Omalizumab
Encyclopedia
Omalizumab is a humanized antibody
drug approved for patients with moderate-to-severe or severe allergic asthma
, which is caused by hypersensitivity
reactions to certain harmless environmental substances. Omalizumab's cost is high ($10,000 to $30,000 per year), as compared to other drugs used for asthma, and hence omalizumab is mainly prescribed for patients with severe, persistent asthma, which cannot be controlled even with high doses of corticosteroids. Like other protein and antibody drugs, omalizumab causes anaphylaxis
(a life-threatening systemic allergic reaction) in 1 to 2 patients per 1,000.
Omalizumab is a recombinant DNA-derived humanized IgG1k monoclonal antibody that selectively binds to human immunoglobulin E
(IgE). IgE is commonly involved with allergies when present in high amounts in the body.
, uncontrollable with corticosteroids. The efficacy is more evident among severe asthmatics than among those with moderately severe disease. The response rates among treated severe "allergic" asthma patients are 60-80%, probably depending on the patient screening procedures used by the various clinical groups of different specialties. Because 30-40% of adult asthma cases are not related to allergy and unresponsive to omalizumab, a reliable way to identify treatable patients has been a subject of considerable research interest. The primary benefits for the responding patients are reduced numbers of exacerbations, improved lung function, reduced numbers of emergency visits to the doctors, reduced days of hospitalization, and increased quality of life measurements. The other major benefit is that most responding patients can reduce or spare entirely the use of corticosteroids.
Due to the lack of sufficient information on the long-term effectiveness and side effects of the drug, omalizumab treatment is not yet very common, and can be expensive. Another barrier to prevalent use is the injectable dosage form, which requires the patient to visit a physician's office or clinic every 2 to 4 weeks during treatment. Additionally, as IgE could be a natural defense against parasitic diseases, treatment is usually not recommended when living in environments where the presence of parasites is common.
.
A warning found on the package insert of the manufacturered product states that during clinical trials there was a small increase in the number of patients who developed cancer
while taking omalizumab as opposed to patients who did not. The increased risk of cancer was not significant occurring in 0.5% of people treated for less than one year as opposed to 0.2% of people not treated. Therefore, it cannot be said for certain whether the increase in cancer was simply random chance or a true adverse effect of omalizumab.
IgE might play an important role in the immune system's recognition of cancer cells, so indiscriminate blocking of IgE / receptor
interaction might have unforeseen problems. There is a possible small increased risk of cancer in those taking omalizumab. Concerns have also been raised about possible induction of Churg-Strauss syndrome
, nasal polyp
s, and adrenal insufficiency
.
on IgE that overlaps with the site to which FcεRI binds. This feature is critical to omalizumab's pharmacological effects because a typical anti-IgE antibody can cross-link cell surface FcεRI-bound IgE and induce mediator release from basophils and mast cells. The epitope to which omalizumab binds is sterically hindered by the receptor when IgE is bound to the receptor and is therefore not accessible to omalizumab binding, preventing an inadvertent anaphylactic reaction. However, by binding to IgE in solution, omalizumab prevents IgE binding to cell surface receptor. Although the binding peptide sequence on IgE that is used to bind to low affinity IgE receptor (FcεRII) is different from the sequence used to bind to FcεRI, omalizumab, by steric hindrance, also prevents binding of IgE to FcεRII. Reduction in surface bound IgE on FcεRI-bearing cells limits the degree of release of mediators of the allergic response. Treatment with Xolair also reduces the number of FcεRI receptors on basophils in atopic patients.
