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New company develops cancer-fighting antibodies

by CIFAR Jan 29 / 15
For CIFAR Senior Fellow Jason Moffat, years of research have spun into what he calls “a geneticist’s dream” — the ability to engineer synthetic antibodies for fighting diseases such as cancer — and a company to get those drugs to patients.

The antibody (blue and red) binds the KIT receptor (green), which is a receptor for stem cell factor (light blue). This leads to inhibition of KIT signalling which drives certain cancers.Image courtesy of Dr. Sidhu (TRAC) in collaboration with Dr. J. Schlessinger and Kolltan Pharmaceuticals.

Moffat and other scientists have founded a new Canadian biotech company called Northern Biologics, securing $10 million in investment funds from the U.S. venture capital firm Versant Ventures. The company will develop drugs that treat cancer and fibrosis.

Their gold mine is a collection of billions of synthetic antibodies that are each designed to rapidly identify individual antibody “nuggets” that can be further developed. Antibodies are naturally occurring molecules, which our bodies manufacture to eliminate viruses and other pathogens. Synthetic antibodies are built from scratch in the lab using nature’s rules, and can easily be altered, copied and scaled-up to produce biotherapeutics. Since synthetic antibodies mimic natural antibodies, these biological drugs are less likely than traditional chemotherapies to cause toxic side effects in patients.

“Antibodies have been shown to be really good drugs,” says Moffat, a professor at the University of Toronto and a senior fellow in CIFAR’s program in Genetic Networks. “People accept them now. That wasn’t the case 10 to 15 years ago.” Antibodies now account for many of the top selling drugs worldwide.

The effort has involved years of research on understanding the fundamental mechanisms that govern the behavior of our cells. One of Moffat’s goals is to identify what is known as the set of “essential genes” in humans. These are genes that are vital for cells to grow and divide, and are often de-regulated in disease. Cancer, for example, is characterized by mutations in the genes, leading to deregulated cell growth.

Moffat’s lab grows cells in dishes and observes their growth and division under various conditions. He engineers mutations and turns genes on or off to discover which genes and proteins are essential for a given type of cancer to grow. Then, he homes in on the antibody targeting space — key proteins that are expressed on the surface of cancer cells.

Advances in technology have made it possible to engineer antibodies that target these cell surface proteins. Researchers build libraries of billions of synthetic antibodies, then test and refine them until they have molecules that can successfully latch onto and kill disease cells. “The interesting thing about antibodies is that they can work directly on diseased cells, but also recruit our natural immune system to fight off disease. By using antibodies to treat disease, we are learning an enormous amount of basic biology at the same time,” Moffat says.

Sachdev Sidhu, one of Northern Biologic’s founders, developed the library of antibodies from which the company will make its drugs using a technique called phage display. Sidhu, who has been a guest at CIFAR’s Genetic Networks meetings, came to the University of Toronto from the pharmaceutical company Genenetch in 2008. He says the science is much the same, but there are differences working in academia.

“The big difference here is we have a lot more collaborations outside of the lab, which is a big advantage,” he says.

Collaboration between Moffat, Sidhu and others including fellow Northern Biologics founders Brad Wouters, Ben Neel and Rob Rottapel (all Princess Margaret Cancer Centre) was central to propelling this science toward industry. CIFAR senior fellows Charles Boone and Brenda Andrews (University of Toronto) collaborated on a Genome Canada grant that led to the foundation of the Toronto Recombinant Antibody Centre (TRAC) at the University of Toronto’s Donnelly Centre in 2010. Andrews says TRAC enabled scientists to build relationships with industrial partners, and the fundamental biology underlying TRAC and Northern Biologics charted the course to business.

“This is a great example of basic research laying the essential foundation for practical applications,” Andrews says.

Moffat agrees, adding that powerful new technology has made it easier to envision applications from the outset. “Science is no longer, ‘Find a cool thing, publish a paper;’ we can bring many of our discoveries very far down the road if we are organized.” Northern Biologics represents a boost to the Canadian biotech sector at a time when scientists say the industry is moving away from small molecule drugs, such as chemotherapy, and more toward biologic drugs.

“They’re downsizing a lot of their medicinal chemistry efforts because frankly, making drugs the old-fashioned way is really slow, cumbersome and expensive,” Moffat says. Small molecule drugs, such as those used in chemotherapy, can take two decades to develop and produce with a team of chemists, he says. By contrast, Northern Biologics aims to be in phase 1 clinical trials about four years from now.