By then, however, salvation was already on the way. It arrived in the guise of antibodies that were considerably less mouse and increasingly human in origin and function. Researchers had begun developing methods to create these blends in the mid-1980s, and the technologies were just beginning to bear fruit around the time Lilly gave up on Hybritech. Chimeric antibodies came first, constructed back in 1984 by joining the gene that generates the constant region of a human antibody, the base of the Y, to the genes that generate the variable regions of mouse antibodies, the outer arms of the Y. The resulting chimera is about a third mouse and two-thirds human. It still binds tightly to the target for which it was designed, while avoiding the bulk of the human antimouse antibody response.
Next out of the research lab were humanized antibodies. Whereas chimerics were one-third mouse, humanized antibodies were less than a tenth. From the mouse came only the very tips of the arms of the antibody Y, just that part of the variable region that binds directly to its target. All the rest was human. But there was a problem: when the tips of a mouse antibody were genetically grafted onto a human framework, the antibody was often unable to grip its target tightly enough.
Cary Queen, a mathematician turned biologist then working at the National Institutes of Health, created an algorithm to analyze the fit between mouse tips and human framework and then figure out just which molecules in the human framework would have to be adjusted, and by how much, to leave the mouse region sitting comfortably atop the arms of the Y and binding tightly to its target. Queen patented the technology and cofounded Fremont, CA-based Protein Design Labs in 1986 to humanize antibodies for its own drug business and for anyone else who might employ its services.
Between chimeric and humanizing technology, antibody drugs started to make it to market, and the industry revival took off. In 1994, the FDA approved the first monoclonal-antibody drug since 1986, Centocor’s chimeric-antibody drug to inhibit clotting following cardiovascular surgery. (Johnson and Johnson acquired Centocor in 1999.) The agency then approved three more monoclonal-antibody drugs in 1997-including San Diego-based Idec Pharmaceuticals and Genentech’s chimeric Rituxan for non-Hodgkin’s lymphoma.
Rituxan and Genentech’s humanized Herceptin, approved the following year for breast cancer, may alone have pushed the antibody business back into the boom phase, simply because they were anticancer therapies and so fulfilled, at least modestly, one aspect of the mid-1980s hype. In any case, approval for five more monoclonal antibodies followed in 1998, and four more since. At the moment, nearly 50 humanized antibodies are in clinical trials, targeting the full spectrum of human diseases from psoriasis to heart disease and cancer.