Taking a new pathway
Caliper, Pfizer launch platform for drug safety
HOPKINTON, Mass.—Caliper Life Sciences Inc. is forging a newoffering based on a panel of cellular assays that measure the effects of drugcandidates on functional activity of proteins called kinases involved incritical cell-signaling pathways.
The technology platform and initial panel of nine assayswere developed in collaboration with Pfizer Inc.
The new offering, called In-Cell KinaseScreen, is availablefor compound screening, profiling and custom assay development services forCaliper Discovery Alliance and Services' (CDAS) clients, ranging from academiato pharmaceutical companies.
The companies certainly aren't strangers. Philippe Mourere,senior director of sales and marketing at Caliper, notes the company and Pfizerhave been collaborating for many years on various contract research programs tosupport Pfizer drug discovery and development.
As for the latest effort, Mourere explains that Pfizer hasactually selected CDAS among other organizations to partner with them for thedevelopment of cellular kinase assays.
"During the selection process, CDAS has demonstrated thevalue of collaborating with a preclinical contract research serviceorganization that already possessed a strong expertise in kinase biologythrough the offering of complete vitro servicesusing purified enzymes and the Caliper LabChip technology; a variety ofcell-based technology platforms and cell models including a wide panel of morethan 200 characterized human cancer cell lines for the aggressive developmentof physiologically relevant assays; and a large footprint of preclinical drugdiscovery services for 'one-stop-shop' drug kinase inhibitor development," he says."CDAS follows up subcutaneous, orthotopic (primary and metastasis) oncologyefficacy animal models, coupled with ex-vivotissue biomarker analysis (multispectral analysis), to expedite vivo drug efficacy screening, drugbio-distribution and PD studies of kinase inhibitors."
According to Kevin Hrusovsky, president and CEO of CaliperLife Sciences, the company is looking forward to the opportunity to collaboratewith Pfizer to develop cellular assays designed to enable better compoundselectivity, which could lead to improved drug safety evaluation.
"This new assay suite is designed to assist scientists indeveloping treatments for a wide variety of therapeutic applications withpotentially fewer side effects," he says. "The In-Cell KinaseScreen is an importantaddition to our portfolio of products and services for predictive toxicologythat are available through our CDAS contract research services division."
Mourere explains that one application of these assays is inthe area of oncology—for example, where kinase inhibitors have been used fortreating a variety of cancers.
"These drugs have led to breakthroughs for treating manycancers; however, wider use of such drugs has exposed the potential for seriousside effects due to 'off-target' activities," he notes. "Assays that measurekinase functional activity in key pathways in a physiologically relevantcellular context enable oncology researchers, as well as researchers in othertherapeutic areas, to better identify compounds that maximize drug targetselectivity and minimize potential side effects."
The specific focus is the development of a number ofphysiologically relevant in-cell kinase assays measuring the activity of akinase of interest in a cell by titrating very specifically the level of immediatedownstream-phosphorylated effector. The use of cell lines expressing endogenouslevels of tyrosine and serine/threonine kinase targets provides a betterrepresentation of the clinical setup.
With nine different kinase assays already developed thus farthrough this collaboration, the partners are well on their way to having animpact on drug development.
"There are two ways that these assays can impact a drugdiscovery process," Mourere explains. "The first one is as a hit confirmationtool following the standard cell-free biochemical screening process. Thisallows investigators to determine whether the compound is able to exert itsinhibitory effect on the target when the target exists in its native statewithin a physiologically relevant cellular environment. The second way is fordrug liability issues, and for the identification of 'off-target' activities.One of the targets in the currently available panel is VEGFR2, and testing acompound to identify any 'off-target' activity against VEGFR2 phosphorylationcould provide early indications of potential cardiovascular disease sideeffects."
Hrusovsky notes that protein kinases are key regulators ofmany 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 beenimplicated in a variety of human diseases including cancer, diabetes,cardiovascular and neurological diseases, psoriasis, asthma and rheumatoidarthritis.
"As a result, protein kinases are now considered to be thesecond most important group of drug targets and represent an important targetclass to consider for potential drug liability issues," he says. "Proteinkinase inhibitors are important not only for their therapeutic properties, butalso as invaluable research tools to study cell signaling."
Biochemical-based kinase assays are important tools toassist researchers in accelerating their lead identification and optimizationefforts while reducing costs. However, it is crucial to confirm the drug/targetinhibition and selectivity in a more physiologically relevant cellularenvironment to limit the chances of false positive or negative data in earlystages of drug development.
Mourere says the number of assays can be greatly expanded tointerrogate more kinase signaling pathways or more kinase targets in a samepathway.
"Our expertise in kinase biology and unique assaydevelopment capabilities including multiplex assays (multiple kinase targetactivities measured from the same cells simultaneously) give CDAS a uniquecompetitive advantage to develop virtually any tyrosine or serine/threonineassay," he says.
Mourere adds that Caliper is actively promoting its In-CellKinaseScreen platform of services, including custom assay development, primaryand secondary screening and functional kinase selectivity assessment.
"The strong interest generated by our recent CDAS In-CellKinaseScreen services webinar presentations is very encouraging and isgradually increasing the demand for compounds screening," he says.
Caliper partnershipwith DxTerity seeks to expand diagnostic testing
HOPKINTON, Mass.—In late October, Caliper Life SciencesInc. also announced a co-development and strategic collaboration agreement withDxTerity Diagnostics Inc., a genomics platform company.
Under their agreement, the companies will perform DxTerity'sNEAT multiplex diagnostic assays on Caliper's LabChip Dx instrument platform,minimizing sample-processing time without compromising data quality. Caliper'sfuture 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 microfluidicseparation technology and enables high-throughput multiplex analysis fordiscovery and validation of nucleic acid and protein biomarkers. The LabChip Dxsystem uses minimal sample volumes and enables automated sample processing andanalysis, providing a robust and cost-effective platform that Caliper says isachieving a high rate of adoption among diagnostic laboratories around theworld.
DxTerity's NEAT assays allow analysis of gene expression anddetection of single nucleotide polymorphisms (SNPs) directly from blood orformalin-fixed paraffin embedded (FFPE) tissue samples, virtually eliminatingcomplex sample preparation processes. Multiplex assays for up to 40 genetargets are routinely performed, delivering unique applications for clinicaldiagnostics and life science research. DxTerity's lead clinical product indevelopment is a blood-screening test that measures a patient's radiationexposure 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 cancerscreening tests based upon the gene signature panels acquired from SourceMDx.