Caliper Life Sciences said this week it will bundle its microfluidics-based LabChip platform with certain of DiscoveRx’s G-protein-coupled receptor assays for drug-research applications.
Nate Cosper, Caliper’s director of marketing, told CBA News this week that the combined offering includes DiscoveRx’s PathHunter β-arrestin and cAMP Hunter assays.
The deal will allow Caliper to expand the use of its LabChip platform to GPCR cellular function assays, which play a role in neurological, cardiovascular, and other disease states, said Cosper.
The partnership also gives Caliper “a very nice additional ‘leg on the stool,’ so to speak, for in vitro, in-house GPCR functional assays,” Cosper said.
According to Theresa Schaub, director of discovery services at DiscoveRx, one novel thing about the LabChip platform is that it gives scientists the ability to look at a number of different types of pharmacologies. “You can readily look at agonists, antagonists, and inverse agonists. Inverse agonism is particularly difficult to measure in a calcium-based assay,” she said.
She added that DiscoveRx scientists are seeing compounds that act as an antagonist at one receptor and an agonist at another receptor. “That is the sort of thing that has been historically difficult or impossible to detect in a FLIPR-type assay,” she said. “So this [alliance] would provide additional information to researchers, which they may find helpful.”
This bundling of our GPCRs on Caliper’s LabChip can give researchers “the ability, particularly in SAR groups, to turn data around really fast, which is something that they did not have the ability to do previously,” Schaub said. “I think these assays will really help speed up SAR efforts.”
In the past, when Caliper has focused on biochemical and kinase assays, it had worked primarily with oncology-based companies, Cosper said. He added that the deal represents “a change for us from oncology into CNS, and from biochemical assays into cell-based GPCR assays.”
For its part, DiscoveRx anticipates gaining a foothold in a new market, and sees the agreement as “a nice opportunity for us to take advantage of a new class of instruments … and having our GPCR assays actually have an application on that platform,” Sailaja Kuchibhatla, vice president of business development at DiscoveRx, told CBA News this week.
“This agreement represents a change for [Caliper], from oncology into CNS, and from biochemical assays into cell-based GPCR assays.”
Kuchibhatla, who called the LabChip platform a “tremendous instrument,” said that until this deal emerged, kinase profiling was “primarily the only reagent platform” that Caliper could offer on its LabChip EZ Reader.
DiscoveRx believes that it has two GPCR assays that have “a good application” on the system: the PathHunter β-arrestin and cAMP Hunter cell lines and detection kits.
“A lot of drug-discovery customers are already using these for screening, so this [agreement] allows us to go into a brand-new market segment,” Kuchibhatla said.
In the first phase of the collaboration, DiscoveRx plans to make available by the end of this month detection reagents specific to the Caliper system for Caliper customers who may already have PathHunter cell lines in-house, said Schaub.
She said the second phase involves developing profiling kits with pathogen-limited cell lines to enable DiscoveRx customers to select from multiple cell lines in defined kits to run on the LabChip.
“We anticipate having 30 kits available by the end of June,” Schaub said. “We are being relatively aggressive in product development.”
Bundles of Joy
For Caliper, the deal is the second bundling alliance for its cell business in recent weeks. At last month’s Society of Biomolecular Sciences meeting in St. Louis, Caliper announced that it would incorporate Horizon Discovery’s oncology cell lines into products sold by Caliper’s Discovery Alliances and Services division (see CBA News, 4/11/08).
That division, known as CDAS, currently provides a variety of screening and profiling services for the cell-based assay market, including GPCRs, ion channels, transporters, ADME/Tox, and drug-combination studies.
Cosper told CBA News at the time that the deal gives the company genetically defined and isogenic human cancer cell lines that could enable researchers to better identify and characterize drugs targeted at specific patient subsets, and that Horizon’s cell lines will help expand Caliper’s presence in the combination-therapy testing market.
That deal, which involves Caliper’s services business, is focused on looking at cancer cell lines that have a specific point mutation in a target of interest, and testing compounds in those cell lines versus native, non-diseased cell lines, Cosper said this week.
However, Cosper stressed that the Horizon partnership does not involve the LabChip platform. “It is just a standard cell-based assay,” he said.
“I think in general, what you are seeing is that Caliper is very excited about the prospect of cell-based assays,” said Cosper. “We see it as an important part of our overall strategy, so we have gone out and found leading companies like Horizon to partner with to bring their cell lines into our services group, and DiscoveRx, to bring their very innovative, functional GPCR assays onto our LabChip platform.”
The DiscoveRx deal is not Caliper’s first foray in the GPCR market. The company has had a strong GPCR presence through CDAS in the past, so its in vitro CDAS business has 150 to 200 GPCR binding assays, and “we have more than 20 years of experience doing GPCR profiling,” said Cosper.
In addition, Caliper’s in vivo business at CDAS has 85 in vivo models that measure 450 different biological parameters, almost all of which are related to GPCRs and CNS disease states, he added.
GPCRs are probably the target that is most often screened in an HTS setting, said Kuchibhatla, adding that researchers are looking for technologies that are “robust, reproducible, and automation-friendly.”
The advantage of using cell-based and functional screening compared to a so-called binding assay or biochemical assay is that the cell-based screens will “allow you to identify compounds as an agonist, antagonist, or inverse agonist, whereas with a biochemical assay such as a binding assay you are only able to tell if a substance that you add into the assay displays the tracer, or label, so that you can detect whether the labeled compound is binding to the protein or cell membrane,” said Paul Lee, a principal scientist at Amgen.
Lee is the corresponding author on a paper published online this week in the Journal of Biomolecular Screening in which he and his colleagues describe a homogeneous high-throughput GPCR assay that they developed.
GPCRs are usually expressed on the cell surface, and biochemical assays use a label to detect where there is binding to the membrane protein. This allows researchers to determine if the compound or substance of interest is able to displace the label bound to the protein, but they have no idea whether it is functioning as an agonist, antagonist, or inverse agonist. With a functional assay, scientists are able to make such a distinction.
However, one disadvantage of cell-based assays is that you are measuring the whole cell function, said Lee. “If, for example, you are interested in a specific GPCR, there may be multiple GPCRs expressed on the cell surface in addition to the one in which you are interested. So the compound that seems to be inducing the function of the cells may not necessarily be active through the GPCR of interest.”
Therefore, although scientists may be observing functional activity of the cell in a cell-based assay, they usually have to follow it with multiple assays to confirm that the functional activity observed is due to the GPCR of interest, rather than another, nonspecific GPCR being expressed on the cell surface.