Clinical pharmacology: natalizumab

1. Domina Petric, MD

2. Integrins are a family of adhesion
molecules on the surface of leukocytes.
They may interact with another class of
adhesion molecules on the surface of the
vascular endothelium: selectins.
Circulating leukocytes adhere to the
vascular endothelium and move through the
vessel wall into the tissue by interaction
between integrins and selectins.

3. Natalizumab is a humanized IgG4
monoclonal antibody targeted against the
α4 subunit.
It blocks several integrins on circulating
inflammatory cells.
It prevents binding to the vascular
adhesion molecules and subsequent
migration into the surrounding tissues.

4. It has shown significant efficacy for a
subset of patients with moderate to
severe Crohn´s disease.
In clinical trials 3 of 3100 patients
developed progressive multifocal
leukoencephalopathy due to reactivation
of a human polyomavirus (JC virus).
JC virus is present in latent form in over
80% of adults.

5. Despite that, FDA approved natalizumab
for the treatment of patients with
moderate to severe disease, who have
failed other therapies, through a carefully
restricted program.
Dosage is 300 mg every 4 weeks by
intravenous infusion.
Patients should not be on other immune
suppressant agents!

6. Approximately 50% of patients
respond to initial therapy with
natalizumab.
Long-term response is maintained in
60% and remission in over 40%.
Other adverse effects are acute
infusion reactions and a small risk of
opportunistic infections.

7. Katzung, Masters, Trevor.
Basic and clinical
pharmacology.