What Are Antibodies? The primary role of the human immune system is to recognize foreign substances, known collectively as antigens, and to protect the body from them. One of the immune system's natural defenses against these antigens (e.g., disease-causing bacteria, viruses) is called antibodies. Antibodies protect the body's healthy cells through their special structural characteristics that allow them to bind specifically to particular antigens and, by doing so, allow the body to safely remove them.

In 1975, British scientists recognized the potential of using antibodies to fight disease and invented a process for generating large quantities of identical antigen-specific antibodies that would later be used to generate "therapeutic antibodies."

Creating Therapeutic Antibodies The first step in creating therapeutic antibodies is to inject a mouse with the specific antigen of interest. The mouse will develop an immune response to the antigen and produce many different antibodies to the antigen from specialized cells found in its spleen, called B lymphocytes. This is called a polyclonal antibody response.

Next, the B lymphocytes are removed from the mouse and fused in vitro (outside the body) to myeloma cells, a transformed type of B lymphocyte that is capable of replicating in high numbers nearly indefinitely. This fusion results in a hybrid cell clone called a hybridoma that produces a specific antibody. This hybridoma will replicate itself and continually produce large quantities of identical antibodies.

The final step in therapeutic antibody development involves isolating and culturing different hybridomas to determine the ability of each to reproduce the desired antibody, and then testing the binding ability of the antibody to the antigen of interest. The hybridoma cells found to secrete the desired antibody can be further cultured to produce more of the antibody, or frozen for production of the antibody at a later time.

Emergence of "Humanized" Therapeutic Antibodies Early therapeutic antibodies were not optimally effective as therapeutics for humans, predominantly because these mouse-derived antibodies were recognized as foreign to the body. As a result, the immune system produced antibodies against them, destroying most of their therapeutic effects. This is known as the Human Anti-Mouse Antibody (HAMA) response.

To overcome the HAMA response, researchers used recombinant DNA technology to create "humanized" therapeutic antibodies, where the majority of the mouse-derived portions of the antibody molecule are replaced with human-derived portions. This modification of the molecule helps to reduce or eliminate HAMA rejection of these therapeutic antibodies by the patient's immune system, thus making them more effective.

Manufacturing a Humanized Therapeutic Antibody: Xolair® (Omalizumab) Since genetically engineered and humanized biologic therapies such as Xolair are produced in living cells, the manufacturing of protein-based therapeutics, specifically humanized therapeutic antibodies, is a complex process, more costly and difficult than the manufacturing of traditional small molecule or chemically synthesized drugs.

Biotechnology's unique approach to making pharmaceuticals has been to use human proteins as drugs rather than the chemicals of traditional pharmaceuticals. The first step in the manufacturing of Xolair is to genetically engineer a cell so that it produces the antibody. This requires introducing the genetic information, or DNA, that provides the cell with the instructions it needs to produce Xolair. Once a cell has been engineered to express the product, it is used to establish a cell line (i.e. thousands of copies of the original cell). This cell line is then frozen and stored for use in the manufacturing process.

To begin the production cycle, a small vial of cells is thawed out and allowed to grow in culture for several days. Once the cells have undergone several rounds of replication, they are transferred to a larger container where they are prepared to undergo fermentation. The media in which the cells are grown and the levels of oxygen, nitrogen and carbon dioxide that exist during the production cycle may have a significant impact on the production process. Growth parameters are determined specifically for each cell line and these parameters are measured frequently to assure optimal growth and production conditions.

When the cells grow to sufficient numbers, they are transferred to large-scale production tanks and grown for approximately two weeks. At this point in the process, the antibody can be harvested. The cells are engineered to secrete the antibody into the cell culture media, so the first step in the purification process is to separate the cells from the media. The media is then subjected to several additional purification steps that remove any cellular debris, unwanted proteins, salts, minerals or other undesirable elements. At the end of the purification process, Xolair is highly pure and is suitable for human use. The bulk product is then filled into glass vials and freeze-dried to obtain finished product in dry powder form. Freeze-drying ensures that Xolair remains stable throughout its shelf life. The finished vials are then packaged and delivered to physicians' offices.