, a biopharmaceutical
company based in Houston, Texas, started the anti-IgE program, created antibody drug candidates, and filed its first patent application on the anti-IgE therapeutic approach in 1987. In the next year, the company converted one candidate antibody to a chimeric antibody (which was later named CGP51,901 and further developed into a humanized antibody, talizumab
). The anti-IgE therapeutic concept was not well received in the early period of the program. In order to seek funding for the anti-IgE program, the two scientist founders of Tanox, Nancy T. Chang, Ph.D. and Tse Wen Chang, Ph.D., visited about 25 pharmaceutical and larger biotech companies in the U.S., Canada, Europe, Japan, and other countries to discuss collaboration throughout 1989. Representatives of Ciba-Geigy (which merged with Sandoz
to form Novartis in 1996) thought the anti-IgE program scientifically interesting and executives from Tanox and Ciba-Geigy signed a collaborative agreement in 1990 to develop the anti-IgE program. In 1991-1995, scientists from Tanox and Ciba-Geigy ran a successful Phase I human clinical trial in Southampton, England and a Phase II trial in patients with severe allergic rhinitis
in Texas on CGP51,901. In the meantime, representatives of Genentech announced in 1993 that it also had an anti-IgE development program. After a lengthy legal entanglement, Tanox, Novartis, and Genentech formed a tripartite partnership to jointly develop the anti-IgE program in 1996. Omalizumab became the drug of choice for further development, because it had a better developed manufacturing process than TNX-901. Omalizumab, trade-named Xolair, received approval by the U.S. Food and Drug Administration (FDA) in 2003 for treating patients 12 years and older with moderate-to-severe allergic asthma. It has also received approval in many other countries for treating patients 12 years and older with severe allergic asthma. Researchers are also developing Omalizumab for pediatric allergic asthma and several other major allergic diseases, including allergic rhinitis. Major trials have also taken place to evaluate the effects of omalizumab on enhancing the efficacy and safety of allergen-based desensitization immunotherapy
. In August 2010, the National Institute for Clinical Excellence in the United Kingdom ruled that Omalizumab should not be prescibed on the NHS
to children under 12, causing widespread condemnation from asthma charities. NICE concluded that the high costs of the compound, over £250 per vial, did not represent a sufficiently high increase in quality of life.
. Previously, the drug could be self-administered.
ian cells. The molecule
is generated over a long fermentation
process in large-scale bioreactor
s. Once the fermentation is over, the product is purified by successive chromatography
steps and finally concentrated by UF/DF (paired ultra filtration / depth filtration). It is considered a highly complicated process in terms of process engineering
and automation
, which partially explains the drug's high cost.
Currently, Omalizumab is manufactured at the Novartis
Huningue
manufacturing site (France) through a partnership agreement with Genentech
.
Chinese hamster ovary cell suspension culture in a medium containing gentamicin is used to produce omalizumab.
Humanized antibody
Humanized antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. The process of "humanization" is usually applied to monoclonal antibodies developed for administration to humans...
drug approved for patients with moderate-to-severe or severe allergic asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
, which is caused by hypersensitivity
Hypersensitivity
Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...
reactions to certain harmless environmental substances. Omalizumab's cost is high ($10,000 to $30,000 per year), as compared to other drugs used for asthma, and hence omalizumab is mainly prescribed for patients with severe, persistent asthma, which cannot be controlled even with high doses of corticosteroids. Like other protein and antibody drugs, omalizumab causes anaphylaxis
Anaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
(a life-threatening systemic allergic reaction) in 1 to 2 patients per 1,000.
Omalizumab is a recombinant DNA-derived humanized IgG1k monoclonal antibody that selectively binds to human immunoglobulin E
Immunoglobulin E
Immunoglobulin E is a class of antibody that has been found only in mammals. IgE is a monomeric antibody with 4 Ig-like domains...
(IgE). IgE is commonly involved with allergies when present in high amounts in the body.
Medical uses
The primary use of omalizumab is for people with moderate to severe, persistent allergic asthmaAsthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
, uncontrollable with corticosteroids. The efficacy is more evident among severe asthmatics than among those with moderately severe disease. The response rates among treated severe "allergic" asthma patients are 60-80%, probably depending on the patient screening procedures used by the various clinical groups of different specialties. Because 30-40% of adult asthma cases are not related to allergy and unresponsive to omalizumab, a reliable way to identify treatable patients has been a subject of considerable research interest. The primary benefits for the responding patients are reduced numbers of exacerbations, improved lung function, reduced numbers of emergency visits to the doctors, reduced days of hospitalization, and increased quality of life measurements. The other major benefit is that most responding patients can reduce or spare entirely the use of corticosteroids.
Due to the lack of sufficient information on the long-term effectiveness and side effects of the drug, omalizumab treatment is not yet very common, and can be expensive. Another barrier to prevalent use is the injectable dosage form, which requires the patient to visit a physician's office or clinic every 2 to 4 weeks during treatment. Additionally, as IgE could be a natural defense against parasitic diseases, treatment is usually not recommended when living in environments where the presence of parasites is common.
Adverse effects
The main adverse effects from omalizumab is anaphylaxisAnaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
.
