Trials Near for New Tumor Killers : Technique Developed That Pushes ‘Magic Bullet’ Research Forward

Physicians in California and Maryland are preparing to begin clinical trials of powerful new therapeutic agents for liver cancer and lymphoma, UC Davis chemist Claude F. Meares said here Thursday at the American Chemical Society meeting.

Meares has developed a new technique for attaching either of two highly radioactive isotopes to monoclonal antibodies that will carry them directly to tumors, where the radiation kills the cancer cells. Both of the isotopes, yttrium-90 and copper-67, are thought to be much more potent tumor-killers than those now in use for the experimental treatment of cancer, but researchers have previously been unable to attach them to the antibodies.

Promising Approach

Researchers from the Scripps Clinic and Research Foundation in La Jolla also reported here that they are seeing good results with anti-cancer drugs attached to monoclonal antibodies, which target the agents directly at the tumors. The use of the antibody-linked drugs and radioisotopes, some scientists believe, represents one of the most promising approaches to cancer therapy.

Researchers are closer than ever before, said chemist Janis Upselacis of Lederle laboratories in Pearl River, N.Y., to developing the “magic bullets,” first predicted nearly a century ago by German physician Paul Ehrlich, that would target tumor cells selectively without damaging healthy cells elsewhere in the body.

Antibodies are complex immune-system molecules that bind to foreign organisms or chemicals and target them for destruction. Biotechnology developed during the 1970s enabled researchers to produce and clone large amounts of antibodies that bind to a specific target, such as a cancer cell.

The monoclonal antibodies themselves can stimulate a cancer patient’s immune system to attack tumors, but researchers quickly found that the cell-killing effect could be greatly enhanced by chemically linking radioactive atoms, such as iodine-131 or indium-111, to them. Radiation produced by the isotopes during their short lifetimes disrupts normal functioning of the cancer cells, causing them to die.

Oncologist Stanley Order of the Johns Hopkins Medical School in Baltimore, for example, has treated more than 300 liver cancer patients with antibody-linked iodine-131 and has produced remissions in about half. According to the National Cancer Institute, such antibodies are currently being tested against about a dozen different forms of cancer in humans.

Oncologists would like to use isotopes that emit higher-energy radiation and thus are more likely to kill the tumor cells.

“Yttrium-90 and copper-67 are at the top of most people’s lists,” Meares said, but they have proved exceptionally difficult to link chemically to antibodies.

Meares took a different approach, developing a group of chemicals called bifunctional chelating agents that “lock” the radioisotopes to the antibodies. One side of the chelating molecule contains four long “arms” that wrap around the metal ion and bind tightly to it. The other side contains shorter chemical arms that can be chemically linked to the antibodies.

The new chelating agents bind yttrium and copper so tightly, Meares said, that no loss of metal ion from the complex can be detected in blood after 18 days.

Animal Tests Awaited

Order has already used an earlier form of the chelating agent developed by Meares to treat liver cancer patients with yttrium-90, and the results were sufficiently promising that he plans to use the new agents as soon as testing in animals is completed, perhaps later this year.

Tests in animals of the copper-binding agent have also been successful, and oncologists Sally and Jerry DeNardo of UC Davis plan to begin clinical trials in June in lymphoma patients. The testing is currently delayed because copper-67 is produced only at the Los Alamos National Laboratory in New Mexico, and the lab produces it only six months a year, when production is piggybacked on other experiments.

Antibodies can also be used to deliver drugs more directly to tumors, thereby reducing the chance of poisoning other cells. The anti-cancer drug doxorubicin, for example, kills many types of tumor cells, but has only limited clinical use because it also damages the heart.

Immunologist Barbara Muller of the Scripps Clinic and Research Foundation in La Jolla reported that she and her colleagues had tested a doxorubicin-antibody combination in mice with malignant melanoma, which usually kills them in 30 to 40 days.

While neither doxorubicin alone nor antibodies alone prolonged the animals’ lives, the combination allowed most of the 12 animals treated to live longer than 120 days, and four of the 12 were completely cured.