But that’s just the beginning, as “fully human” antibodies are now hitting the pharmaceutical pipelines. There are two ways to develop these drugs. In the first, researchers remove the full complement of antibody genes from human B cells and transplant them into bacteria-specific viruses known as “phages.” The viruses promptly generate the appropriate antibodies from the newly acquired genes and then “display” the antibodies on their surfaces-one antibody per phage.
“Now we put all those phages into a test tube,” explains David Chiswell, cofounder of Cambridge Antibody Technology in Cambridge, England. “Anytime we want antibodies to a particular target, we essentially dip the target into the test tube-which can be thought of as a library of antibodies-and hook out just that subset of 100 billion antibodies that happens to bind specifically to the target.”
Method number two is the transgenic mouse with a human immune system-Lonberg’s original dream at Medarex, also pursued by competitor Abgenix. Put a target molecule into such a mouse, and you’ll get a human antibody out-no human antimouse antibody response to worry about. To make the mice, researchers cloned the gene segments responsible for generating the millions of possible human antibodies, put them all into mouse embryonic stem cells and grew the mice to maturity. It was a challenge, says Abgenix’s Davis, “because nobody had ever put that much DNA into a transgenic mouse.” They also had to inactivate the genes that produced mouse antibodies, which they did in another set of mice, and then bred the two lines together.
While the transgenic mice are the latest antibody technology to come to market, it’s still an open question whether they’re actually better than any of the other techniques for generating new antibody drugs. “All of these technologies probably produce antibodies that will behave essentially identically when used in people,” says Robert Kirkman, Protein Design Labs’ vice president for business development. “How do you get the best antibody against the given target is the ultimate question. And that is probably not always going to be the same technology.”
Whichever technology ultimately rules the field, it’s safe to say that antibodies will play a huge role in genomics and in the biotech industry. If nothing else, says Lonberg, bringing a monoclonal-antibody drug to market can give pharmaceutical companies a way to tackle diseases while they spend the extra years necessary trying to develop a small molecule that will do the same task.
Drug makers are pursuing this separate track because monoclonal antibodies still have two serious drawbacks compared to small-molecule drugs. One is that they are large proteins. This means that they have to be given intravenously rather than in pill form, so they won’t be chewed up in the digestive system-although researchers hope to soon solve that problem. (The flip side is that they last considerably longer in the human body, which means they can be administered perhaps once a month rather than once a day.) And the second is that they’re expensive to produce.
None of the methods used to generate chimeric, humanized or fully human antibodies can produce antibodies in commercial quantities. At the moment, companies are making antibody drugs by first inserting the gene for a specific antibody into cells culled from hamster ovaries and then growing the cells by the trillions in enormous vats, through a fermentation process not unlike that used to make beer.
The cells in each vat then secrete a single type of antibody that can be harvested from the surrounding fluid every few months. The process is expensive, however, so researchers have been pursuing dramatic biotech solutions to accomplish the same task. In particular, they’re creating genetically engineered fruits and vegetables-say corn, alfalfa or bananas-loaded with the desired antibodies, or even transgenic animals to serve as living monoclonal-antibody factories.
Somewhere in central Massachusetts is a “biopharm production facility” built by Genzyme Transgenics. While the company does not like to say exactly where it is, it says that it looks a lot like any other farm-except for the 2,000 or so resident goats that have been genetically engineered with human genes to express monoclonal antibodies or other large-protein drugs in their milk.
According to Jack Green, Genzyme Transgenics’ chief financial officer, a few monoclonal-producing goats lactating for a year can match the productivity of an entire fermentation vat of hamster cells. And the goats come with the built-in advantage that if a drug suddenly has a bigger market than anticipated, you don’t have to finance a whole new vat at the cost of a few hundred million dollars: you just breed more goats. “The generation time for a new goat is seven months to sexual maturity,” says Green, “so in a year you can get to however many goats and whatever scale of production you desire.”
After a quarter-century of struggle, monoclonal antibodies have survived to become a mature and exciting technology. And the skeptics are long gone. The question now is how much of 21st-century medicine will be dominated by these remarkable molecules. “Suddenly all this looks real,” Lonberg says.
“Monoclonal antibodies are no longer somebody’s fantasy.”
Antibodies on the Attack
Company Drug/Target Disease Stage Ortho Biotech (Raritan, NJ) Orthoclone/Heart, liver and kidney transplant rejection Approved June 1986 Centocor (Malvern, PA)/
Eli Lilly (Indianapolis, IN) ReoPro/Post-cardiovascular-surgery clotting Approved December 1994 Genentech (South San Francisco, CA)/
Idec Pharmaceuticals (San Diego, CA) Rituxan/Non-Hodgkin’s lymphoma Approved November 1997 Centocor Remicade/Crohn’s disease, rheumatoid arthritis Approved August 1998 Genentech Herceptin/Metastatic breast cancer Approved September 1998 Millennium Pharmaceuticals (Cambridge, MA) Campath/Chronic lymphocytic leukemia
Campath/Multiple sclerosis Approved May 2001
Phase II clinical trials ImClone Systems (New York, NY) Erbitux/Various cancers Phase II and III clinical trials Abgenix (Fremont, CA) ABX-CBL/Transplant rejection Phase II/III clinical trials Tanox (Houston, TX) AD-439/HIV, AIDS Phase II clinical trials GlaxoSmithKline (Middlesex, U.K.) SB-240563/Asthma, allergy Phase II clinical trials Medarex (Princeton, NJ) MDX-010/Malignant melanoma, prostate cancer Phase I clinical trials BioTransplant (Charlestown, MA) AlloMune/Non-Hodgkin’s lymphoma, Hodgkin’s disease Phase I clinical trials