Fern Saitowitz’s advanced
breast cancer was controlled for about a year by the drug
Herceptin and a toxic
chemotherapy agent. But her hair fell out, her fingernails turned black and she was constantly fatigued.
Bryce Vickmark for The New York Times
John Lambert, executive vice president for research
and development at
ImmunoGen, worked on the class of drugs for 30 years.
She switched to an experimental treatment, which also consisted of
Herceptin and a chemotherapy agent. Only this time, the two drugs were
attached to each other, keeping the toxic agent inactive until the
Herceptin carried it to the
tumor. Side effects, other than temporary nausea and some
muscle cramps, vanished.
“I’m able to live a normal life,” said Ms. Saitowitz, 47, a mother of
two young children in Los Angeles. “I haven’t lost any of my hair.”
The experimental treatment, called T-DM1, is a harbinger of a new class of
cancer drugs that may be more effective and less toxic than many existing treatments. By harnessing
antibodies
to deliver toxic payloads to cancer cells, while largely sparing
healthy cells, the drugs are a step toward the “magic bullets” against
cancer first envisioned by
Paul Ehrlich, a German Nobel laureate, about
100 years ago.
“It’s almost like we’re masking the chemotherapy,” said Dr. Edith Perez,
a breast cancer specialist at the
Mayo Clinic in Jacksonville, Fla.
One such drug, Adcetris, developed by Seattle Genetics, was approved last August to treat
Hodgkin’s lymphoma
and another rare cancer. TDM-1, developed by Genentech, could reach the
market next year. Data from a large clinical trial of T-DM1 is expected
to attract attention at the annual meeting of the American Society of
Clinical Oncology this weekend in Chicago.
Numerous other companies, from pharmaceutical giants to tiny start-ups,
are pursuing the treatments, which are known variously as antibody-drug
conjugates, armed antibodies or empowered antibodies. “I don’t think
there is a major pharma or a midsized pharma with interest in cancer
that doesn’t have a program or isn’t scrambling to put one together,”
said Stephen Evans-Freke, a managing general partner at Celtic
Therapeutics, an investment firm that recently committed $50 million to
create a new company, ADC Therapeutics, to develop antibody-drug
conjugates.
About 25 such drugs from a variety of companies are in clinical trials,
according to Alain Beck, a French pharmaceutical researcher who closely
tracks the field. Genentech alone has eight in clinical trials besides
T-DM1, and another 17 in earlier stages of development.
Many of the drugs use technology from either Seattle Genetics, based in
Bothell, Wash., or ImmunoGen of Waltham, Mass., which supplied the toxin
and linker used in T-DM1.
The armed antibodies do not work for all patients and they are not
totally free of side effects. T-DM1, for instance, can lower blood
platelet levels. The drugs are also likely to be expensive. Adcetris
costs more than $100,000 for a typical course of treatment.
Biotechnology drugs called monoclonal antibodies, like Herceptin, Rituxan and
Erbitux,
are already mainstays of what is called targeted cancer therapy. These
laboratory-produced molecules mimic the antibodies made by a person’s
immune system to fight infection. But instead of attacking pathogens
these antibodies attach to specific proteins on the surface of cancer
cells.
But antibodies by themselves have a limited ability to kill
tumors.
So the antibodies are usually given with more conventional cell-killing
chemotherapy drugs, which cause side effects because they can also
attack healthy cells.
The new approach chemically attaches a toxin to the antibody, increasing
its killing power while reducing the need to give toxic drugs
separately. After the antibody binds to a cancer cell, it is taken
inside the cell like a Trojan horse, and the toxin is released.
While armed antibodies are sometimes likened to guided missiles with
toxic warheads, they actually cannot guide themselves to tumors.
Rather, they float through the bloodstream, bumping against various
cells. But they stick only to the cells bearing the target protein.
“These are like floating sea mines,” said K. Dane Wittrup, a professor
of chemical and biological engineering at the Massachusetts Institute of
Technology. “But when they end up in a particular harbor, they blow
up.” Less than 1 percent of the drug actually makes it to the tumor, he
estimated.
The antibody used in Adcetris, which binds to a protein on malignant
cells called CD30, had little effect on cancer when tested alone, even
at doses 20 times as high as used now. But when linked to a toxin, it
shrank tumors in 75 percent of those with Hodgkin’s lymphoma.
Aimee Blaine, a petroleum engineer from Bakersfield, Calif., who has had
Hodgkin’s lymphoma since 2004, was virtually out of options after
traditional chemotherapy and a
stem cell transplant failed to cure her disease.
But four days after taking Adcetris in a clinical trial, the unbearable
itching that accompanied her disease vanished, she said.
Eventually, so did the cancer. Ms. Blaine, 40, has been in remission
since her last dose in January 2011 and recently returned to work for
the first time in seven years.
Like Herceptin, T-DM1 binds to what is known as the HER2 protein and is
meant to treat only the roughly 20 percent of breast cancer cases
characterized by an abundance of that protein.
n one trial involving 137 women, including Ms.
Saitowitz, T-DM1 proved both more effective and less toxic than a
combination of Herceptin and the chemotherapy drug docetaxel as an
initial treatment for metastatic breast cancer.
Those who received T-DM1 went a median of 14.2 months before their
disease worsened, compared with 9.2 months for those getting the
two-drug combination. Yet only 46 percent of the T-DM1 patients suffered
a severe side effect, half the rate of the other group.
At the cancer conference, researchers will present results of a pivotal
trial involving nearly 1,000 women. Though armed antibodies are easy to
envision, it has taken more than three decades to make them practical,
with many failures along the way.
With the first armed antibody to reach the market, Mylotarg, the toxin
sometimes fell off the antibody prematurely, causing side effects.
Approved in 2000 to treat acute myeloid leukemia, Mylotarg was removed
from the market by its manufacturer, Pfizer, in 2010 after new studies
showed it did not prolong lives and had safety problems.
Since then, two antibodies linked to radioactive isotopes have been
approved to treat non-Hodgkin’s lymphoma — Bexxar from GlaxoSmithKline
and Zevalin from Spectrum Pharmaceuticals. These drugs, while effective,
are more cumbersome to use than antibodies linked to chemical toxins.
Researchers first tried to use existing chemotherapy drugs as the
payloads, but they were simply not toxic enough. That is because less of
a drug gets to the tumor when carried on an antibody than when the drug
floods the body by itself.
Seattle Genetics and ImmunoGen use toxins that are hundreds of times as
potent as typical chemotherapy agents. They are too toxic to be given by
themselves.
The linkers have proved even tricker to develop since they must keep the
toxin attached to the antibody while in the bloodstream, but then
release the toxin inside the cancer cell.
Dr. John Lambert, executive vice president for research and development
at ImmunoGen, will be in the audience at the cancer conference as the
fruits of 30 years of work are presented.
“To get to this point is an indescribable feeling, actually,” he said.
