Another protein degradation biotech emerges, with the promise of a new approach from an old hand
The money keeps pouring in for protein degradation.
A field that six years ago had the financial equivalent of tumbleweed is now flush with cash. Last month, a pair of biotechs, now backed with big pharma and big biotech deals, landed a total of $222 million in funding on consecutive days. And in October, Plexium launched out of San Diego with $28 million in Series A financing and a promise for a different approach to a barely adult field.
The newest addition comes out of Scotland and a former fellow of the field’s godfather, Alessio Ciulli. Ciulli has for the last couple years been helping incubate the company, known as Amphista, in his lab at the University of Dundee, until last October, when Amphista moved to their own lab outside Glasgow. Today they announced a $7.5 million Series A – with the promise of a larger Series B later this year – but they’re keeping the specifics of the technology close to the vest.
“I can’t go into too much detail about exactly how we’re doing this,” CEO Nicola Thompson told Endpoints News. “What I can say is that with our novel approach and our novel bifunctional molecule and our degrade-inducer warhead, we’re independent of the traditional approaches.”
Meaning that Amphista works differently — however they define differently — than protein degradation has so far, quite possibly by using a few different proteins.
In 2001, Craig Crews and Raymond Deshaies published a paper in the Proceedings of the National Academy of the Sciences explaining how you could use a molecule to take disease-causing protein and basically shoot it directly into the body’s garbage disposal system.
The molecule, called PROTAC or proteolysis-targeting chimera, looks like a dumbbell. On one side are atoms that bind to the protein researchers want to remove. On the other side are atoms that bind to a protein known as an E3 ligase. The E3 ligase sends the targeted protein to a molecular shredder. One of the advantages of such an approach over traditional small molecules and antibodies is that it doesn’t require an active site; you can use it to drug troves of the previously inaccessible proteins and the diseases they caused.
Protac-1, as the prototype was called, was too large to work as a drug in humans. But in 2012, with funding from GlaxoSmithKline, Crews, his grad student and a former fellow in his lab – Ciulli – found a small molecule binder for an E3 ligase called von Hippel–Lindau disease tumour suppressor, or simply VHL. The next year Crews founded Arvinas, which in 2019 became the first company to bring a protein degrader into the clinic, and a host of biotechs and large drugmakers soon joined the game.
These biotechs and pharma companies, though, almost exclusively use VHL or one of three other E3 ligases, out of the hundreds that exist in the human body. A major goal of the field has been to expand that short list of usable ligases, and with them, the potential of protein degradation as therapy. That appears to be where Ciulli and Amphista step in, although it’s unclear.
“We’re independent of the traditional E3 ligases that are used commonly by the field,” Thompson, who previously worked in drug discovery and business development for Roche and GSK, said. “We don’t use those E3 ligases.”
Asked if they used other E3 ligases, Thompson declined to comment.
The idea, Thompson said, is that using their approach they’ll be able to overcome some issues recently seen with the current ligases, citing resistance mechanisms.
The company will start in oncology, with plans to announce an initial target later this year. Amphista now consists of 10 employees, primarily biologists and chemists, working out of a lab in BioCity just outside of Glasgow, although Thompson declined to answer if work was being done at the lab amid the Covid-19 pandemic.
“We are having to think about working differently,” Thompson said. “At the moment, I’m not seeing a big impact on our overarching timelines.”