Researchers Find Opportunities Sniffing Out Allergy Treatments

MULTIDISCIPLINARY APPROACH: Researchers who understand "'nouveau technologies' of biology" are needed to develop allergy treatments, notes Hoechst Marion Roussel’s Martin Wasserman. It happens like clockwork: allergy season. Every spring, more than 20 million Americans sneeze, wheeze, and curse the flowers. But if scientists have their way, things might be different in the years to come. Across the United States, biotech and university labs are unraveling the basic biochemistry behind allergies. The effort should lead to new drugs and improved therapies-and jobs for researchers who design them. Allergies are the immune system's way of overreacting. After growing sensitized to allergens-like pollen, pet dander, and dust-the body's immune system responds to these chemicals whenever they appear. According to the Washington, D.C.-based Asthma and Allergy Foundation of America, Americans spend $2 billion annually seeking allergy relief. Antihistamines, the classic form of drug relief, block histamine, a critical chemical in the allergic response. A handful of drugs dominate the prescription antihistamine market. Earlier this year, when the Food and Drug Administration moved to withdraw approval of Hoechst Marion Roussel Inc.'s Seldane, at least three other drugs-Hoechst's Allegra; Claritin from Madison, N.J.-based Schering-Plough Corp.; and Zyrtec from New York-based Pfzer Inc.-were waiting in the wings. Each has a similar biochemical effect, stifling sniffles for a short time after they have begun. Today, however, many scientists are venturing beyond histamine. Rather than soothe itchy throats and watery eyes after an allergy attack, researchers would like to prevent these attacks in the first place. Similar to the way they study asthma-which also can have an allergic component (K.S. Brown, The Scientist, March 17, 1997, page 1)-scientists are probing the biochemical cascade that leads to an allergic response (E. Garfield, Current Contents, No. 13, pp. 3-15 [April 1, 1985]; No. 15, pp. 3-13 [April 15, 1985]; No. 42, pp. 3-13 [Oct. 21, 1985]. Reprinted in Essays of an Information Scientist, Vol. 8, Philadelphia, ISI Press, pp. 119-31, 140-50, 392-402). Both allergy and asthma involve complex inflammatory reactions that have perplexed researchers for years, explains Donald MacGlashan, a professor of medicine at Johns Hopkins University. "Imagine you've got a cobweb," MacGlashan says. "It's hard to know which thread would change the behavior of the system most." For example, researchers may think they have discovered a critical cytokine-only to find that previously hidden cytokines can rise to action and compensate for this star player when needed. The mystery remained, in part, because industry hadn't always paid attention to these conditions, acknowledges Martin Wasserman, head of the respiratory diseases group at Hoechst Marion Roussel Inc. in Cincinnati. "People usually don't die from common allergies," Wasserman says, noting that life-threatening diseases get the most attention from drug companies. "In the past, many companies have only sought to make slight improvements and [new] versions of already existing medications. But now, they're taking it more seriously. This is an important population, with 5 percent of adults and 10 percent of children [half of whom often 'outgrow' the pediatric disease] being affected." New molecular tools and a few years of persistence are finally giving scientists a better feel for how allergies work, he reports. "We now have a greater understanding of the problem." At the heart of the problem is immunoglobulin E, or IgE. Allergy sufferers apparently produce far more IgE antibodies than other people do. These antibodies bind to IgE receptors on the surface of mast cells. When an allergen is inhaled, it travels to the mast cell and binds to the surface IgE antibodies. This kick-starts chemical reactions inside the mast cell, which responds by releasing the allergic mediators histamine, tryptase, leukotrienes, and cytokines. These chemicals, in turn, cause the stuffy noses and sore throats so familiar to allergy victims. Bit by bit, scientists are pulling apart this web of allergy-causing chemicals and looking for points that can be easily interrupted. The most popular target is IgE itself. Several labs are working to short-circuit IgE. Researchers at publicly owned Genentech Inc. in South San Francisco, Calif., and Tanox Biosystems Inc., a private company in Houston, are collaborating on allergy research to create monoclonal antibodies that would bind to and disable IgE molecules, blocking them from their normal receptors on mast cells. "The IgE antibody-receptor binding is at the core of a whole spectrum of allergy manifestations, from mucus secretion to inflammation," says Fran Davis, director of project administration at Tanox Biosystems, which also began collaborating with Swiss giant Ciba-Geigy Corp. in 1990. "This is a key point in the biochemical pathway." According to Davis, Tanox has completed Phase II clinical trials with an anti-IgE monoclonal antibody to treat allergic rhinitis, or hay fever. Meanwhile, Genentech scientists have crafted a monoclonal antibody to stifle allergic reactions to the common dust mite. ATTACKING THE SOURCE: Thomas Jefferson’s Robert Korngold and collegues have developed two peptides to bind to and disable IgE. Also taking aim at IgE are scientists at King's College in London and at Thomas Jefferson University in Philadelphia. This team has developed two peptides that bind to and disable IgE, again preventing it from meeting its destined receptor on mast cells. The idea is that small peptides-the mainstay of drug design-could be relatively easy to create and mass-produce, according to Robert Korngold, a professor of microbiology and immunology at Jefferson. "This approach has a lot of potential, but we have to improve the peptides," Korngold says. "We'd like to get a better binding affinity [to