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Published On September 22, 2012

CLINICAL RESEARCH

Designer Drugs

"Large molecule" therapies, tailored to home in on otherwise untreatable ills, have become medicine's hottest commodity.

MAKING ANY KIND OF DRUG IS AN EXACTING PROCESS. Manufacturers must make sure that whatever form the medicine takes, each dose is exactly like any other. Still, as involved as it is to blend the chemical compounds of traditional pharmaceutical products, creating any of a class of medications known as biologics is several orders of magnitude more difficult. These therapies, made from living organisms, are among today’s most effective and best-selling drugs, and they’re not manufactured so much as grown, in specialized tanks called bioreactors.

To make a monoclonal antibody—a class of biologic drug that, while perhaps not as well known as the influenza vaccine or insulin (two other kinds of biologics), is highly prevalent—scientists start by inserting a gene into a cell that will enable it to produce a desired protein. The target cell, typically taken from the ovary of a Chinese hamster, then begins to generate thousands of identical copies of itself. Those cells are transferred into small flasks in which they’re fed a special nutrient medium of amino acids, proteins, sugars and hormones. Paddles rotate through the flasks as the cells continue to multiply.

Once the small flasks are full of cells, their contents are siphoned into a larger container—and then into another, still larger, and another and another until there are enough specialized cells to fill a 12,000-liter vat. It is in this final tank that the engineered cells are stimulated to secrete the protein product—the monoclonal antibody itself, a protein derived from the mammalian immune system that can bind to a very specific target in the body, such as a tumor cell. Monoclonal antibodies are large, complicated proteins that must then be separated and purified, first in centrifuges and after that with liquid chromatography.

This is shiny new technology, and it’s used to manufacture the three drugs that pharmaceutical forecasters predict will be this year’s top-selling medicines—the monoclonal antibody drugs Humira (adalimumab) and Remicade (infliximab), and Enbrel (etanercept), another kind of biologic known as an Fc fusion protein. All three are therapies for rheumatoid arthritis, an autoimmune disorder that previously had few effective treatments. They’re expected to outsell two other blockbusters: the cholesterol drug Lipitor (atorvastatin) and the blood thinner Plavix (clopidogrel bisulfate).

The ascendancy of these biologics could mark a kind of changing of the guard in the pharmaceutical industry. Lipitor and Plavix are small-molecule drugs, a class of treatment that includes everything from aspirin to many of today’s most sophisticated drugs. Biologics, in contrast, are also known as large-molecule drugs—because they are literally huge. An aspirin molecule, for example, has just 21 atoms, compared with about 25,000 for a molecule of a typical monoclonal antibody.

Monoclonal antibodies now account for roughly half of all new therapeutic products under development, and those already on the market generated $48 billion in global sales in 2010. Five of the drugs saw more than $5 billion in sales. (These compounds are often referred to as mAbs; their scientific drug names end with the suffix “mab.”) And several more breakthrough mAbs are on the way. Last year the Food and Drug Administration approved Benlysta (belimumab), the first new treatment for systemic lupus erythematosus in more than 50 years, and Yervoy (ipilimumab), the first drug shown to prolong the lives of patients with melanoma.

The power of mAbs comes from their specificity—they work on a chosen target and only on that target. That makes them less likely to cause side effects than a conventional drug that may find its way to unintended parts of the body. Researchers are also finding ways to manipulate mAbs to make them even more powerful, and to craft them to work in combination with other drugs—for example, by delivering cancer-killing drugs directly to a tumor. And though the large size of biologic molecules limits their potential uses—they’re too big to get inside a cell and must attach themselves to extracellular proteins—there seems little doubt that mAbs will play an increasingly crucial role in disease treatment.

ALTHOUGH DRUGS USING MONOCLONAL ANTIBODIES are relatively new—the first to win Food and Drug Administration approval hit the market in 1986—physicians have been working with antibodies to treat disease for more than a century. Beginning in the 1890s, Emil von Behring, a Prussian military physician, and Shibasaburo Kitasato, a Japanese physician and bacteriologist, collaborated on research in which they injected animals with weakened bacterial pathogens such as typhoid, tetanus and diphtheria. Then they injected the blood into other animals infected with the diseases. Antibodies—large proteins that white blood cells manufacture to fight specific invaders—quickly and efficiently annihilated the bacteria.