A warning found on the package insert of the manufacturered product states that during clinical trials there was a small increase in the number of patients who developed cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
while taking omalizumab as opposed to patients who did not. The increased risk of cancer was not significant occurring in 0.5% of people treated for less than one year as opposed to 0.2% of people not treated. Therefore, it cannot be said for certain whether the increase in cancer was simply random chance or a true adverse effect of omalizumab.
IgE might play an important role in the immune system's recognition of cancer cells, so indiscriminate blocking of IgE / receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
interaction might have unforeseen problems. There is a possible small increased risk of cancer in those taking omalizumab. Concerns have also been raised about possible induction of Churg-Strauss syndrome
Churg-Strauss syndrome
Churg–Strauss syndrome is a medium and small vessel autoimmune vasculitis, leading to necrosis. It involves mainly the blood vessels of the lungs , gastrointestinal system, and peripheral nerves, but also affects the heart, skin and kidneys. It is a rare disease that is non-inheritable and...
, nasal polyp
Nasal polyp
Nasal polyps are polypoidal masses arising mainly from the mucous membranes of the nose and paranasal sinuses. They are overgrowths of the mucosa that frequently accompany allergic rhinitis. They are freely movable and nontender.-Description:...
s, and adrenal insufficiency
Adrenal insufficiency
Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones , primarily cortisol, but may also include impaired aldosterone production which regulates sodium, potassium and water retention...
.
Mechanism of action
Omalizumab inhibits the binding of IgE to the high-affinity IgE receptor FcεRI by binding to an epitopeEpitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...
on IgE that overlaps with the site to which FcεRI binds. This feature is critical to omalizumab's pharmacological effects because a typical anti-IgE antibody can cross-link cell surface FcεRI-bound IgE and induce mediator release from basophils and mast cells. The epitope to which omalizumab binds is sterically hindered by the receptor when IgE is bound to the receptor and is therefore not accessible to omalizumab binding, preventing an inadvertent anaphylactic reaction. However, by binding to IgE in solution, omalizumab prevents IgE binding to cell surface receptor. Although the binding peptide sequence on IgE that is used to bind to low affinity IgE receptor (FcεRII) is different from the sequence used to bind to FcεRI, omalizumab, by steric hindrance, also prevents binding of IgE to FcεRII. Reduction in surface bound IgE on FcεRI-bearing cells limits the degree of release of mediators of the allergic response. Treatment with Xolair also reduces the number of FcεRI receptors on basophils in atopic patients.
History
TanoxTanox
Tanox was a biopharmaceutical company based in Houston, Texas. The company was founded by two biomedical research scientists, Nancy T. Chang and Tse Wen Chang in March 1986. Nancy was the President and CEO of the company in its 21 year history, while Tse Wen was responsible for creating most of the...
, a biopharmaceutical
Biopharmaceutical
Biopharmaceuticals are medical drugs produced using biotechnology. They include proteins , nucleic acids and living microorganisms like virus and bacteria where the virulence of viruses and bacteria is reduced by the process of attenuation, they can be used for therapeutic or in vivo diagnostic...
company based in Houston, Texas, started the anti-IgE program, created antibody drug candidates, and filed its first patent application on the anti-IgE therapeutic approach in 1987. In the next year, the company converted one candidate antibody to a chimeric antibody (which was later named CGP51,901 and further developed into a humanized antibody, talizumab
Talizumab
Talizumab is a humanized monoclonal antibody being developed by Tanox in Houston, Texas. It was designed to target immunoglobulin E and IgE-expressing B lymphocytes specifically, without binding to IgE already bound by the IgE receptors on mast cells and basophils...
). The anti-IgE therapeutic concept was not well received in the early period of the program. In order to seek funding for the anti-IgE program, the two scientist founders of Tanox, Nancy T. Chang, Ph.D. and Tse Wen Chang, Ph.D., visited about 25 pharmaceutical and larger biotech companies in the U.S., Canada, Europe, Japan, and other countries to discuss collaboration throughout 1989. Representatives of Ciba-Geigy (which merged with Sandoz
Sandoz
Founded in 2003, Sandoz presently is the generic drug subsidiary of Novartis, a multinational pharmaceutical company. The company develops, manufactures and markets generic drugs as well as pharmaceutical and biotechnological active ingredients....