About Xolair

• Xolair® (omalizumab) for subcutaneous use is an injectable, prescription medicine for patients ages 12 and older. It is for patients with moderate to severe persistent allergic asthma caused by year-round allergens in the air. A skin or blood test is done to see if a person has allergic asthma. Xolair is for patients who are not controlled by asthma medicines called inhaled steroids.
• Xolair helps reduce the number of asthma attacks in people with allergic asthma who still have asthma symptoms even though they are taking inhaled steroids.
• Xolair has not been proven to work in other allergic conditions. Xolair is not a rescue medicine and should not be used to treat sudden asthma attacks. Xolair should not be used in children under 12 years of age.

Important Safety Information

XOLAIR should always be injected in a doctor’s office. Patients should read the Medication Guide before starting XOLAIR treatment and before each and every treatment.

A severe allergic reaction called anaphylaxis has happened in some patients after they received XOLAIR.  Anaphylaxis is a life-threatening condition and can lead to death. Patients must seek emergency medical treatment right away if symptoms occur. 

Signs and symptoms of anaphylaxis include:

• wheezing, shortness of breath, cough, chest tightness, or trouble breathing
• low blood pressure, dizziness, fainting, rapid or weak heartbeat, anxiety, or feeling of "impending doom"
• flushing, itching, hives, or feeling warm
• swelling of the throat or tongue, throat tightness, hoarse voice, or trouble swallowing

Anaphylaxis from XOLAIR can happen:

• right after receiving a XOLAIR injection or hours later
• after any XOLAIR injection.  Anaphylaxis has occurred after the first XOLAIR injection or after many XOLAIR injections.

A patient’s healthcare provider should watch the patient for some time in the office for signs or symptoms of anaphylaxis after injecting XOLAIR.  If patients have signs or symptoms of anaphylaxis, they must tell their healthcare provider right away.

Patients must not receive XOLAIR if they have ever had an allergic reaction to a XOLAIR injection. Patients should not use XOLAIR if they are allergic to any of its ingredients.      

In clinical studies, a variety of cancer types, including breast, skin, prostate, and parotid (a type of salivary gland), were reported in more patients who received XOLAIR than in patients who did not receive XOLAIR.

XOLAIR is not a rescue medicine and should not be used to treat sudden asthma attacks.

XOLAIR is not a substitute for the medicines patients are already taking.  Patients must not change or stop taking any of their other asthma medicines unless their doctor tells them to do so.

Some patients on XOLAIR may have an abnormal increase in eosinophils (a type of white blood cell) in the blood or tissues, sometimes causing an inflammation of blood vessels which can lead to rash, worsening of respiratory symptoms, heart trouble, and/or nerve pain and weakness. 

Joint inflammation or pain, rash, fever, and swollen lymph nodes have been seen in some patients taking XOLAIR after the first or subsequent injections.  Patients should talk to their doctor if they have experienced any of these signs and symptoms. 

The most commonly seen side effects occurring more frequently in patients receiving XOLAIR than in patients who received placebo (an injection with no active medicine) were joint pain, pain (general), leg pain, tiredness (fatigue), dizziness, fracture, arm pain, itching, inflammation of the skin, and earache. 

In asthma studies, the most common side effects in patients, who either needed to stop XOLAIR or needed medical attention, were injection site reaction, viral infections, upper respiratory tract infection, sinusitis, headache, and sore throat.  These side effects were seen at similar rates in XOLAIR-treated patients as in patients that did not receive XOLAIR.   

There are other possible side effects with XOLAIR.  Patients should talk to their doctor for more information and if they have any questions about their treatment.

XOLAIR has not been studied in pregnant women.  Pregnant women exposed to XOLAIR are encouraged to enroll in the XOLAIR Pregnancy Exposure Registry.  Patients can get more information by calling 1-866-4XOLAIR (1-866-496-5247) or by speaking with their doctor.

Please visit www.xolair.com for the full Prescribing Information, including Boxed WARNINGS and Medication Guide for additional important safety information.