Three Companies Bet Their Futures On Catalytic Antibodies' Potential

Scientists inside and outside the industry debate the commercial possibility of using antibodies as enzymes WASHINGTON - Catalytic antibodies are the stuff of Steven Benkovic's dreams. He hopes these immune system molecules, when put to work speeding up chemical reactions, will function as magic bullets to fight disease and infection. Benkovic, a physical organic chemist at Pennsylvania State University, is not alone in his reverie. More and more scientists and their corporate cohorts are envisioning a world of pharmaceuticals, diagnostic kits, and agricultural chemicals that home in on a biological target - whether an enemy virus or the molecular bond of a useful, but frustratingly complex, protein - with an accuracy not possible with current technology. At least three companies are in hot pursuit of catalytic antibodies, the technology expected to make such products possible. They tout the advantages - billions of antibodies to choose from; each homes in on a very specific target - that get even academicians excited about their potential. "This is the sort of [basic research level] work where, even in purely academic labs, everyone has a possible application in the back of his mind," says David Hansen, a chemist at Amherst College in Massachusetts. Whether those dreams metamorphose into a useful reality depends on the work now being done by small biotechnology companies like Igen of Rockville, Md., and two California firms, Affymax and Stratagene, as well as by scientists in university laboratories around the world. The strengths of catalytic antibodies have yet to be proved, and their weaknesses must still be overcome. Catalytic antibodies also will have to compete against better known catalytic agents, like enzymes and chemical catalysts. The search for substances to hasten biological reactions has a long and rich history. Since the late 1800s the favored approach has been to use enzymes. More than 20 years ago William Jencks at Brandeis University hypothesized that antibodies might do the same, but scientists were unable to prove it. They had to wait until 1986, when two biochemists independently demonstrated that antibodies, too, can act as catalysts. That discovery, by Richard A. Lerner of the Research Institute of the Scripps Clinic and Peter G. Schultz of the University of California, Berkeley, prompted enterprising companies to pursue practical applications. The biotech tools they envision would couple the supreme specificity of the antibody with the catalytic power once attributed solely to the enzyme. So far these small companies like what they see. First of all, there are tens of billions of different kinds of antibodies to choose from. In the case of enzymes, industry chemists have had to make do with relatively few variations. This has often left them in the frustrating position of having a potentially powerful - and impossibly slow - chemical reaction in mind and no catalyst to speed it up. Researchers believe such an antibody probably exists. Secondly, the antibody's ace card is its selectivity, its ability to latch onto specific chemical targets. That characteristic enables them to ignore substances that look very much like the targets. This inherent specificity might one day allow scientists to tailor biochemical reactions and cleave peptide chains with an accuracy not possible with enzymes or chemical catalysts. This technique, in turn, may enable scientists to manipulate proteins more precisely. Even if antibodies prove incapable of changing the course of all chemical reactions, they have already altered the direction of companies that are developing them. Igen, a company founded in 1982 to develop and market monoclonal antibodies for industry, began experimenting with catalytic antibodies in 1986. Richard Massey, executive vice president and one of the founders of the company, says he had not heard of Schultz and Lerner's work when he began to wonder if he could use antibodies to purify and separate his compounds. He and his lab partners then tried to use an antibody to cleave the bond of an ether. "We were surprised when the catalytic reaction actually worked," says Massey. In short order, Igen expanded its commercial mission. "Catalytic antibodies moved us away from the industrial to the medical field," says Massey. He sees many profitable applications in that field, and believes that other biotechnology firms just haven't caught on. "There's a learning curve in scientific development," he says. It takes a while for people "to realize something's important enough to start working on. Industry is still in a lag phase because not enough information has accrued. Everybody's waiting to see where the technology can be used." Massey's not one of them. He's already boasting at scientific meetings about the future of these new chemicals, and he says that by the end of the year Igen will begin studies in animals of catalytic antibodies for therapeutics. In the works are drugs to fight cancer, to treat drug overdoses, and to battle infectious diseases like AIDS. Nor will Igen stop there. Its researchers are also developing catalytic antibodies for biosensors and for new chemical tools to be used in the synthesis of pharmaceuticals. The work on biosensors to monitor industrial processes or sick patients involves fundamental research, while the development of new biochemical tools to synthesize pharmaceuticals stands somewhere between basic research and animal trials. "Which of the three areas has the most success [in getting to market] depends on what kinds of reactions can be catalyzed in the laboratory," says Massey. At least two other biotech companies are also betting on catalytic antibodies. Affymax, in Palo Alto, Calif., appears to be a step behind Igen. The Dutch-based company was started two years ago to develop faster and more efficient methods of rational drug design, including a system for quickly screening compounds for biological activity. "We're in the process [with catalytic antibodies] of shifting from model systems in [academic research] to commercially interesting problems," says Leighton Read, executive vice president of Affymax. That commercial development has been bolstered by the research of Berkeley's Schultz, who helped pioneer the concept of catalytic antibodies. Besides generating pharma- ceutical precursors, Read and Mark Gallop, coordinator of the company's catalytic antibody program, foresee a new world of environmentally friendly agricultural chemicals. By taking advantage of the antibody's supreme specificity, they hope to fashion pesticides that don't harm benevolent organisms. Despite the euphoria about the invention of catalytic antibodies, scientists and