to form Novartis in 1996) thought the anti-IgE program scientifically interesting and executives from Tanox and Ciba-Geigy signed a collaborative agreement in 1990 to develop the anti-IgE program. In 1991-1995, scientists from Tanox and Ciba-Geigy ran a successful Phase I human clinical trial in Southampton, England and a Phase II trial in patients with severe allergic rhinitis
Allergic rhinitis
Allergic rhinitis, also known as pollenosis or hay fever, is an allergic inflammation of the nasal airways.It occurs when an allergen, such as pollen, dust or animal dander is inhaled by an individual with a sensitized immune system...
in Texas on CGP51,901. In the meantime, representatives of Genentech announced in 1993 that it also had an anti-IgE development program. After a lengthy legal entanglement, Tanox, Novartis, and Genentech formed a tripartite partnership to jointly develop the anti-IgE program in 1996. Omalizumab became the drug of choice for further development, because it had a better developed manufacturing process than TNX-901. Omalizumab, trade-named Xolair, received approval by the U.S. Food and Drug Administration (FDA) in 2003 for treating patients 12 years and older with moderate-to-severe allergic asthma. It has also received approval in many other countries for treating patients 12 years and older with severe allergic asthma. Researchers are also developing Omalizumab for pediatric allergic asthma and several other major allergic diseases, including allergic rhinitis. Major trials have also taken place to evaluate the effects of omalizumab on enhancing the efficacy and safety of allergen-based desensitization immunotherapy
Immunotherapy
Immunotherapy is a medical term defined as the "treatment of disease by inducing, enhancing, or suppressing an immune response". Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies. While immunotherapies that reduce or suppress are...
. In August 2010, the National Institute for Clinical Excellence in the United Kingdom ruled that Omalizumab should not be prescibed on the NHS
National Health Service
The National Health Service is the shared name of three of the four publicly funded healthcare systems in the United Kingdom. They provide a comprehensive range of health services, the vast majority of which are free at the point of use to residents of the United Kingdom...
to children under 12, causing widespread condemnation from asthma charities. NICE concluded that the high costs of the compound, over £250 per vial, did not represent a sufficiently high increase in quality of life.
Delivery
The drug is administered subcutaneously once every 2 or 4 weeks. As of May 10, 2008, the company began requiring that the drug be administered by a patient's health care provider, due to a risk of anaphylaxisAnaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
. Previously, the drug could be self-administered.
Manufacturing
Omalizumab is a glycosylated monoclonal antibody expressed by mammalMammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
ian cells. The molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
is generated over a long fermentation
Fermentation (biochemistry)
Fermentation is the process of extracting energy from the oxidation of organic compounds, such as carbohydrates, using an endogenous electron acceptor, which is usually an organic compound. In contrast, respiration is where electrons are donated to an exogenous electron acceptor, such as oxygen,...
process in large-scale bioreactor
Bioreactor
A bioreactor may refer to any manufactured or engineered device or system that supports a biologically active environment. In one case, a bioreactor is a vessel in which a chemical process is carried out which involves organisms or biochemically active substances derived from such organisms. This...
s. Once the fermentation is over, the product is purified by successive chromatography
Chromatography
Chromatography is the collective term for a set of laboratory techniques for the separation of mixtures....
steps and finally concentrated by UF/DF (paired ultra filtration / depth filtration). It is considered a highly complicated process in terms of process engineering
Process engineering
Process engineering focuses on the design, operation, control, and optimization of chemical, physical, and biological processes through the aid of systematic computer-based methods...
and automation
Automation
Automation is the use of control systems and information technologies to reduce the need for human work in the production of goods and services. In the scope of industrialization, automation is a step beyond mechanization...
, which partially explains the drug's high cost.
Currently, Omalizumab is manufactured at the Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
Huningue
Huningue
Huningue is a commune in the Haut-Rhin department of Alsace in north-eastern France. Huningue is a northern suburb of the Swiss city of Basel. It also borders Germany . In 2008 it had a population of 6503 people...
manufacturing site (France) through a partnership agreement with Genentech
Genentech
Genentech Inc., or Genetic Engineering Technology, Inc., is a biotechnology corporation, founded in 1976 by venture capitalist Robert A. Swanson and biochemist Dr. Herbert Boyer. Trailing the founding of Cetus by five years, it was an important step in the evolution of the biotechnology industry...
.
Chinese hamster ovary cell suspension culture in a medium containing gentamicin is used to produce omalizumab.