A Man-Made, Plastic Antibody Works In Mice

Researchers say they've created nano-sized antibodies out of chemical components and used them to clear a toxin injected into mice. The antibodies latched on to and "disarmed" the toxin in much the same way natural antibodies do. Chemist Kenneth Shea describes the work.

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IRA FLATOW, host:

This is SCIENCE FRIDAY from NPR. I'm Ira Flatow.

(Soundbite of film, "The Graduate")

Mr. WALTER BROOKE (Actor): (As Mr. McGuire) I just want to say one word to you, just one word.

Mr. DUSTIN HOFFMAN (Actor): (As Benjamin Braddock) Yes, sir?

Mr. BROOKE: (As Mr. McGuire) Are you listening?

Mr. HOFFMAN: (As Benjamin Braddock) Yes, I am.

Mr. BROOKE: (As Mr. McGuire) Plastics.

FLATOW: Ah, yes, remember that famous line from "The Graduate?" Well, of course, he turned out to be right because the uses for plastics in the last 40 years have become endless, and now, plastic molecules and immunology are turning up.

If you get stung by a bee, or you catch the flu, or you get a vaccine, you'll end up with what are called antigens in your blood stream. These are microscopic molecules that your body recognizes as being foreign, and if these antigens are causing a problem, which they often do, your body can get rid of them by making antibodies.

But sometimes, your body might need a little help, an antibody boost, and while biotech companies can make antibodies, it's an expensive and time-consuming job, and what we need is a faster, cheaper antibody. How about a plastic antibody?

And that's what my next guest has made, nano-particle-size plastic antibodies, and it looks like they function, at least in mice. Joining me now to talk more about it is Kenneth Shea. He is a professor of chemistry at the University of California at Irvine. Thanks for talking with us today.

Dr. KENNETH SHEA (Professor of Chemistry, University of California, Irvine): Thank you, Ira.

FLATOW: So tell us what these antibodies do.

Dr. SHEA: Well, we have found that the antibodies can function in a living organism, much the same as natural antibodies, in the sense that they're able to capture an antigen. In this case, it's the bee venom toxin, melittin -capture them and then be cleared from the blood stream and diminishing the toxological consequences of these venoms.

FLATOW: When you say capture them, what do you mean by that?

Dr. SHEA: Well, just as antibodies work, we're dealing with an area called molecular recognition - that is, at the molecular level, the ability of some entity, a molecule such as an antibody, to recognize another entity and recognize involves also associate with or capture that entity.

You referred to them earlier as antigens. And so antibodies in the bloodstream, in fact, can recognize when a substance in the blood is foreign, it doesn't belong there, and in fact capture it and remove it from the blood as part of our natural immune system.

FLATOW: And so you tried this with bee venom in these laboratory mice.

Dr. SHEA: That's correct.

FLATOW: And it captured and prevented the bee venom from functioning?

Dr. SHEA: Yes, in this case, after a series of preliminary tests that were done in vitro, with cells; and with tests that established that these plastic antibodies were not themselves toxic. The mice were administered a lethal dose of toxin, melittin, followed on by an injection of these plastic antibodies.

Control populations were also administered the toxin without any antibodies, and a difference in their survival rates were noted. The control group, in fact, did not survive, and there was a substantial improvement in survival of the mice that had been administered these plastic antibodies.

FLATOW: How easy is it to make these things?

Dr. SHEA: Well, I'm a synthetic chemist, and these, the chemical reactions that are used to make these plastic antibodies are polymerization reactions. And quite frankly, technically, they're not very challenging.

We use an assortment of commercial monomers in a polymerization reaction that takes approximately an hour or two. These nano-particles of course have to be purified after the reaction, but the process is rather straightforward.

FLATOW: And how soon well, of course, how soon would they be ready for humans, but we're not even close to that yet, I would assume?

Dr. SHEA: I think that would be correct. Certainly, any intervention or injection of drugs or possible therapies in humans require a long series of protocols that have to be established, so that there are no unintended consequences and that they are effective for the intended purpose.

FLATOW: You know, when we put foreign objects into anybody, we sort of reject them. How come, you know, plastic hasn't been rejected by the mouse?

Dr. SHEA: Well, that's an interesting question and I have to be careful because longer-term unintended consequences, in fact we have not had an opportunity to pursue this. But as I indicated, the tests that led up to the experiments that we just published established that when therapeutic doses of these nano-particles were injected into mice, and the mice were observed over a period of several weeks - and again, compared with controls that did not have these particles injected - there were no differences in weight gain and/or other behavioral observations. Furthermore, autopsies of these mice, after two weeks, revealed again, no secondary symptoms of toxicity or immunogenicity.

