Couple Lead Quest For New Allergy Drug

A husband-and-wife team and their biotech firm rush to develop medicine that will stop allergic reactions before they even begin The allergy market is nothing to sneeze at. Consumers spend millions of dollars annually on medications to treat symptoms of allergic reactions. But at least one small biotechnology company is hoping to make this market disappear. Nancy and Tse Wen Chang and their Houston company, Tanox Biosystems Inc., appear to be front-runners in this first leg of a race to create a drug that will stop an allergy attack before it starts. Such a drug would be devastating to the current $500 million United States market for over-the-counter medications to stop the sneezing, dripping, and itching of allergies. It would mean former sufferers could, if they wished, picnic in fields of ragweed. Microbiologist, heal thyself. That variation on the old physician's saw could well be the working credo of a couple trying to design the ultimate cure for the allergies that cause them to sniffle their lives away in the laboratory. Nancy and Tse Wen Chang may be the best team to conquer this problem. They both suffer from allergies, and they both have earned high praise from their mentors and colleagues. Harvard Medical School professor Fred Goldberg has called Tse Wen Chang "one of the most talented graduate students ever to come through Harvard." And Goldberg says that the pair, who graduated in the late 1970s, "blend the sophistication of basic science with a special ability to want to do something good in medicine." Their resumes are nearly identical. Each is a native of Taiwan. Each received an undergraduate degree from the National Tsing Hua University (where they met and married) and doctorates from Harvard (hers is in biological chemistry; his is in cell and developmental biology). They have both worked for giant pharmaceutical companies: Nancy for Hoffmann-LaRoche Inc. and Tse Wen for Ortho Pharmaceutical Corp. From 1981 to 1986 they both held research positions at Centocor Inc., a Malvern, Pa., biotechnology company that pioneered monoclonal antibody research. One investor in the Changs' research, Moshe Alafi, describes the couple as so dedicated they practically sleep in the lab. He says that they write elegant research papers and have a well-developed "venture capital spirit." "Nancy claims that she wanted to invent an allergy product because she and her husband suffer so much," says David Anderson, Tanox's vice president of corporate research. "I have never seen anyone who is more allergic." The problem runs in the family as well, affecting their two daughters, ages 9 and 4. "My youngest's foot swelled up to twice its size from a fire ant sting," says Tse Wen. Notwithstanding those similarities, there are some differences between the two microbiologists. Nancy leads the overall direction of their company, Tanox Biosystems, and leaves the science to her husband. "We complement each other's strengths," she says. "We let each person do what they do best." The Changs say that they were driven to venture out on their own after years of working at the slow pace of pharmaceutical companies and academia. "We have risk-taker personalities," says Nancy. "We are the type of people who look forward, who are very optimistic in nature. So when the chance came to start our own company, we said, `Let's just do it.' " And this new generation of medications for the nation's estimated 22 million allergy sufferers could be a gold mine for the individuals and companies that are fostering it. It also could have broader applications as part of a new class of drugs that treat an immune system gone awry. The same techniques could possibly treat rheumatoid arthritis--perhaps even depression and drug addiction. That potential excites scientists in the field. "Tanox's approach is extremely reasonable, given recent advances in developing humanized antibodies," says Henry Metzger, scientific director for the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at the National Institutes of Health and an immunologist who has done pioneering work in this area. "They can clearly move ahead on it, and they should be able to test quickly if it works." Indeed, the Changs say that human trials for their drug, a monoclonal antibody, should start in less than two years if Tanox's progress stays on track. Their goal is to market a drug in seven years--a miserably long time for those with allergies, but a relatively short period compared with the decade or more needed to incubate most biotech products. Based on what has been reported to the scientific community in conferences and journals, other companies and scientists are plodding along at a much slower pace. Part of the reason is the complexity of the immune system. "The field is booming, but it is so incredibly complicated," says Charles Reeds, an allergy researcher at the Mayo Clinic in Rochester, Minn. In fact, Alan Kaplan, past director of the American Academy of Allergy and Immunology, refuses to forecast when breakthroughs will lead to a new allergy drug in the medicine cabinet. By his reckoning, such a wonder drug could be "from five to 50 years away." Owing to this uncertainty, the scramble to design a big money-making allergy medicine also shapes up as a proving ground for two approaches to the problem of translating the advances of molecular biology into profitable products. One approach, exemplified by a small biotechnology company like Tanox, is