Harnessing monoclonal antibodies, radioisotopes to cure melanoma

February 1, 2007

Bronx, N.Y. - Monoclonal antibodies carrying radioisotopes are a new therapeutic approach to treating melanoma. The treatment is about to enter the first human clinical trial.

The hope is to develop a highly targeted therapeutic that will home in on the deadly cancer with minimal side effects on other cells.

"Melanin is a very complex pigment with radiation-shielding properties. That is one of the reasons why melanoma is so difficult to treat," says Arturo Casadevall, M.D., Ph.D., chairman of the department of microbiology and immunology at Albert Einstein College of Medicine, Bronx, N.Y.

Homing device

The approach that Dr. Casadevall and his colleague Ekaterina Dadachova, Ph.D., in the department of nuclear medicine, have developed homes in on melanin itself.

Monoclonal antibodies made a big splash in the 1970s and expectations were high - a mix of enthusiasm and hype. One of the problems with using them in treating cancer has been the complexity of the tumors.

Dr. Casadevall tells Dermatology Times, if one targets the antigen to a receptor on the tumor, often, "You select for cells that don't express that tumor antigen, so when the tumor grows back, you're left with a therapy that doesn't work."

Focusing on melanin may avoid that problem.

Dr. Dadachova says the monoclonal approach has been tried before with melanoma but without great success, largely due to the crudeness of the available tools. Researchers believe that by targeting melanin rather than a tumor antigen, and using an isotope with a shorter half-life (about 17 hours), they can better target the tumor and reduce side effects.

Their confidence is enhanced by that fact that the Food and Drug Administration has approved monoclonal antibodies using two different radioisotopes for treating recurrent or refractory non-Hodgkin's lymphoma.

She says, "It is extremely effective and there are almost no side effects."

Targeting melanin is safe for normal skin because melanin normally resides in organelles within the cell, and the large antibody cannot penetrate the cell membrane, Dr. Dadachova says.

"We've done a tremendous amount of work showing that there is no problem with pigmented tissues," she says.

But cells become more penetrable as they die, and the rapidly expanding tumor outgrows its blood supply, which also results in cell death. The decomposing cell releases granules of melanin into and around the tumor, which the antibody can latch onto and deliver radiation to its intended target.

While most melanomas contain ample melanin to achieve this purpose, a small portion of tumors contain very little. Yet the therapy appears to have roughly the same effect on both types of tumors. Computer modeling helped to understand why that is the case.

"When you have a lot of melanin in the tumor, the antibody binds on the periphery, but with little melanin, the antibody penetrates deeper until it finds those melanin granules," Dr. Dadachova explains.

Standard radiation as 'assassin'

Dr. Casadevall says one possible approach might be to use standard radiation to kill off tumor cells, which release melanin and "provide you with a lot more target" for the isotope-carrying antibody to home in on.

"But if the initial radiation deposits essentially a lot of charcoal on the surface of the tumor, then it may prevent penetration," he adds.

The addition of monoclonal therapy to standard treatments for breast or colon cancer "is beginning to improve the bottom line" for those diseases.

He points to childhood leukemia as a reason to be optimistic. In the 1960s it was nearly always fatal, but today the cure rate is about 90 percent.