Cashing In On Cracking The Code Of Autoimmunity

Dozens of research teams vie for a vast commercial market awaiting those who discover how to protect the body against itself BOSTON--A decade ago, disorders like Graves' disease, myasthenia gravis, and systemic lupus erythematosus--diseases in which the immune system attacks the body's own tissues--were mysteries that eluded reliable or effective treatment. Too little was known about how the immune system works and, consequently, why it goes awry in these diseases. But research during the past five years has provided many insights into the immune system. The result is a growing number of scientists in both industry and university labs who are examining what makes the body turn against itself. And on the horizon, say business analysts, is a commercial market of virtually unlimited potential. Armed with a better understanding of the immune system, scientists are developing increasingly sophisticated weapons against autoimmune diseases, disorders in which the body mistakes its own tissues as foreign and mounts attacks on itself. At one time, the best they could offer was relief from the symptoms of those attacks by deactivating the entire immune system. They moved on to inflammation, which often underlies the progression of these diseases. More recently, great strides have been made in identifying and targeting for treatment the specific elements involved in the initiation and perpetuation of autoimmune reactions. This refined approach is made possible by monoclonal antibody technology and by the knowledge that activation of the disease process involves certain receptors, molecules at the surface of cells. Different types of cells have different receptors; each receptor binds to just a few molecules. As scientists characterize and identify receptors, they are able to use that knowledge in developing new therapeutic approaches. They can then make monoclonal antibodies that are able to bind to those receptors. One company, Xoma Corp. in Berkeley, Calif., has taken a first step in narrowing the target of immune suppression therapies. It is performing clinical trials on a drug that kills all the mature T cells, suppressing some but not all of the immune response. That drug, XomaZyme-CD5Plus, involves a monoclonal antibody that attaches to these T cells. Taking a different tack, some researchers hope to make a monoclonal antibody that could target another molecule important in recognition and activation of the immune system response. This molecule, called the major histocompatibility complex (MHC), is a go-between. It picks up the disease-eliciting antigen and then presents it to the T cell. The body has six types of this class of MHC molecules. Usually just one type is involved in recognizing one of the body's peptides as foreign and, consequently, in activating autoimmunity. So with this therapeutic approach, scientists plan to knock out just that one type, leaving intact the rest of the immune system. And there are other molecules involved in immune response that may be potential venues for treatment. An even more specific strategy is trying to pinpoint which T cells are reacting against the body. This involves looking for the T cell receptors that bind to antigens from the body's own tissues. "The goal is to try to define the smallest T cell subset that is critical to the disease," says Brian Kotzin, who is working on this approach with Philippa Marrack and other colleagues at the National Jewish Hospital and Research Center in Denver. "The difference is the potential for this to be a selective form of therapy." Such treatments would target just the offending T cells. That could be done by vaccinating someone with the proper T cell receptor protein, so that the body would attack and destroy only those T cells carrying that receptor. Or one could make a monoclonal antibody that homes in on that receptor, and attach a toxin to that antibody so the T cell would be destroyed once the antibody reached its target. "I think it's one of the most promising approaches that is being explored," says David Webber, an analyst at Alex. Brown & Sons, an investment banking firm. Academic scientists have reported progress in using these approaches in animal models. Irun Cohen, an immunologist at the Weizmann Institute in Israel, has used a piece of heat-shock protein to vaccinate against diabetes. Lawrence Steinman, an neuroimmunologist at Stanford, made an antibody to one receptor of the T cell responsible for allergic encephalomyelitis, a disorder that researchers have created in mice as a model for multiple sclerosis. When this antibody was injected into the mice, they recovered. It also seemed able to prevent symptoms from developing in mice expected to get this disease. Leroy Hood of the California Institute of Technology in Pasadena has reported even greater success by using a two-antibody antidote in this animal model. And there are hints of improvements in some patients as well. "We believe that the strategy and theory apply to many autoimmune diseases," says Susan Primrose, who handles investor relations for T Cell Sciences Inc. in Cambridge. The company devotes about half of its $7 million research budget to autoimmune disorders. However, Steinman says that the problem may be more complicated than he and his colleagues first realized. It appears, for example, that not all the receptors implicated in multiple sclerosis in humans are alike, which may make these treatment strategies more difficult to pursue. A treatment that works for one person with the disease might not work for another person if that person's autoimmune reaction involves a different receptor. It also may be difficult to identify which molecule is the key to the disease process. Says Weizmann's Cohen, "It's difficult to determine these antigens. With animal models, all an investigator has to do is inject the alleged antigen and see if the disease appears. In the human being, you can't do that. You have to