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