Medical Pike
New Antibody Targets Only Cancer Cells, Wipes Out Brain Tumors in Mice
Effective without a "warhead"
June 25, 2000 -
DURHAM, N.C. - A new monoclonal antibody that targets a mutated protein found only in
cancer cells can eradicate tumors in mice without the aid of additional toxic substances, Duke
Comprehensive Cancer Center researchers and others reported June 20th.
Injecting the antibody directly into implanted brain tumors almost tripled average survival and
even "cured" one-quarter of the 177 mice treated during nine experiments, the scientists reported
in the June 20 issue of the Proceedings of the National Academy of Sciences.
The researchers said this is the first report that a tumor-specific antibody with direct tumor-killing
abilities can effectively treat tumors in the brain, although the studies so far have been limited to
mice. Brain tumors can arise from within the brain or when a cancer spreads, and they are
frequently the cause of death for an otherwise treatable cancer because of limited options for
long-term recovery.
Unlike other antibody-based cancer treatments in which the antibody simply transports the
cell-killing radioactive atom or drug to the tumor, this antibody, called Y10, acts as both the
vehicle and the assassin, which improves tumor specificity and reduces unwanted secondary
toxicity.
"We first showed that this antibody would recognize only tumor cells," said lead author Dr. John
Sampson, assistant professor of neurosurgery and pathology at Duke University Medical Center.
"It is truly remarkable in this field to find something that kills tumors so specifically and without
any toxicity. Now we have a very exciting set of pre-clinical data, but there is still work to be
done to translate this into clinical trials in human patients."
Even though Y10 recognizes the human protein, in humans it might be destroyed before it can
work, Sampson pointed out. "Mouse antibodies have been used in humans before, but
'humanized' antibodies appear to work much better," he said. "We're close, but we're not there
yet."
Y10 is a mouse antibody that targets a common mutation in the human epidermal growth factor
receptor gene (EGFR). The mutation, known as EGFRvIII, is found in many human brain tumors
and in cancers that frequently spread to the brain, such as breast, ovary and lung cancer, but not
in any normal tissues. The result of this mutation is a specifically altered protein that enhances the
ability of cells to form tumors, which leads to a worse prognosis than for cancers without the
mutation.
In the PNAS article, the scientists reported that Y10 kills in more than one way. Generally,
antibodies fend off unwanted invaders by turning on the bodyÃs natural defenses, the immune
system. While Y10 does help immune cells recognize tumor cells displaying the mutated protein,
it also directly inhibits DNA synthesis and cellular division and can induce cell death all by itself.
"It is possible that if cancer cells are resistant to one of these mechanisms, they might still be
susceptible to treatment with Y10 because of the other pathways," said Sampson.
In mouse studies, the researchers, including then-undergraduate Laura Crotty, found that Y10
injected into the abdominal cavity eradicated EGFRvIII-expressing melanoma tumors implanted
under the skin in all 20 mice treated. The injection also created long-term immunity, and a second
injection of the cancer cells months later also failed to develop into tumors. Because the antibody
is so specifically targeted to EGFRvIII-containing cells, no toxicity other than cancer cell death
was seen in any mouse, Sampson said.
The scientists then examined Y10's effects on tumors implanted into the brains of mice. The
researchers found that Y10 had to be directly injected into the tumor to be therapeutic. Direct
injection tripled average survival and left 26 percent of the 177 mice with no evidence of tumors
even 100 days after treatment. Control mice treated with an inactive antibody succumbed to
tumors in just 17 days in one experiment. While Y10 didn't produce a long-term immune
response in the brain, this could be a blessing, said Sampson.
"This failure to produce long-term immunity in the brain may provide a 'comfort zone' in using this
antibody," he said. "In particular, it could mean that there's less risk of inducing an uncontrollable
self-perpetuating immune response that could lead to inflammation in this especially sensitive
organ."
The study was funded by the Pediatric Brain Tumor Foundation of the U.S., the Cancer
Research Institute/Partridge Foundation and the National Institutes of Health.
Based on the promise that targeting EGFRvIII shows as a possible method of treating brain
tumors, Sampson was named one of 10 Kimmel Scholars nationwide, an award from the Sidney
Kimmel Foundation for Cancer Research that is awarded to promising young professors engaged
in cancer research.
Co-authors on the study are Laura Crotty, Samson Lee, Gary Archer, Carol Wikstrand, Laura
Hale, Allan Friedman, Henry Friedman, and Darell Bigner, all of Duke University Medical
Center, and also David Ashley of the University of Melbourne, Australia, and Clayton Small and
Glenn Dranoff of the Dana-Farber Cancer Institute.
Links
Therapeutic Antibody Center (TAC) Oxford, U.K.:
Antibodies and Therapy
Antibody research and development for prostate cancer: Procyon Biopharma Inc.(Montreal)
E-mail [email protected]