That technique, known as serum therapy, was ultimately doomed by a serious drawback: the risk of serum sickness, which occurs when the body reacts to other, nonantibody proteins contaminating the injected blood. So the nascent pharmaceutical industry took a different tack, using a series of techniques to produce small-molecule drugs. At first, researchers looked to nature for effective compounds such as aspirin, based on salicin, the substance that gives willow bark its medicinal power. That was followed in the 1920s and 1930s by the discovery of penicillin and other infection-fighting antibiotics, extracted from bacteria and fungi. After the Second World War, scientists began synthesizing compounds that could work in the same way as the natural versions, and in the 1970s, researchers shifted strategies again, attempting to identify disease-causing proteins and only then looking for drugs that acted on those proteins. That produced a class of drugs known as angiotensin-converting enzyme, or ACE, inhibitors that hit the market in the early 1980s, and during the next 25 years or so, there followed a string of blockbuster small-molecule drugs that included such familiar names as Lipitor, Zantac and Prozac.

Still, scientists never gave up on the idea of harnessing the body’s ability to fight disease, and in 1975, Georges Köhler and César Milstein, molecular biologists working at the Medical Research Council’s Laboratory of Molecular Biology in Cambridge, England, achieved a breakthrough that would revive this field of research. They fused mouse B cells—antibody-producing cells of the immune system—with human myeloma (also known as B cell cancer) cell lines in a new technique called hybridoma technology. That was the first means of producing large amounts of monoclonal antibodies. (For their work, Köhler and Milstein were awarded the 1984 Nobel Prize in Physiology or Medicine, together with immunologist Niels Jerne, whose theories about antibodies informed Köhler and Milstein’s laboratory experiments.)

IN THE HUMAN BODY, each kind of monoclonal antibody binds to a specific protein called an antigen, typically found sticking out of a bacterium or virus. Yet because they were derived from mice, early monoclonal antibodies appeared as foreign invaders to the human immune system, triggering something called the human antimouse antibody (HAMA) response. That activity destroyed the antibodies before they could be effective, and in some patients it caused severe allergic reactions. Mouse-derived monoclonal antibodies, aside from a few exceptions, were deemed failures.

But biotechnology companies continued to work with mAbs, and in the 1980s, as scientists grew skillful at manipulating DNA to engineer particular proteins, they came up with several innovations to reduce the HAMA response. Researchers fused part of a mouse-derived antibody to part of a human antibody (creating chimeric mAbs) and grafted even smaller bits of mouse antibodies into human antibodies (humanized mAbs).

Those methods held sway for more than a decade. Muromonab, approved in 1986 to prevent rejection of transplanted organs, is a chimeric mAb, and so is Rituxan (rituximab), a B cell lymphoma treatment approved in 1997. It turns out that rituximab can also work for diseases such as rheumatoid arthritis, multiple sclerosis and other autoimmune conditions in which overactive B cells in the immune system contribute to the inflammation and degradation of healthy tissue.

A few other successful monoclonal antibodies were approved as treatments shortly after Rituxan hit the market, but it would take still another technological leap before mAbs really came into their own. The breakthrough arrived in the form of genetically engineered mice that, thanks to inserted human genes, made antibodies that were fully human. Not only are human antibodies less likely to provoke an unwanted immune reaction, but in some cases they could also be given subcutaneously, once every four to six weeks, rather than through weekly intravenous treatments, according to Anthony Coyle, vice president and chief scientific officer of the Centers for Therapeutic Innovation at Pfizer.

Around the same time that transgenic mice began to be used to produce human antibodies, scientists also started employing a genomic technology called phage display to build massive libraries of human antibody genes that could be screened quickly.” These phage libraries have tremendous diversity, so you can use them to find very unique antibody protein sequences that target specific molecules within disease pathways,” says Coyle.

The first mAb based on this technology, Humira (adalimumab), reached the market in 2002 and became a blockbuster. It acts on TNF alpha, a small protein involved in systemic inflammation and autoimmune disease, to treat rheumatoid arthritis. In addition, it helps counter ulcerative colitis and several other autoimmune disorders. But it also just works really well, providing relief from debilitating symptoms for many patients who have no other options. “Some of the TNF alpha inhibitors for rheumatoid arthritis have dramatically improved the lives of patients who were basically wheelchair-bound before,” says Coyle. “And rituximab radically changed how we thought about the treatment of non-Hodgkin’s lymphoma.”

