One of the most innovative tools in the fight against cancer - monoclonal antibodies - may soon have to make way for an even newer approach, a genetically engineered protein that acts like an antibody but is much smaller.
An antibody, which is made by lymph tissue, defends the body against bacteria, viruses and other foreign substances.In a study published recently in the journal Science, researchers from Genex Corp., in Gaithersburg, Md., reported they have found a way to make proteins that "are expected to have significant advantages over monoclonal antibodies in a number of applications," including the diagnosis and treatment of cancer.
Robert Bird, who headed the research team, said the protein is one-sixth the size of a monoclonal antibody, consisting of just one chain of amino acids compared to the antibody's four complexly folded chains.
The single-chain protein has the ability to home in on specific targets in the body just like a whole antibody because it contains the part of the antibody that binds to antigens - substances normally foreign to the body, such as tumors, viruses and pollen.
Developed by British researchers in 1975, monoclonal antibodies are the result of taking short-lived, antibody-forming white blood cells and fusing them to immortal cells to make hybrid cells that produce large quantities of a single type of antibody.
Monoclonal antibodies are now employed in many diagnostic tests, which detect conditions ranging from pregnancy to cancer, and to fight rejection of kidney transplants. In addition, they are the focus of many experimental efforts to carry chemotherapy drugs to cancerous tumor sites. Currently, the manufacture of such antibodies must involve cells from laboratory mice or cultures of human tissues.
In contrast, the single-chain proteins developed by Genex can be made by inserting recombinant genes in a bacteria named Escherichia coli, which in turn cranks out the desired proteins. The use of bacteria, rather than more costly animals or tissue cultures, means "once the gene is designed, single-chain proteins will be cheaper to make," Bird said.
Although the protein Bird's team made is modeled on the immunoglobulin GI antibody, he said the tactic can be used to make other types because the antigen-binding structures on most antibodies are similar.
The expected advantages of single-chain proteins, which are not yet being tested in humans, lie mainly in their small size and their specificity.
Due to their streamlined design, the new proteins do not contain as many of the antibody structures known to trigger immune reactions. That means tests and therapies using the proteins should cause fewer side effects in patients, the researchers wrote.
Bird said the proteins are expected to be cleared from the blood faster than larger monoclonal antibodies, producing faster results in efforts to image cancerous tumors and other problems inside the body.
"You want to devise an agent that binds to the disease site and you want the rest of it that does not bind to the site to leave as fast as possible so you get a clear image very quickly," Bird said.
Preliminary results of animal tests to determine if clearing time is speeded up "have been encouraging," Bird added.
Another biotechnology firm, Creative Biomolecules of Hopkinton, Mass., has also succeeded in producing a single-chain protein using an approach similar to Genex.