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HERCEPTIN®, A Monoclonal Antibody

Antibodies are the body’s natural response to antigens (antibody generators). Naturally, a whole range of antibodies of different specificity are produced by the body as an answer to a specific antigen, hence given a polyclonal antiserum. The cells responsible for the production of antibodies are the plasma cells, mature B cells being stimulated by theantigen. The cancerous B cells would grow in culture; these are called myelomas.

Monoclonal antibodies as therapeutic agents with defined specificity have their beginnings in the latest quarter of the 20th century.
Monoclonal antibodies are produces in bulk quantities in laboratories. Production starts from a single cell, thus all replicas are identical, hence their name. Myeloma cells are taken inorder to produce hybrid cells (hybridomas) when combined with plasma cells. This would grow In Vitro and continue to secrete antibodies with defined specificity which are the ‘monoclonal antibodies’.
Humanized monoclonal antibodies have to be used in order to be accepted by the human body. They are normally 90% human -10% mouse to reduce the body’s immune response.

Herceptin® (Trastuzumab)from Genentech Inc. was the first recombinant DNA-derived humanized monoclonal antibody approved by the FDA in 1998 for the treatment of patients that test HER2 positive in breast cancer.
The drug is used for breast cancer treatment in 30% of the cases, when HER2 protein is over-expressed, i.e. in excess.
As HER2 is both normal gene and one that has the ability to cause cancer, it is calledoncogen.

Monoclonal antibodies are named according to their composition. All of them end with the suffix “mab” for monoclonal antibody. If the source is purely from mouse an ‘o’ is added, giving “omab”; chimeric antibodies from combining mouse and human get the letters ‘xi’ before the suffix, giving “ximab”; finally humanized antibodies get the letters ‘zu’ before the end, giving “zumab”, as intrastuzumab.

The Human Epidermal growth factor Receptor 2 (HER2) is a gene that controls cell growth, division and repair. This gene produces HER2 receptors in cancer cells. In some breast cancers it is common that there are too many copies of the HER2 genes or the HER2 receptors grow too fast. It is in this cases that trastuzumab is used.

Patients with early breast cancer detection should becheck for possible treatment with trastuzumab. The drug is a monoclonal antibody binding to HER2 receptors, which is the protein that is overexpressed is one third of the breast cancers. It has been proved that if used at an early stage reduces risk of recurrence.

The two main receptors that are present in some breast cancers are estrogen hormone receptors and progesterone hormone receptors.Those are the ones that would respond to hormone therapy.

To accurately diagnose the type of breast cancer that the patient has and to target specific HER2 receptors, two major tests are available. Those should test positive to HER2 overexpression in order to proceed with Trastuzumab treatment. The tests are approved by the FDA and are the IHC and FISH tests.

Fluorescence In Situ Hybridization(FISH) test:
This test measures gene amplification, i.e. multiple copies of a gene present on the same chromosome. Fluorescent probes are used to mark HER2 genes in tumour cells. The FISH test gives positive if the cell copies of the HER2 gene is more that two which would be the normal.

ImmunoHistoCHemistry (ICH) test:
This test evaluates the HER2 receptor protein overexpression in tumours.It is based on the actual number of hormone receptors whose measure is given by values 0 (none), +1, +2, +3 (large amount of receptors).

It has been stated by multiple studies that patients that are rated +2 by the IHC test should be confirmed with the FISH test for HER2 positive.

The basic concept behind the structure of trastuzumab is based in the relation antigen-antibody.

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