IN 2010 AND 2011, SEVEN NEW mAbs hit the market, upping the number of FDA-approved mAbs to 34. Yet despite their surging popularity, biologics aren’t about to replace small-molecule drugs entirely. mAbs work best with extracellular targets, big proteins that stick out of cell surfaces. But the mechanisms involved in most diseases are inside cells, and reaching those requires small molecules, at least for now. To solve that problem, Harvard chemical biologist David Liu, together with colleagues, is working with what he calls “supercharged” proteins, which are studded on the outside with amino acids that hold only a positive charge. (Normally, proteins have a mix of positively and negatively charged and neutral amino acids.) “These proteins have a unique ability to deliver proteins and nucleic acids inside the cell,” says Liu. “Evidence suggests that they do this by binding to negatively charged receptors that adorn almost all mammalian cells.” There are still kinks to work out, Liu notes—once the proteins get inside the cell, many get stuck and can’t reach their targets—but this strategy has the potential to deliver monoclonal antibodies or other large proteins directly to intracellular pathways implicated in disease.

In the meantime, biologic and small-molecule drugs often complement each other: The monoclonal antibody can reach the target more effectively, allowing the small-molecule drug to do its work more efficiently at the target site rather than being scattered through the bloodstream. For example, Avastin (bevacizumab), used to treat metastatic colorectal cancer, didn’t significantly lengthen patients’ survival times because it didn’t kill enough cancer cells—until it was combined with a proven chemotherapy regimen. Researchers are also engineering mAbs to carry small molecules, including other chemotherapy agents, to exactly where they’re needed, thus reducing damage to noncancerous tissue. The first of these antibody-drug combinations, Adcetris (brentuximab vedotin), was approved by the FDA in 2011 to treat lymphoma.

EVEN AS SCIENTISTS CONTINUE TO INNOVATE more powerful mAbs, however, several complications could slow this therapeutic juggernaut. One problem is that many current drugs act on a comparative handful of proteins. For example, multiple mAbs and fusion proteins all take aim at CD20, the B cell target that rituximab first homed in on. And while there are advantages to having multiple drugs for a single target—sometimes, for reasons unknown, patients will stop responding to a particular mAb, says Coyle—having many drugs treat the same condition can also lead to market saturation and competition. And once a promising target has been identified, pharmaceutical companies race to create new drugs—sometimes including small molecules, which have the advantage of being able to be taken orally and to get inside a cell.

Another issue is the complexity of producing mAbs, and academic researchers have begun working with the drug industry to develop new ways to streamline the process. They’re looking at growing antibodies not only in mice, but also in insect, plant and yeast cells. The Biomanufacturing Research Program, or BioMAN, at the Center for Biomedical Innovation at Massachusetts Institute of Technology, is bringing university scientists together with manufacturers, regulators and vendors of biologics. “We’re asking how we can define better rules for manufacturing,” says J. Christopher Love, a chemical engineer at MIT. “That means everything from picking the right cell lines to using the best methods for purification and formulation.”

Biosimilars—“generic” versions of biologics—might also eventually help shape the future of large-molecule drugs. But because the manufacturing process for mAbs and other biologics is so complex and is often patented, a maker of a biosimilar for a particular drug pretty much has to reinvent the wheel. (That’s different from manufacturing a small-molecule generic, which will have the exact chemical structure of the brand-name drug.) And while a few biosimilars have emerged in China and Europe, none has reached the United States. The discussion on how best to evaluate, regulate and approve biosimilars is just getting under way, and it remains to be seen what effect this will have on innovation and the biologics industry.

Yet one thing is clear: Major pharmaceutical manufacturers, originally skeptical about the prospects for large-molecule therapies, have long since joined the race to develop the treatments, acquiring, merging or partnering with small companies working on mAbs and other biologics. The giant firms are counting on this class of drugs to bolster profits that will be hurt by the imminent expiration of patents on many small-molecule blockbusters. And as industry and academic researchers uncover more details about the molecular pathways of diseases, fruitful new targets for mAb-based therapies and their biologic cousins will almost certainly emerge.

 

DOSSIER

1. Therapeutic Monoclonal Antibodies: From Bench to Clinic, edited by Zhiqiang An [Wiley, 2009]. Not a light read, this tome is bursting with information about monoclonal antibodies, from the history of how these therapies were first developed to new approaches such as conjugate therapy, which combines antibodies with small-molecule drugs.

2. “What’s Fueling the Biotech Engine—2010 to 2011‚” by Saurabh Aggarwal,Nature Biotechnology, December 2011.An industry analyst examines sales in the biologics sector, analyzing trends and discussing new challenges in the sales of monoclonal antibodies and other types of biologics.

3. “Development Trends for Human Monoclonal Antibody Therapeutics,” by Aaron L. Nelson, Eugen Dhimolea and Janice M. Reichert, Nature Reviews Drug Discovery, October 2010. An outlook piece that analyzes data on fully human mAbs, a rapidly growing category of mAbs boasting promising therapeutic advantages, with an eye to trends in their development and approval.

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