that is involved in an important cancer cell process, is found abundantly in an accessible place on the surface of cancer cells, and has minimal presence on healthy cells. Few targets like this exist in the human body, but Genentech had shown this to be the case for HER2, the target of Herceptin. “We knew HER2 was special, and as validated a target as you could get. We said if we can’t get it to work on HER2, then it ain’t going to work,” Sliwkowski says.
Then came the antibody itself. The good news was that because Genentech had an FDA-approved antibody for breast cancer cells, the manufacturing wing was churning out vats of it by the kilogram, not the usual micrograms that basic researchers need to scrape by with. That meant the scientists had more than enough raw material to run every experiment they could possibly think up, Sliwkowski says. It may sound trivial, he says, but projects in academic labs or small companies often stall because they only have enough resources to produce very small quantities of a drug, forcing them to do pretty limited experiments. Since they had lots of bulk drug, and it easy to link the antibody to all different types of toxins, the scientists went at it, Sliwkowski says. They had the luxury to think systematically, to try hundreds of combinations of antibodies and toxins in the petri dish, review the data, and tinker with one variable at a time until they got what they wanted.
“I didn’t think people were assessing the full potential of these things. I really wanted to turn the crank. And we did,” Sliwkowski says.
The third key variable was with the linker system that was meant to attach the antibody to the toxin. This is the part where Genentech leaned on the expertise of its partners at ImmunoGen, and later, at Seattle Genetics. Getting a linker that was stable in the bloodstream, and get the toxin exactly where it was supposed to go inside the cell, was the key challenge.
The fourth major variable, Sliwkowski says, was figuring out how to deal with the toxin. These molecules, because they are being directed to tumors in small doses, need to be super-potent, i.e. more than 1,000-fold more potent cell-killers than the usual chemotherapy drugs, which circulate throughout a cancer patient’s body. Nobody knew when Genentech first got going on this project whether the antibody, a relatively huge Y-shaped protein in molecular terms, should be loaded with one, two, five, 10 or 20 different toxins to get the ideal tumor-killing punch. They really didn’t where those toxins should be strategically placed on the antibody backbone, or what kind of difference that might make.
But having confidence in the cell target, and the antibody itself, helped scientists narrow down their options from the start. Even so, most of their preconceptions were wrong, Sliwkowski says. Some people thought that if loading more toxins on the antibody would give it more punch. Actually there was a sweet spot in the middle that was most effective. Others, Sliwkowski included, thought that maybe the Herceptin antibody wasn’t really the best vessel because it was so big and bulky, and that an antibody fragment might be a more efficient vehicle for delivering toxin to tumor. Wrong again.
“We did those experiments with fragment. The efficacy was fantastic. Toxicity was horrible,” Sliwkowski says. “It was jaw dropping. You’d injected the rats, and the guys would call you up the next morning, saying ‘they’re all dead.”
Despite the setbacks, Genentech’s senior managers gave this program some vital support early on. When Sliwkowski came asking for significant resources, one key supporter was Richard Scheller, now the executive vice president of research and early development.
Scheller’s role was important, because he had authority to do
