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.

Nic­ki Thomp­son

“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.

Alessio Ciul­li

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.”

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Despite rapid advances in the field of immuno-oncology that have transformed the cancer treatment landscape, many cancer patients are still left behind.1,2 Not every person has access to innovative therapies designed specifically to treat his or her disease. Many currently available immuno-oncology-based approaches and chemotherapies have brought long-term benefits to some patients — but many patients still need other therapeutic options.3

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Fangliang Zhang (Imaginechina via AP Images)

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