Now, these are relatively short-term experiments, done only over several weeks, and that was the green light for us to proceed with the subsequent tests. But the issue of immunogenicity is an important one.

One of the interesting possibilities is that these nano-particles or plastic antibodies are not pure substances. I'll use a Lewis Black(ph) analogy, that they're something like snowflakes. And that might, in fact, confuse, at least for a while, the immune system and delay any serious immunogenic response.

FLATOW: So if by delaying it, if the animals were to live longer, they might show up?

Dr. SHEA: Well, this would depend upon what the therapeutic application was. Here, we're dealing with an immediate threat to the organism, a toxin that's life-threatening, and what's most important is to reduce or remove that toxin before it does its damage.

We're not talking about sustained injection over long periods of time, but eventually, how these particles are removed from the organism is an important question that would have to be addressed before any human applications are, in fact, realized.

FLATOW: Would the same mechanism, then, apply to other kids of insults? I'm thinking of snake venom, immediately, because of bee venom, or other kinds of, you know, reactions that we might any other attacks on the body that we might make plastic antibodies for.

Dr. SHEA: Absolutely. In fact, this has opened the door for us, and we are currently pursuing the applications of this in a number of different areas.

You had mentioned toxins. Bee stings, although for some people they can be quite harmful and dangerous because of immune reactions, there are far more serious toxins that act more quickly, okay, and they present much greater threats to human life.

These are toxins that are released by microorganisms, for example, bacterial infections, and also you indicated, snake and spider venom. And so, in fact, we are pursuing potential development of plastic antibodies that are capable of neutralizing these substances, as well.

FLATOW: What about things from the body itself, like food allergies?

Dr. SHEA: Yeah, allergens are another interesting area, and in fact we have begun the pursuit of although I'm certainly not an expert in this area -allergic reactions in people, okay, come from a variety of sources, some internal from ingesting food and others external, for example hay fever.

And those allergic responses or reactions are triggered by oftentimes proteins or peptides that are on the surface of polymolecules. And so we've given some thought to use of plastic antibodies that might minimize the allergic response that comes from these immunogenic peptides or proteins on the surface of pollen particles.

FLATOW: Or even, you know, peanut allergies, which can kill you.

Dr. SHEA: Yes, exactly.

FLATOW: And have something immediately to take if you've swallowed some peanut particle or something like that.

Dr. SHEA: Yes. Now, there are, in fact, some responses to those sorts of things, but timeliness is very, very important. There are also issues and this is where we think the plastic component of this could have a leg up in certain instances, that is antibodies, a common therapy, are protein molecules.

And so they can only be used under certain circumstances. They're vulnerable to protein molecules that when it's injected into living organisms.

They also have storage issues. They're not as stable as synthetic polymers are. And so long-term storage and availability, particularly in settings that the appropriate storage conditions, such as refrigeration, are not available, this again could be another application of these materials.

FLATOW: And what happens to the nano-particles themselves? I mean, do they accumulate someplace in the body?

Dr. SHEA: Well, we found in this particular case, the nano-particles, together with the toxin - they were shown to be together by fluorescent labeling studies - they wound up in the liver, associated with macrophages. Macrophages are sort of the garbage collectors of the bloodstream, responsible for picking up things that don't belong there and clearing them into the liver.

So they were cleared into the liver. Now, clearage mechanisms depend upon a number of things: the size of the foreign entity, its immunogenic response and things of that sort. In our case, they did wind up in the liver, and that would be expected for a particle of the size that we're working with, which is approximately 40 nanometers.

The question that you raised earlier, are they going to stay in the liver, well, this is a short-term experiment, once again to address an immediate threat, a toxin to the organism.

The long-term fate of these particles are something that has to be addressed and something that we're working on, as are others in the field of nano-medicine.

These particles can be viewed as sort of a three-dimensional spider web, and the links holding the individual strands together are called cross links. Now, our cross links are relatively stable, and so the particles are relatively stable. They don't readily break down in the body, just as we have issues with the plastics in the environment that are readily biodegraded.

But this is a chemical problem that can be addressed by the introduction of cross links that are more vulnerable.

FLATOW: That would break down.

Dr. SHEA: That would break down over a period of time.

FLATOW: All right, Dr. Shea. I want to thank you for taking time to be with us today.

Dr. SHEA: It was my pleasure.

FLATOW: Good luck to you.

Dr. SHEA: Thank you.

FLATOW: Kenneth Shea is professor of chemistry at the University of California at Irvine.

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