Carbohydrate Research Offers Sugar-Coated Opportunities

Long the poor cousins of proteins--and now the darlings of the biotechnology industry--carbohydrates are coming into their own as objects of research. Among the four basic biochemicals of life (along with fats, proteins, and nucleic acids), they are the focal point of a hot new area of inquiry, dubbed "glycobiology" by some of its proponents. And the number of startups capitalizing on new discoveries about carbohydrates by designing novel drugs is growing. "I think the biotechnology of complex carbohydrates, and the research that derives from it, is something that will blossom into a scientific revolution, like molecular biology did in the early '70s and '80s," says Howard C. Krivan, president of three-year-old MicroCarb Inc., a Gaithersburg, Md.-based company dedicated to developing infectious disease diagnostics and vaccines based on human carbohydrate cell-surface receptors. "The understanding of the vital biological role of carbohydrates and their applications in medicine--such as the binding of disease-causing microorganisms to carbohydrates on cells, which is what my company focuses on--is growing rapidly." Such enthusiasm for the study and commercial exploitation of carbohydrates in the pharmaceutical industry is a recent phenomenon. Although carbohydrates have long been of interest to the food industry, only a few carbohydrate-based drugs are currently marketed for clinical use, such as heparin, a drug that prolongs blood clotting. According to James N. BeMiller, director of the Whistler Center for Carbohydrate Research at Purdue University in West Lafayette, Ind., "there was a lot of feeling for a long time--and probably there still is some-- that no good pharmacological activity could come out of carbohydrates." Much of biotechnology researchers' attention in the past was focused on the commercialization of proteins. Alpha-Beta Technology Inc. (Worcester, Mass.; founded 1988): The firm is using genetic engineering to manipulate yeast- derived carbohydrate polymers. Its immunostimulant, Betafectin, just entered phase I clinical trials on healthy human volunteers. Chembiomed Ltd. (Edmonton, Alberta; founded 1976): Carries out research on the identification of carbohydrates from natural sources. Cytel Corp. (San Diego; founded 1987): Acquired GlycoGen Inc. from Genencor International Inc. of South San Francisco, Calif., in October 1991. In its carbohydrate efforts, the firm is focusing on interrupting the action of adhesion molecules. Initial public offering November 1991. Glycomed Inc. (Alameda, Calif.; founded 1987): The first company in the U.S. devoted to developing carbohydrate-based drugs, it concentrates on cardiovascular and inflammatory diseases and tissue repair. Greenwich Pharmaceuticals Inc. (Fort Washington, Pa.; founded 1972): Its monosaccharide drug, Therafectin, is in phase III clinical trials with rheumatoid arthritis patients. MicroCarb Inc. (Gaithersburg, Md.; founded 1991): Known as BioCarb Inc. before a managerial buyout. Developing receptor- based diagnostics and adhesion vaccines to detect and combat infectious diseases in animals and humans. Oxford GlycoSystems (Oxford, England; founded 1988): Created to market technology developed at Oxford University, the firm is a collaboration between Oxford University and Chicago-based Searle, a subsidiary of Monsanto Chemical Co. of St. Louis. In November 1991, Oxford University and Searle opened the Glycobiology Institute in Oxford to study sugar in living organisms. --L.M. A Shift In Focus That orientation has shifted now, owing in large part to recent discoveries that have shown that carbohydrate structures in the body perform an important function in cell- cell interactions, particularly during the process by which the body responds to injury and foreign intruders such as viruses or bacteria. "Before, it was all just pretty much synthesis and analysis of structures, and really no one knew what they were for," Krivan says. "Now you are seeing a trend where scientists out there are beginning to assign a function to the carbohydrate sequence they've characterized." The carbohydrate structures that have attracted the most attention are part of cell adhesion molecules. Named for the role they play in attracting white blood cells to specific areas, these molecules are crucial to the workings of the immune system. When a portion of the body is infected by a virus or a bacterium, cells lining the interior of blood vessels in that region will "call" white blood cells to the rescue with a portion of their surfaces known as receptors. White blood cells circulating in the blood will, in turn, respond with structures dubbed ligands as "calling cards." The two structures, the receptor and the ligand, create an interlocking match. In this manner the white blood cell is seized at the site where it is needed. Once snared, the white blood cell will then exit the bloodstream and enter the threatened tissue, where it attacks the invader. An Exciting Discovery The precise mechanism by which the body accomplishes this had not been well understood until now. What has excited scientists is the discovery of the action of the cell adhesion molecules, particularly the active role of the cells lining the interior of blood vessels, known as endothelial cells. The carbohydrate nature of some of the cell adhesion molecules has also been a surprise. In some cases the molecule is a glycoprotein, a protein attached to a carbohydrate group, but even then it is the carbohydrate portion that is active in cell adhesion. This new knowledge provides a better understanding of inflammation, the massing of white blood cells to an injured area that is the immune system's response to threat. More significantly, at least from the pharmaceutical point of view, these discoveries also offer insight into how an immune system run amok might be stopped. Inflammation, usually the right response, can have a Mr. Hyde face. When the immune system makes a misidentification and causes the body to attack itself, sending armies