Discovery of meditopes could finally harness the immune system

July 30, 2013 | by Nicole White

The notion of using the body’s own immune system to fight disease has been around since at least 1900, becoming one of medicine’s most sought-after goals.

City of Hope researchers recently received a $1 million Keck Foundation grant to study meditopes. Researchers here discovered a sit in the middle of a monoclonal antibody where a peptide can easily attach, acting as a "hitch" that allows them to easily attach drugs to the antibodies. In this way, there's potential to harness the immune system to fight cancer and other diseases. City of Hope researchers recently received a $1 million Keck Foundation grant to study a "lock and key" interaction they discovered and have named a meditope. Meditopes are sites in the middle of  monoclonal antibodies where peptides can easily attach, acting as "hitches" that allow researchers to easily attach drugs to the antibodies. The discovery offers the potential to finally, and effectively, harness the immune system to fight cancer and other diseases.

Many researchers have focused on monoclonal antibodies, attempting to wield them to target cancerous cells, for example. Monoclonal antibodies are proteins that the body naturally produces to identify bacteria and viruses and to alert the immune system to clear out those invaders. But finding a way to turn these cells against cancer – and prompt the immune system to do the same – has been achieved for only a handful of tumor-associated targets.

The successes have been limited because of the difficulty in actually harnessing antibodies, with most researchers trying to genetically re-engineer the proteins or trying to chemically attach drugs to them.

City of Hope researchers may have found a better way.

They discovered a hole in the middle of the monoclonal antibody and a peptide molecule that fits neatly into it, like a lock and a key, potentially allowing the antibody to become a guided system for delivering drugs directly to cells affected by disease.

“Think of a tractor and a trailer,” said John Williams, Ph.D., associate professor in the Department of Molecular Medicine at City of Hope, who led the team that discovered the “lock and key” interaction and named it a meditope.

“Previously, you would have to weld the trailer to the truck, and it could only deliver one kind of cargo. The meditope interaction is like a hitch, and with this specific hitch, you can take any tractor and hook up any trailer, effectively allowing you to mix-and-match the appropriate equipment for a specific job.”

The potential is enormous.

In fact, the W.M. Keck Foundation recently awarded City of Hope a three-year, $1 million grant to continue its study of meditopes, a word that comes from the Greek and Latin words for “middle” and “place.”

Meditopes have potential to fight not only cancer, but numerous other diseases, including rheumatoid arthritis, Crohn’s disease and macular degeneration. They also have biodefense applications. Further, meditopes could be an important tool for imaging, allowing radioactive molecules to be delivered immediately to tumor sites, which would give clinicians a way of identifying and treating smaller tumors while protecting healthy tissue.

The team working on the funded research is led by Williams, an expert in biophysics and structural biology, who discovered the meditope interaction. He is joined by David Horne, Ph.D.,  interim director of Beckman Research Institute of City of Hope and chair and professor of the Department of Molecular Medicine, who will direct synthesis of novel meditope compounds.

Also on the team are Tijana Jovanovic-Talisman, Ph.D., an advanced molecular imaging expert joining City of Hope as an assistant professor in the Department of Molecular Medicine from the University of Hawaii, and Jinha Park, M.D., Ph.D., assistant professor in the Department of Diagnostic Radiology. Park specializes in antibody-mediated diagnostic imaging and imaging-guided therapy.

Williams said the discovery has the potential to dramatically change oncology, radiology and many other disciplines. The peptide can be linked to drugs, but also to other meditopes, to create a chain of antibodies and medicines that can be delivered to the surface of cells – an approach already known to be effective.

“There is so much to do, but we are fortunate to work closely with physicians such as Dr. Gagandeep Singh and Andrew Raubitschek  at City of Hope who have given our group terrific insight, meaningful direction and an abundance of encouragement,” Williams said.

He also called attention to the efforts of his and Horne’s scientific team in the early stages of characterizing the interaction, and specifically lauded the work of Cindy Zer, Ph.D., Joshua Donaldson, M.D., Ph.D., Kendra Avery, Ph.D. and Krzysztof Bzymek, Ph.D., in his group, and Yuelong Ma and Jun Xie in Horne’s group.

“We have this hole, and we have the hitch,” he said. “We don’t know what all the applications are yet, but it’s like the iPhone. We know there’s this great device, and there are great ways of making applications for it.”

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