info on tras-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.
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.
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Hybrid Mode