IgE]." Rather than head off free-floating IgE, publicly owned Ariad Pharmaceuticals Inc. in Cambridge, Mass., is working inside the mast cell to prevent the intracellular part of the IgE receptor from wreaking havoc when an allergen approaches. Ariad researchers are creating small-molecule compounds that might block a mast cell protein called Syk, which normally binds to the intracellular IgE receptor and launches the release of histamine and other symptom-causing chemicals. These approaches all involve new technologies, particularly molecular genetics or combinatorial chemistry (K.S. Brown, The Scientist, May 13, 1996, page 1). Ariad, for example, is using combinatorial chemistry to screen lead compounds for their binding affinity to Syk. The company's chief operating officer, Charles C. Cabot III, reports that job-hunters comfortable with both small-scale biology and large-scale, automated drug design are in demand. "Everybody's looking for bioinformatics people," Cabot says, "and molecular modelers, too. These are definitely two hot areas that span all sorts of molecular drug discovery." While many labs hunt for novel allergy targets, others see room for improvement in existing therapies. The weekly injection is the hallmark of traditional allergy treatment. With these shots, people are given small doses of the pollen, pet dander, or other allergens that provoke their misery. Over time, a person becomes desensitized to these allergens, and his or her immune system stops overreacting every time it encounters them. But allergy shots are inconvenient. They can take years to work, require weekly trips to the doctor, and sometimes cause side effects. Researchers at privately owned ImmuLogic Pharmaceutical Corp. in Waltham, Mass., recently have cloned the genes for allergens contained in cat dander and ragweed pollen. With genes in hand, they isolated the most potent portions of the allergens and then used just those portions to create refined allergy shots. In theory, these shots will deliver more therapeutic punch-over the course of just a few weeks-and fewer side effects. ImmuLogic is currently testing its cat dander and ragweed shots in clinical trials. INJECTION ALTERNATIVE: Nasal sprays produce "a purely local, efficient immune response," says Harold Nelson of Denver’s National Jewish Medical and Research Center. For allergy victims who hate shots, a nasal spray could make spring more bearable. "It's an attractive approach because it works differently from injection immunotherapy," explains Harold Nelson, a senior staff physician at National Jewish Medical and Research Center in Denver. "It produces a purely local, efficient immune response." Nasal sprays to treat allergies aren't a new idea, Nelson says. But they have been improving. Older nose sprays caused allergic reactions because they were essentially allergens in a water solution. Using a spray, patients would endure allergy symptoms until their bodies built up a tolerance to the allergen at hand. But researchers have learned that giving patients a spray of cromolyn sodium first can stifle a nasal spray's allergy-inducing response, while still providing protection against the allergen. According to the Washington, D.C.-based Asthma and Allergy Foundation of America, Americans spend $2 billion annually seeking allergy relief. Ariad Pharmaceuticals Inc. http://www.ariad.com Genentech Inc. http://www.gene.com Hoechst Marion Roussel Inc. http://www.hoechst.com National Jewish Medical and Research Center http://www.njc.org/pa Pfizer Inc. http://www.pfizer.com Schering-Plough Corp. http://www.myhealth.com Tanox Biosystems Inc. http://www.tanox.com No matter what their goal, researchers who want to join the immunology field-whether in allergy or in asthma-will find opportunities, lab scientists say. "Fifteen or 20 years ago, all you needed to put together a drug discovery group was a bunch of pharmacologists and chemists," says Wasserman at Hoechst Marion Roussel. "Today, you need immunologists, biochemists, enzymologists, molecular biologists, and molecular geneticists. You need people who can use the 'nouveau technologies' of biology and who understand things at the level of the cell or below." As labs begin to unravel the biochemistry of allergy, they also desperately need researchers who can quantitatively assess the proteins involved, observes Hopkins' MacGlashan. For example, until now, scientists have simply been identifying the regulatory molecules that affect levels of IgE. However, to create a drug that alters those molecules, researchers need to understand them in a qualitative sense. On the cellular level, it's like going from general taxonomy to the dynamics of population biology. To make this transition, MacGlashan says, labs need biophysicists and biochemists. At the moment, universities offer fewer allergy research opportunities than industry does, MacGlashan adds. "In academics, the jobs are solely a function of how well-funded NIH [the National Institutes of Health] is," which affects the amount of money available for research support. "We still see a reasonable influx of people," he continues, "but nobody's coming in thinking, 'I know! I'll go into allergy.'" He and others note that job hunters with an immunology background may enter allergy or asthma research-or another disease area entirely. Tanox's Davis agrees, saying versatility is key. Her company's idea for anti-IgE monoclonal antibodies began with the brainstorming of scientists who did not specialize in allergy research. "No one in Tanox had worked in the area of allergy before," Davis says. "We were immunologists, not allergists. It was an openness of ideas that brought [the anti-IgE product] forward." Similarly, she says, an openness of ideas can bring new opportunity to anyone hoping to enter allergy research. Kathryn S. Brown is a freelance science writer based in Columbia, Mo.

Researchers Find Opportunities Sniffing Out Allergy Treatments

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