commercial developers must first overcome several problems if the antibodies are to compete with enzymes and chemical catalysts in the marketplace. "Number one is specificity, which is what antibodies are all about," says chemist David Hansen at Amherst College in Massachusetts. In theory, the human body is capable of producing 10 billion different antibodies, while the number of enzymes is limited. This means the number of reactions that can be catalyzed by enzymes is set - and relatively small. Antibodies, on the other hand, should be able to catalyze a seemingly infinite number of reactions. But there's a catch. Until recently, scientists had access to only a few kinds of antibodies, and those were not always good catalysts. For example, when an antigen is injected into a laboratory mouse, the mouse produces several antibodies that attach to different parts of the antigen, depending on the chemical configuration of the particular antibody. Each antibody will have a different combination of heavy and light chains that matches up more or less well with the chemical structure of the antigen. For reasons scientists don't yet understand, not every antibody will act as a catalyst. Also, producing the strongest catalyst is not the goal of the immune system, so the mouse might not produce the best possible catalytic antibody at all. Recent work by Richard Lerner and Steve Benkovic at the Research Institute of the Scripps Clinic to overcome this has resulted in "combinatorial libraries" that contain hundreds of millions of different antibodies. In theory, those libraries should include the best possible catalysts, but that is not certain. "It has yet to be demonstrated that you can reap more catalytic antibodies" with the libraries, cautions Hansen, who sees the technology as a potentially powerful tool that is still in its infancy. In addition, catalytic antibodies havestill another shortcoming: They don't speed up reactions as much as enzymes can. Enzymes can increase the rate of a chemical reaction by as much as a billion times. When Berkeley's Peter Schultz and Lerner created monoclonal antibodies that would bind to a substance and accelerate a reaction, in terms of speed, the new substances were not even in the same league as enzymes. The antibodies used by the West Coast scientists increased the rate of the desired reaction - the hydrolysis of carboxylic esters - by only 1,000 to 1,500. Though the different laboratories have now upped rates by a million times all told, that's still at least a thousand-fold slower than enzymes. --D.M. A third company, Stratagene, has worked with Lerner and other scientists at Scripps to develop a method that increases the number of antibodies available for commercial development. Of its own work, the La Jolla biotechnology firm will say only that it is now in the early - and uncommitted - stage of looking into two applications, one in industry and the other in therapeutics. Even if these companies succeed in overcoming the scientific challenges, their antibodies may not have the application their promoters hope. "Catalytic antibodies can never compete in the arena of enzymes or chemical catalysts," says biotechnology and health industry analyst Philip Rotheim. "To succeed commercially, they'll have to discover their own niche." Rotheim says that rules out the food industry, which relies on enzymes - already a proven commodity - to make such things as cheese and corn syrup. Enzymes also have shown themselves to be powerful catalysts in the production of therapeutics, such as steroids and antibiotics. In addition, chemical catalysts such as palladium, platinum, and zeolite are used heavily in the petrochemical industry. Unlike either enzymes or antibodies, they tolerate high temperatures, extremes of pH, and other impurities that would dismantle any enzyme. Even the most enthusiastic supporters of catalytic antibodies say that they need to be improved before they can grab a significant share of any market. Researchers have yet to find ones that work as fast as they would like, and only recently have figured out ways to increase the number of antibodies to choose from (see accompanying story). Indeed, the most likely proving ground for antibodies will be in biomedicine - an area that chemical catalysts and enzymes have not yet commandeered. In that arena, speed is at times less critical. "The question is how [desirable] as a catalyst are these guys," says Hansen. On one hand, many industries can ill afford a catalyst that operates below a certain speed. On the other hand, a slow catalyst may be better than no catalyst. "If you're working in the lab and you want to cut a peptide chain and it takes a few days, that's fine," Hansen says, especially if there is no other known catalyst that can cut the protein at the exact site the scientist is interested in. Enzymes may be fast, but they offer antibodies no competition when it comes to targeting one link on a long chain of amino acids. Catalytic antibodies that act as sequence-specific proteases, chopping up peptide chains, will be especially useful in the production of pharmaceuticals. Other scientists say that new techniques for designing and engineering antibodies may help them overcome some of the antibodies' shortcomings. Already, combinatorial libraries have moved researchers ahead light-years by giving scientists more antibodies to screen and choose from. Other techniques may take them even further. "You get a certain amount of rate enhancement through screening," says Read at Affymax. "But you can get it even better through engineering." Under Schultz's guidance, he says, his company is developing many kinds of synthetic antibodies and getting good results. For example, by attaching chemicals to antibodies, Schultz has been able to speed up some reactions by a factor of 60,000. Scientists can also genetically engineer the antibodies to improve their performance. But overall, catalytic antibodies have yet to show they can perform the many tricks companies like Igen and Affymax have set for them. The early catalytic processes that Schultz and Lerner demonstrated involved cleaving fairly simple bonds. To be most useful in the development of new drugs, for example, catalytic antibodies must be able to break more complicated bonds, like those between amino acids in peptide bonds. "Within the next three to five years we will know if the initial promise will be fulfilled," says Hansen. "The Holy Grail is sequence-specific antibody proteases. If scientists can't do that within five years, people will begin to lose interest, and catalytic antibodies will return to the academic labs."

Three Companies Bet Their Futures On Catalytic Antibodies' Potential

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