October 3, 2000

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The Birth, Death and Rebirth of a Novel Disease-Fighting Tool


Biotech companies have developed strains of mice that make antibodies, compatible with humans, that can be designed to attack proteins involved in disease. This mouse was produced by Abgenix.

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  • Richard Belmont, an airline pilot, went to the emergency room on Christmas Eve in 1989 for what he thought was a pulled abdominal muscle. It turned out to be non-Hodgkin's lymphoma, a usually incurable cancer. "I think it's your last Christmas," Mr. Belmont recalled being told by the doctor.

    Chemotherapy put the cancer into remission, but made Mr. Belmont terribly sick and weak. When the cancer returned in 1997, Mr. Belmont shunned chemotherapy in favor of an experimental drug known as Zevalin, which is made up of specially designed proteins known as monoclonal antibodies attached to radioactive isotopes. Like guided missiles, the antibodies homed in on the tumors in Mr. Belmont's body and delivered their radioactive payload to kill the cells.

    After a single treatment, the cancer disappeared and has stayed away for the three and a half years since. "To me it's a miracle," said Mr. Belmont, 61, who lives in Long Grove, Ill.

    Zevalin had not worked that well for everyone who took it. But it is a symbol of new life not only for Mr. Belmont but for monoclonal antibodies themselves, a treatment tool that in the early 1990's was almost abandoned by the pharmaceutical industry.

    Antibodies are the body's first line of defense, latching onto foreign proteins on the surface of bacteria or viruses. In 1975, two scientists developed a way to make highly uniform antibodies that could be aimed at a particular protein. The manufactured antibodies were called monoclonal antibodies, and scientists were immediately intrigued with the idea of using them as "magic bullets" to attack diseased cells while leaving healthy ones unscathed, thereby minimizing side effects.

    But numerous attempts to use antibodies as drugs failed. "It was very difficult to harness this lightning in the body," said Dr. Louis M. Weiner, chairman of medical oncology at the Fox Chase Cancer Center in Philadelphia.

    The long development time demonstrates that even in the fast-paced world of biotechnology, it can take decades to iron out the kinks in a powerful new tool. And that, said Viren Mehta, a pharmaceutical analyst at Mehta Partners in New York, should give pause to patients and investors who expect an immediate medical payoff from the latest big breakthrough the sequencing of the human genome.

    Now, as the field of monoclonal antibodies celebrates its 25th anniversary, some drawbacks remain, but the old barriers have largely been overcome. Monoclonal antibodies do not cure everyone who takes them, and they are not entirely free of side effects. But they are becoming an important category of drugs. And those who study them say their promise is beginning to be realized.

    "Antibodies have gone through sort of a birth, death and rebirth," said Dr. Samuel D. Waksal, president and chief executive of Imclone Systems Inc., a New York company that is developing antibodies.

    Moreover, many scientists say antibodies are poised to play an even bigger role. New techniques allow human antibodies to be made in genetically engineered mice or viruses. And having a rough map of the human genetic code is expected to result in the discovery of thousands of new genes and the proteins they code for that play roles in disease. That means thousands of potential new targets for antibodies. Indeed, the quickest way to turn a gene discovery into a drug is to make an antibody that binds to the protein and interferes with its function.

    "Now people are pulling things out of databases and they are immediately able to get a candidate therapeutic molecule," said Dr. Nils Lonberg, a scientist at Medarex Inc., an antibody company, who was referring to genome databases. Medarex, based in Princeton, N.J., recently started patient tests of an antibody 12 months after first deciding upon the protein target, far faster than the years it would take to synthesize a chemical that could bind to the protein.

    There are now nine approved monoclonal antibody drugs, up from only two in 1996, and they include some of the industry's most important new products Genentech Inc.'s Herceptin for breast cancer, Genentech and Idec Pharmaceuticals Corporation's Rituxan for lymphoma, the Centocor unit of Johnson & Johnson's Remicade for Crohn's disease and rheumatoid arthritis, and MedImmune Inc.'s Synagis, which prevents a deadly lung infection in premature infants.

    And there are more than 70 monoclonal antibody drugs now in clinical trials, according to a survey released earlier this year by the Pharmaceutical Research and Manufacturers of America, a trade group. Antibodies represent about 20 percent of all the biotechnology drugs in clinical trials. For Genentech, the oldest biotechnology company and one of the most successful, antibodies account for two-thirds of the drugs it is testing.

    Among the most promising antibodies expected to reach the market in the next two years, industry analysts say, is an asthma and allergy treatment being developed jointly by Genentech, Novartis and start-up Tanox Inc. In clinical trials, some asthmatic children using it have been able to reduce or eliminate steroids, which have undesirable side effects.

    Another is Imclone's C225 for colorectal cancer and head and neck cancer. "I have patients who respond to it after they failed to respond or stopped responding to standard treatments," said Dr. Leonard B. Saltz of Memorial Sloan-Kettering Cancer Center in Manhattan, who is leading one test of the drug.

    While about half the antibodies in development are aimed at cancer, others are being tested against psoriasis, vision deterioration, bacterial infections, heart attacks, stroke and rejection of transplanted organs. One company is testing an antibacterial antibody to prevent tooth decay. Another is testing one to reduce the severity of allergic reactions to peanuts.

