JC virus, raising PML risk.

2. How often is natalizumab given?
Standard dosing is every 4 weeks via IV infusion.

3. Is JC virus testing required?
Yes—patients must be monitored regularly for JC virus antibodies and MRI changes.

4. Can it be used with TNF inhibitors?
No—combined immunosuppression significantly increases infection risk.

5. Can therapy be paused?
Interrupting treatment may lead to disease rebound; decisions must be made carefully.

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References

• Prescribing Information: Natalizumab (Tysabri)
• PubMed: Natalizumab mechanism in MS and Crohn’s
• DrugBank: Natalizumab Summary
• StatPearls: Natalizumab in MS
• PubMed Central: Mechanism of leukocyte trafficking inhibition