January 15, 2013 (Vol. 33, No. 2)

PolyBatics Produces Novel Biobeads with Attached Proteins, Antibodies, and Ligands

PolyBatics wants to improve the way that polymer beads, such as those used in home pregnancy kits, are manufactured. The company’s technology platform uses microorganisms to produce biodegradable polymer beads, or biobeads, that display functional proteins on the surface. Not only do microbes manufacture the biobeads, but the polymer-forming enzyme can be genetically programmed to combine desired proteins and other ligands with the biobeads.

It’s known that many bacteria produce polyester granules when nutritionally stressed. Bernd Rehm, Ph.D., a professor and chair of microbiology at Massey University, discovered that the enzyme polyester synthase remains attached to the surface of polyester granules when stored. It was assumed that the granules crystallize when harvested and stored.

Using molecular biology tools, Dr. Rehm showed that green fluorescent protein, enzymes, and other ligands can be produced on the surface of the polyester granules via polyester synthase. “This was the eureka moment that launched the company. We realized we could engineer the polymer forming enzyme to do all sorts of additional things,” says Tracy Thompson, CEO. A wide range of ligands, antigens, enzymes, signal proteins, and antibodies have been attached to biobeads. PolyBatics’ researchers have produced biobeads with up to three separate functions on a single bead.

Thompson, a veteran of several biotechnology and medical diagnostic companies in Silicon Valley, California, went to New Zealand to help a government agency commercialize agricultural products. When he heard about the microbial biobead platform at Massey University, he co-founded PolyBatics in 2009 with Dr. Rehm, now CSO.

Advantages of Biobeads

Researchers at PolyBatics mainly engineer biobeads in Escherichia coli, the most prolific microbe. But various types of Bacillus and Lactococcus also make biobeads. The nutrients fed to the microbes determine the composition of the biobeads. “If we feed them glucose, we get polyhydroxybutyrate. If we feed them other substrates, they make different polymers,” says Thompson.

The production of conventional bioseparation resin beads is expensive, laborious, and environmentally unfriendly. Functional proteins are synthesized separately, then captured, washed, and purified. The protein is attached onto a resin bead in a separate process. Toxic solvents are required to make the resin bead and attach proteins to its surface. In contrast, PolyBatics’ method uses simple sugars, salts, and buffers to make completely functional beads.

Moreover, the microbes used by PolyBatics create the bead and attached protein simultaneously in a cost-effective system, Thompson says. The lead product in the company’s pipeline, PolyBindZ, is a disposable replacement for agarose immobilized protein A. Standard methods for making protein A-based beads cost up to $15,000 per liter. PolyBatics makes PolyBindZ for a fraction of that cost.

Using protein A as a model, researchers at PolyBatics isolated only the binding region, called the Z domain. Then they cloned the Z domain into a vector to increase binding efficiency. This produces biobeads with an attached protein in a single step. “So the cost of production is less than for conventional resin beads,” says Thompson.

A further advantage of the microbe-based manufacturing system is that multiple proteins can be attached to a biobead. The insertion of hybrid genes programs bacteria to attach multiple components to the biobead. This results in novel combinations of products with broad applications, explains Thompson. For example, beads with both Gold Binding Protein and antibodies could be used in immunochromatography tests. “It’s a very robust platform. All we have to do is change the gene for the functional domain, be it an enzyme or different ligand,” he notes.

E. coli shown filled with engineered polyester bead inclusions: Once removed from the host, these beads can be used in a variety of applications from diagnostics to vaccines to separations media and more.

Upcoming Applications

PolyBatics will release its first products in the first quarter of 2013. The types of biobeads will include PolyBindZ as well as protein G, Streptavidin, and magnetic versions of these respective protein beads. Proteins A and G target antibodies, but certain subclasses of IgG antibodies bind to one but not the other. Streptavidin biobeads bind to any biotinylated target and are widely used in life science research.

Companies that perform bioseparations and target enrichment of proteins, DNA, and cells will be among the first market sectors. This includes biotechnology and pharmaceutical companies that produce monoclonal antibodies. “There’s a low barrier to entry in this market,” says Thompson.

Biobeads also are used in pharmaceutical manufacturing. When coated with enzymes and attached to a column, biobeads serve as biocatalysts to produce active pharmaceutical ingredients or drug intermediates. This scalable function could be applied across the drug discovery and pharmaceutical manufacturing process.

A promising larger market for biobeads lies in vaccines. Studies show that biobeads, which are just 100 to 200 nanometers in diameter, trigger viral-like immune responses. When vaccine antigens are cloned onto biobeads and injected into mice, the mouse immune systems reacts to the biobeads as though they’re a virus and generates cell-mediated and humoral responses.

“We demonstrated this for Mycobacterium tuberculosis and hepatitis C vaccines,” says Thompson. Additionally, the biobead’s polymer core is biocompatible and produces no adverse reactions on its own. Collaborations are under way in several of these areas.

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