Monoclonal antibodies are the most widely used form of cancer immunotherapy at this time.

Monoclonal antibody therapy uses antibodies made in large numbers outside the body (in the lab) rather than by a person's own immune system. This type of treatment is considered a form of passive immunotherapy. These treatments often do not require the person's immune system to take an "active" role in fighting the cancer.

The first monoclonal antibodies were made in the lab by fusing a myeloma (a type of bone marrow cancer) cell from a mouse with a mouse B cell that makes a specific antibody. The cell that results from this fusion is called a hybridoma.

Combining a B cell that can recognize a particular antigen and a long-lived myeloma cell makes the resulting hybridoma cell a long-lasting, antibody-making factory. Because the antibodies made are all identical clones made from a single (mono) hybridoma cell, they are called monoclonal antibodies (sometimes abbreviated as MoAbs or MAbs).

The first MAbs were made entirely from mouse cells. One problem with this is that the human immune system can see these antibodies as foreign (because they're from a different species) and can mount a response against them. In the short-term, this can sometimes cause allergic-type reactions. In the long-term, it means that the antibodies may only be effective the first time they are given; after that, the body's immune system is primed to destroy them before they can be helpful.

Over time, researchers have learned how to replace some parts of these mouse antibody proteins with human parts. Depending on how much of the MAb is human, these are called chimeric or humanized antibodies. Some MAbs are now fully human, which means they are likely to be safer and may be more effective than older MAbs.

An even newer approach uses fragments of antibodies instead of whole ones. Smaller pieces may be better able to reach a tumor, which may make them more effective.

Over the past 10 years or so, the Food and Drug Administration (FDA) has approved several MAbs for the treatment of certain cancers, as seen in the table below.

Clinical trials of monoclonal antibody therapy are also in progress for people with almost every type of cancer. As researchers have found more cancer-associated antigens, they have been able to make monoclonal antibodies against more and more cancers.

Monoclonal antibodies used to treat cancer

MAb Name	Trade Name	Used to Treat:	Approved in:
Rituximab	Rituxan	Non-Hodgkin lymphoma	1997
Trastuzumab	Herceptin	Breast cancer	1998
Gemtuzumab ozogamicin*	Mylotarg	Acute myelogenous leukemia (AML)	2000
Alemtuzumab	Campath	Chronic lymphocytic leukemia (CLL)	2001
Ibritumomab tiuxetan*	Zevalin	Non-Hodgkin lymphoma	2002
Tositumomab*	Bexxar	Non-Hodgkin lymphoma	2003
Cetuximab	Erbitux	Colorectal cancer Head & neck cancers	2004 2006
Bevacizumab	Avastin	Colorectal cancer Non-small cell lung cancer Advanced breast cancer	2004 2006 2008
Panitumumab	Vectibix	Colorectal cancer	2006

*conjugated monoclonal antibodies

Two types of monoclonal antibodies are used in cancer treatments:

• Naked monoclonal antibodies are those without any drug or radioactive material attached to them.
• Conjugated monoclonal antibodies are those joined to a chemotherapy drug, radioactive particle, or a toxin (a substance that poisons cells).

Naked monoclonal antibodies

Naked MAbs are the most commonly used MAbs at this time. Although they all work by attaching themselves to specific antigens, they can be effective in different ways.

Some naked MAbs attach to cancer cells to act as a marker for the body's immune system to destroy them. Antibodies now in use in this group include:

• Rituximab (Rituxan): Rituximab is used to treat B-cell non-Hodgkin lymphoma and some other diseases. It is a monoclonal antibody against the CD20 antigen, found on B cells.

• Alemtuzumab (Campath): Alemtuzumab is an antibody against the CD52 antigen, which is present on both B cells and T cells. It is used to treat some patients with B-cell chronic lymphocytic leukemia (B-CLL).

Some naked MAbs don't really interact with a person's own immune system. Their effects come from their ability to attach to the specific antigens, which are functional parts of cancer cells or other cells that help cancer cells grow. Examples of FDA-approved MAbs of this type include:

• Trastuzumab (Herceptin): Trastuzumab is an antibody against the HER2/neu protein. A large amount of this protein is present on tumor cells in some cancers. When HER2/neu is activated, it helps these cells grow. Trastuzumab stops these proteins from becoming active. It is used to treat breast cancers that have large amounts of this protein.

• Cetuximab (Erbitux): Cetuximab is an antibody against the EGFR protein, which is present in high amounts on some tumor cells and helps them grow and divide. Cetuximab blocks the activation of EGFR. It is used to treat some advanced colorectal cancers as well as some head and neck cancers.

