Xencor’s 20 Year Journey in Antibody Therapeutic Development
Bassil I. Dahiyat, Ph.D., president and CEO of antibody engineering firm Xencor
Innovation in antibody design is about identifying therapeutic opportunities, being willing to invest in new technology, and, most importantly, forging the right partnerships.
Bassil I. Dahiyat, Ph.D., president and CEO of antibody engineering firm Xencor, shared this market view at the Antibody Engineering and Therapeutics US conference in San Diego, Calif. He told delegates that collaboration has been a focus for the firm since day one.
“We’re developing our own internal pipeline of drugs, currently focused in mostly oncology, but also autoimmune disease,” Dahiyat said.
“But because of the nature of the technology we develop, we do a lot of partnerships. And it’s based on our work building FC domains and using that as the basis for trying to create differentiated drugs.”
FC domains
For the uninitiated, the FC domain is the part of the antibody that does not vary much, unlike the fragment antigen-binding region (Fab), which is different on each molecule.
At Xencor, this near ubiquity of the FC was a big draw, according to Dahiyat, who said, “The beauty of FC domains that really resonated with us is that they are constant, roughly for all antibodies. And so it occurred to us, if you make a better FC domain, you could use it. A lot of times that was really the central drive for us to go into FC engineering.
“So we went all in on it — even as early as 2003 when we were a tiny company — really trying to figure out how to use protein engineering tools to make interesting drugs.”
According to Dahiyat, the first technology Xencor developed, an engineered FC that bound CD16 and CD32 receptors more tightly than the “wild type” molecule, quickly attracted industry interest.
“So within a year and a half of this data we’d put four small deals into the bank and proved to our investors we should still be alive,” he said.
Half-life extension
Xencor had a similar experience with a half-life extension tech, which makes therapeutic antibodies last longer in circulation, according to Dahiyat, citing its ULTOMIRIS partnership with Alexion (now owned by AstraZeneca).
“It [the technology] took ULTOMIRIS from an every-other-week dosing schedule to every other month. Because of the use of this half-life extension technology and a tweak they did in the variable domain to drop the antigen at low pH in the lysosome, they are getting 40, 50-day half-lives in humans,” he said.
And demand for half-life extension is likely to increase, according to Dahiyat, adding “there’s been an entire cottage industry springing up of new companies whose entire purpose is to make long-acting versions of either recently validated antibodies.”
Plug and play
The deals — and others Xencor has formed for its more recently developed bispecific antibody technology — underline the value of developing modular technologies that have multiple potential applications, Dahiyat said.
“The plug-and-play approach lets you really expand the pipeline and have other people pay you while you figure out how to do things internally.
“And other very successful antibody companies have managed to sing this song. And it’s a model that I think is important for any tech company in biotech to understand how you fit in,” he said.
Dahiyat added, “This is how technology, just simple engineering tools, when you pull them together can really start opening the door to new biology. That’s really why we’re here.”
Outlook
According to Dahiyat, technology and collaboration will continue to shape the antibody therapeutics market. “It always comes down to engineering tools because that opens the door to new biologies.
“I think things like long, half-life bispecific are just at the beginning of what they’re going to do. As we now know how to play with affinity and formats and we can make these things and try them out, their adoption curve is going to explode,” he said.
“I think multispecifics are still very complicated, but they will eventually emerge.
“And of course I have to mention, at least in passing, antibody drug conjugates. Again, they are really expanding and are going to replace chemotherapies,” Dahiyat said.
