How Xolair (Omalizumab) Works
Xolair is a recombinant humanized monoclonal antibody that selectively binds to the Fc portion of circulating IgE, preventing IgE from attaching to high-affinity receptors (FcεRI) on mast cells and basophils, thereby blocking the allergic cascade. 1
Primary Mechanism of Action
Omalizumab binds to free circulating IgE at the Cε3 domain, which is the specific site where IgE normally attaches to its high-affinity receptor (FcεRI) on effector cells 2, 1
This binding prevents IgE from attaching to mast cells and basophils, rendering these cells unable to recognize allergens and preventing their activation by antigens 3, 4
Without surface-bound IgE, mast cells and basophils cannot release histamine and other inflammatory mediators in response to allergen exposure, thus preventing allergic and asthmatic symptoms 3, 4
Secondary Downstream Effects
Omalizumab causes down-regulation of FcεRI receptor expression on the surface of basophils, mast cells, and dendritic cells 2, 1
Free serum IgE levels are reduced in a dose-dependent manner by greater than 96% within 1 hour following the first dose when using recommended doses 1
In allergic asthmatics, omalizumab inhibits IgE-mediated inflammation, as evidenced by reduced blood and tissue eosinophils and reduced inflammatory mediators including IL-4, IL-5, and IL-13 1
The reduction in basophil FcεRI receptor expression occurs rapidly, while the time course for decreased FcεRI expression in skin mast cells is slower but still associated with decreased acute allergen wheal size 5
Important Pharmacodynamic Considerations
The immune complexes formed between IgE and omalizumab are relatively small (molecular weight <1 million) and therefore unlikely to cause organ damage 6
Omalizumab does not bind to IgE already attached to cell surfaces, nor does it induce histamine release from basophils or recognize IgG 6
Total serum IgE levels increase during treatment (by 1.5-8.6 fold) as IgE-omalizumab complexes accumulate, while free IgE levels fall by 45-98% 7
Clinical Context and Indications
The National Asthma Education and Prevention Program recommends omalizumab as adjunctive therapy for patients aged 12 years and older with severe persistent allergic asthma inadequately controlled with high-dose inhaled corticosteroids plus long-acting beta-agonists 2, 8
Omalizumab is specifically indicated for patients with documented atopy and proven sensitivity to perennial aeroallergens, not for non-allergic asthma 2, 8
In chronic spontaneous urticaria, omalizumab binds to IgE and lowers free IgE levels, subsequently causing IgE receptors to down-regulate, though the exact mechanism by which this improves urticaria symptoms remains unknown 1