to seize on an idea, move quickly, obtain sufficient financial backing, and try to rush a product to market. The other approach, common among large pharmaceutical companies, is to acquire knowledge through in-house and academic research and then move slowly and cautiously, first through drug development and then through the regulatory maze. If this latter approach makes such giant firms long-distance runners, then Tanox represents a sprinter in the industry. Despite that analogy, Tanox is showing no signs of tiring out. In four years, its staff has grown from six to 29, including 13 Ph.D. scientists. In addition to its allergy drug research, Tanox is working on monoclonal antibody drugs for AIDS and rheumatoid arthritis, diseases that other companies are also trying to tackle through biotechnology. With this research and its unconventional approach to a new antiallergy drug, Tanox has been able to present itself in a very attractive light to investors. Because of the company's potential, Ciba-Geigy Ltd., the Swiss pharmaceutical conglomerate, decided earlier this year to pump millions of dollars into Tanox to bolster its research. (Tanox, which is privately held, declined to reveal the precise amount of the investment.) Allergic reactions are the body's way to attack and kill parasites. And because the body somehow regards components of pollen, feathers, and hundreds of other substances in the same light, these substances also trigger a reaction. Allergens stimulate the production of immunoglobulin E (IgE) antibodies. IgE antibodies attach to mast cells at their IgE receptors, and when this interlocked complex meets an allergen, the mast cell literally explodes. The chemicals spewed out, such as histamines, cause allergic symptoms: airways constrict, blood vessels dilate, and mucus is produced. Allergic individuals have lots of IgE in their blood, while nonallergic people do not. Most allergy medications treat the allergic reaction. They relieve nasal stuffiness and dry up drip or soothe itchy eyes. Antihistamines counter histamines. But advances in molecular and cell biology are making it possible to short-circuit allergic reactions. Three strategies seem most promising. One area of research aims to decrease the amount of available IgE in the body. A second keeps IgE from binding to mast cells. And a third keeps the mast cell from reacting to the IgE once it has become bound to the receptor. In the first approach, several companies and research scientists are trying different ways to stop the initial production of the IgE antibody in B cells. DNAX Research Institute of Palo Alto, Calif., is working to understand the role of a lymphokine called interleukin-4 (IL-4) in IgE synthesis. This lymphokine appears to direct the growth and function of the immunoglobulin-producing B cells. Along these same lines, scientists at Immunex Corp. of Seattle isolated a mouse IL-4 receptor molecule. And Kimishige Ishizaka, of the La Jolla, Calif., Institute for Allergy and Immunology, is focusing on the B cells themselves to develop what he calls an "IgE suppressive factor." The problem with this approach is that scientists must avoid triggering a general immune suppression response when they turn off a specific part of the immune system. Researchers speculate that IgE could have some unknown beneficial function, and they worry about what would happen if all IgE in the body were eliminated. Tanox's approach falls primarily into the second category of research, that of stopping the action of B cells and IgE. The company's monoclonal antibodies are meant to target and eliminate B cells after they have been produced as part of the immune response. They would also attach to free-floating IgE antibodies, preventing them from connecting with mast and basophil cells. The question is whether Tanox can produce antibodies that can function so precisely. The company says that it has already succeeded in doing so. Another way to stop IgE reactions is to design and insert a block between the IgE antibody and its cell receptor. Scientists at Hoffmann-LaRoche Inc., for example, are screening thousands of chemicals to find a small molecule that will cap a section of the IgE receptor. They also are trying to derive the three-dimensional crystalline structure of the IgE receptor in order to design a surface-binding chemical. This structure has several key side chains, two of which have been worked out by immunologists Jarema Kochran of Hoffmann-La-Roche and NIH's Jean-Pierre Kinet. The NIH team, under immunologist Henry Metzger, determined the structure of the third side chain. The laboratory and the drug firm have a cooperative R&D agreement, sharing a patent on cloning the IgE receptor. Much more needs to be known before scientists can develop the third antiallergy strategy. Toward that end, Metzger is studying what happens after the IgE binds to the receptor and before histamines are released. He wants to know how activation of the receptor is translated into activation of the allergic reaction. He says this process--or the effort needed to halt it--could take "10 steps or 1,000 steps." "The pharmaceuticals like bio-tech companies," says Nancy Chang, "because we often produce protein drugs that pose fewer problems than chemicals." Putative chemical drugs often turn out to have unforeseen side effects, and their toxicity prevents them from being developed. It is hoped that proteins will not have that same track record. Adds her husband, "And we like