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SUMMER 2005
Building Better Antibodies
by Kathleen Cason

In Weber’s opera Der Freischütz, a lovesick hero uses enchanted bullets to win a shooting contest and the hand of the fair Agathe. The “magic bullets” — you see — always hit the marksman’s target.

In the body’s fight against disease, antibodies are nature’s “magic bullets.” These precisely tailored molecules trawl the body’s bloodstream, seeking and destroying invaders such as bacteria, viruses and toxins. They hit their mark — and only their mark — without harming the patient.

This high-precision, “magical” trait led drug developers to create therapeutic (also called monoclonal) antibodies that combat a wide range of diseases, including breast cancer, non-Hodgkin’s lymphoma and rheumatoid arthritis. For the past decade, antibodies have comprised a quarter of all newly introduced drugs derived from biotechnology research and they now make up about a fifth of biotech drugs in the development pipeline. But these industrially derived antibodies, their magic notwithstanding, could work better.

A team of researchers has developed new technology that may help drug makers create longer-lasting and more potent therapeutic antibodies. Led by Geert-Jan Boons, a synthetic-carbohydrate chemist at UGA’s Complex Carbohydrate Research Center, the team focused on an antibody called immunoglobulin G, or IgG for short.

Whether this Y-shaped magic bullet works depends fully on its molecular architecture. Its arms must be sculpted “just so” to seize a foreign substance. The stem must be shaped precisely to dock with the biological components that trip defense mechanisms or recruit other cells to gobble up captured intruders. And the shape of the stem — the business end of the molecule — depends on sugars.

Two chains of sugars wedge between the stem’s protein strands, producing the shape that gives the molecule the power to destroy (see illustration). These sugar chains, or oligosaccharides, can vary in composition, length and arrangement.

Boons was convinced that certain sugar combinations and arrangements would make antibodies more effective. So his team developed a way to create and attach custom-made oligosaccharides to antibodies, in hopes of discovering which structures gave the best biological activity.

Postdoctoral associate Greg Watt, now assistant editor at Nature Chemical Biology, built synthetic sugar chains — sugar by sugar — in a grueling process that took three years. At the end, he could create well-defined chains up to five sugars long and he also had developed a new way to link those chains to the stem.

“For the sugar to control the biological activity, the atomic dimensions have to be precise,” said molecular immunologist Roy Jefferis, a collaborator from the University of Birmingham, England. “And trying to design a linker, where the sugar chains bolt on, with the precise atomic dimensions as the natural linkage was the challenge.”

By tinkering with the gene that makes the stem, the team substituted the natural link with one that they could modify at will.

When the researchers checked the new molecules for biological activity, they discovered: No sugar, no activity; short chains of sugars gave a weak response; and the longer the chain, the stronger the response.

One structure that occurs naturally in about 5 percent of antibodies gave the best reaction, suggesting that the “right” architecture might produce a more effective “turbo-antibody.”

Chemist Carolyn Bertozzi, a Howard Hughes Medical Institute Investigator at the University of California, Berkeley, credits Boons’ group with developing “a generalizable method for chemical modification of monoclonal antibodies, the fastest growing class of drugs on the market.”

Reed Harris, director of analytical development at Genentech, the leading U.S. producer of therapeutic antibodies, says that Boons’ approach could accelerate improvements to therapeutic antibodies, but he cautioned that there are still “significant technical hurdles” and that antibodies engineered using this procedure would require testing for side-effects.

Medical applications may be years off, but Watt said that this is a big step.

“No one had attached such complicated oligosaccharide (sugar) structures onto a protein. And they haven’t done it so specifically,” he said.

Ultimately, the Boons team’s approach could lead to higher-performing “magic bullets” available at lower doses and lower costs.

“It was a high-risk project when we started it,” Boons said. “Will it be economically viable? In another five years, maybe.”

The team’s findings were published in the September 2003 issue of Chemistry and Biology.

For more information, contact Geert-Jan Boons at gjboons@ccrc.uga.edu.