Targeting Tumors Nature's Way

By mimicking a natural way of distinguishing one type of cell from another, investigators now report they can more effectively target and destroy cancer cells while sparing healthy ones.

The new tumor targeting strategy, presented March 25, 2007, at the annual national meeting of the American Chemical Society, held in Chicago, IL, USA, ingeniously harnesses one of the body's natural antibodies and immune responses. "The killing agent we chose is already in us,” commented University of Wisconsin-Madison (USA) chemistry professor Dr. Laura Kiessling, who led the work with postdoctoral researcher Dr. Coby Carlson. "It's just not usually directed toward tumor cells.”

In a series of cell-based experiments, the scientists' strategy recognized and destroyed only those cells displaying high levels of receptors known as integrins. These molecules, which tend to position themselves on the surfaces of cancer cells and tumor vasculature in large numbers, have become significant targets in cancer studies.

In contrast, an established tumor-homing agent associated with the cell toxin doxorubicin killed cells even when they expressed very little integrin, indicating this strategy has the potential to destroy cancerous and healthy cells indiscriminately. "This study suggests that the cell recognition mode we used can direct an endogenous immune response to destroy cancer cells selectively,” said Dr. Kiessling. "We think this could lead to a new class of therapeutic agents not only for cancer but also for other diseases involving harmful cells.”

Cancer cells usually display higher levels of specific receptors on their surfaces than do healthy cells, evidence that allows scientists to target tumor cells hiding among the body's vast quantities of cell types. A well-accepted approach utilizes a cell-binding agent, such as a monoclonal antibody, that is powerfully attracted to the target receptor and holds tight to any cell displaying it.

Although this approach has advantages, it is not natural, according to Dr. Kiessling. Cell recognition in living systems instead involves binding agents that attach only weakly to any single target receptor, and thereby adhere to cells only when several receptors are displayed together. These weak "multivalent” interactions decrease instances of mistaken identity, because if the agent contacts the wrong cell type, it can be easily displaced.

The investigators got the plan to mimic this process from efforts to transplant pig organs into primates. The surfaces of most mammalian and bacterial cells express large amounts of a carbohydrate, called alpha 1,3-Galactosyl (alpha-Gal), while the cells of humans and other higher primates do not. What humans and primates do produce in abundance is an antibody against the carbohydrate, called alpha 1,3-Galactosyl antibodies (anti-Gal).

When scientists tried transplanting pig organs into primates, the anti-Gal antibodies bound to the alpha-Gal on the organ's cells, unleashing a powerful immune response that caused immediate organ rejection. But consistent with natural cell recognition, the immune response occurs only when clusters of many alpha-Gal molecules are present for anti-Gal to bind with.

Armed with this information, Dr. Kiessling's group engineered an agent known to bind tightly to integrin and attached it to alpha-Gal. When they combined this molecule with cells displaying high levels of integrin, the agent, by attaching to the receptor, adorned the cells with large amounts of alpha-Gal. In cell cultures containing human serum, the alpha-Gal then initiated the cell-destroying immune reaction.

In cells with low concentrations of integrin, the agent still bound, but the resulting levels of alpha-Gal were not enough to trigger the immune response, and the cells survived. The same was not true if the cell-binding agent delivered doxorubicin to cells instead: they were killed regardless of the amount of integrin they carried.

Because target receptors on cancer cells usually also reside on healthy cells--although in lower numbers--therapies aimed at these receptors are always expected to have devastating side effects. That is why Dr. Kiessling's strategy holds such potential. "What we've shown is that you don't need a receptor that's found solely on tumor cells,” she commented. "You just need one that's found in significantly higher numbers on cancerous cells than on normal ones.”

Dr. Kiessling is now collaborating on in vivo studies in animals and working to increase selectivity even further by developing cell-binding agents that bind two different receptors.


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