Herceptin for Treatment of Breast Cancer

Herceptin 

Trade Name: Herceptin Generic Name: Trastuzumab

Structure:

In 2018 Herceptin was number 4 in the Top 10 Biopharmaceutical Drugs, based on USA sales monitoring 2017, Biotech Industry. Global sales in 2017 were $7.4 billion.

Description of disease:

Herceptin is a major drug for treating HER2-positive breast cancer, it is a humanized monoclonal antibody that binds the extracellular domain IV of HER2. Herceptin is very efficient in patients with breast cancer, but it often poses therapeutic challenges due to resistance of its effects. Clinical data showed that some patients either originally do not respond to Herceptin or become resistant during the treatment with the majority of cancers that initially respond to Herceptin beginning to progress again within 1 year.

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Breast cancer making up approximately 25% of all cancer diagnoses in 2012 and being one of the most common types of cancer it is fortunate that HER2 targeted therapies were developed such as trastuzumab known as Herceptin in the 90s by (F. Hoffmann-La Roche Ltd). It helps to combat aggressive cancer. Breast cancer remains put at the second leading cause of death in women but there any many advances in treatment and diagnostics which have dramatically lowered death rates.

HER2 which stands for Human epidermal growth factor receptor 2 is a transmembrane tyrosine kinase. HER2 controls cellular division and repair in breast cancer cells. HER2+, which is also known as an overexpression of HER2 can result in uncontrolled growth and division of cells. HER2+ is among 20% of all invasive breast cancers. Only 2-5% of HER2+ breast cancer patients were seen as long term survivors before new treatments such as Herceptin became available.

The use of Herceptin in pregnancy should be questioned. It may be associated with reduced amniotic fluid volume. It is also associated with reversible and irreversible kidney damage.

Drug Type:

Herceptin is an Antibody Drug. Antibodies also known as immunoglobulins, which are naturally produced glycoproteins. They are produced when foreign particles called antigens invade. These foreign particles may be microorganisms and viruses. They play a major role in immune defence to protect against infections and diseases. Antigens identified and bound by antibodies can be proteins for example receptors on cancer cells, sugars on bacterial and viral cell surfaces, chemical compounds hormones and nucleic acid structures. An epitope is the region of an antigen that interacts with an antibody. Herceptin was the first monoclonal antibody used to treat cancer successfully. Herceptin is designed to attach to a protein known as HER2.

Manufacturer:

Herceptin is a Medicine owned by Genentech which is now a subsidiary of Roche. Genentech campus is based in the south of San Francisco, California and serves as Genentech’s headquarters, which is also headquarter for Roche pharmaceutical operations in the US. Genentech is a top biotechnology company that discovers, further develops, manufactures and markets pharmaceuticals for human’s medical needs which are unmet. Genentech markets 6 of their 11 currently marketed biotechnology products directly in the US. The company is traded on the stock exchange in New York and the Pacific Exchange. It is found under the symbol GNE.

Genentech and Wyeth Pharmaceuticals reached an agreement that Wyeth would manufacture Herceptin bulk drug substance for Genentech at Wyeth’s production facility in Andover, Massachusetts.

FDA approval record:

Herceptin was first approved in September 1998 by the FDA as the first antibody-targeted therapy used for breast cancer. It is indicted for treatment of patients as both first-line therapy together with paclitaxel and as a single agent in second and third-line therapy.

In clinical trials of HER2-positive metastatic for breast cancer patients, Herceptin in together in combination with chemotherapy was the first anti-HER2 agent to show an improvement in survival in a trial at Phase 3. Genentech received FDA approval in December 2001 to include in the product label, data that showed an improved median survival overall for women with HER2 positive metastatic breast cancer initially treated with Herceptin and chemotherapy, compared to chemotherapy alone.

Since 1998. Herceptin has been given to more than 1.3 million patients worldwide. Research continues to make it easier to administer the drug. A new formulation of the drug was approved in Europe in September 2013, which allows it to be given to patients by Injection which takes 5 minutes and opposed to intravenous drip which took up to 90 minutes previously.

Production method:

In 1982 the HER2 protein was discovered in neurological tumours in rats. Then in 1985, the first monoclonal antibodies to target against HER2 showed they could reduce tumour growth in mice and extend survival. In 1987 researchers showed high levels of HER2 in women with breast cancer was linked with a low survival rate. This meant that just like mice the monoclonal antibody could work in humans too.

Researchers then began injecting mice with HER2 to develop an antibody treatment to target HER2. Antibodies develop when the mouse’s immune system tries to get rid of the HER2 protein. The B-cells that manufacture the antibodies were extracted from the mouse’s spleen. These cells have a limited lifespan therefore they cannot be grown in the lab long enough to produce sufficient antibodies for medical testing. The spleen cells are then fused with special human myeloma cells. These cells can replicate immediately and are used regularly by scientists for research. The fused cells are called hybridomas. Once grown enough the cells are screened to find a cell that produces an antibody targeting HER2. Monoclonal antibodies are produced from an original single cell meaning there is no mixture of different types of antibodies. Side effects are then reduced as all of the antibodies given to the patient work in the same way.

It can trigger an immune reaction if a mouse antibody is given directly to humans. The human immune system recognises that it is foreign. The genes for producing the Herceptin antibody are altered to make them more human like, to avoid this happening. Herceptin is made by DNA that is 95% human and 5% mouse. It tricks the immune system into thinking that is it human and so ignoring it, but it keeps HER2 targeting section from the mouse at the tips of the antibody, so it can bind to HER2.

The new humanised gene for the antibody is then placed inside Chinese Hamster ovaries. These cells can then be grown in unlimited amounts and the antibodies are extracted from them and given to the patients.

Mechanism of action/how it treats diseases.

Treatment methods for breast cancer are not very specific and they all have their disadvantages. Therefore, scientists are looking for new ways in which specifically affect cancer cells.

Herceptin works by blocking the chemical signals on the surface of cancer cells. They stimulate the uncontrollable growth of cancer cells.

On the surface of breast cancer cells, the Herceptin works by attaching to the HER2 receptors. The Herceptin then blocks the receptors from receiving growth signals. Due to the blocking of the signals the Herceptin can slow down or stop the growth of breast cancer, an example of an immune targeted therapy is Herceptin. Herceptin also helps to fight breast cancer by alerting the immune system to kill cancer cells which are attached, as-well as blocking the HER2 receptors.

Fig: Proposed mechanism of action for Herceptin.

References:

Images:

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