Despite the convenience of mouse models, Dr. Leonard Chess, professor of medicine in the division of rheumatology, has always studied human T cells to be closer to translating his findings into treatments for autoimmune diseases. Such a drug may be forthcoming now that Columbia University has licensed two patents based on Dr. Chess research to Biogen, of Cambridge, Mass., for clinical development.
The patents Biogen licensed from Columbia describe antibodies that may be able to treat a wide variety of autoimmune diseases, including rheumatoid arthritis, Crohns disease, juvenile diabetes, and multiple sclerosis. This is an important license for the Columbia pipeline, says Sara Gusik, associate director of Science and Technology Ventures (STV) at the Health Sciences campus, who negotiated the deal with Biogen. Given the large number of inflammatory diseases and the large patient population, it could generate significant revenue in the future.
But until recently, Dr. Chess may have been one of the few people who saw the antibodies potential value. Nearly 20 years ago, with the help of postdoctoral fellow Dr. Ilan Bank, now at Tel Aviv University, Dr. Chess made a monoclonal antibody to a molecule called VLA-1, which is present on the surface of activated human T cells. Activated T cells migrate from the blood stream to sites of infection where they release molecules to attack foreign invaders. But in autoimmune diseases, the T cells attack the bodys own tissue. The constant supply of activated T cells to the affected site eventually destroys the tissue.
Because Drs. Chess and Bank found that VLA-1 (very late antigen 1) was an integrin, a molecule that helps T cells latch onto the collagen lining the blood vessel and migrate through to inflammation sites, they envisioned that blocking VLA-1 may help reduce the chronic inflammation caused by all kinds of autoimmune diseases. They approached STV, and the patents on the monoclonal antibodies to VLA-1 and their use in disease treatment were issued in 1995 and 1998, respectively.
But the fact that the antibodies were against a human protein prevented Dr. Chess from doing studies in mice that might have led to subsequent human studies. Also, no one seemed interested in the patents and, at the time, antibodies as potential therapies were falling out of favor with drug companies. Antibody drugs promised to inactivate or kill a specific target, but the human immune system recognized the foreign mouse antibodies and launched an attack against the drug.
The patents remained tucked away in STV until interest in antibody treatments grew again with the help of a Columbia patent held by Dr. Sherie Morrison (now at UCLA) and collaborators at Stanford. The Morrison patent described a technique for making chimeric antibodies, molecules with mouse and human components, that are better tolerated by the human immune system.
Centocor, of Malvern, Pa., licensed the Morrison patent and used the technique to replace most of the non-specific parts of a mouse antibody against a cell adhesion molecule with human domains. The resulting drug, ReoPro, was one of the first successful antibody drugs, according to Dr. Philip Gotwals, Biogens manager for the VLA-1 project. Approved by the Food and Drug Administration in 1994, cardiac surgeons routinely use the drug during percutaneous coronary interventions (balloon angioplasty, stent placement, and atherectomy) to reduce clots and subsequent heart problems.
Dr. Gotwals says that once ReoPro became a success, other drug companies rushed to develop their own therapeutic antibodies. About three years ago, researchers at Biogen and elsewhere started looking at VLA-1 and used antibodies to the mouse version of the integrin to conduct in vivo experiments.
Drs. Chess and Bank showed if you look into the inflamed joint of rheumatoid arthritis patients, youll see activated T cells with the VLA-1 molecule, Dr. Gotwals says. Weve shown in a wide variety of mouse models that if you use the antibody to block the cells from migrating to the site, then youll moderate the disease course. In arthritis models, we can suppress disease by 80 percent to 90 percent as measured by clinical endpoints, such as the ability of the mice to walk or how crippled the paws are.
Once Biogen had in vivo data supporting the antibodys therapeutic effect, they approached Dr. Chess and STV about licensing the patents. The licensing contract went into effect Dec. 18, 2001.
Biogen will develop humanized VLA-1 antibodies and produce enough material to begin safety trials in patients probably in the first half of next year. But a meaningful clinical result about a candidate antibody products effectiveness wont likely come until 2005.
Dr. Chess hopes any drug that evolves from Biogens research will prove to be less toxic than the immunosuppressive regimens used to treat autoimmune diseases today. The regimens have been tremendously important in saving lives, Dr. Chess says. For example, people with lupus 30 years ago died three or five years after the onset of the disease. But now the major complications result from the toxic side effects of long-term treatment.
Collaboration between medical scientists and companies like Biogen is extremely important, Dr. Chess says, because they have the resources to translate basic scientific discoveries into drugs that will be useful for society.