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Gentronix Launches Human Cell-Based Genotox Assay; Invitrogen's CRO Arm May Aid Adoption

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British biotech Gentronix this week said it has commercially launched its human cell-based genotoxicity assay, which is designed to help pharmaceutical scientists more accurately weed out genotoxic drug candidates earlier in the drug-discovery process.
 
Gentronix will initially only sell the assay, called GreenScreen HC, in ready-to-use reagent kits, a company executive said this week. However, the company also hopes the product will receive a boost as several contract research organizations – including Invitrogen’s BioReliance subsidiary – adopt it over the coming months.
 
GreenScreen HC will make its official trade show debuts at Select Biosciences’ Screening Europe conference this month in Barcelona, Spain, and at March’s Society of Toxicology annual meeting in Charlotte, NC. However, Gentronix is taking orders for the product now, Richard Walmsley, the company’s founder and scientific director, told CBA News this week.
 
The launch follows the completion of beta-testing at GlaxoSmithKline, Johnson & Johnson, and Unilever; and the September publication of a peer-reviewed research paper by GSK and Gentronix researchers validating the assay’s efficacy (see CBA News, 8/18/2006).
 
“Over the last five or six months we had an early adopter program with people we knew from our earlier yeast work,” Walmsley said. “We wanted to make sure that the protocols could be followed and that we spotted any first-in-the-market issues.” According to Walmsley, the bulk of this work was done with GSK.
 
Prior to beta-testing, last summer Gentronix conducted a “multi-lab robustness and reproducibility trial” with GSK, J&J, and Unilever.
 
“Before we did the early adopter program, we said, ‘Let’s just ship it to a few different places’ to make sure we spot anything,” Walmsley said. “That exercise helped us to define the protocol. It helped us to write the instructions, and also to make sure we made very specific recommendations about the plasticware and things like that inside the lab. They’re trivial things, but they’re very important in product definition.”
 
GreenScreen HC is Gentronix’s third product: In 2002, the company introduced GreenScreen GC, a yeast cell-based assay for genotoxicity testing on which the HC version is based; and GreenScreen EM, an environmental monitoring product based on the same core technology.
 
That core technology is a green fluorescent protein reporter gene that is co-expressed with a specific gene known to be active during DNA repair. In yeast cells, that gene is called RAD54, and is an evolutionarily conserved, recombinatorial DNA-repair gene induced by all yeast-mutating agents.
 
In August, Walmsley told CBA News that although the yeast cell version of GreenScreen had seen modest success in the pharmaceutical toxicity testing market, most of Gentronix’s customers requested a human or rodent cell-based version for increased relevancy.
 
Gentronix based the GreenScreen HC assay on the human gene GADD45, a well-characterized gene that plays a similarly central role in DNA damage in human cells. In the assay, that gene is co-expressed with GFP in a human lymphoblastoma cell line called TK6.
 
“The key thing about it is that it’s [a] p53 competent [cell line],” Walmsley said this week. “The experiments we’ve done suggest that was actually a key feature of the whole system, because it allows GADD45 to do its job properly, and therefore to be much more accurate in identifying a genotoxin as positive. We think that apart from using GADD45, using it in a p53 competent cell line contributes greatly to the accuracy of this test.”
 
CRO Goals
 
As Gentronix rolls GreenScreen HC out, it hopes to gain some additional exposure for the assay through its use in various CRO toxicity testing services. Walmsley told CBA News that Invitrogen contract research unit BioReliance has also been beta-testing the assay, and will be offering it as part of its services.
 

“Gentronix will sell stuff to people to do the tests, and over the next couple of months it will be available through select contract research organizations.”

“BioReliance has done an early-adopter trial, as well, to make sure that they can run the test according to our results, and they’ll be offering it as a service,” he said. “So if people want to do it, and can’t do it themselves, we’ll tell them to go to BioReliance.”
 
A spokesperson for Invitrogen’s BioReliance division told CBA News that he is familiar with GreenScreen HC, but that he couldn’t discuss the company’s interest in the technology, primarily because Invitrogen is in a quiet period ahead of its Q4 2006 earnings release.
 
Nevertheless, Walmsley told CBA News that he remains confident that Gentronix “will sell stuff to people to do the tests, and over the next couple of months it will be available through select contract research organizations.” Walmsley said that there are a few other CROs in a “similar position” to Invitrogen, but he declined to disclose them, primarily because they, along with BioReliance, need to navigate the relatively complex GFP minefield.
 
GE Healthcare owns an umbrella license to GFP, which means that any for-profit entity wishing to sell an assay based on the popular fluorescent tag must negotiate a sub-license with GE. Gentronix has done just that, which has allowed it to sell GreenScreen HC worldwide. However, “to go through a third party, we just have to adjust our license agreement,” Walmsley said. GE Healthcare “is happy to do this, but of course it takes ages going through everybody’s lawyers,” he added.
 
For Invitrogen, the process may be expedited since it owns some components of the IP that falls under the GE Healthcare GFP licensing umbrella, although the extent to which Invitrogen has taken action in this area remains unclear.
 
Currently, Gentronix recommends several bulk fluorescence readers for conducting the GreenScreen HC assay in 96- or 384-well format. These readers include Tecan’s Ultra 384 and Evolution; BMG Labs’ POLARStar Optima and Galaxy; PerkinElmer’s Victor and EnVision; Bio-Tek’s Synergy; ThermoFisher’s VerioSkan; and Molecular Devices’ SpectraMax M5.
 
Interestingly, Gentronix has also internally demonstrated that it can collect data from the assay using flow cytometry, “which is very good for us, because people collect other data from cells using flow cytometry, so this could be very efficient,” Walmsley said.
 
“This means there is another platform GeneScreen can operate on,” he added. “We’ll probably launch a fluorescence-activated cell sorting protocol later in the year. We do it here already, but it’s a productization issue at the moment. But the initial findings show that we’ll be able to use flow cytometry instead.”
 
Lastly, Gentronix thinks that it can increase the scope of GreenScreen HC to screen for drugs that become genotoxic following metabolic activation.
 
“A lot of things that actually do turn out to be damaging to DNA or carcinogenic actually only become that way after they’ve gone through your liver and had some chemistry done to them,” he said. “With the yeast test, we never really got that to work. But with the human one, we did proof of principle in the paper we did last year, but we now have proof of principle of doing that with flow cytometry … and are hoping that will be a general protocol.”

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