Pharmaceutical companies are increasing their usage of cell-based assays to determine what effect — positive or negative — their lead compounds have on a variety of cell types.
In some cases, pharmaceutical companies have the expertise to develop such assays in house, but some have begun to look for outside partnerships with companies that specialize in developing cell-based assays and high-throughput screening processes.
Seizing on this trend, Odyssey Thera, of San Ramon, Calif., has recently signed a number of agreements with major pharmaceutical companies based on its protein-fragment complementation (PCA) and other assays.
On April 8, Odyssey announced that it had signed an agreement with F. Hoffman-La Roche to profile certain Roche compounds with a variety of Odyssey’s cell-based assays. The goal of the research will be to characterize the mechanism of action and pathway activity of these compounds.
It was the fourth such deal Odyssey struck with a major pharmaceutical company in the last six months. Two of these have been made public, while two are still unannounced. The other known agreement, announced in November of last year, was made with Pfizer. Financial terms of the deals also have not been disclosed.
The foundation of the company’s technology lies in intellectual property developed several years ago by Stephen Michnick of the University of Montreal, for which he was awarded US Patent 6,270,964 in Aug. 2001. The patent covers the PCA technique, in which fragments of a reporter protein — for instance, a fluorescent protein — can be separately expressed with proteins that are known to interact. If the known protein interaction is part of a disease pathway, then the reporter protein becomes a convenient way to tell whether a particular compound is having an effect on that pathway.
Since that time, two additional US patents have been issued for specific applications of the technique in drug screening. Like many other cell-based assay companies, Odyssey also conducts a variety of other cell phenotype assays to assess the overall reaction of a cell to a given compound, because a desired effect all too often has peripheral undesired effect associated with it.
“The idea is that even a very specific compound against a protein target is never 100 percent specific when it hits a cell,” said Odyssey president and CEO Marnie MacDonald. “It can contact other proteins, and inhibit other enzymes or targets.”
According to MacDonald, the company uses a variety of techniques to analyze the results of all of its assays, including automated microscopy, well-plate scanning, and flow cytometry. “In most cases we do fluorescence image analysis,” MacDonald said. “We use whatever analysis method is most efficient and most cost-effective.” She added that Odyssey uses a variety of off-the-shelf instrumentation from several companies to conduct the analyses.
Odyssey also guards proprietary image analysis algorithms, which are used to provide meaning to the scores of data points being generated by PCAs and other assays. The high-throughput potential of the assays, MacDonald said, lies partly in these algorithms, partly in the instrumentation being used, and partly in the PCA assay itself.
“It starts all the way with a large full-length human gene collection which allows us to express tiny amounts of proteins in these cells that are tagged in such a way that we can generate these fluorescent signals,” she said. “It is high-throughput sub-cloning, quality control, and transfection. The drug treatments are done with automated systems and robotics. The images are automatically analyzed… so the entire process is high-throughput starting from the very beginning.”
Known and Unknown
According to MacDonald, the compounds being profiled in the recent agreements are all oncology related, though she didn’t specify in which areas. She was also quick to point out that the Odyssey platforms are not limited to oncology.
“This type of analysis can be applied to any disease area,” she said. As an example, she mentioned an ongoing unannounced partnership with a pharmaceutical company in the area of metabolic disease.
Odyssey is not just in the business of signing agreements with pharmaceutical companies, as it also conducts its own drug discovery research, albeit with a slightly different goal than most of its partners.
“Unintended or surprising effects of drugs can have either negative or beneficial consequences,” MacDonald said. “So in the case of a lead compound, that kind of effect might be something that you don’t want to have happen.”
“On the other hand, we’re using this to identify new indications for known drugs” she added. “So we’re taking known drugs and screening broadly using this approach across cancer pathways, and we’re identifying completely surprising effects and activities of known drugs… and taking those through to oncology clinical trials. So we’re reindicating known drugs.”
Currently, Odyssey’s drug development pipeline is focused on only these known drugs, but the agreements with pharmaceutical companies are all for the purpose of lead optimization.
The company’s assays are also tailored for even more cutting-edge therapeutic approaches — for example, siRNA. Last year, Odyssey formed an alliance with an siRNA reagent provider, Lafayette, Colo.-based Dharmacon, as reported by RNAiNews (see RNAiNews, 9/19/2003), a sister publication to Inside Bioassays. The crux of that agreement was to develop a system of using siRNA to measure the inhibition of cellular signaling pathways associated with angiogenesis, apoptosis, and inflammation.
Although there are several competitors to Odyssey in the cell-based assay business, there aren’t really any for the specific PCA application. “In general, the major competitors there would be microarrays,” MacDonald said. “However, what you get with a microarray is a consequence of the pathway activity, resulting sometime later in the change in transcription of a number of genes, and it’s very difficult to sort back to the mechanism of action that caused that… change.”
“All the pharmaceutical companies are already doing that in-house,” she added. “So we’re competing against the historical paradigm, if you will, of the last five to ten years where people try to do these things using microarrays.”