New Antibody Technique Expands Therapeutic Uses
Researchers at the Scripps Clinic in San Diego have developed a powerful new technique that will allow scientists to identify and isolate specialized antibodies, especially human antibodies, for medical and other uses far more quickly and inexpensively than was previously possible.
The advance in producing so-called monoclonal antibodies holds potentially important implications for use in medical therapy, particularly for treating cancer, transplant rejection and autoimmune diseases, such as diabetes, multiple sclerosis and arthritis.
Combined with technology recently developed at Scripps for mass-producing monoclonal antibodies in plants, the new development reported today in Science magazine places Scripps at the forefront in developing a new technology that rivals genetic engineering in its potential scientific and financial importance.
Monoclonal antibodies are already widely used in medical treatment and diagnostics.
But therapeutic uses have so far been limited by allergic reactions to the antibodies, which were previously produced only in animal cells. By making it possible to produce purely human antibodies, the new technology should greatly expand their use.
“This technology is very interesting, very exciting and potentially very useful,” said immunologist Jeffrey Schlom of the National Cancer Institute. According to Schlom, the technology could reduce the time required for producing a new therapeutic antibody from the current 18 months to only a few weeks.
Schlom noted that the Cancer Institute will begin testing the new technology as soon as possible “to see if we can use it to accelerate the kinds of things we are doing.”
The technology has so many potential applications, in fact, that La Jolla-based Stratagene Inc., which cooperated with Scripps scientists in developing the new technology, is establishing a new company to explore uses.
Stratagene has already employed the technology to develop monoclonal antibodies that can be used in research laboratories for isolating and purifying proteins and other biological molecules, according to Stratagene’s chief executive officer, Joseph A. Sorge. And the new company, called Stratacyte Corp., will be aggressively developing potential therapeutic antibodies.
Even so, the company will be licensing the technology to others on a broad basis, Sorge added. “We couldn’t touch 5% of the applications on our own,” he said.
Financial analysts are predicting that sales of monoclonal antibodies will grow tenfold to $3.5 billion per year by 1995. The new Scripps technologies could make that market higher still, experts said.
Antibodies are complex proteins produced by white blood cells that target invading microorganisms and foreign chemicals for destruction by the immune system. Their key property is that a given antibody will bind to only one invading chemical or cell, ignoring all others.
The medical use of antibodies was revolutionized in 1975 by the discovery of techniques for producing large quantities of a single antibody. British researchers injected mice with a specific chemical or cell (called an antigen) and then isolated single, short-lived white blood cells that produced an antibody against that antigen and fused them with long-lived cancer cells.
The resulting cells, called hybridomas, inherit immortality--but not the ability to produce disease--from the cancer cell, as well as the white blood cell’s ability to produce one antibody. Their progeny continue to produce the same antibody, called a monoclonal antibody because it is derived from a single, cloned cell.
Monoclonal antibodies are widely used in physicians’ offices, in hospitals and even in home test kits for measuring minute quantities of such biological materials as drugs, hormones and vitamins. They are also used to carry toxins and radioactive atoms directly to tumor cells in the body so that healthy cells will not be injured.
But the process of preparing hybridomas and selecting the antibodies desired for a particular application is a time-consuming, labor-intensive process. In producing diagnostics, for example, “the real costs are in the manpower for the screening and selection process,” according to Sidney Aroesty, president of Los Angeles-based Diagnostic Products Corp.
The new technology should greatly reduce both the time and the cost of developing new antibodies, according to molecular biologist William D. Huse, who headed the Scripps team. They achieved these reductions by duplicating in bacteria the process by which antibody diversity occurs in humans and other animals.
Huse and his colleagues developed a way to insert two antibody genes into special viruses, called phage, that infect and kill bacteria. As the phage replicate, the antibody genes undergo mutations similar to those that occur in white blood cells.
Within a few days, the researchers have an antibody repertoire containing the genes for billions of distinct antibody molecules. Using a simple screening process they developed, the Scripps researchers can then quickly sift through all of these to find one or more antibodies that bind to a desired antigen.
The new technique could have its greatest potential for making human antibodies. Clearly, it is not ethical to inject humans with an antigen, such as a cancer cell, to stimulate formation of appropriate white blood cells. Furthermore, human white cells are extremely difficult to fuse with cancer cells to make hybridomas.
By eliminating both of these steps, the Scripps researchers say their technique could make the manufacture of human monoclonal antibodies routine.
