Squibb Takes Dead Aim At CancerJohn Carey
Scientists long have dreamed of designing potent anticancer drugs that could home in on tumors without harming healthy cells. The future looked bright in 1975, when researchers found a Nobel prizewinning way to make large quantities of so-called monoclonal antibodies, specialized versions of the body's own intruder-fighting substances. In theory, combining a toxic "warhead" with an antibody "guidance system" would create a weapon that could deal a death blow to cancer cells. But for years such "smart bombs" mostly have turned out to be duds.
Now, nearly two decades of research are beginning to pay off. In the latest advance, reported in the journal Science on July 9, a team of scientists at Bristol-Myers Squibb Pharmaceutical Co. combined an antibody and a cancer drug to cure rats and mice afflicted with human lung, colon, and breast cancers. "We finally think we have something interesting," says Dr. Karl Erik Hellstrom, one of the team's leaders.
The Bristol-Myers experiment isn't the only encouraging advance. Late last year, Cytogen Corp. in Princeton, N.J., received Food & Drug Administration approval to market the first monoclonal-antibody-based product. Instead of carrying a drug, the antibody carries a radioactive marker to colon and ovarian tumors, allowing doctors to make more precise diagnoses of the cancers. Immunomedics Inc. in Morris Plains, N.J., has similar products awaiting approval. Cytogen and Immunomedics, as well as other companies and research centers, also are already testing experimental monoclonal therapies in people. Furthest along are efforts that use combinations of antibodies and radioactive isotopes to seek out and kill leukemia and lymphoma cells, which are easier to attack than solid tumors. "Based on our studies in leukemia, I would like to think that we are close to a drug," says Dr. David A. Scheinberg, chief of the leukemia service at Memorial Sloan-Kettering Cancer Center in New York.
CHEMICAL GLUE. What the Bristol-Myers study showed was that monoclonals could also kill common solid cancers--at least in animals. "It's a shot in the arm for the whole field," says Dr. David M. Goldenberg, chairman of Immunomedics. The secret was a particularly ingenious strategy. First, Hellstrom and his team created an antibody that not only seeks out cancer cells but, after attaching to a cell's surface, is swallowed. The Bristol-Myers approach makes it possible to deliver the drug where it does the most harm to the cancer--inside the cell. Scientists have tried to do this for years, but finding the right antibody to make it work has been tough.
The Bristol-Myers researchers also used a clever chemical glue to attach the drug--a common anticancer agent called doxorubicin--to the antibody. The glue holds the toxin tightly as the antibody zips through the body, preventing the drug from killing sensitive heart and bone-marrow cells. Once inside the cancer cell, a more acidic environment breaks the bond, releasing the drug to do its lifesaving work. That's why "our results look better than anyone else's," says Hellstrom.
Still, it's a long way from lab to hospital. The next step is for Bristol-Myers to get FDA permission for clinical trials on humans. "Until it's actually been in patients, we just don't know if it will work," cautions Hellstrom. One major worry, for example, is that the antibody's guidance system may not be precise enough. In addition to homing in on tumors, the monoclonal antibody also attaches to cells in the digestive tract. If enough of these cells are killed, the result would be dangerous and unpredictable side effects.
Scientists also worry that the monoclonals could prove to be too apparent to the body's defense system, and thus could be counterattacked before they can deliver their drug payload. That's why researchers at a number of companies are using genetic-engineering techniques to make the antibodies less easily spotted by the body. "We still have a way to go to make silver bullets" against cancer, says Goldenberg. What we have now are "bronze bullets," he says. Still, they may be aimed true enough to slow cancer in its tracks.