Plastic antibodies?

Antibodies are the main ingredient in a wide range of biopharmaceuticals, but making them is no picnic. Now, chemists have good evidence there may be an easier way: plastic. Currently, in order to manufacture antibodies, mice (or other live animals) are injected with a foreign antigen over several weeks, stimulating B cells in the bloodstream to produce antibodies. Those B cells must then be harvested from the mouse's spleen and transferred to a bioreactor where they are often fused with another cell type, like immortal tumor cells, that allows them to replicate and survive outside the animal. The cultured cells then produce the antibody. If the antibody is for human use, at some point it must be humanized -- modified through recombinant DNA technology to resemble natural human antibodies. The process is long, difficult, and expensive. But what if a substance introduced years ago as a cheap, durable replacement for natural materials could replace yet another one of nature's materials?Plastic antibodies Kenneth Shea In a landmark paper published earlier this month in the Journal of the American Chemical Society, synthetic chemists at the University of California, Irvine, report the first successful use of a plastic antibody in vivo. The synthetic counterpart seems to work just like a natural antibody, binding and neutralizing a toxin in the bloodstream. Such molecules could someday make a splash in the clinic as well as in pharmaceutical and biotech companies for protein purification and diagnostic applications, scientists believe. "It's really remarkable," said linkurl:Kenneth Dawson,;http://www.ucd.ie/research/people/chemistrychemicalbiology/professorkennethadawson/home/ a chemical biologist at the University College Dublin in Ireland who reviewed the paper. "It could really do something important...it's almost a dream." That "dream," of rapidly and cheaply producing synthetic antibodies, has been a pursuit for the last 10 to 15 years, said Das Prayaga, chief scientific officer of linkurl:Antibody Research Corporation,;http://www.antibodyresearch.com/files/contact.html an antibody production and manufacturing company in St. Charles, Missouri. While companies have made many attempts in vitro, "this is the first to show in vivo that it is effective," said Prayaga, who was also not involved in the research. linkurl:Kenneth Shea;http://www.chem.uci.edu/faculty/kjshea/ and his team at UC Irvine produced the synthetic antibodies through a process called molecular imprinting. It's like making a plaster cast of one's hand, only on a nanoscale. They began with a combination of monomers -- compounds that bind together to form polymers, or plastics -- with a high affinity to melittin, the cytolytic component of bee venom and their toxin of choice. By mixing the monomers together in the presence of melittin, the tiny molecules conglomerated around the antigen, forming a mold encasing it. Once the monomers had solidified into a polymer, the poison was washed out, leaving behind tiny plastic nanoparticles with melittin-shaped depressions. The researchers then made the risky jump from the "pristine confines" of their chemical laboratory to a living organism. "There were all sorts of ways that things could go wrong," Shea told The Scientist. In collaboration with scientists at the University of Shizuoka in Japan, the team tested the effectiveness and safety of the antibody in mice, hoping the particles wouldn't be toxic to the mice or become coated with proteins in the bloodstream and be unable to bind melittin. Happily, neither happened. Mice were injected with a lethal dose of melittin. Of those who received solely the poison, 100 percent died. Of those treated subsequently with the plastic antibody, most survived and with no observable toxicity over two weeks. The scientists also labeled both melittin and the antibody with a fluorescent dye, so they could observe the binding in real time, watching the colors converge in macrophages in the bloodstream, then settle in the liver. The next step will be determining how and if the plastic antibodies are cleared from the body, which the current study did not address. Nanoparticles capable of plucking one or two proteins from the blood have a potentially enormous range of uses, said Dawson, who studies the interaction of nanoparticles and living systems in Dublin. "Out of the over 3,700 proteins in the blood, we can [use nanoparticles to] pick out half-a-dozen of them. Now, what it looks like from this paper, is that if you provide a bit more structure on the surface [of the nanoparticle], you can get down to one protein," he said. Isolating one protein out of blood or other solutions with a cheap, easy-to-make plastic would be "enormously valuable," said Dawson, especially for harvesting and purifying proteins in the biotech industry, as well as in diagnostics, where a plastic antibody could be used to bind and identify a bacterial or viral protein during a blood test. "This had a very bright future," said Prayaga. "Maybe in 10-15 years, we'll see some of these in the clinic...I'm sure it will be done." The biggest question is simply how generally applicable the technology will be when applied to more complex antigens, said Dawson. Shea and his team have already begun to address that question, trying to make antibodies specific to glycopeptides and proteins on the surface of bacteria and viruses, a very different challenge. "This opens a lot of opportunities," said Shea, who is "very likely" to partner with pharmaceutical or biotech companies to develop the technology. "It's been a busy few weeks," he laughed. Y. Hoshino et al. "Recognition, neutralization, and clearance of target peptides in the bloodstream of living mice by molecularly imprinted polymer nanoparticles: a plastic antibody," J Am Chem Soc., 132:6644-45, 2010. **__Related stories:__***linkurl: Building Better Proteins;http://www.the-scientist.com/2010/6/1/68/1/ [1st June 2010]*linkurl: Reinventing the Antibody;http://www.the-scientist.com/article/display/54478/ [1st April 2008]*linkurl: Antibodies Go Recombinant;http://www.the-scientist.com/article/display/53131/ [5th May 2007]

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