Monoclonal antibodies

One way the immune system normally attacks foreign substances in the body is by making large numbers of different antibodies. An antibody is a “sticky” protein that targets a specific antigen. Antibodies circulate in the body until they find and attach to the antigen. Once attached, they recruit other parts of the immune system to destroy the cells containing the antigen.

Many copies of a specific antibody can be made in the lab. These are known as monoclonal antibodies (mAbs or moAbs). These antibodies can be useful in fighting diseases because they can be designed specifically to only target a certain antigen, such as one that is found on cancer cells.

Monoclonal antibodies are now used to treat many diseases, including some types of cancer. A major advantage of these drugs is that because they are so specific, they may have only mild side effects, unlike some other cancer treatments. But researchers first have to identify the right antigen to attack. For cancer, this is not always easy, and so far mAbs have proven to be more useful against some cancers than others. Over the past 15 years or so, the US Food and Drug Administration (FDA) has approved about a dozen mAbs to treat certain cancers.

As researchers have found more antigens that are linked to cancer, they have been able to make monoclonal antibodies against more and more cancers. Clinical trials of newer mAbs are now being done on many types of cancer.

Types of monoclonal antibodies

Two types of monoclonal antibodies are used in cancer treatments:

• Naked mAbs are antibodies that work by themselves. There is no drug or radioactive material attached to them. These are the most commonly used mAbs at this time.
• Conjugated mAbs are those joined to a chemotherapy drug, radioactive particle, or a toxin (a substance that poisons cells). These mAbs work, at least in part, by acting as homing devices to take these substances directly to the cancer cells.

Naked monoclonal antibodies

Most naked mAbs attach to antigens on cancer cells, but some work by binding to antigens on other, non-cancerous cells, or to even free-floating proteins.

Naked mAbs can work in different ways. Some may boost a person’s immune response against cancer cells. Others work by blocking specific proteins that help cancer cells grow. (Some may do both.)

Some naked MAbs attach to cancer cells to act as a marker for the body's immune system to destroy them. An example of this is alemtuzumab (Campath^®), which is used to treat some patients with chronic lymphocytic leukemia. Alemtuzumab is an antibody that binds to the CD52 antigen, which is found on immune cells called B cells and T cells. Once attached, the antibody triggers the destruction of the cell by the immune system.

Some naked mAbs work mainly by attaching to and blocking specific antigens that are important signals for cancer cells (or other cells that help cancer cells grow or spread). For example, trastuzumab (Herceptin^®) is an antibody against the HER2/neu protein. A large amount of this protein is present on the cells in some types of cancer. When HER2/neu is activated, it helps these cells grow. Trastuzumab stops these proteins from becoming active. It is used to treat breast and stomach cancers that have large amounts of this protein.

Conjugated monoclonal antibodies

Monoclonal antibodies attached to a radioactive substance, drug, or toxin, are called conjugated mAbs. The mAb is used as a homing device to take one of these substances directly to the cancer cells. The mAb circulates in the body until it can find and hook onto the target antigen. It then delivers the toxic substance where it is needed most. This lessens the damage to normal cells in other parts of the body.

Conjugated mAbs are also sometimes referred to as tagged, labeled, or loaded antibodies. They can be divided into groups depending on what they are linked to.

• mAbs with radioactive particles attached are referred to as radiolabeled, and treatment with this type of antibody is known as radioimmunotherapy (RIT).
• mAbs with chemotherapy drugs attached are referred to as chemolabeled.
• mAbs attached to cell toxins are called immunotoxins.

Radiolabeled antibodies: Radiolabeled antibodies have small radioactive particles attached to them. Ibritumomab tiuxetan (Zevalin^®) and tositumomab (Bexxar^®) are examples of radiolabeled mAbs. Both of these are antibodies against the CD20 antigen, but they each have a different radioactive particle attached. They deliver radioactivity directly to cancerous B cells and can be used to treat some types of non-Hodgkin lymphoma.

Chemolabeled antibodies: These mAbs have powerful chemotherapy drugs attached to them. (The chemotherapy drug is often too powerful to be used on its own – it would cause too many side effects if not attached to a mAb.)

There are only 2 chemolabeled antibodies approved by the FDA to treat cancer at this time: brentuximab vedotin (Adcetris^®) and ado-trastuzumab emtansine (Kadcyla^™). Brentuximab vedotin is made up of an antibody that targets the CD30 antigen (found on B cells and T cells), attached to a chemo drug called MMAE. It is used to treat Hodgkin lymphoma and anaplastic large cell lymphoma that is no longer responding to other treatments. Ado-trastuzumab emtansine is made of an antibody that targets the HER2 protein attached to a chemo drug called DM1. It is used to treat advanced breast cancer in patients whose cancer cells have too much HER2.

Immunotoxins: These mAbs have cell poisons (toxins) attached to them, which makes them similar in many ways to chemolabeled mAbs. At this time no immunotoxins are approved to treat cancer, although many are being studied.

However, a related drug known as denileukin diftitox (Ontak^®) is being used to treat some cancers. It consists of an immune system protein known as interleukin-2 (IL-2) attached to a toxin from the germ that causes diphtheria. Although it’s not an mAb, IL-2 normally attaches to certain cells in the body that contain the CD25 antigen, which makes it useful for delivering the toxin to these cells. Denileukin diftitox is used to treat lymphoma of the skin (also known as cutaneous T-cell lymphoma). It is also being studied to be used against a number of other cancers.

Possible side effects of monoclonal antibodies

Monoclonal antibodies are given intravenously (injected into a vein). Compared with the side effects of chemotherapy, the side effects of naked mAbs are usually fairly mild and are often more like an allergic reaction. These are more common while the drug is first being given. Possible side effects can include:

• Fever
• Chills
• Weakness
• Headache
• Nausea
• Vomiting
• Diarrhea
• Low blood pressure
• Rashes

Some mAbs can also have other side effects that are related to the antigens they target. For example, bevacizumab (Avastin^®), an mAb that targets tumor blood vessel growth, can cause side effects such as high blood pressure, bleeding, poor wound healing, blood clots, and kidney damage.

Conjugated antibodies may pack more of a punch than naked mAbs, but they often cause more side effects. The side effects depend on which type of substance they're attached to.