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Understanding blood clots
How monoclonal antibodies first produced decades ago are helping scientists develop drugs for cardiovascular disease
BY LYNN LOVE
Fine wine and single malt scotch are well known to improve with age, but rarely do scientific discoveries have much staying power, usually being supplanted by the next big thing in weeks to months. But two monoclonal antibodies produced by Barry Coller 25 years ago are still providing valuable new information.
A pair of recently published studies from Coller’s Rockefeller lab have yielded new knowledge about deadly blood clots that trigger heart attacks and strokes, with potential new implications on how an entire family of receptors change shape with activation.
“Somebody told me about monoclonal antibodies over lunch one day while I was at Stony Brook University in the late 1970s, and I knew immediately what I wanted to do,” Coller recalls. Normally, antibodies are manufactured in breathtaking variety by the body’s immune system, and function to help the body fight diseases. Unlike their naturally occurring counterparts, however, monoclonal antibodies are derived in the lab, from just one mouse spleen cell making an antibody to a molecule of interest. Thus, they usually bind to just one site on a protein. If the site is important in receptor function, they can be highly useful tools due to their specific ability to block the receptor’s normal function. And they can be used to study proteins anywhere in the body, not just those of the immune system.
The only problem with developing monoclonal antibodies is their sheer randomness: “Researchers easily can create hundreds of monoclonal antibodies. But systematically testing each one to determine if it binds to a target protein you are studying is painstaking work. Many researchers frankly don’t have the infinite patience to stay with this task,” says Sarah Schlesinger, associate research professor with appointments to both David Ho and Ralph Steinman’s Rockefeller labs. (Schlesinger should know; her first project as a summer intern in Steinman’s laboratory in 1977 was to assist in creating a monoclonal antibody that could bind to dendritic cells.)
Coller, who is today Rockefeller’s physician-in-chief and David Rockefeller Professor, created and tried hundreds of monoclonal antibodies in the 1970s and 1980s before striking gold. In 1994 he successfully converted one to medical use as the basis for the drug abciximab, which has been administered to more than 2 million people worldwide. Abciximab, known in the marketplace as ReoPro, keeps coronary arteries open in patients who’ve undergone angioplasty and stent replacement to clear blockages from their arteries, often as part of the treatment for a heart attack. By connecting to and blocking the platelet integrin receptor, , which normally binds fibrinogen, abciximab prevents platelets from aggregating one with another, thus preventing unwanted clotting.
Yet despite this success, the integrin receptor has continued to vex scientists. Now in two recent publications, one in The Proceedings of the National Academy of Sciences and one in Nature, two of Coller’s early monoclonal antibodies, known as 7E3 and 10E5, are helping explain the secret of how the fibrinogen receptor functions, and are hinting at how even more effective drugs to treat cardiovascular disease could be designed.
Coller and his colleagues in the Laboratory of Blood and Vascular Biology localized the binding site for 7E3 to a region on one of the two subunits of the receptor. This site undergoes a major change in conformation when platelets are activated and detailed studies of the binding of 7E3 report this change. These new data help to confirm crystallography.
Many years ago Coller used another one of his antibodies, 10E5, to hold the two subunits of the receptor together. More recently, in collaboration with Timothy Springer and his group at Harvard Medical School, they used 10E5 to hold the subunits of a fragment of the receptor together during purification for crystallography. This led to the first crystallographic structure of the receptor — published in Nature — and defined precisely where 10E5 binds on the other subunit of the receptor. They also produced the first crystal structures of the receptor in complex with several existing drugs used to treat cardiovascular disease. In addition, the data localized sites of conformational changes associated with ligand binding and thus open the door for more precise drug tailoring for life-threatening vascular events.
“Many people make monoclonal antibodies, but they don’t always study the details of their binding properties,” says Coller. “When we made ours, we made the decision to characterize them in great detail. And it paid off. It helped to obtain this aesthetically beautiful crystal structure, which has generated exciting new information.”


May 13, 2005



 

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