    And while most drugs use antibodies alone, drug companies are now also starting to combine antibodies with chemical toxins or radioactive isotopes to enhance their ability to kill cancer cells. The first antibody linked to a chemical toxin, Mylotarg from American Home Products Corporation's, for treatment of acute myeloid leukemia, was approved by the Food and Drug Administration in May.

    Zevalin, the drug used to treat Mr. Belmont's lymphoma, is expected to come up for approval next year, according to Idec Pharmaceuticals, its manufacturer. Zevalin is vying with Bexxar, made by Coulter Pharmaceutical Inc., to become the first approved antibody with a radioactive warhead.

    The technique for producing monoclonal antibodies was developed in 1975 by Dr. Cesar Milstein and Dr. Georges Kohler at the Laboratory of Molecular Biology in Cambridge, England. A mouse is injected with the target protein causing the mouse to develop thousands of antibodies to it. B-cells, which are blood cells that produce antibodies, are removed from the mouse's spleen. Each B-cell makes only one type of antibody and a promising one can be chosen for making a drug. But because B-cells by themselves cannot survive long outside the body, they are fused to tumor cells that live indefinitely, forming cells known as hybridomas, which can produce the particular antibody nonstop. Since all the antibodies come from the clone of a single B-cell, they are uniform and called monoclonal.

    The accomplishment earned the two scientists the Nobel Prize in Medicine in 1984.

    The specificity of the antibodies in seeking out a single protein made them immediately useful in diagnostics. One early use was the home pregnancy test, in which antibodies latch onto a hormone in urine that is associated with pregnancy.

    But the use of monoclonal antibodies as drugs met with disappointment after disappointment. The antibodies could not penetrate some tumors to reach their target proteins. They were also very difficult, and expensive, to produce in the large quantities needed.

    The biggest problem, however, was that the antibodies were mouse proteins, which the human immune system attacked as invaders. Patients suffered allergic reactions and the antibodies quickly lost their effectiveness.

    But scientists have since learned to "humanize" antibodies using genetic engineering, a technique pioneered in part by Protein Design Labs Inc. The part of the antibody that grips the target still comes from a mouse. But that part is then grafted onto the rest of a human antibody. That reduced the immune response to levels that were generally tolerable. All the antibodies approved for use as drugs in the last few years are humanized in some way.

    Now, researchers are starting to produce fully human antibodies. Both Abgenix Inc. of Fremont, and Medarex have developed genetically altered mice that can produce fully human antibodies. They have done this by knocking out the mice's own antibody-producing genes and inserting the corresponding human genes.

    Other companies, led by Cambridge Antibody Technology Group and MorphoSys, are producing fully human antibodies using a technique called phage display. Human antibody genes are inserted into viruses known as phages, which display them on their surfaces. Each phage produces a different antibody and a library of billions of antibodies can be created in a drop of water. The whole library can be poured over the target protein to see which antibodies stick.

    Having fully human antibodies should largely eliminate any immune response to the antibodies. "Something that's fully human or that's part mouse which would you rather have as a patient?" said R. Scott Greer, chief executive of Abgenix. Moreover, the fully human antibodies can be made quicker than the humanized ones because they do not have to be tinkered with once they come out of the mouse.

    Still, only a few fully human antibodies have entered clinical trials, and some experts say it is not proven how much is really gained by using them instead of humanized antibodies.

    Monoclonal antibodies still have their drawbacks as drugs. Since they are proteins that would be destroyed by the acids in the stomach, they must be given by injection or intravenous infusion, not orally. Relatively large quantities are needed, making the drugs expensive. Rituxan, for instance, costs a patient $10,000 a year.

    And since they are big molecules, antibodies cannot penetrate cell membranes to enter cells. They are limited to targets that are floating in the bloodstream or are on the surface of cells. That could limit their effectiveness against viruses that replicate inside cells.

    Some companies, like Eukarion Inc. , are trying to attach fatty chemicals known as lipids to antibodies to allow the antibodies to pass through cell membranes. Other scientists are trying to make smaller molecules that mimic the shape of antibodies but would be cheaper to make and could possibly be taken orally.

    "We'll make little molecules that actually work better than antibodies," said Dr. Mark I. Greene, a professor of medicine at the University of Pennsylvania.

    In many cases, the antibodies drugs work just because of their ability to bind to a particular shape, not in their true immune system role of starting a process to kill invaders. Centocor's Reopro, for instance, prevents blood clots by binding to platelets and preventing the platelets from clumping together.

    In treating cancer, however, the aim is usually to kill cells. But some of the antibodies merely slow down the cells. In most cases, doctors say, antibodies do not appear any more effective than chemotherapy in inducing remissions, though they have fewer side effects. So the best results might come from using antibodies along with these other treatments.

    "It's quite clear to everyone in the cancer field that there is no single agent that's going to cure," said Dr. Ellen Vitetta, director of the cancer immunobiology center at the University of Texas Southwestern Medical Center in Dallas. "The antibodies will provide another angle to hit the tumor cells."

    Still, for some patients, antibodies have clearly made a difference. "I used to cry the nights before I used to get chemo," said Betsy Patterson, a nurse in Spartanburg, S.C., who has non-Hodgkin's lymphoma. But Rituxan made the lymphoma disappear for now without the debilitating side effects like weakness, nausea and hair loss. "I feel better than I have for 10 years," she said.

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