WASHINGTONMonoclonal antibodies are the basis of many
diagnostic tests, but now are catching on as therapy as well, said
Neil Bander, MD, surgical director, Urologic Oncology Program,
Cornell University and New York Presbyterian Hospital, New York.
This particular type of approach has now been validated
clinically and is being used to treat patients with various types of
cancer, Dr. Bander said at the Kidney Cancer Association Annual Convention.
Monoclonal antibodies (MoAbs) already approved include treatments for
breast cancer and non-Hodgkins lymphoma [rituximab (Rituxan)].
Another is in the pipeline: Bexxar is under FDA review on
fast-track status, he said. It is expected to become the first
approved radiolabeled MoAb therapeutic.
The MoAb edrecolomab (Panorex, Centocor), approved for adjuvant colon
cancer treatment in Germany, is in phase III testing in the United
States. About one quarter of all of the drugs in late-stage
clinical trials in the area of cancer are monoclonal antibodies,
Dr. Bander and his colleagues are developing MoAb treatments for
kidney cancer. One uses the G250 antibody to target carbonic
anhydrase 9, which is not present in normal kidneys but is expressed
in clear cell renal carcinomas. The clear cell variation
represents 85% to 90% of all kidney cancers, he said.
In clinical trials several years ago, Dr. Banders team showed
that G250 was excellent at being able to target kidney tumor
sites, while avoiding normal tissues. Some 150 patients
have received the antibody, he said, and wherever the
tumor site iskidney, bone, liver, lung, etcwe can get
antibody to the site.
However, in early trials, the researchers were limited to giving the
antibody in a single dose because it was mouse-derived and
patients immune systems mounted a quick reaction. Using genetic
engineering, researchers were able to convert the mouse version of
G250 to a version that is at least partially human. So far,
none of the patients to whom it was given have developed an adverse
immune reaction, he said, and the antibody targets just
as well as the original antibody. We are now in a mode where we are
giving multiple doses of the antibody.
Two ongoing phase I trials, one in Holland and one in New York, are
using the G250 antibody carrying 131-iodine in kidney cancer
patients. In the Dutch trial, patients receive a high dose of the
radioactive agent; in New York, patients are given up to 27 lower doses.
The New York trial, a collaboration between Cornell-New York
Presbyterian and Memorial Sloan-Kettering Cancer Center (with C.
Divgi, MD, as principal investigator), will last until the end of the
year, at which time a phase II trial will begin, and all of the
patients will receive the maximum tolerated dose. So far,
patients have experienced no significant toxicity, Dr. Bander said.
A second approach targets prostate-specific membrane antigen (PSMA).
We and others fortuitously found that in addition to being
present in prostate cancers, PSMA is expressed in the blood supply to
other tumor types, Dr. Bander said. In a recent paper (S. Chang
et al), Dr. Banders team reported that in 65 tissue specimens
from 17 kinds of cancer (including renal cancer), the blood supply
was positive for PSMA in 96% of the samples. Normal vessels were
The antibody may be an important approach because kidney
cancers are among the most vascular cancers known, he said. The
size of the tumor would present no hindrance because, regardless of
size, it would have a blood supply.
The antibody could be used with a thrombogenic agent to induce clots
in the tumors blood vessels, he said, or a cytotoxic drug or
isotope could be attached to the antibody to kill blood vessel
tissue. A third approach would be to induce a blood vessel leak so
that conventional cytotoxic drugs would leak into the tumor more
readily than they would into normal tissues. The mouse version of the
PSMA antibody is in phase I clinical trials for prostate cancer,
while phase I trials of the new human version are slated to begin by
We need to build on our ability to target the tumor by adding
other mechanisms that would lead to the destruction of cancer
cells, Dr. Bander said. If the success that we are seeing
in other cancers is any indication, I feel very optimistic about
being able to translate this approach to success in patients with
kidney cancer over the next few years.