T-DM1 success inspires a wave of antibody-drug combos

The success of T-DM1 to control breast cancer tumors in the clinic has pumped new life into the field of antibody-drug conjugates and inspired Genentech to build a pipeline of some 50 programs that are aimed at bombing tumors with antibody-drug combos.

"We take this far more seriously than we did previously," Genentech's Mark Sliwkowski tells Xconomy's Luke Timmerman. "We are investing a lot of money and resources into this. That should answer your question."

T-DM1's success--it's likely headed to the FDA for marketing approval soon--owes a lot to the inspired notion that by adding toxins to an antibody the scientists could make a "smart bomb" that could do far more damage to tumors than the original genetically engineered antibody, Herceptin, that was approved back in 1998.  In clinical trials the drug was credited with shrinking the tumors of one third of the 110 patients with advanced breast cancer.

In Xconomy's detailed article, Timmerman focuses on the key hurdles the drug development team faced in designing T-DM1. One of the most critical was finding a stable way to attach toxins to the antibody. And they needed to deliver the payload precisely where it was needed in the cell.

By using a "thioether" linker from ImmunoGen, investigators created a powerful covalent bond between the antibody and the toxin which allowed its transport into the cell, where it was degraded by particular enzymes. That broke it into toxin-armed blocks that went about the business of attacking the tumor.

- here's the article from Xconomy

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