As monoclonal antibodies make a comeback, nobody’s claiming miracle cures anymore. Having passed through the cycle of “Holy Grail to dirty word,” says Lehman Brothers biotech analyst Rachel Leheny, monoclonal antibodies have become a working technology with an established set of strengths and weaknesses.
Monoclonal antibodies are designed by the immune system to bind only to specific target molecules, making them much more precise than typical small-molecule drugs, the relatively simple compounds that have been the staple of the pharmaceutical industry. And unlike other protein therapeutics, which can activate or block only one specific biological process each, monoclonal antibodies can be developed for any target protein or cell type imaginable. This combination of built-in precision and flexibility can mean faster development and lower toxicity. The risk of a potential antibody drug failing in clinical trials because of unwanted side effects is considerably less than it is for small molecules.
“The probability of success is much higher, and the time course of developing them is much quicker,” says Geoff Davis, chief scientific officer at Abgenix, a Fremont, CA-based antibody drug company. Considering that pharmaceutical companies now spend an average of 15 years and $800 million to bring a new drug to market, saving a few years in development and reducing the risk of a drug’s failing in clinical trials can translate into an enormous profit.
The latest boost to the monoclonal-antibody revival comes from the sequencing of the human genome and the burgeoning genomics industry. Suddenly, pharmaceutical and biotech researchers are deluged with genes, tens of thousands of them, many of which may be valuable drug targets. The result is a gold rush mentality, as researchers race to establish which of these genes and their accompanying proteins are the best targets for inhibiting disease processes. Here monoclonal antibodies-in the guise of laboratory tools that will bind to specific proteins and knock them out of action-represent one of the quickest ways to answer those questions. And once a viable target is nailed down, the low risk and precise targeting of monoclonals can make them the easiest drugs to get to market against it. “They cut right to the chase,” says Immunex’s Carter.
The object of the pursuit, the antibodies themselves, are Y-shaped proteins that constitute the immune system’s first line of defense. They will bind to anything the immune system finds unfamiliar and hence potentially dangerous-say a bacterium or virus-and then hold on tight, calling forth the full range of the immune system’s forces to neutralize or destroy the target (see “Mobilizing Immunity”).
Over the course of a lifetime, the human body generates roughly 100 billion different antibodies. In each case, the base of the Y is virtually identical; the arms of the Y differ from antibody to antibody, thus providing the vast variability that maximizes the possibility that the immune system will spot almost any conceivable invader.
Researchers have long envisioned inducing antibodies to cure or treat diseases that the immune system either ignores, such as cancer, or causes, like rheumatoid arthritis, lupus and other autoimmune diseases. Biologists have known for decades that if you immunize a mouse with a human cancer cell, or even a single protein from such a cell, the mouse will respond by generating its own antibodies to fight the foreigner off-in effect, an anticancer antibody. If you inject the same cancer cell over and over and over again, your mouse will generate antibodies exquisitely specialized to target the cancer cells you put in.
Illustration by John MacNeill