Toxic target: The toxin melittin, labeled purple in these fluorescent images, spreads throughout the body of an untreated mouse, shown at bottom. The mouse at top has been injected with an artificial antibody, also fluorescently labeled, that binds to the toxin and takes it to the liver. The spread of the toxin throughout the treated mouse’s body is also more limited, which is why less of its body appears purple in this image.
Kenneth Shea
Polymers that mimic the body's natural defenses could be a new class of inexpensive therapeutics.
For the first time, researchers have shown that a nonbiological molecule called a plastic antibody can work just like a natural antibody. In animal tests, the plastic particles bind to and neutralize a toxin found in bee stings; the toxin and antibody are then cleared to the liver, the same path taken by natural antibodies. Researchers are now developing plastic antibodies for a wider range of disease targets in hopes of broadening the availability of antibody therapies, which are currently very expensive.
For more than 20 years, biochemists have attempted to mimic antibodies' ability to zero in on their targets, as part of a strategy to make more effective and cheaper therapeutics and diagnostics. "Though antibodies are produced on an industrial scale today because they're so important, the cost is very, very high," says Kenneth Shea, professor of chemistry at the University of California, Irvine. That's because antibodies are grown in animals; they're complex molecules that can't be made in a test tube, or even by bacteria. And antibodies, like other proteins, are very fragile. Even under refrigeration, they last just months. The question Shea and others have asked for 20 years, he says, is "would it be possible to design them from inexpensive, abiotic starting materials?" Such plastic antibodies could be made cheaply and then sit on the shelf, in theory, for years.
In 2008, Shea's group, working with researchers from the Tokyo Institute of Technology, demonstrated for the first time that plastic antibodies made using a technique called molecular imprinting could bind to a target as strongly and specifically as natural antibodies. Molecular imprinting involves synthesizing a polymer in the presence of a target molecule. The polymer grows around the target, "imprinting" it with the target's shape. It's analogous to making a plaster cast of one's hand, says Shea.
Looking to the properties of natural antibodies, Shea's group tailored the method for making polymers that more specifically target large proteins in biological solutions. Antibodies and their targets fit together like a key in a lock, or like a hand into a plaster cast. But they are also bound to their targets by chemistry and attracted by electrical interactions. Shea's methods involve looking to the properties of the target molecule and selecting starting materials that have an affinity for that target--in this case the protein melittin, the toxin in bee stings. At the same time, the method screens for starting materials that are not attracted to other, more common blood proteins. And the group took care to make the plastic antibody smaller than previous molecularly imprinted polymers, which were too big to be recognized by the body.
Artificial antibodies could sniff out viruses and toxins
So these antibodies meet their target and then go to the liver. I'm not aware of liver being able to break down plastic into reusable or non-toxic components. Wouldn't they cause liver damage negating their positive effect?
My question exactly--what happens in the liver? Can the body (at least of a mouse) safely clear these complexes?
And what uses do the researchers envision: strictly using these plastic antibodies as anti-venins/anti-toxins, or could they be used to treat cancer, autoimmune diseases, and other conditions as biofactured antibodies are?
The plastic antibodies would have to be designed to be broken down as a water soluble glucuronide, (or some other form) which than can be excreted in the urine.
The liver does this all the time with many natural chemicals such as hemoglobin, and "natural" antibiotics.
Other issues include Absorption by the Gut so oral meds could be given,(If not, given by IV or IM) and lastly, the ability to cross the blood brain barrier, for brain infections; and toxicity issues would have to be addressed,... just like the medicines that we take today.
This is exciting. There is no reason that a designer antibiotic could be made on demand, (in a relatively short time) for the ever increasing multiple resistant antibiotics that we see today. Other uses are mentioned above.
Ron Hansing 6.15.10
"The new immunology graduate was given advice by the older man - I have one word for you, my boy, Plastic; yes Plastics – that’s the future of immunology!"
Well maybe, but maybe not. The previous commenters have raised a key question about this new approach, which raises two more questions: a) what are the polymers used; and 2) what happens to them in the liver. I've read the original paper Hoshino, Kodama, Okahata, and Shea. It describes the polymers as "acrylamides such as N-isopropylacrylamide”. They synthesized various copolymers using different types of substituted acrylamides. There have been some studies showing harmful effects of acrylamides. However, it’s important to keep in mind that “the dose makes the poison”. The harmful effects of acrylamides may occur at concentrations greater than would be involved in using such molecules as synthetic antibodies. Also, there is the issue of the particular metabolic pathways involved. Perhaps someone who understands liver biochemistry, e.g., the last commenter, could help us out here.
Anyway, the article in JACS focused mainly on how the polymer composition was adjusted to optimize binding to the antigen. They also determined that the antibody-antigen complex had little or no interaction with blood components: albumin and fibrinogen. There was no discussion about toxicity or liver metabolism. The authors described the results as a starting point for the preparation and evaluation of synthetic antibodies for key antigens. I’m guessing that if the idea pans out, and if the polymers they used pose a toxicity problem, other polymers could be synthesized that avoided the problem.
This is cool stuff! I wonder if these MIPs could be used as a vaccine to prompt the body to make natural antibodies.
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drothman911
2 Comments
Interesting, probably valuable, not exactly new
The idea of plastics mimicing antibodies is not new. We were making such polymers in an industrial research lab in the mid-1990's, based on earlier published work from Sweden.
A book on the subject: Molecularly Imprinted Polymers, 23 edited by B. Sellergren
Hardbound, 582 pages
Published: DEC-2000
ISBN 10: 0-444-82837-0
ISBN 13: 978-0-444-82837-8
Imprint: ELSEVIER
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