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New 'library' aids detection of antibodies

Department of Energy scientists and an MIT colleague have created a library of 1 billion human antibodies on the surface of yeast cells. The work will speed the search for new antibodies, proteins that are effective tools for recognizing specific molecules. It also promises to make the hunt less expensive.

"Antibodies are assuming increasingly important roles in such diverse fields as sensors, proteomics, diagnostics, and therapeutics. We have captured a broad sample of the antibody diversity present in adult humans, and expressed it on the surface of yeast cells in a format suitable for quantitative screening," said K. Dane Wittrup, J.R. Mares Professor of Chemical Engineering and Bioengineering.

The technology, reported in the February issue of Nature Biotechnology, "provides a robust and direct route to the isolation of useful antibodies" outside a living body, he continued. As a result, it could replace the need to produce antibodies within animals, such as mice. It also opens up new possibilities for rapidly designing medical treatments more acceptable to the human immune system.

Scientists at the Department of Energy's Pacific Northwest National Laboratory (PNNL) led by Michael Feldhaus built the library of human antibodies, expressing them on the surface of yeast cells using a platform designed by Wittrup.

"Our antibody library offers many advantages over traditional approaches," said Feldhaus. For example, "our unique identification process means we can screen for antibodies in days rather than the months it may take using other approaches."

Antibodies are proteins produced by white blood cells as part of the immune response. When antibodies bind to a specific protein on bacteria, it signals other cells to either kill or remove the bacteria.

In medical treatments, antibodies are being injected into the body to seek out specific proteins on cancerous cells, for example, and target treatment to those cells. Biowarfare detectors can use antibodies to locate proteins as a way of identifying harmful agents. Antibodies also are expected to play a major role in helping scientists to more fully understand various biological processes by identifying which proteins are present and if they interact with any other proteins in the cell.

PNNL's new approach for generating synthetic antibodies uses high-speed flow cytometers to sort cells. Most importantly, by incorporating Wittrup's yeast surface display method, PNNL scientists can readily modify how an antibody binds to proteins. Being able to increase how tightly a protein and antibody bind together, for example, could increase antibody effectiveness for detecting pathogens or disease.

Wittrup originally developed the yeast surface display as a way to improve the binding of antibodies to chemicals while working at the University of Illinois in the late 1990s. Now he uses PNNL's antibody library with his display platform in a multitude of studies, many directed at development of novel cancer therapeutics.

This research was conducted with funding from the National Science Foundation, the Hereditary Disease Foundation, and internal research support from PNNL's Biomolecular Systems Initiative. PNNL has received additional funding from the Department of Energy to implement the antibody library for bioterrorism detection.

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