Magic Bullets Fly Again

DeepOcean

From : Scientific American



Magic Bullets Fly Again



Molecular guided missiles called monoclonal antibodies were poised to shoot down cancer and a host of other diseases--until they crashed and burned. Now a new generation is soaring to market

By Carol Ezzell

The unbridled optimism that surrounded monoclonal antibodies in the 1980s was



infectious. You had to be the world's toughest cynic not to be dazzled. Got cancer?

No problem. Like heat-seeking missiles, monoclonal antibodies tipped with poisons

or radioactive isotopes would home in on malignant cells and deliver their deadly

payloads, wiping out cancer while leaving normal cells intact. How about an

infectious disease? All would be well. Monoclonals would surround marauding

viruses and bacteria like goombahs from Tony Soprano's crew, muscling them into

secluded byways where killer cells of the immune system would make them an offer

they couldn't refuse.

If only things had been so simple. Monoclonal antibodies are highly pure

populations of immune system proteins that attack specific molecular targets.

Unfortunately, people who received infusions of the early therapeutic monoclonal

antibodies tended to develop their own antibodies against the foreign ones, which

caused them to become even sicker for reasons that are not entirely clear. And

the liver showed a predilection for these early monoclonals, sopping them up

before they could target their quarries. Clinical trials failed. Stocks plunged.

Millions of dollars were lost. And a generation of scientists and biotechnology

Business people developed the skepticism shared only by the once burned, twice

shy.

Luckily, some of those individuals soldiered on despite the bad news and found

ways to overcome the failings of the early versions of the drugs. Now many are

hoping that 2001 will be the Year of the Monoclonals, when their perseverance

will pay off in the form of lots of effective monoclonal antibody-based drugs

approved or under evaluation by the U.S. Food and Drug Administration. "Antibodies

will be surging ahead," says Franklin M. Berger, a biotech analyst with JP Morgan

Securities. He predicts that soon there will be so many monoclonal antibodies

awaiting approval by the FDA that they will cause a bottleneck in the review

process.

Ten monoclonals have reached the market, and three await FDA approval, including

the first two that would be equipped to deliver a dose of radiation [see table].

Another 100 or more antibodies are being tested in humans, having already shown

promise in tests involving animals. But this summer the FDA sent a message that

could slow the monoclonal juggernaut. In July the agency told Genentech, located

in South San Francisco, Calif., that it would have to present additional data

from human (clinical) trials to prove the long-term safety of its monoclonal

antibody for asthma, Xolair, which mops up the antibodies that play a role in

asthma and allergies. Some observers have interpreted the move as an indication

that the FDA might be particularly rigorous in scrutinizing the side effects of

monoclonal antibodies, especially those that patients would take for years for

chronic conditions. The announcement sent a brief chill through investors, who

drove down the stocks of monoclonal developers for a week or so.

Nevertheless, the advantages of monoclonals are hard to ignore. Donald L. Drakeman,

president and CEO of monoclonal maker Medarex in Princeton, N.J., says that

antibodies are simply easier to develop than traditional drugs composed of small,

inorganic molecules. Because they are large molecules, they might not be suitable

for every disease, but he emphasizes that it takes only one or two years to come

up with a monoclonal antibody suitable for testing, versus the five years required

for small molecules. That speed translates into savings: it costs only $2 million

to ready a monoclonal antibody for clinical testing, Drakeman estimates, compared

with $20 million for a traditional drug. And despite the FDA's hesitancy to approve

Genentech's asthma therapy, he states that monoclonals have so far had a higher

success rate than small-molecule drugs in clearing regulatory hurdles.

"Antibodies are almost never toxic," he explains.

Ironically, monoclonals might be victims of their own success: market analysts

are predicting that companies won't have sufficient production facilities to make

them all. But the biotechnology industry has anticipated this problem. Some of

the more inventive proposals include the manufacture of monoclonals in the milk

of livestock or in plants.





Monoclonal Methods

The past failure of monoclonals stemmed in part from the way they were originally

made. The classic manufacturing technique was devised in 1975 by immunologists

Georges J. F. Kler and Car Milstein of the Medical Research Council's

Laboratory of Molecular Biology in Cambridge, England, who were awarded the 1984

Nobel Prize in Physiology or Medicine for their innovation. The basic process

involves injecting an antigen--a substance the immune system recognizes as

foreign or dangerous--into a mouse, thereby inducing the mouse's

antibody-producing cells, called B lymphocytes, to produce antibodies to that

antigen. To harvest such antibodies, scientists would ideally pluck only the B

cells that make them. But finding the cells and getting them to make large

quantities of the antibodies takes some doing.

Part of the complex procedure involves fusing B cells from the mice to immortalized

(endlessly replicating) cells in culture to create cells called hybridomas

[see illustration]. The drawback of these particular hybridomas is that they

produce murine antibodies, which the human immune system can perceive as

interlopers. Patients who have received infusions of murine monoclonals have

experienced a so-called HAMA response, named for the human anti-mouse antibodies

they generate. The HAMA response includes joint swelling, rashes and kidney

failure and can be life-threatening. It also destroys the antibodies.

To avoid both the HAMA response and the premature inactivation of mouse antibodies

by the immune system, scientists have developed a variety of techniques to make

murine antibodies more human. Antibodies are Y-shaped molecules that bind to

antigens through the arms, or FAb regions, of that Y. The stem of the Y, the Fc

region, interacts with cells of the immune system. The Fc region is particularly

important in eradicating bacteria: once antibodies coat a bacterium by binding

to it through their FAb regions, the Fc regions attract microbe-engulfing cells

to destroy it.

One approach involves replacing all but the antigen-binding regions of murine

monoclonals with human components. Four of the monoclonals now for sale in the

U.S. are such chimeric--part mouse, part human--antibodies. Among them is ReoPro,

made by Centocor in Malvern, Pa., which prevents blood clots by binding to a

specific receptor on platelets; it had sales last year of $418 million. (The body

usually doesn't make antibodies targeted to healthy tissues, or autoimmune

disease would result. But such antibodies, delivered as drugs, can help treat

certain disorders.)

Another strategy, called humanization, is behind five more products on the market,

including Herceptin, the breast cancer-targeting monoclonal antibody developed

by Genentech. Humanization entails using genetic engineering to selectively

replace as much as possible of the murine antibodies--including much of their

antigen-binding regions--with human protein [see illustration].



Campath--thought by its maker, Millennium Pharmaceuticals in Cambridge, Mass.,

to be the first humanized antibody ever made--received F