Cesar Milstein, 74; Nobel Winner

Dr. Cesar Milstein, the 1984 Nobel Prize winner who created “magic bullets,” which revolutionized the pharmaceutical and diagnostics industries, has died at 74.

The Argentine expatriate, who spent most of his research career at Cambridge University in England, died at Aldenbrooke’s Hospital in Cambridge Sunday. No cause of death was announced.

In 1975, Milstein and postdoctoral fellow Georges J.F. Kohler invented monoclonal antibodies, biological molecules with unique power and precision. Monoclonal antibodies have the ability to seek out and bind to specific chemicals, ranging from an enzyme in the blood to a cell in a tumor. That ability can be used to measure the concentration of a specific chemical in the bloodstream or carry a cell-killing agent to tumor cells while ignoring other tissues.

They are “a new, powerful biological tool for fighting human disease,” said William H. Rastetter, chief executive of IDEC Pharmaceuticals in San Diego, one of many biotechnology companies established in the last two decades to exploit the capabilities of monoclonal antibodies. Their greatest impact will occur in cancer therapy, he said, where their great specificity will “spare patients the ravages of chemotherapy.”

Among the powerful new drugs based on monoclonal antibodies are Rituxan, Herceptin and Zevalin to fight cancer, Orthoclone OKT3 and Zenapax to block transplant rejection, ReoPro to prevent blood clots in heart patients, and Remicade to combat rheumatoid arthritis and Crohn’s disease.

In addition, there are literally thousands of diagnostic tests being marketed that are based on monoclonal antibodies. Such tests can identify levels of specific hormones in the bloodstream, bacteria in foods, viruses in humans or pollutants in tap water.

All of these have grown from a relatively simple idea of Milstein’s to manipulate the immune system.

The human immune system--like that of other animals--can make at least 2 million different antibodies, each of which binds to one specific target. Scientists have long made antibodies for research purposes by injecting biological molecules or other chemicals--the targets--into mice and harvesting antibodies. But such harvests provided only complex mixtures of antibodies, unsuitable for medical uses.

Milstein and Kohler, like many researchers, attempted to isolate immune cells that produced only one antibody and grow them in the laboratory to produce the antibody in large amounts. But despite their best efforts, the cells would die after a few replications.

Their inspiration was to take the antibody-producing immune cell and fuse it with a tumor cell to make it immortal. The result, which they called a hybridoma, was a cell that would replicate and grow indefinitely in the laboratory and that would produce a single or “monoclonal” antibody.

The antibodies have a variety of uses. Because they are antibodies, their binding is sufficient to trigger an immune response on its own. But their cell-killing ability can be greatly enhanced by attaching a toxin--such as ricin--or a radioactive atom to them to increase lethality. Attaching a fluorescent chemical or other marker molecule allows them to be used to measure quantities of specific chemicals.

The scientific community recognized the significance of Milstein and Kohler’s discovery virtually immediately. It was only nine years later that they received their Nobels in medicine--an unusually rapid recognition in the slow-moving world of science.

And it was only two years later that Orthoclone OKT3, the first monoclonal antibody drug, came on the market. But further progress occurred more slowly, in part because the original monoclonal antibodies were made in mice. Mouse monoclonal antibodies produced an antibody reaction in humans, which limited their utility until researchers found ways to deceive recipients’ immune systems by “humanizing” the drugs--replacing segments of the mouse protein with their human analogs.

There are now 11 such drugs approved by the Food and Drug Administration and two more awaiting approval. Hundreds of others are in earlier stages of animal and human testing.

Milstein was born in Bahia Blanca, Argentina, on Oct. 8, 1927, the son of an itinerant Jewish immigrant. His mother, the daughter of a poor immigrant family, was a teacher.

Milstein received his doctoral degree at the University of Buenos Aires. After postgraduate work at Cambridge, he returned to a faculty position at the National Institute of Microbiology in Buenos Aires. But disheartened by anti-intellectualism and the firing of many colleagues after a military coup, he returned to Cambridge, where he spent the rest of his career.

He is survived by his wife Celia. They had no children.