For researchers and pharmaceutical manufacturers, making small-molecule drugs like aspirin is like building bicycles // Making large-molecule drugs, like jet planes // But with complexity comes complications
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.