The idea is simple in principle, and works somewhat like a Trojan horse. First clamp something onto the insulin molecule that prevents it from binding to the cells where it does its work. Then, after the modified insulin is in the body, a specially designed antibody removes the clamp, and the insulin goes to work.
The idea was conceived by Dr. Richard A. Lerner, president of the Scripps Research Institute in California, says Dr. Jerrold M. Olefsky, director of the Whittier Diabetes Institute at the University of California, San Diego (UCSD), and lead author of a paper describing the work in the Nov. 13 issue of the Proceedings of the National Academy of Sciences."He had been working for many years to make use of the fact that antibodies, in addition to fighting infection, have another function," Olefsky says. "They are enzymes that catalyze [speed up] chemical reactions. We were talking about the idea that he could link a certain chemical group to a drug by a linkage that does not occur in the body naturally but is broken by a catalytic enzyme. So then the antibody in the body could release the drug."
A practical application would be to avoid the necessity of insulin pumps or daily injections by people with Type I diabetes, whose body does not produce enough insulin. (Type II, or adult-onset diabetes, the more common form of the disease, can be treated without injections.)
So the Scripps and UCSD researchers went to work, identifying specific locations on the insulin molecule where an attached molecule would render it biologically inactive. Once they located that site, they did the molecular manipulations that enabled them to add the disabling molecule -- one that could be removed by the antibody developed by Lerner, designated 38CE.
The researchers say tissues in laboratory culture show the treated insulin is 96 percent inactive, and that adding 38CE restores normal function. They then tried the system in rats, and preliminary studies found that the results mirrored those of the laboratory tests.
"The hope is that you give the antibody to a person. It circulates for weeks. Then you administer the treated insulin and the antibody slowly releases it to become active," says Olefsky.
More animal studies are needed, but Olefsky says, "If it works as we hope, we may give it to patients someday."
Other projects designed to deliver insulin to people with Type I diabetes have run into problems. Years of work on an inhaled form of insulin has been delayed recently by fears that it might trigger an adverse response from the body's immune system.
The new idea could have much wider applications, the researchers say. A combination of clever molecular modifications and specific antibodies could change many properties of drugs. "For example, one could modify a therapeutic protein to create a very stable formulation that is only slowly susceptible to antibody catalysis, yielding a sustained-release therapeutic," they write.
What To Do
The payoff from this sort of research will not come for years, so persons with diabetes should take their insulin as their doctors direct.
Information about diabetes is offered by the National Institute of Diabetes and Digestive and Kidney Diseases and the American Diabetes Association.