Omalizumab

Description

Omalizumab is a recombinant humanized construct of murine IgG1k monoclonal antibody introduced for the treatment of allergic asthma. It forms complexes with free, circulating serum IgE, which results in the inhibition of binding of IgE to the high-affinity IgE-receptor (FCeRI) on the surface of mast cells and basophils. Reduction in surface-bound IgE on FceRI-bearing cells limits the degree of release of mediators of the allergic response. Omalizumab is produced by a Chinese hamster ovary cell suspension culture in a nutrient medium containing the antibiotic gentamicin. The recommended dosage is 150–375 mg administered subcutaneously every 2 or 4 weeks. Omalizumab has an average absolute bioavailability of 62% and an average terminal half-life of 26 days. Following a single SC dose, omalizumab is absorbed slowly, reaching peak serum concentrations after 7–8 days. However, serum levels of free IgE begin to decline in a dosedependent manner within an hour after the first injection and typically lead to ＞96% reduction in free IgE concentrations. The omalizumab-IgE complexes have a longer half-life and are eliminated more slowly than free IgE. After 16 weeks of dosing, total serum IgE (free plus bound IgE) is five times higher than pretreatment levels. Clearance of the omalizumab-IgE complexes occurs via the Fcg receptors reticuloendothelial system. The efficacy and safety of omalizumab in the treatment of inhaled corticosteroid-dependent (ICS) asthma was evaluated in a 28-week doubleblinded, placebo-controlled clinical study, which entailed co-administration of ICS for 16 weeks, followed by a gradual reduction in ICS dose over 12 weeks. A significant reduction in steroid dose with fewer exacerbations during steroid withdrawal phase was noted and more subjects receiving omalizumab were able to discontinue their ICS than in the placebo group (39.6 vs 19.1%, respectively; p ＜0.001). Omalizumab was well tolerated and the most common adverse effects were arthralgia, generalized pain, leg pain, and injection-site reactions.

Originator

Genentech (US)

Uses

Treatment of atopic disease (asthma; rhinitis) (monoclonal antibody).

brand name

Xolair (Genentech).

Mechanism of action

Additional amino acid sequences have been incorporated into the antibody so that a humanized product resulted that only differs by 5% nonhuman amino acid residues. In vitro, omalizumab has been shown to complex with free IgE, forming trimers consisting of a 2:1 complex of IgE to omalizumab or a 1:2 complex of IgE to omalizumab. In addition, larger complexes also are formed, consisting of a 3:3 ratio of each. Omalizumab does not bind to IgE already bound to mast cells and, therefore, does not cause the degranulation that might be expected from such interaction. Thus, omalizumab effectively neutralizes free IgE and, aside from the obvious decrease of available IgE, also causes the down-regulation of FcεRI receptors on the mast cell surface, resulting in a decrease of IgE bound to the mast cell.

Pharmacokinetics

The bioavailability after subcutaneous administration is 62%, with slow absorption resulting in peak serum levels in 7 to 8 days from a single dose. Steady-state plasma concentration is reached in 14 to 29 days with multiple dosing regimens. The elimination of omalizumab is not clearly understood; however, studies have determined that intact IgE is excreted via the bile and that omalizumab:IgE complexes are cleared faster than uncomplexed omalizumab and slower than free IgE. This means that over time, total IgE concentrations (free and complexed IgE) increase, because the complex is cleared more slowly. The metabolism of omalizumab is not known, and the clearance of the complex is similar to the liver elimination of another immunoglobulin, IgG. The reticuloendothelial system degrades IgG, and it is believed that the same process occurs for the omalizumab:IgE complex.

Clinical Use

The clinical role for omalizumab is in the treatment of allergic asthma. It is approved for the treatment of adults and adolescents 12 years of age and older whose symptoms are not controlled with inhaled glucocorticoids and who have a positive skin test for airborne allergens.

Raw materials

Preparation Products