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Steven Pelech on Developing Antibodies to Study Protein Kinases

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At A Glance

Name: Steven Pelech

Age: 47

Background: Founder, CEO, Kinexus Bioinformatics, 1999 - present.

Founder, CEO, Kinetek Pharmaceuticals, 1992 - 1998.

Professor, Department of Medicine, University of British Columbia, 1997 - present.

Postdoc in Edwin Krebs’ lab, University of Washington, Seattle, 1983 - 1987.

Postdoc, Philip Cohen’s lab, University of Dundee, Scotland, 1982 - 1983.

Postdoc and graduate student, Dennis Vance’s lab, University of British Columbia, 1979 - 1982.

 

How did you get into developing antibodies for protein kinases? Did you always work with antibodies?

I’ve always had an interest in protein kinases. My PhD research was done in the University of British Columbia, working on the regulation of lipid metabolism — phosphatidylcholine biosynthesis — and what happened was it turned out that enzyme CTP phosphocholine cytidylyltransferase is the rate-limiting enzyme for the synthesis of phosphatidylcholine. It turned out to be phosphorylated, so I did a lot of the early work on the first phosphorylation of that protein. Surprisingly, I’ve been doing an analysis of the human phophoproteome recently, and it’s one of the more heavily phosphorylated proteins that’s been described in the scientific literature. This was about 1980. I was fascinated by the prospect that there were kinases themselves that themselves might be phosphorylated and regulated. So it didn’t take very long to think that there might be networks of protein kinases.

What led to you starting your own protein kinase antibody company?

So then what happened was there was an opportunity for me to set up my own laboratory back in Vancouver at the Biomedical Research Center at the end of 1987. Around 1990 we were starting to make antibody probes for a number of the protein kinases since we knew already at that point what their gene sequences and primary structures were. We would make antibodies in rabbits. We had some of the first antibodies ever made against things like MAP kinases. And I was contacted by Upstate Biotech Technology, a small company out of Lake Placid. They had heard that we had some antibodies against protein kinases, and we actually started to sell some of our excess antibodies through that company. And then, there’s always politics — some of the scientists at the institute I was in were upset that we were doing what was perceived as commercial activities, even though the revenues were actually coming back to the center, so I was basically told that I had to do that activity elsewhere. So I actually started a biotech company called Kinetek Pharmaceuticals, and the idea was that we initially had revenues from the production of antibodies and enzymes that were sold initially exclusively through Upstate Biotech. And it was actually a pretty profitable business because what we did was we took the profits that came from the sale of our antibodies and made more antibodies. Eventually we were producing about 100 different antibodies against protein kinases. And I think it was facilitating a lot of the early research in this area because Upstate was really one of the first companies to have such a range of these protein kinase antibodies. And then I convinced Upstate that they should be getting into selling enzymes — the actual protein kinases. So a lot of the protein kinases were purified from the starfish oocyte system and they were sold through Upstate, and it’s actually a very successful product line for Upstate because I think they can track now more than 140 different kinases in doing specificity panels for looking for drugs that are inhibitors for these kinases to ensure that they’re specific. They provide that specificity screening to the pharmaceutical companies today. But all that original work of selling enzymes and using enzymes all came from our academic collaboration and then the Kinetek work with them. They were used primarily for Western blotting and immunoprecipitation purposes.

What happened to the company after that?

We made a decision to transition the company into a drug discovery company, and the investors decided that we should dissolve ourselves of the reagent business and focus our energies into looking for inhibitors of protein kinases, which is what we did. I guess I was the founder, president and CSO of Kinetek for about six years. When I left the company, it had about 50 employees. We were ready to go public, actually. And then we brought in this guy from a pharmaceutical company. Unfortunately, the story there was as usual politics, and the company went some directions that I didn’t particularly like myself, but I really had no control of the company at that point. So the sad side is when I left the company about six years ago, it probably had a valuation of pretty close to $40 million, and they actually were successful in doing a financing about three years ago that would’ve raised the value of the company closer to about $80 million. And then they recently sold the company in the end of March for $3.6 million. So they ran the company to the ground. They ran out of cash.

What did you do after you left Kinetek?

What happened after that was I had an idea for another company. I was really fascinated by how all these protein kinases interact, and I believed that if you can map the protein kinase pathways then in a sense you’re probably mapping the disease pathways, because most of the common diseases in aging involve defects in protein kinase signaling systems. There’re over 400 different diseases that link to defects in kinase pathways, of which cancer is only one example. The thought was that if you take a look at the 518 protein kinases that are predicted, for more than half of them we have no reagents to study them at the protein level at all. There are companies that sell antibodies that claim to look at these proteins, but in fact they’re not validated antibodies and I would say 80 percent of the time they don’t actually work. And I can say that because when I started Kinexus five years ago, the concept was that we were going to try to map these pathways, and we were going to do this in a way that was totally different from what anyone had tried before, and the frustration of being a researcher in this field is the research proceeds based on the tools that are available. I had made about 100 protein kinase antibodies previously which I had access to, and so that was a start to do the analyses, but we needed to look at more of these protein kinases simultaneously. So the idea was let’s go out there and test as many of the commercial protein kinases that we can procure. And so to date, we’ve probably done more than 600 protein kinase antibodies, but we’ve also tested additional antibodies and phosphorylation site-specific antibodies. Probably close to 2,500 antibodies now. So our experience is that 80 percent of the pan-specific antibodies — those are the ones that pick up both the phosphorylated and dephosphorylated forms of proteins — are non-specific and impotent. They don’t actually work. They’re not suitable to use for research purposes in crude cell lysates anyways. With phosphorylation site-specific antibodies, the success rate is closer to 40 percent. Sixty percent of the [phosphorylation-specific] antibodies that we test fail our test. So the idea was ok, we first developed and identified the best probes that are commercially available, including our own. Then how can we improve the ability to track as many proteins as possible on one single gel? So we developed a multi-blotting process. We can now track as many as 50 target proteins on one mini-gel, and that was the basis of the service that we created. Because the other component of our business plan was to offer a service where the clients send us their different experimental model systems —different tissues and cells that have been treated with drugs and hormones and are in different disease states — as much diversified experimental material, both human and animal, that we could go and interrogate that material for the expression levels of these protein kinases. At this point our company contracts well over 150 different protein kinases. That’s still only about less than a third of the human proteome, but it’s more than anyone else can do at this time.

We’ve been doing this for the last five years, so we have about a million data points in hundreds of different model systems. So this is actually what you would call a real functional proteomics database.

How do you plan to promote the database?

The first plan we have for the database is that we’re going to be putting that information online early next year so that people will be able to through the internet, at the Kinexus website, for a subscription fee that could be in the range of about $1,000 per year, be able to probe that database anytime to get different answers. This will actually pull the data from the database and create a data table to answer your specific query.

What other services does your company provide?

Right now, we charge about $750 to track 700 different protein kinases. We’ll do all the analyses and give back to the customer pictures of the immunoblots, plus quantitative data with linearity. We don’t sell the antibodies to them. We do the analysis for them within three weeks. If they see changes in these proteins, they contact us and we tell them where we sourced the antibody from. Then they can go and follow-up with the same antibodies. We don’t sell the antibodies. We’re strictly an information company.

How many customers do you have?

We’re close to 500 labs now — about 100 companies and 400 academic labs. As more people use our services, our database grows faster. We think there’s at least 150,000 scientists out there involved in cell signaling research that could benefit from this kind of knowledge.

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