It was back in 1975 that Csar Milstein and Georges Khler, immunologists at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England, developed a technology to mass-produce such antibodies and, in the process, launched an industry. Khler and Milstein fused the antibody-producing cells from mice-known as B lymphocytes-with tumor cells that would keep those B cells alive forever in a laboratory.
In the body, immature B cells reside in the bone marrow and contain a full complement of the gene segments that code for antibodies. As the cells mature and migrate into the bloodstream, the segments undergo rearrangement so that each mature B cell makes just one type of antibody-a monoclonal antibody (see “Genes to Antibodies”). Each of Khler and Milstein’s cell lines would pump out an uninterrupted supply of a single monoclonal antibody, depending on the B cell it arose from. In 1984, their discovery earned the pair a share of the Nobel Prize in medicine, by which time there were roughly a thousand companies trying to cash in on the technology. Most of them would fail.
The problem was inherent in the antibody sources available at the time. Antibodies could be obtained by immunizing mice, as with Raritan, NJ-based Ortho Biotech’s Orthoclone, designed to fight organ transplant rejection and the first antibody drug approved by the FDA. (Ortho Biotech has been a Johnson and Johnson subsidiary since 1990.) Or they could be harvested directly from the human victims of a particular disease, as with Centocor’s Centoxin.
The catch was that mouse antibodies are, well, not human. The human immune system still considers them foreign and does its best to fight them off-a response known as the “human antimouse antibody” response, which not only destroys the antibodies but can lead to kidney failure and death.
When Orthoclone came on the market in 1986, the pharmaceutical industry suddenly learned just how bad the response could be. While most recipients were fine (and, in fact, Orthoclone is still in use), some patients had severe reactions. “Here was a drug that was specifically designed to suppress the immune system, and you still got a strong response,” says Lonberg.
As for antibodies harvested directly from human patients, they simply don’t bind to their targets tightly enough to stem disease-or at least that was the case with Centoxin, and the reason its highly publicized clinical trials failed.
Centoxin’s failure, says Lonberg, “caused everyone, at least on Wall Street and big pharma, to throw up their hands in despair with antibodies and walk away.” Eli Lilly was a classic example. Lilly had purchased Hybritech, the original monoclonal-antibody company, in 1986 for nearly $500 million. After building Hybritech up to 1,400 employees, Lilly sold the company in 1995, post-Centoxin, for only a fraction of what it paid for it.
Illustration by John MacNeill