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Taking a new pathway
HOPKINTON, Mass.—Caliper Life Sciences Inc. is forging a new offering based on a panel of cellular assays that measure the effects of drug candidates on functional activity of proteins called kinases involved in critical cell-signaling pathways.
The technology platform and initial panel of nine assays were developed in collaboration with Pfizer Inc.
The new offering, called In-Cell KinaseScreen, is available for compound screening, profiling and custom assay development services for Caliper Discovery Alliance and Services' (CDAS) clients, ranging from academia to pharmaceutical companies.
The companies certainly aren't strangers. Philippe Mourere, senior director of sales and marketing at Caliper, notes the company and Pfizer have been collaborating for many years on various contract research programs to support Pfizer drug discovery and development.
As for the latest effort, Mourere explains that Pfizer has actually selected CDAS among other organizations to partner with them for the development of cellular kinase assays.
"During the selection process, CDAS has demonstrated the value of collaborating with a preclinical contract research service organization that already possessed a strong expertise in kinase biology through the offering of complete vitro services using purified enzymes and the Caliper LabChip technology; a variety of cell-based technology platforms and cell models including a wide panel of more than 200 characterized human cancer cell lines for the aggressive development of physiologically relevant assays; and a large footprint of preclinical drug discovery services for 'one-stop-shop' drug kinase inhibitor development," he says. "CDAS follows up subcutaneous, orthotopic (primary and metastasis) oncology efficacy animal models, coupled with ex-vivo tissue biomarker analysis (multispectral analysis), to expedite vivo drug efficacy screening, drug bio-distribution and PD studies of kinase inhibitors."
According to Kevin Hrusovsky, president and CEO of Caliper Life Sciences, the company is looking forward to the opportunity to collaborate with Pfizer to develop cellular assays designed to enable better compound selectivity, which could lead to improved drug safety evaluation.
"This new assay suite is designed to assist scientists in developing treatments for a wide variety of therapeutic applications with potentially fewer side effects," he says. "The In-Cell KinaseScreen is an important addition to our portfolio of products and services for predictive toxicology that are available through our CDAS contract research services division."
Mourere explains that one application of these assays is in the area of oncology—for example, where kinase inhibitors have been used for treating a variety of cancers.
"These drugs have led to breakthroughs for treating many cancers; however, wider use of such drugs has exposed the potential for serious side effects due to 'off-target' activities," he notes. "Assays that measure kinase functional activity in key pathways in a physiologically relevant cellular context enable oncology researchers, as well as researchers in other therapeutic areas, to better identify compounds that maximize drug target selectivity and minimize potential side effects."
The specific focus is the development of a number of physiologically relevant in-cell kinase assays measuring the activity of a kinase of interest in a cell by titrating very specifically the level of immediate downstream-phosphorylated effector. The use of cell lines expressing endogenous levels of tyrosine and serine/threonine kinase targets provides a better representation of the clinical setup.
With nine different kinase assays already developed thus far through this collaboration, the partners are well on their way to having an impact on drug development.
"There are two ways that these assays can impact a drug discovery process," Mourere explains. "The first one is as a hit confirmation tool following the standard cell-free biochemical screening process. This allows investigators to determine whether the compound is able to exert its inhibitory effect on the target when the target exists in its native state within a physiologically relevant cellular environment. The second way is for drug liability issues, and for the identification of 'off-target' activities. One of the targets in the currently available panel is VEGFR2, and testing a compound to identify any 'off-target' activity against VEGFR2 phosphorylation could provide early indications of potential cardiovascular disease side effects."
Hrusovsky notes that protein kinases are key regulators of many critical cellular processes including cell cycle, proliferation, metabolism, differentiation and apoptosis.
"More than 500 protein kinases are identified in humans, representing approximately 2 percent of the genome," he says.
Kinase dysfunction, Hrusovsky points out, has been implicated in a variety of human diseases including cancer, diabetes, cardiovascular and neurological diseases, psoriasis, asthma and rheumatoid arthritis.
"As a result, protein kinases are now considered to be the second most important group of drug targets and represent an important target class to consider for potential drug liability issues," he says. "Protein kinase inhibitors are important not only for their therapeutic properties, but also as invaluable research tools to study cell signaling."
Biochemical-based kinase assays are important tools to assist researchers in accelerating their lead identification and optimization efforts while reducing costs. However, it is crucial to confirm the drug/target inhibition and selectivity in a more physiologically relevant cellular environment to limit the chances of false positive or negative data in early stages of drug development.
Mourere says the number of assays can be greatly expanded to interrogate more kinase signaling pathways or more kinase targets in a same pathway.
"Our expertise in kinase biology and unique assay development capabilities including multiplex assays (multiple kinase target activities measured from the same cells simultaneously) give CDAS a unique competitive advantage to develop virtually any tyrosine or serine/threonine assay," he says.
Mourere adds that Caliper is actively promoting its In-Cell KinaseScreen platform of services, including custom assay development, primary and secondary screening and functional kinase selectivity assessment.
"The strong interest generated by our recent CDAS In-Cell KinaseScreen services webinar presentations is very encouraging and is gradually increasing the demand for compounds screening," he says.
Caliper partnership with DxTerity seeks to expand diagnostic testing
HOPKINTON, Mass.—In late October, Caliper Life Sciences Inc. also announced a co-development and strategic collaboration agreement with DxTerity Diagnostics Inc., a genomics platform company.
Under their agreement, the companies will perform DxTerity's NEAT multiplex diagnostic assays on Caliper's LabChip Dx instrument platform, minimizing sample-processing time without compromising data quality. Caliper's future LabChip Dx instruments will include specific diagnostic identification, scoring and reporting software, developed in collaboration with DxTerity.
The LabChip Dx system is based on Caliper's microfluidic separation technology and enables high-throughput multiplex analysis for discovery and validation of nucleic acid and protein biomarkers. The LabChip Dx system uses minimal sample volumes and enables automated sample processing and analysis, providing a robust and cost-effective platform that Caliper says is achieving a high rate of adoption among diagnostic laboratories around the world.
DxTerity's NEAT assays allow analysis of gene expression and detection of single nucleotide polymorphisms (SNPs) directly from blood or formalin-fixed paraffin embedded (FFPE) tissue samples, virtually eliminating complex sample preparation processes. Multiplex assays for up to 40 gene targets are routinely performed, delivering unique applications for clinical diagnostics and life science research. DxTerity's lead clinical product in development is a blood-screening test that measures a patient's radiation exposure following a nuclear event, such as the recent disaster in Fukushima, Japan. The initial release of this product is scheduled for June of 2012.
DxTerity is also developing low cost, blood-based cancer screening tests based upon the gene signature panels acquired from SourceMDx.