Ablexis Maps Out New Antibody Drug Strategy with $12M From Third Rock, Pfizer

Antibodies that can zero in on specific diseased cells are some of the biggest-selling and fastest-growing fields in all of biotech. Yet after three decades of R&D, if you talk to people who try to discover these things, they’ll tell you it’s a long and risky slog to get any good candidates for clinical trials. San Francisco-based Ablexis is betting that it has created a more effective way to generate promising antibodies, and revamped its business model to try to generate real cash.

The company made some news earlier this month when it attracted a $12 million financing from Boston’s Third Rock Ventures and New York-based Pfizer Venture Investment. The Third Rock team, which consists of well-known biotech executives like Mark Levin, Bob Tepper and Cary Pfeffer, is doing their usual roll-up-the-sleeves-and-get-involved routine along with CEO Larry Green, a co-inventor of a pioneering antibody discovery technique of years past, the Abgenix Xenomouse. I heard more about the company’s strategy during a chat with Green when I was in San Francisco a couple weeks ago to prepare for the launch of Xconomy San Francisco.

The idea of antibody drugs that can specifically zero in on diseased cells, while mostly sparing healthy ones, has captivated the imagination of scientists and biotech investors since they were first discovered by Georges Kohler and Cesar Milstein in 1975. It took more than two decades for the idea to be translated into real products. But over the last decade, antibodies have become one of the backbone technologies of the life sciences industry. The antibody drug market was expected to generate $30 billion in worldwide sales in 2009, with an annual growth rate of 14 percent through 2012, according to Datamonitor.iStock_000003186804XSmall

But there have always been major technical challenges with these Y-shaped proteins. The earliest engineered antibodies came from mouse DNA. When these drugs were injected into people, the human immune system often identified them as foreign, creating severe side effects. That gave rise to years of effort to “humanize” the antibody drugs, so they wouldn’t provoke a nasty immune reaction. The work of companies like Protein Design Labs, Abgenix, and Medarex who plugged in certain snippets of human DNA to make these drugs more palatable became one of the key enabling technologies underpinning many of today’s successful antibodies, like Roche’s trastuzumab (Herceptin) for certain forms of breast cancer.

But Ablexis, Green says, still sees plenty of room for improvement and a major business opportunity for anyone who can seize it. Many of the prior “humanization” technologies have been acquired by big drugmakers who have made it more difficult for them to be widely used throughout the industry, Green says. And the existing technologies often force highly-skilled molecular biologists to do all sorts of tinkering with the antibodies to make them “humanized,” which can often introduce new characteristics into the antibodies that make them less potent binders against the desired targets. That’s a serious problem, because if a drug isn’t potent enough, its less likely to work at the desired doses.

Green was pretty coy when I pressed him about exactly what Ablexis is doing that’s new and truly innovative. It is clear that Ablexis is creating genetically modified mice that are intended to churn out a wide diversity of fully-human antibodies against a certain target. Instead of creating these antibodies in a lab dish, or even something futuristic like on a computer, the product that Ablexis sells to Big Pharma customers is an actual mouse. These mice, in all the vast complexity of their live immune systems, will be able to offer a better guide to antibody discovery teams as they try to pick candidates that are likely to pass the gauntlet of clinical trials required by the FDA before a drug can be sold in the U.S.

“The great thing is by putting the human genes in the context of an in vivo immune response, especially like the one of the mouse which is remarkably similar to humans, you get to harness a very efficient process that’s evolved over millions of years to ward off life-threatening things,” Green says. “It has to move fast. It has to be efficient. It’s possible to get high quality antibodies out of these systems in a short time.”

Third Rock, which likes to talk to innovators about compelling concepts before it invests, says it heard repeatedly from scientists that there’s a need in the marketplace for a new genetically modified mouse that can efficiently pump out antibody drug candidates. Barbara Dalton, vice president of venture capital at Pfizer said in a statement earlier this month, “We expect that Ablexis’ innovative transgenic mouse platform will fulfill a strategic need for many companies like Pfizer.”

There are a number of competitors out there, like Lebanon, NH-based Adimab, which uses a fast-dividing yeast platform to churn out antibody drug candidates for Big Pharma customers. Germany-based MorphoSys is another. Green’s former company, Fremont, CA-based Abgenix, could have been considered one before it was acquired by Amgen back in 2006.

Green is a first-time CEO at Ablexis, but he goes way back with the Third Rock crew. Green was one of the scientists at Cell Genesys when that company spun off Abgenix, a transaction back in the early 1990s that Third Rock partners Mark Levin and Bob Tepper were involved in, Green says. They helped guide not just the investment, but the new strategy of Ablexis, which used to be called Aliva Biopharmaceuticals. The company dropped the biopharmaceuticals from the name, because it’s not focusing on drug development, but on doing partnerships with big drugmakers that want access to its technology.

Ablexis just really came out of stealth mode, so there aren’t any big deals to talk about yet. “Our focus for the foreseeable future is in creating these mice and monetizing them,” Green says. When I pressed him for details on how the Ablexis technology stacks up with the competition on speed, cost, and reliability, he said all those things are confidential at the moment.

He did say that he’s got a record of success to build on, however. Other technologies which depend on picking antibodies that bind with cell targets in lab dish haven’t performed as well over time as those from genetically modified mice. He counts six such antibodies that come from these mouse models, including Amgen’s latest expected blockbuster for osteoporosis, denosumab (Prolia).

In fact, Green couldn’t resist telling me the anecdote about how he woke up on the morning of June 2 to read a congratulatory e-mail from a colleague who told him about the FDA’s approval of denosumab. The product relied on the Abgenix Xenomouse technology, which Green had a hand in creating years ago. That was an extra dose of good news, because it was the same day Ablexis announced its $12 million financing. If Ablexis’ technology is really a step ahead, then there should someday be more big drugs that arise from its platform, like denosumab.

“Our goal is to put our mice in the hands of the best antibody drug discoverers, and let them be creative,” Green says. “We want to let them discover drugs.”

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