Highly specific biological agents attack mechanisms of treatment resistance

Conjugated Herceptin dramatically improves Herceptin-alone results against breast cancer

A Herceptin-DM1 conjugate produced complete regressions in mice bearing human breast cancer where Herceptin alone slowed tumor growth, according to new data presented here today.

Approximately 25% of all breast cancer patients carry extra copies of HER2, a protein that instructs their tumor to grow. Herceptin is a monoclonal antibody that binds to HER2 and suppresses its growth signal.

Were looking for ways to enhance the clinical benefit of Herceptin, such as attaching to it agents that might be synergistic, such as DM1, a compound that blocks cell division, said Ralph H. Schwall, Ph.D., senior scientist at Genentech, Inc., South San Francisco, CA, and lead author of the current study

In this study, Herceptin was chemically bound to DM1 and tested against three different experimental breast cancer systems that have extra copies of HER2. In the first two, which used human breast cancer cells growing in mice, Herceptin-DM1 resulted in the complete disappearance of all tumors, whereas Herceptin as a single agent slowed tumor growth but did not cause regression.

The third experiment used a breast tumor from a transgenic mouse engineered to have high levels of HER2. The growth of this mouse tumor did not respond to Herceptin, but Herceptin-DM1 caused the tumor to shrink by more than 90%, indicating that Herceptin-DM1 can work in a tumor that is resistant to Herceptin. Tumors began to regrow four to six weeks after the final dose of Herceptin-DM1, but regressed again when retreated with Herceptin-DM1.

Genentech manufactures Herceptin and partnered with ImmunoGen, Inc., of Cambridge, MA, to develop the linked molecule. Were pursuing additional animal studies to get a realistic safety profile of this conjugate, Dr. Schwall said.

DM1 is a member of the maytansine family of tubulin-blocking compounds. Tubuli

Contact: Peter Vigliarolo
American Association for Cancer Research

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