Production of Human Antibodies in Mice Reported : Science: Two California companies achieve a genetic engineering breakthrough. It may allow advances in treatment of a wide variety of diseases.

In a development that could lead to major improvements in the treatment of autoimmune diseases, cancer, AIDS and organ rejection in humans, two California companies report today that they have been able to genetically engineer mice so that they produce human antibodies.

Mouse cells that produce these antibodies can then be grown in laboratory vats to produce large amounts of so-called monoclonal antibodies that, when given to patients, can attack and destroy diseased cells.

Monoclonal antibodies have shown great promise in treating many diseases in humans, but they suffer a major drawback: Existing monoclonals have all been produced in mice or other rodents, and the body quickly develops an immune reaction to them, limiting their use to only one or two treatments.

The human antibodies, whose development is reported today in the British journals Nature and Nature Genetics, represent a major advance because they should not provoke an immune response in people, allowing long-term therapy with the biotechnology drugs.

Although the two companies have more studies to conduct in animals, they predict that trials in humans could begin as early as next year, probably for use in transplants and autoimmune diseases such as rheumatoid arthritis.

“This is a significant breakthrough,” said UCLA immunologist Sherie L. Morrison. “They have really established the feasibility of a new way of making human antibodies.”

“We are really excited because this is a tremendous opportunity for new therapeutic agents,” added molecular biologist Robert M. Kay, vice president for research and development at GenPharm International of Mountain View, one of the two companies. “We hope we will be able to treat diseases that we have not been able to adequately address in the past.”

The second company is Cell Genesys Inc. of Foster City.

Monoclonal antibodies were first produced 20 years ago, a feat that earned their creators a Nobel Prize. They are produced by fusing a single antibody-producing mouse spleen cell with a mouse tumor cell to produce a new cell known as a hybridoma. Hybridomas can be grown in vats to produce large quantities of the antibody and, because of their heritage from the cancer cells, are effectively immortal.

Human hybridomas cannot be readily produced, however, because it would be necessary to inject a human volunteer with the disease-related chemical or cell that researchers desire to produce an antibody against; then they would have to remove the spleen to isolate the few cells that produce antibodies against that specific substance. Neither act is ethically defensible.

GenPharm and Cell Genesys achieved their feats in a similar fashion. In both cases, they disabled the mouse genes that produce antibodies and replaced them with comparable human genes. The human antibodies thus become a functioning part of the mouse’s own immune system. The process involves sophisticated genetic engineering techniques that have not been available until recently.

The new developments are substantially different from earlier feats in which intact human immune systems were produced in mice by injecting human bone marrow and other tissue into mice with no immune system of their own. Although those mice are valuable in their own right, they cannot be used to produce monoclonal antibodies. The production of monoclonal antibodies is viewed as one of the areas of greatest growth potential in the biotechnology industry. According to a recent estimate by Frost & Sullivan Market Intelligence of Mountain View, sales of the proteins totaled $740 million in 1993 and are expected to grow to $3.8 billion by 1998.

Many of those commercial monoclonal antibodies are used for medical imaging. When injected into a cancer patient, for example, the appropriate monoclonal antibody will bind to the tumor cells, showing them up more clearly on X-rays. The proteins are also widely used in laboratory diagnostic tests to help physicians determine the concentration of important chemicals in the blood.

But their use in therapy has been limited so far. The most successful product is an antibody called OKT3 that is used to suppress rejection episodes in organ transplant recipients. Although it is very successful, OKT3 can generally be used only once in a given patient because of the immune response against it. Transplant surgeons hope the development of human monoclonal antibodies will allow a comparable drug to be used repeatedly.

Many different monoclonal antibodies for the treatment of cancer are also in various stages of testing.

Kay said his company has already used the genetically engineered mice to produce human monoclonal antibodies against CD4, an immune cell that plays a crucial role in autoimmune diseases; against immunoglobulin E, which mediates allergic reactions; and against carcinoembryonic antigen, a distinctive marker found on the surfaces of colon and ovarian cancer cells. GenPharm plans to begin animal studies with the antibodies as soon as possible, he added.

Cell Genesys said it is now immunizing its mice in an attempt to produce antibodies against a variety of human proteins.