MIAMI BEACHTrastuzumab (Herceptin), the monoclonal antibody that
blocks HER-2, has been chemically linked to the maytansinoid DM1, a powerful
cytotoxic agent that attacks tubulin, resulting in a conjugate that is dramatically more effective than
trastuzumab alone in breast cancer models.
Genentech, Inc. and ImmunoGen, Inc., which owns the new drug, plan to file
an investigational new drug (IND) request with the FDA sometime in 2002 to
allow human trials to begin.
Ralph H. Schwall, PhD, senior scientist at Genentech, South San Francisco,
California, reported data from three in vivo preclinical studies of the
conjugate at the Molecular Targets and Cancer Therapeutics meeting (abstract
652), sponsored by the American Association for Cancer Research, National
Cancer Institute, and European Organization for Research and Treatment of
Dr. Schwall said that DM1, a cytotoxic molecule developed by ImmunoGen
(Cambridge, Massachusetts), is too toxic for traditional clinical use, but
conjugating DM1 to trastuzumab allows precise targeting to cancer cells, thus
preventing the systemic toxicity that limits the use of the parent DM1
"When the Herceptin antibody binds to a tumor cell expressing HER-2,
the Herceptin/DM1 complex is internalized. The intracellular environment favors
freeing of the DM1 from the antibody, makes the DM1 active, and kills the
cell," Dr. Schwall said.
Three Breast Cancer Models
The conjugate was tested in three models. The first was a line of MCF7-HER2
human breast cancer cells engineered to express high levels of HER-2 and
transplanted into nude mice. The conjugate caused complete tumor regression in
all mice treated, while trastuzumab alone only slowed tumor growth. This
experiment was repeated several times, with 9 to 10 mice per group. "With
the conjugate, all of the tumors just disappeared," Dr. Schwall said.