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AB Sciex and University of Melbourne Partner on MS Workflow Studying Biopharmaceutical Metabolism

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By Adam Bonislawski

AB Sciex and researchers at the University of Melbourne announced this week a collaboration to develop a new mass spectrometry-based technique for studying the metabolism of protein-based biopharmaceuticals.

The technique, which is being developed on AB Sciex's QTRAP 5500 and TripleTOF 5600 machines, could allow drugmakers to more comprehensively track the metabolism of their biopharmaceutical agents in vivo, improving studies of their efficacy and safety, Anthony Purcell, associate professor at the University of Melbourne and the project's lead scientist, told ProteoMonitor this week.

The method involves uniformly labeling a protein biopharmaceutical of interest with the isotope N15. After the biopharmaceutical is metabolized, researchers take plasma or other tissue samples and use mass spec to search for low-mass ions containing N15. They then use these N15-containing ions to trigger precursor ion scans, allowing them to identify any compound that has incorporated an N15-labeled amino acid.

"It's almost like radioactively labeling the whole [biopharmaceutical] compound and being able to trace all the heavy atoms that come from the pharmaceutical we've introduced and being able to identify what all those compounds and metabolites are," said Purcell.

Current methods of studying biopharmaceutical metabolism typically rely on predictive approaches with researchers looking for expected metabolites or techniques using antibodies to pull out parts of the introduced biopharmaceutical after it's been metabolized.

Metabolite analysis is further complicated by the fact that biopharmaceuticals are typically based on compounds found naturally in the body, meaning that there may only be a few amino acid sequences unique to the drug.

The approach Purcell is developing allows scientists to isolate all of a compound's metabolites, whether or not they've been predicted, and also allows researchers to isolate and identify metabolites that aren't necessarily unique to the drug under investigation, he said.

"We can look down to the next level now and ask what are all the metabolic products derived from this material because we know that all the metabolites will contain at least one of these N15 molecules that we've introduced," he said. "We can take it to a new level where there are no assumptions made. I think we're going to get some nice data coming out of this that will show that even for drugs we think we know well, there will be new metabolites we simply haven't anticipated."

In fact, Purcell noted, his group currently has a paper under review in which they used the N15-labeling technique to demonstrate that the brain protein alpha-synuclein is metabolized differently when injected as a vaccine compared to when it is functioning naturally.

"It really highlights how this technology can rapidly highlight these metabolic differences and then you can go into the data and actually pull out what those [differing] compounds are," he said.

Access to this sort of data could both improve and complicate drug companies' biopharmaceutical development work, Purcell said. While more complete metabolic data could be useful in optimizing their products, regulators could also begin demanding that more comprehensive metabolic data be included in submissions.

"Just looking at what's happened over the last 20 years in terms of getting [US Food and Drug Administration] approval, the bar has been raised several times, and I think that with technology like this the bar may be raised [again]," he said. "But one would hope that the bar would be raised and the result would be more effective drugs."

Purcell said that his team has entered into "preliminary conversations" with several drug companies regarding the technique and was "looking to enter into a collaboration in the fairly short term."

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Dominic Gostick, director of biomarker mass spectrometry at AB Sciex, told ProteoMonitor that its pharmaceutical customers had likewise responded to news of the workflow with interest.

"This is something that they've been doing on the small-molecule side, but up to this point people haven't had the ability to do this from a large-molecule perspective," he said. "They could certainly see that it could be a useful toolkit for them."

Prior to signing the collaboration agreement this week with Purcell's team, AB Sciex had tested the workflow with a "very limited number of people just to get a sense from the [pharmaceutical] industry as to whether we were on the right path," Gostick said.

With the agreement in place, the company now "plans to go back to many more of our customers more directly to see how this fits in with their workflows," he added. "We think obviously that there is a potential here that could in the future be part of development for biological drugs. If that's the case, then obviously this becomes a very interesting technology, and that's clearly what's fueled our interest in collaboration."

As for potential regulatory implications, Gostick said he didn't want to "get too drawn on the regulatory aspects of it, but clearly that's the other angle."

Claudia Gutjahr-Loser, head of corporate communications for German pharmaceutical company MorphoSys, told ProteoMonitor that the technique sounded like a potentially promising tool for biopharmaceutical development.

"Sometimes, you inject an antibody in a patient and it disappears very fast, and you don't know where it goes," she said. "It could have been internalized, it could have been degraded – it's very difficult to find out what happened."

Current techniques for tracking the metabolism of biopharmaceuticals, such as radiolabeling of antibodies or performing immunohistochemistry on tissue samples, "don't really give you the answers you need," she added.

According to Purcell, the next step in the development of the method is building software tools to streamline the process.

"We've developed an in-house capacity to do this work, and what we're looking at now is [developing] more tools in the bioinformatic area to really fast-track interpretation of the data and potentially also making some firmware improvements in the QTRAP instrument just to make things work a little more smoothly," he said.

So far, Purcell has been developing the workflow on AB Sciex's QTRAP 5500 instrument; however, he recently spent several days with AB Sciex representatives exploring the possibility of developing it for the TripleTOF 5600 machine, which the company introduced this May at the American Society for Mass Spectrometry annual meeting (PM 05/28/2010).

He noted that the 5600's high mass accuracy and scanning speed make it attractive as a discovery platform, but that the 5500 might still work better for the targeted MRM analysis of the various metabolites.

The method could potentially be applied to other platforms as well, he said.

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