Predicting adverse events: Odyssey Thera, UMontreal develop cell-based assay

Randall C Willis
STORY UPDATES
MONTREAL—April 10, 2007—Signal transduction specialist Odyssey Thera announced it has leveraged its protein-fragment complementation assay platform into a third drug discovery collaboration with Abbott Laboratories. Financial details were not disclosed.
SAN RAMON, Calif.—June 20, 2006—Odyssey Thera announced the granting of U.S. Patent No. 7,062,219 by the USPTO, covering single- and multi-color protein-fragment complementation assays (PCA) in drug discovery. The broadly phrased patent provides methods for constructing and applying diverse live-cell assays that will allow scientists to monitor changes in protein complexes and biomolecular pathways via automated, high-throughput, high-content screening. Co-signatory on the patent is Dr. Stephen Michnick of the University of Montreal, who invented the PCA technique.
 
 
SAN RAMON, Calif.—In a recent Nature Chemical Biology, scientists at Odyssey Thera and Quebec's University of Montreal described a high-throughput assay to test for unusual or unexpected side effects of various drugs in living cells. If widely applicable, the assay should help drug developers prevent adverse drug events that cost the global healthcare system billions each year.
 
According to Dr. John Westwick, Odyssey president and CSO: "The FDA critical path white paper Innovation or Stagnation? estimated that even a 10 percent improvement in predicting failures before clinical trials would save $100 million in development costs per drug."
 
The high-content protein-fragment complementation assay (PCA) was first developed by Dr. Stephen Michnick's group at the University of Montreal. In PCA, fragments of a fluorescent reporter protein are linked to various pairs of proteins involved in metabolic pathways. The interaction of these proteins in the cell can then be monitored by changes in fluorescence. If the interaction is perturbed, such as with a small-molecule drug candidate, then the fluorescence pattern changes.
 
According to Michnick, it was critical that these changes be monitored in the native environment of the cell. First, it is simpler and more reliable to study protein interactions in cells because it is nearly impossible obtain the appropriate biological conditions in vitro. And secondly, he says: "Many of the changes in protein complexes that are induced by perturbations are not simply increases or decreases in the quantities of these complexes, but also changes in the location of complexes; often it is these latter that are the most biologically relevant."
 
"We are all wrestling with the $800 million question," Westwick explains. "How can we make drug discovery an economically viable process? Vioxx and other withdrawn drugs are foremost in everybody's mind, but in most cases it is the poor success rate of the routine discovery process that is driving the costs to unsustainable levels. The farther along the development chain the failure occurs, the higher the cost of failure.
 
"Obviously we'd all like to identify failures at an earlier stage of the process. Off-pathway or off-target drug effects are generally to blame for the failure of targeted therapeutics. And one truism we can note after looking at thousands of drugs is that every compound has some level of off-target activity, so we need good methods to broadly assess the level and nature of compound activity in the cell."
 
Odyssey Thera has already incorporated the assay into its own drug discovery efforts in the area of oncology, and according to Westwick, company scientists now gain more knowledge in a few weeks than they used to get in a few years using traditional methods.
 
He also states that the company is getting a lot of attention from top-tier pharmaceutical firms that are looking to form drug screening partnerships.
 
As for Michnick, his group is looking at how they might be able to scale up the number of interactions analyzed in a single assay. "On a practical level, the work described is forcing us to think about economies of scale," he says. "We can bring down the material costs and time to achieve what was described in the paper, so that very large screens could be performed for a moderate cost."

Randall C Willis

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