First Monoclonal Cancer Therapeutic
By Sean Henahan, Access Excellence
Francisco, CA (11/26/97)- The approval by the FDA of the first antibody-based
therapy for cancer represents good news for some patients with non-Hodgkin's
lymphoma (NHL), as well as a milestone in biotech drug development.
NHL occurs when B-cells, the cells that produce antibodies, begin to
grow abnormally. The B-cells (or, more rarely, T-cells) divide too rapidly
and grow out of control. Tumors result when too much tissue is formed.
Because the lymphatic system is distributed throughout the body, the cancer
cells may spread to other organs including the liver, spleen or the bone
The new compound, called Rituxan or rituximab, is a genetically-engineered
monoclonal antibody that targets a receptor called CD20 found on some B-cells.
The Rituxan antibody marks the B-cells for destruction by the immune system,
after which new B-cells are generated by stem cells. Stem-cells and B-cells
bearing antibodies are spared by Rituxan, since they lack the CD20 antigen.
Graphic: Step involved
in making monoclonal antibodies
In a clinical trial conducted at 31 U.S. medical centers, 166 patients
with NHL who had failed to respond to conventional treatment with radiation
and chemotherapy received a series of four infusions of Rituxan. About
half of the patients saw their tumors shrink by at least half, while six
percent had a complete remission of disease.
"Rituxan represents an important turning point in the treatment of lymphoma,"
said Myron Czuczman, M.D., Assistant Professor of Medicine, Roswell Park
Cancer Institute, Buffalo, New York, and a key investigator. "Although
it is not a cure, we finally have a cancer agent that can be effective
with less serious side effects than with conventional chemotherapy. Treatment
can also be completed in 22 days, unlike the typical four- to six-month
chemotherapy regimens. This is exciting news, especially for elderly patients
and relapsed patients who have failed at least one standard treatment regimen."
Rituxan will initially be used to treat patients with low-grade NHL
who have failed conventional chemotherapy and radiation treatments. The
new agent offers a number of potential advantages over current treatments.
First, it may work when all else has failed. Some patients fail to respond
to standard therapies, and others may develop resistance to treatment.
Rituxan is also considerably less toxic than chemotherapeutic agents or
radiation, causing none of the hair loss, nausea and life-threatening complications
these agents can cause. Conventional treatments also may cause sterility
and are sometimes associated with the development of other types of cancers.
As an added advantage, Rituxan can be administered on an outpatient
basis, sparing patients the inconvenience and discomfort (and cost) of
a hospital stay. While chemotherapy and radiation treatments may require
lengthy hospitalization, Rituxan is administered as four infusions over
a 22-day period.
Rituxan is a specific type of drug known as a chimeric monoclonal antibody.
Chimeric antibodies take their name from the chimera, a mythical beast
with the head of a lion, the body of a goat and the tail of a dragon. The
Rituxan chimera is a hybrid of antibodies from both human and murine (mouse)
sources. The CD20 antigen is injected into a mouse, encouraging the production
of antibodies. Antibody producing cells are then isolated from the spleen
of the animal. These are then combined with immortal cells called myeloma
cells. This results in a cell line that will go on producing the antibody
indefinitely. Further genetic engineering removes the elements of the mouse
cell that would normally produce an immune (allergic) reaction if
injected into a human.
Early monoclonal antibody-based therapies for cancer were plagued with
a host of problems. In the early experiments, allergic reactions to the
foreign (mouse) part of experimental antibodies, called HAMA (human
anti-mouse antibody) limited their usefulness and preventing them from
being used more than once. The developers of Rituxan overcame this problem
by removing the antigenic part of the mouse portion of the chimeric antibody.
Lymphomas are cancers involving the lymphatic system, the network of
glands and vessels that circulate lymph throughout the body. Lymph is a
clear, colorless, watery fluid that contains the white blood cells
that form the basis of the immune system. Tumors may form on lymph nodes,
small, bean-shaped organs found throughout the lymph system, specifically
around the neck, under the arms, in the groin and abdomen.
Non-Hodgkin's lymphoma, also called B-cell lymphoma, is the most common
type of lymphoma. It is the sixth most common type of cancer in the US.
Each year, some 54,000 new cases are diagnosed each year and more than
24,000 die from the disease. The overall incidence of NHL has increased
more than 80% since the 1970s, a fact that is attributed to the AIDS epidemic
and the aging population. One-half of NHL patients have low-grade or follicular
lymphoma. A portion of these patients will have multiple relapses and may
be eligible for Rituxan therapy.