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Biolog Wins SBIR Grant to Develop Tox Applications for Mammalian Cell Arrays

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First there were gene arrays, followed by protein arrays. Now, biotech firm Biolog is one step closer to commercializing the first living mammalian cell arrays for drug-discovery and -development applications.

The Hayward, Calif.-based company announced last week that it has received a $2.5 million Phase II SBIR grant from the National Institutes of Health to develop predictive toxicology assays for human and mouse cells on its Phenotype Microarray cellular array technology.

The Phase II grant — typically awarded once the commercial viability of a technology has been proven — follows on the heels of a $250,000 Phase I grant Biolog received last June to develop the toxicology assay technology.

According to Tim Mullane, Biolog’s president and CEO, the funding is specifically to “apply the Phenotype Microarrays as a toxicology tool to potentially replace animal models.” But the vote of confidence is also a huge overall boost toward generally commercializing the human and mouse cell arrays for a variety of drug-discovery applications.

The term “Phenotype Microarray” refers to the basic idea of testing a cell line against thousands of conditions — or drugs — in a highly multiplexed fashion in multiwell plates. It could be considered a form of high-content screening that can be performed in high throughput, as well.

Biolog already has Phenotype Microarrays on the market, for bacterial and fungal cells. It introduced those in 2000, and took the arrays to market the following year. The bacterial and fungal arrays find use in highly multiplexed gene-expression, diagnostics, and drug-response studies, and have carved out a unique market niche for Biolog (see Inside Bioassays 5/4/2004). They have also provided the company with enough profit to develop the mammalian microarrays, which have an even greater market potential.

“The company’s profitable,” Mullane said. “Our microbiology diagnostic and identification business is a profitable, growing business, and it’s funded a lot of our growth. So this is a logical evolution of our technology, which [allows] us to grow in to new areas [and] to grow the business.”

It’s safe to say that there’s a lot of room for growth. Drug developers are certain to be seeking better ways to determine the toxicology profiles of compounds in light of recent blockbusters that have flopped because of such concerns. Mullane sees a few ways that Phenotype Microarrays can help.

“These assays are very reproducible compared to other microarray assays,” Mullane said. “So the idea is that you can take a series of chemicals, be able to fingerprint [them] with some number of the arrays that you’re interested in, and get a very characteristic fingerprint for a drug. The hope is that we’ll be able to differentiate very subtle differences biologically in drugs that would also allow you to compare them … to drugs that have already been tested by other means and have been determined to be toxic, for whatever reason.

“The other thing is that it will hopefully elicit a little bit about the biology that’s going on there,” he added. “So as you see various assays that are being affected by that chemical, you could hone in on biology, because you are testing the cells in various areas. Maybe there would be a way to moderate that chemical that would move it from one that might fail for toxicology reasons, to one that you could move forward.”

Biolog also has an instrument on the market called the OmniLog that is optimized for use with any of its cellular arrays. OmniLog is a confocal-based, non-fluorescent imager that captures information from 96-well plates. Each well of each plate contains aliquots of the same cell line, but is exposed to different conditions or compounds.

“It gives you a kinetic response curve, and we use this curve to basically create patterns of information,” Mullane explained. “The cells will respond differently to pre- and post-experimental conditions. So you have a normal cell line, you expose it to a drug, certain assays will go down, certain assays will go up, and the timing and extent to which those assays respond is captured in that kinetic response curve.”

Mullane said that although Biolog’s desire is to sell the assays and instrument as a package, he can envision scenarios where customers might not want to use the OmniLog — a situation that he would be comfortable with.

“I think we’re pretty agnostic on that right now,” he said. “Some people may just want to run endpoint detection on a microplate reader. There are a lot of reasons to want the kinetic response curve for certain applications that we think our system is pretty well-developed for. But … if someone wants to develop the assay using [another] reader, we’d focus on that.”

If all goes well, Mullane said he expects the mammalian cell arrays to be commercially available in the first quarter of 2005, with the toxicology model available “later down the road.” The company envisions the mammalian Phenotype Microarray’s first drug-discovery application to be quality control of cells, with some basic research applications to follow.

“The grant was funded around toxicology, and that’s a very major application, but the first application to come out will be quality control of cell cultures, because it’s much simpler,” said Barry Bochner, Biolog’s vice president for research and development. “But we can test hundreds of thousands of properties of cell lines all at once, whereas other types of high-content screening methods just test a handful — three, five, or ten properties of a cell — as far as I’m aware.”

He also said that there is a possibility of using the arrays with cell lines that have been “genetically altered by RNAi or some other genetic approach,” adding, however, that “we haven’t done anything with that yet.”

Mullane said that various companies are currently beta-testing the mammalian cell arrays, but he declined to identify them. Regarding price, Mullane told Inside Bioassays earlier this year that a full set of assays for a bacterial strain costs between $500 and $700, and that this price would likely not change significantly for the mammalian arrays. The OmniLog instrument costs about $90,000 — significantly less than most high-content screening platforms.

It remains to be seen how profitable Biolog’s foray into mammalian cells will be, but Mullane said he is confident based on the success of the bacterial and fungal assays. Adding that to the fact that the company is not actively seeking VC cash leads one to assume the company is well-poised for further growth.

“We’re really happy with the first quarter, which runs from July to September,” Mullane said. “As far as seeking financing, we’re not really. I hate to say we don’t need it, because when can a company not use more money? But we’re not actively seeking to take in VC money right now.”

— BB

 

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