• Panitumumab (Vectibix): This MAb also targets the EGFR antigen. It is used to treat some cases of advanced colorectal cancer.

• Bevacizumab (Avastin): Bevacizumab targets the VEGF protein, which is normally made by tumor cells to attract new blood vessels to feed their growth. Bevacizumab attaches to VEGF, which blocks it from signaling for new blood vessels to form. This MAb is used along with chemotherapy to treat some colorectal, lung, and breast cancers, and is being studied for use against other cancers.

Some of these antibodies have been used for many years. At first they were used mostly after other treatments had stopped working. But more studies have been and continue to be done. Today these antibodies are being used earlier in the course of cancer treatment.

Side effects

Monoclonal antibodies are given intravenously (injected into a vein). Compared with side effects of chemotherapy, the side effects of naked MAbs are usually fairly mild and are often related to an allergic-type reaction. If they do occur, it is most often 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 also have effects that are specific to the antigens they target. For instance, some can affect the bone marrow, like most chemotherapy drugs do. This can result in lower levels of blood cells, which can lead to an increased risk of bleeding and infection in some people.

Conjugated monoclonal antibodies

Conjugated MAbs are joined to drugs, toxins, or radioactive substances. The MAbs are used as delivery vehicles to take these substances directly to the cancer cells. The MAb acts as a homing device, circulating in the body until it finds the target antigen. It then delivers the toxic substance to where it is needed most. This lessens the damage to normal cells in other parts of the body.

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

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 this type of therapy is known as radioimmunotherapy (RIT).

• MAbs with chemotherapy drugs attached are often referred to as chemolabeled.

• MAbs attached to toxins are called immunotoxins.

Radiolabeled antibodies

Two radiolabeled antibodies have been approved to treat cancer.

• Ibritumomab tiuxetan (Zevalin) delivers radioactivity directly to cancerous B lymphocytes. It is used to treat B-cell non-Hodgkin lymphoma that has not responded to standard treatment.

• Tositumomab (Bexxar) is used to treat certain types of non-Hodgkin lymphoma that no longer respond to rituximab (Rituxan) or chemotherapy.

Aside from being used to treat cancer, radiolabeled antibodies can also be used along with special cameras to help detect areas of cancer spread in the body. While some radiolabeled antibodies such as ProstaScint (for prostate cancer) have been approved by the FDA, their role in helping to detect cancer has been very limited so far.

Chemolabeled antibodies

These are being studied and are available in the United States only through clinical trials at this time.

Immunotoxin

Immunotoxins are made by attaching MAbs to bacterial toxins such as diphtheria toxin (DT) or pseudomonal exotoxin (PE40), or to plant toxins such as ricin A or saporin.

Immunotoxins have shown some early promise in shrinking a few cancers, particularly lymphomas. But some major problems still need to be solved before this new form of cancer treatment can be used more widely.

The only immunotoxin approved for treating cancer is gemtuzumab ozogamicin (Mylotarg). It has a toxin called calicheamicin, attached to an antibody against the CD33 antigen, which is present on most leukemia cells. Gemtuzumab is used to treat some people with acute myelogenous leukemia (AML).

Another immunotoxin, BL22, showed promising results in early studies against some forms of chronic leukemia, even in patients who no longer responded to chemotherapy. In early clinical trials, about 2 out of 3 patients had complete responses to the treatment (no evidence of cancer) that lasted up to 2 years. A newer, improved version of this immunotoxin, known as HA22 (CAT-8015), is now being studied.

Clinical trials of other immunotoxins are also being done in people with certain leukemias, lymphomas, brain tumors, and other cancers.

Other targeted therapies containing toxins

Scientists are also studying toxins linked to hormone-like substances called growth factors. Many cancer cells have large numbers of receptors for growth factors on their surfaces. This makes growth factors more likely to attach to these cells. When these growth factor receptors are stimulated the cancer cells reproduce and grow faster.

Researchers have learned how to make growth factors attached to toxins. When the growth factor/toxin reaches the cancer cell's growth factor receptors, it delivers its payload of toxin that kills the cell. The concept behind these growth factor/toxin drugs is similar to that of immunotoxins. But because the growth factor/toxin drugs do not contain antibodies, they are not classified as immunotoxins.

The only growth factor/toxin currently approved by the FDA is denileukin diftitox (Ontak). It is a growth factor known as interleukin-2 (IL-2) attached to a toxin from the germ that causes diphtheria. Denileukin diftitox is used to treat a rare type of skin lymphoma (cutaneous T-cell lymphoma). It is also being studied to be used against a number of other cancers.

Revised: 03/18/2008