MIAMI BEACH-Trastuzumab (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
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 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.
The second model was nude mice transplanted with MDA-MB-361 breast tumor cells, which naturally express high levels of HER-2. As in the first experiment, the conjugate induced complete tumor regression in all 10 mice treated, while unconjugated trastuzumab only slowed tumor growth.
The third model was mammary tumors from MMTV-HER-2 transgenic mice transplanted into the mammary fat pads of 10 nontransgenic nude mice. The transplanted tumors grew aggressively and were allowed to reach 100 mm³ before treatment was initiated. "For reasons we don’t understand, Herceptin is not very effective against these tumors, even though they express high levels of HER-2," Dr. Schwall said.
When the mice were treated with the trastuzumab/DM1 conjugate, tumors regressed by more than 90% in all mice within 20 days. This effect was seen only in tumors overexpressing HER-2. "The tumors shrink and stay small for 60 to 70 days then start to grow back. When we treated them again, they responded again at similar levels," he said.
Maximal efficacy in this model was seen at a DM1 dose of 300 µg/kg, which corresponds to about 18 mg/kg of the conjugate, given once a week for 5 consecutive weeks. "These results show that Herceptin/DM1 has better activity than Herceptin alone in both Herceptin-responsive and Herceptin-resistant breast tumor models," Dr. Schwall said.
Some concerns remain about trastuzumab cardiotoxicity, which has been observed in about 7% of patients treated with the monoclonal antibody, but Dr. Schwall is optimistic that this will not be a major problem with the conjugate.
"The cardiotoxicity seen with Herceptin is almost exclusively in patients previously treated with doxorubicin," he said. "This conjugate works more like paclitaxel [Taxol], and Herceptin plus paclitaxel is well tolerated in patients who have not received doxorubicin. Now that clinicians are aware of the cardiac risk associated with Herceptin, it is managed medically quite well, and we are doing safety studies in primates with Herceptin/DM1 to address those issues."