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(Drug information on 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 Cancer.
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 compound.
"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.