look at populations [of people] and do statistics." --E.P. "In the last couple of years, people have learned a lot about how [the immune system] works," says Philippa Marrack, an immunologist at the National Jewish Hospital and Research Center in Denver. "Now it's all going to come together in a full frontal attack. In the next year we're going to learn a lot about autoimmune diseases that we didn't know before." Scientists have long been interested in the mechanisms of immunity because of the critical role it plays in infectious diseases, including AIDS. But not until advances were made in genetic engineering and computer modeling were researchers able to make significant progress in probing the molecular details of the body's defenses. So investigators who were working on seemingly different and disconnected problems now find that they are able to piece together a map that may lead to putative treatments for a wide variety of human ills. This new understanding of how the body recognizes antigens, substances that elicit an immune response, has paved the way for more effective weapons against autoimmune diseases, say immunologists. At a November meeting here, sponsored by the journal Nature, researchers discussed strategies for treating diabetes, rheumatoid arthritis, and multiple sclerosis. They didn't always agree on details of how the immune system operates, but they concurred that enough is known to start creating new medications. At the forefront of this effort are about a dozen new companies, many biotechnology and pharmaceutical firms, and prominent academic immunologists across the country. Opportunities abound because scientists now know what kinds of treatments are likely to work. And because so many people are affected by these types of disorders, the payoff for companies that succeed in making such treatments will be huge. Between 5 percent and 10 percent of the population suffers from at least one of about 50 autoimmune disorders, according to immunologist Hugh McDevitt of Stanford University, Calif. In each case, the body's lymphocytes have turned on the body, attacking one particular type of tissue. "You're talking about a very large, very unsatisfied market that is currently inadequately treated," says David Webber, biotechnology analyst for the investment banking firm of Alex. Brown & Sons. In the United States alone, he says, there are about 2 million people with rheumatoid arthritis, and each spends about $1,000 a year on medications that either have severe side effects or often don't work. "With those numbers, you very quickly go off the scale [on potential revenues]," Webber says. "And if you come up with anything that will be more effective or just equally effective with a better side-effects profile, you can charge even more." Great Potential That potential has increased the demand for research talent. "You just have to look at the back sections of Cell, Nature, or Science and see the increase in job advertisements from large pharmaceutical companies for people specializing in autoimmunity," says Bruce Rogers, an immunologist at ImmunoLogic Pharmaceutical Corp., a three-year-old Cambridge, Mass., company. "Obviously, people are very interested." In addition, two new journals in the field have appeared since 1988--the Journal of Autoimmunity, published by Academic Press in London, and Autoimmunity, put out by Harwood Academic Publishing in London. In 1989, a journal series, Autoimmunity Forum, was begun by World Medical Communication of Cedar Knolls, N.J. Investors are also excited, says Webber, citing the more than $30 million raised last year by Icos Corp., a Bothell, Wash., immunology startup, in its first round of private financing. "That's unheard of," Webber says about the response to a company that has no products and no track record in research. Driving this boom is a clearer understanding of the molecular basis of antigen recognition, made possible by new technologies. Scientists have been using monoclonal antibodies and transgenic animals to characterize the immune response. Computer graphics have made it possible to visualize some of the molecules involved in this process. Investigators now recognize that only some T cells--lymphocytes that kill cells perceived as foreign--lie at the heart of each autoimmune reaction. They realize that the body has subsets of T cells that home in on specific antigens. Each subset has a particular type of receptor, a molecule that, because of its shape, attaches to a given antigen. Not all the T cells are necessarily involved in a particular autoimmune disease. Once scientists understood this, they began working to characterize individual T cell repertoires--first in mice--to better understand the subset of cells that is attacking the body's own tissue. "Now the technology is building up so that you can go directly to humans and define the T cell repertoire," says Brian Kotzin, who studies patients with rheumatoid arthritis as an associate professor of medicine at the National Jewish Hospital and Research Center. Scientists are now attempting to pinpoint the renegade T cells and the antigens responsible and to understand the steps involved in recognition and activation of autoimmunity. "What you're seeing is a coalescing of knowledge of immune mechanisms and technologies for looking at the problem," explains John Rice, who scouts out promising technologies for his company, Sentron Medical Inc. of Chicago. Rice says autoimmune diseases are high priorities for potential investors. Thanks to that coalition, companies like Sentron are likely to be pleased with what they find, say immunologists. They believe that the lure of commercial products will prove irresistible. Says Irun Cohen, an immunologist studying autoimmunity at the Weizmann Institute in Israel, "This kind of stuff is attractive to companies because they can develop it [into a product]."

Cashing In On Cracking The Code Of Autoimmunity

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