of white cells to destroy its own tissue, autoimmune disease has occurred. Diseases of this type include rheumatoid arthritis, type I diabetes, psoriasis, and multiple sclerosis. Autoimmune disease is part of a larger category known as inflammatory disease. Inflammatory diseases include adult respiratory distress syndrome; asthma; and reperfusion injury, a condition that occurs following resuscitation after a heart attack, when white blood cells damage tissue that had been deprived of oxygen. Current treatments for inflammatory diseases are not ideal. In the case of chronic diseases like rheumatoid arthritis or psoriasis, most of the drugs provide only symptomatic relief. And, when they are taken day after day, their potency causes undesirable side effects. "You're not getting at the fundamental issues of the disease, so you get these horrible feedback loops," says Pamela Murphy, vice president of corporate administration for Greenwich Pharmaceuticals Inc., a Fort Washington, Pa.-based company working on a carbohydrate drug for autoimmune disease that is the only carbohydrate drug under development in the United States in phase III trials. "It would be better to help the immune system to shut off that mechanism when it's so out of whack." Hope For Autoimmune Disease Carbohydrate-based drugs offer that hope. The majority of the new carbohydrate companies are working toward designing drugs that would mimic the action of the cell adhesion molecules and act either as decoy receptors or ligands. While the endothelial cells might still wrongly call white blood cells to the attack, a drug acting like the ligand on a white blood cell could theoretically respond and lock into the receptor, thereby blocking the white blood cell's action. Or, conversely, drugs could be designed that would act as receptors, locking onto the white blood cell ligand and preventing the white blood cell from attaching. Understanding the role carbohydrates play in inflammation is the first step toward interfering with an immune system that has gone awry. Yet this opportunity alone doesn't explain the mounting interest in applying this basic research to drug development. A pair of key numbers offers an explanation. According to analysts at the Technology Management Group, a market research firm in New Haven, Conn., the market for a new class of carbohydrate-based drugs aimed at regulating autoimmune disease could be $700 million worldwide by 1996 and $2.5 billion by 2001. Proponents of carbohydrate-based therapies also note that carbohydrates are stable, are easy on the stomach, and can be administered orally. These advantages, the opportunities opened by recent basic research, and the size of the autoimmune disease market all offer what John F. Wong, biomedical technology analyst for L.H. Alton & Co., an investment banking firm, calls "definite motivation" for pharmaceutical companies to enter this field. Biochemical engineers David Easson and Spiros Jamas got motivated five years ago as postdocs working in carbohydrate engineering. "At MIT, particularly during the last year we were there [1987], a lot of companies coming around were interested in the work we were doing," says Easson. "And we thought that instead of someone just licensing the technology, we would license it ourselves and commercialize it." Easson and Jamas are now executive vice president-chief operating officer and president-chief executive officer, respectively, of Worcester, Mass.-based Alpha-Beta Technology Inc., a company they founded in 1988. The firm has a number of licensing agreements with MIT and Brigham and Women's Hospital/Harvard Medical School in Boston. In early January, Alpha-Beta Technology started Phase I clinical trials of Betafectin, a carbohydrate-based compound under development for the treatment of infections related to surgery and cancer chemotherapy. The company hopes this study will assess the drug's safety in healthy human volunteers. The firm then plans to do trials in immune-compromised patients to further evaluate safety and study dosing and biological activity. Challenges For Entrepreneurs While positive parallels with the wave of 1980s biotechnology startups exist, the new carbohydrate companies also face the same pitfalls: years of expensive R&D, the watershed of clinical trials, achieving Food and Drug Administration approval, and the task of producing a new drug in mass quantities. This last challenge is made especially difficult by the very nature of complex carbohydrates. Carbohydrates are composed of sugar groups, and while a single sugar group, known as a monosaccharide, is relatively easy to synthesize and to mass- produce, the larger molecules are much more complicated. "You talk to people and they'll tell you, `Well, a disaccharide, no problem,' " says Jay D. Kranzler, president and CEO of San Diego-based Cytel Corp., a biotechnology company working to develop carbohydrate drugs to stop the disease-causing action of cell adhesion molecules. " `A trisaccharide, difficult, but we're really good; we can probably do that. And a tetrasaccharide, forget it.' The reason why is if you try to link these four sugars together, there are over 35,000 combinations--only one of which has biological activity." By comparison, there are only 24 possible variants for a protein composed of four amino acids. Cytel has risen to the tetrasaccharide challenge, however. It is concentrating its carbohydrate efforts on synthesizing a ligand known as sialyl Lewis X, a cell adhesion molecule, not with traditional organic chemistry but with enzymes, the same way the body produces the carbohydrate. Other companies are circumventing the stereochemistry problem by sticking to mono- or disaccharides. Not surprisingly, carbohydrate analysis is also a fast- growing field. As Krivan notes, "Until you know what you're working with, it's difficult to manipulate it or have any impact on it." Liz Marshall is a freelance science writer based in Pittsburgh

Carbohydrate Research Offers Sugar-Coated Opportunities

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