No More Sneezing, Itching, Coughing?

A purring cat curled up on an old sofa might seem bucolic, but for many allergy sufferers the scene signals misery: itchy eyes or nose, an uncontrollable urge to sneeze, a tightening throat. Before long, invisible assailants--cat dander and dust mites--send their sniffling victims racing for tissues and antihistamines.

Within a decade, however, the hankies might be gone for good. At laboratories in drug companies such as Genentech Inc. and Ciba-Geigy Corp., as well as in universities, scientists are scrambling to decipher the complicated pathway that leads to an allergy attack. The researchers' discoveries have helped them identify a handful of new approaches to drugs that may halt allergic reactions before the first sneeze. "Where the action is in allergy drugs is not in symptomatic relief but in stopping the allergic process altogether," says Dr. Francis Cuss, vice-president for discovery research at Schering-Plough in Kenilworth, N.J.

Allergies affect nearly 20% of the U.S. population. Some 24 million people suffer from the sneezing and runny-nose variety known as allergic rhinitis. Asthma--which is most often caused by allergies--affects an additional 10 million Americans. Food, insect venom, and chemical allergies plague still others.

LAND MINE. There seems to be more of the misery around than ever, too. Sales of prescription and over-the-counter remedies in the U.S. could rise 8% next year, reaching $4.5 billion, estimates POV Inc., a health-care publishing company in Montclair, N.J. The bulk of those sales are antihistamines and steroids, which, although effective in many cases, are usually taken after symptoms have already begun. Their side effects can range from sleepiness to more serious metabolic problems associated with long-term steroid use.

Companies are aiming to capture this huge market with new preventive drugs that could be taken safely for years. To do that, they are attacking the underlying cause of allergies, which is that the immune systems of allergic people treat such innocuous substances as pet dander or mold with a vigor usually reserved for viruses or other dangerous invaders. It's still not clear why their bodies are so vigilant, but doctors have identified one main culprit. It turns out that allergic people churn out a lot of an antibody called immunoglobulin E, or IgE, when exposed to allergens. This IgE--which is produced only in minute amounts in people without allergies--attaches to a docking site, or receptor, on so-called mast cells that line the surface of the lung, nose, and other areas.

Once in place, the IgE acts like the trigger on a land mine. When cat dander or another allergen hooks onto the free end of IgE, it causes the mast cell to explode, spewing a potent cocktail of histamines and other substances that lead to the stuffy nose, itchy eyes, and other symptoms of allergies.

One approach then, is to disarm the trigger, IgE. Two companies, Tanox Biosystems Inc. in Houston (in a partnership with Ciba-Geigy) and Genentech in South San Francisco, are conducting clinical tests of drugs that do just that. Their approaches are similar and involve using a so-called monoclonal antibody that specifically grabs onto IgE and prevents it from attaching to mast cells. Tanox' drug not only stops IgE short of its goal, it seems to stop production of fresh IgE. "With our antibody, the IgE in the blood disappears almost immediately," says Tse Wen Chang, Tanox' vice-president for research and development.

Monoclonal antibodies do have limitations. For one, they must be injected--in this case, says Chang, weekly, and possibly for life. Also, because the antibodies are originally derived from mice, there is the possibility that the human immune system could see them as foreign and mount an attack against them.

Still, both Genentech and Tanox estimate that their antibodies could be available in three years. That is, unless legal wrangling slows the process down. The companies are battling in court over who owns the anti-IgE technology.

FRANTIC MESSAGE. Meanwhile, researchers at other labs envision tackling allergies even before IgE is produced. The process starts, they discovered, with the sentinels of the immune system--the so-called T-cells. People who are allergic have a high proportion of particularly alarmist T-cells, says Dr. Marshall Plaut, chief of the allergic mechanisms section at the National Institute of Allergy & Infectious Diseases. When they detect an allergen in the bloodstream, these sentinels send out a chemical message urging B-cells to make IgE. This chemical message is a substance called interleukin-4, or Il-4.

Research into Il-4 and its effect on the immune system is still quite new, but Schering's Cuss says that scientists at his company and its affiliate, DNAX Research Institute of Molecular & Cellular Biology Inc., are already working on developing drugs that would target the substance. They would either keep Il-4 from being produced, soak it up once it's been released, or prevent it from attaching to B-cells.

There's some concern, though, that interfering with Il-4 might hurt the immune system's ability to fight disease. "Il-4 is not a mistake of nature," says Dr. Donata Vercelli, a chief scientist at San Raffaele Scientific Institute in Milan and an expert on Il-4. Cuss says the promise of Schering's speculative work outweighs the risk of failure. "If we are right, it is going to be very useful to humans with allergies and asthma, and it will make us a lot of money, too."

Another approach that targets Il-4 is a vaccine that takes its cue from weekly allergy shots. With allergy shots, people are given very small doses of dander, ragweed, or whatever makes them allergic. The idea is that over time, the person will be desensitized. Recently, researchers discovered that rather than inciting the T-cells to produce Il-4, the constant low doses of allergen actually inhibit its production. Instead, the T-cells make another substance, IgG, that halts the allergic process.

The problem with allergy shots, says Plaut, is that it can take years to get the proper result. That's because there is a delicate balance between giving a person enough allergen to shut off the immune system and giving so much that it sets off an allergic reaction. To be safe, doctors usually only inject very small doses of the offensive substance into a patient--too small to have a timely effect.

GENETIC TRAIL. But scientists at ImmuLogic Pharmaceutical Corp. in Waltham, Mass., have a way around that problem. Instead of injecting the whole allergen, says Dr. Robert J. Gerety, president and CEO of ImmuLogic, "We identified the pieces that can turn off the immune system." These pieces of the allergens--called epitopes--are injected over the course of several weeks, not years. Gerety says clinical trials of the vaccines for cat dander and ragweed are in phase III, or late-stage, trials. In earlier tests on the cat vaccine, some 86% of people who received four weekly injections saw their symptoms abate for several months, says Gerety.

ImmuLogic hopes to begin marketing its first two vaccines--Allervax Cat and Ragweed--by early 1998. The company is teamed with Hoechst Marion Rousel to develop these and three other vaccines--for house-dust mites, Japanese cedar pollen, and grass. So far, Hoechst has contributed some $40 million to ImmuLogic, says Gerety.

For the time being, the assault on allergies is continuing on two parallel fronts. As companies race to develop the next billion-dollar remedy, academic researchers are identifying the genes that make people asthmatic or allergic in the first place. If they succeed, scientists will be able to intervene even earlier in the allergic process. For allergy sufferers, that's nothing to sneeze at.

New Angles Against Allergies

Most allergy drugs work by mopping up histamines. But several companies are working on drugs that would stop the allergic "cascade" are produced

DRUGS that block other immune cells, called B-cells, from getting Il-4's message to produce IgE antibodies.

Companies: Schering-Plough with DNAX.

VACCINES that stop immune cells called T-cells from producing a chemical alarm called Il-4.

Companies: ImmuLogic with Hoechst Marion Rousel.

DRUGS that stop IgE antibodies from attaching to mast cells that line the nose and throat, preventing them from spewing histamine and other chemicals.

Companies: Genentech, Tanox.

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