New research into primitive protective proteins from the immune systems of sharks could lead to more versatile drugs to battle diseases such as cancer and dangerous bacterial infections and to robust diagnostic kits that could easily leave the lab, an area of intense research following the anthrax attacks of 2001.
In a study published Thursday online by the journal Science, researchers at The Scripps Institute in La Jolla, CA, and the University of Maryland at Baltimore determined that the structure of the primitive antibody that marks a difference between the immune systems of sharks and mammals is unusually simple.
Ian Wilson, a Scripps structural biologist, and Martin Flajnik, an immunologist at the University of Maryland, collaborated on the study, which marks the first time the precise physical structure of a nonmammalian antibody has been uncovered. Flajnik discovered these so-called IgNAR antibodies in sharks in 1995. Like antibodies found in humans, mice, and other mammals, IgNAR antibodies specifically recognize and bind to foreign molecules, such as those from invading bacteria or viruses. However, these antibodies are about half as complex and, as the new study reveals, much more flexible than the typical mammalian versions.
Wilsons lab successfully grew crystals of an IgNAR antibody from a nurse shark as it was bound to a protein from a chicken egg. X-ray images of these crystals were used to create a very high-resolution model of the antibodys structure. While conventional antibodies contain sets of molecules called “heavy chains” and “light chains,” IgNAR antibodies are made of a single heavy chain. The molecules small size and unique structural features make them probably indestructible, Flajnik says.
Gary Litman, a University of South Florida immunologist, says the work is a significant contribution to understanding the evolution of immunity. From an evolutionary stand, its an important contribution to understanding how single heavy-chain antibodies function, he says. I also see considerable potential in terms of bioengineering. Indeed, Wilson notes that the simplicity and small size of the IgNAR antibodies could make it much simpler to engineer small antibody fragments for use as drugs. There are a lot of therapeutic antibodies on the market, or about to go on the market, Wilson says. Several recent cancer drugs, for example, are antibodies targeted against tumor proteins. Theres a huge business going on in antibody engineering, he adds. This gives another example of a template that might be used for such engineering.
Flajnik is optimistic that IgNAR antibodies could be useful in and of themselves, both for diagnostics and as drugs. Their tough nature, he says, makes them particularly well suited for use in field diagnostics that might be used to quickly identify diseases or bioterror threats away from the lab. Other antibodies have a short half-life when youre using them for detections, he says. This one should last for a long time.
That quality could also be helpful in a drug; many protein therapeutics are degraded quickly inside the body and must be administered fairly often. In addition, the team found that the specific IgNAR antibody they studied had a groove with 2 bumps on it. These bumps can actually insert themselves into the foreign protein the antibody targets, blocking any catalytic activity it may have. Regular antibodies arent so good at that, Flajnik says. He believes this could make IgNAR antibodies more effective than their normal cousins at tackling foreign proteins such as toxins produced by invading bacteria.
If such predictions hold up, these primitive antibodies will turn out to be as resilient as the animal they come fromand could lead researchers to the type of shark attack anyone would welcome.
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