them [large pharmaceutical companies] because we need a deep pocket to share some of that [financial] risk with, as well as a little of that reward." The effort to find a cure-all for allergies is part of an emerging era of drug research that focuses on immunology and the new science of molecular cell communication via receptors. "We are all extremely interested in the way a cell communicates with the outside environment and its control inside," says NIAMS' Metzger. Metzger and his group have had several breakthroughs in cloning the receptor for immunoglobulin E (IgE), the antibody that plays a central role in triggering allergies. And while his team is not trying to design the ultimate antiallergy pill, it has linked up, through a cooperative research agreement, with Hoffmann-LaRoche Inc. of Nutley, N.J., which does have that as a goal. "This is a big area of concentration," says Philip Askenase, an allergy scientist at Yale University. "Receptor technology is emerging as a huge drug field. And something to block the IgE receptor has been on people's minds for a while. Now, in the age of molecular development, the race is on." In the race, the Changs are betting that they can cut short allergic reactions by eliminating IgE, something people with allergies have too much of. An allergic reaction is a series of biological and chemical events in which IgE is a main player. IgE antibodies are produced when an allergen enters the body. The antibodies attach to IgE receptors located on the surface of basophils, a type of white blood cell, and mast cells, which line the mucous membranes in the air passages of allergy sufferers. When the interlocked IgE antibody/cell complex encounters an allergen, the result is like touching wires to set off a bomb. These cells virtually explode, releasing histamines and dozens of other chemicals throughout the bloodstream. It's the body's way of removing what it considers to be an attacking marauder. But it's misery for the sufferer. The Changs have developed a monoclonal antibody that homes in on and deactivates the cells that produce IgE. The antibody also targets and disarms free-floating IgE. "Our approach is very simple," says Tse Wen Chang, Tanox's scientific director. "Other approaches are very scientifically interesting, but we are closer to a product." Nancy Chang, who is president of the company, is equally optimistic. "We will be the first into the clinics," she predicts. Her optimism stems in part from her husband's contribution to the development of OKT3, an antibody used to prevent rejection of kidney transplants, at Ortho Pharmaceutical Corp. of Raritan, N.J. That drug was the first monoclonal antibody approved by the U.S. Food and Drug Administration, and the only one so far to make it to market. Although OKT3 and Tanox's allergy medicine treat different diseases, the knowledge and technology needed to develop medications like these, which involve monoclonal antibodies, is similar. "Very early on, scientists were afraid of the potential risks of biopharmaceuticals," says Tse Wen Chang. "After a decade of research, everyone has realized they are not that toxic. I thought it is about time to develop something biopharmaceutical for less serious diseases like allergies." Such a goal will not be easily realized, the Changs acknowledge. "Like other drug biotech companies, we are product-oriented," Nancy Chang explains. "We ask critical questions about applicability, rather than about the basic science. We are the ones risking everything." The Changs know that technical obstacles exist. Because monoclonal antibodies are derived from mice, they must be "humanized"--whereby the antibody is made more similar structurally and chemically to that of a human--in order to be accepted by the body's immune system. This is a difficult process that accounts for much of the delay that Tanox has had in starting human trials. In addition, monoclonal antibodies must be injected rather than swallowed, and they do not last long in the body. All in all, these promise to be expensive drugs. Researcher John Hakimi calls Tanox's approach "an interesting long shot." As head of allergy research at Hoffmann-LaRoche's laboratory, he is taking another tack in harnessing knowledge about IgE to make antiallergy medicine. His company is taking a broader look at new antiallergy strategies, and he's enlisted staff and academic scientists in this effort. His allergy research unit has quadrupled in size these past few years, encompassing 10 scientists in New Jersey and more than that in the company's Japanese lab. And his company has a cooperative research and development agreement with NIAMS' Metzger, in which Hoffmann-LaRoche provides support for a postdoctoral fellow at NIH in exchange for previews of papers, increased collaboration, and a share of the royalties from any patents that come out of the research. Together, they are pursuing a deeper understanding of how IgE works. Their perspective makes them wary of quick-fix approaches like Tanox's. But they admit that, right now, it's not clear which approach will succeed. "The issue with Tanox is whether their antibody can be as selective as they say it is," says Hakimi, "whether it can clear out cells that produce IgE but no others. At the same time, they may get lucky. It could just be the ultimate drug." Renee Twombly is a freelance writer based in Chapel Hill, N.C.

Couple Lead Quest For New Allergy Drug

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