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Humanized Monoclonal Antibody Therapies in Neoplastic Disease

Posted on October 21, 2018 in Uncategorized

In the last ten years the treatment of many types of cancer has been revolutionized by monoclonal antibody therapies. There are many, many print and audiovisual advertisements for these drugs bringing them into the public mainstream.. So, this brings to point some important questions: 1) What are monoclonal antibodies? 2) What types of cancer are treatable by this therapy? 3) What is the basic mechanism of action, i.e., How do these drugs work?

Antibodies are the body’s natural immune defense against invading pathogens. They are produced by specific cells of the immune system termed B cells. When an infection of the body occurs, the immune system takes note. After a brief time, when the front line defenses of the immune system battle the infection, [termed the innate immune response- the first line of battle], the cellular part of the fight takes over [the adaptive response]. The adaptive immune response involves antigen presenting cells, T and B cells. Very briefly, what happens within your body when an infection occurs is this: Circulating “detectives” called macrophages and dendritic cells find the infection and literally eat it or eat cells infected [in the case of a viral infection]. The cells then “present” specific protein parts of the eaten pathogen [bacteria or virus–called antigens] to cells called T and B cells. This is a call to arms: this is literally a scream saying “time to kick butt” by the immune system. The T cells are activated by the B cells upon finding the presenting antigen. The B cells then decide that they can better fight by changing themselves into a plasma cell. This is where the action happens. The B cell changes into a protein pumping machine, the protein being antibodies. The antibodies then go find from the blood the pathogen that the original antigen presenting cells early in the infection encountered. When the antibodies find their target, they bind to it and mark it for death. Think of this as a ball with toilet plungers attached. The wooden handle is what tells the immune system, “this thing needs to die”.

This is the basic theory behind monoclonal cancer therapy. Except in the context of monoclonal antibody cancer treatment, the antibodies are produced to a single epitope (a particular protein that the immune system readily sees from a cancer cell). These cells are then taken into the laboratory, grown and stimulated to produce a single antibody that “sees” a cancer cell.

An example of monoclonal antibody treatment in cancer is Herceptin. Herceptin is a monoclonal antibody specific for an antigen called HER2. HER2 is a protein that is more prevalent on cancer cells of the breast than in normal cells. This protein is from a family of receptors that tells normal cells to grow. The drug then takes advantage of this and can specifically target cancer cells of the breast in order to kill them. This drug too has side effects of being NOT heart friendly.

Another good example of neoplastic cancer therapy is the drug termed Rituxan (Rituximab). Rituxan is a monoclonal antibody directed towards the antigen CD20 on circulating lymphocytes of the blood and is indicated for the treatment of non-Hodgkin’s lymphoma. It works by depleting the blood of cells that have over-produced cells that have CD20 on their cell surface. When the antibody binds, like Herceptin, the body sees those cells as foreign and kills them.

So, the question is now that we know what neoplastic antibody therapy is, how does this killing work?
The current research and thinking is that when cancer cells are coated by these antibody drugs, the extending end of the antibody [called the Fc portion] attracts Natural Killer, NK, cells from the immune system. These cells actually have receptors that recognize this very event. When NK cells find antibody coated cells, they bind to them tightly and commence to kill them. The close proximity of the two cells allows the NK cell to release protein degradating enzymes, and other cytotoxic elements to kill the target.
This entire process is termed Antibody Dependent Cellular Toxicity, ADCC.

ADCC is a powerful tool being utilized by numerous biotech companies with the intent to augment the immune response with other, novel drugs. Such drugs that come to mind are TLR agonists, chemotherapy drugs and gene transfer strategies.

Genentech makes Herceptin, while Rituximab is in combination with Biogen Idec/Genentech. Both drugs are multimillion dollar assets to both companies. The side effects of Herceptin have been documented and are under intense research to understand them. Rituxan continues to be a key element to the bottom line of both companies with it’s successful treatments.

Herceptin is produced by Genentech.
Rituxan is another monoclonal antibody treatment indicated for the treatment of lymphoma.