Johns Hop­kins spin­out spot­lights a show­case an­i­mal test for an­ti­body-lig­and I/O traps — match­ing check­points with a rein on Tregs

With the block­buster pop­u­lar­i­ty of PD-1/L1 check­points chang­ing the way tu­mors are treat­ed around the world, the spot­light in re­search has shift­ed away from the suc­cess­ful though lim­it­ed and some­what crude first gen­er­a­tion of these ther­a­pies to new ways to amp up their ef­fi­ca­cy and dura­bil­i­ty.

One of the key hur­dles, in­ves­ti­ga­tors have found, is the gen­er­a­tion of reg­u­la­to­ry T cells — Tregs — that sup­press the im­mune re­sponse to can­cer cells. And now a re­search team at Johns Hop­kins led by At­ul Be­di, a prac­tic­ing on­col­o­gist and as­so­ciate pro­fes­sor at Johns Hop­kins Uni­ver­si­ty School of Med­i­cine, say they have de­vel­oped an an­ti­body/lig­and with a bi­fur­cat­ed war­head that can do a bet­ter job on the check­point side while blunt­ing the Tregs that both pre­vent ef­fi­ca­cy as well as help trig­ger a grad­ual loss of po­ten­cy, lead­ing to re­cur­rence.

Work­ing with soft­ware from the AI/ma­chine learn­ing spe­cial­ists at Bal­ti­more-based In­sil­i­co Med­i­cine, re­searchers were able to do a sig­nif­i­cant amount of path­way ex­plo­ration. They found that ac­ti­va­tion of the trans­form­ing growth fac­tor-β (TGFβ) path­way was linked to the pres­ence of the FOXP3 bio­mark­er, spot­light­ing its link to Tregs. So the re­search team un­der Be­di cre­at­ed a Y-trap: fus­ing a CT­LA-4 an­ti­body as well as a PD-1 with a “TGFβ trap” de­signed to turn off, redi­rect and delete Tregs.

“This Y-trap not on­ly dis­ables CT­LA-4 func­tion, but dis­rupts the TGFβ feed­back loop that is nec­es­sary for in­duc­tion and main­te­nance of Tregs in the tu­mor,” says Be­di, who li­censed the tech through Johns Hop­kins to a start­up called Y-Trap, Inc, which he man­ages with San Fran­cis­co-based CEO So­nia Bhan­ot.

This first project is still very much at the pre­clin­i­cal phase, with re­searchers work­ing with mouse mod­els of can­cer. And longterm suc­cess with mouse mod­els of can­cer is rare. But the use of AI com­bined with bet­ter drug de­sign has de­liv­ered what the re­searchers vow is a su­pe­ri­or an­ti­body-lig­and con­struct, with an­i­mal da­ta to back up its claim that the Y-traps are able to sur­pass ate­zo (Roche’s PD-L1 Tecen­triq) and avelum­ab (Baven­cio from Pfiz­er and Mer­ck KGaA) with a promise to be able to break out of the 1 in 5 or so ra­tio on ef­fi­ca­cy with a bet­ter prog­no­sis for dura­bil­i­ty. And they’re fo­cused ini­tial­ly on can­cers where there’s a known re­sis­tance to check­point ther­a­pies.

Be­di ex­plained to me that his work on Y-traps has been evolv­ing for the past 6 years. Boot­strap­ping the work with grants from the NIH as well as re­gion­al groups, he says he’s brought in a seed round from pri­vate in­vestors and built the frame­work for an ad­vanced pre­clin­i­cal plat­form com­pa­ny with a new tech­nol­o­gy that can branch out in­to a va­ri­ety of dif­fer­ent fields, in­clud­ing in­fec­tious dis­eases, where the im­mune sys­tem plays a key role. And he has a full set of I/O Y-trap pro­grams that can be brought to­geth­er to at­tack dif­fer­ent hur­dles — like cell ex­haus­tion — fac­ing the first gen­er­a­tion of check­points, get­ting straight in­to the tu­mor mi­croen­vi­ron­ment.

With AI and ma­chine learn­ing, says Be­di, you can feed in da­ta on re­spons­es “that gives you clues as to which Y-traps are best to ad­dress them.” Go fur­ther down the road, he says, and even­tu­al­ly you’ll be able to per­son­al­ize these Y-trap con­structs to in­di­vid­ual pa­tients, rather than just cer­tain sub­groups based on key bio­mark­ers.

Alex Zha­voronkov

“My aim in this field is ag­ing re­search,” notes Alex Zha­voronkov, the CEO at In­sil­i­co Med­i­cine, “look­ing at new ways to make the im­mune sys­tem look younger; im­mune senes­cence, wak­ing up the im­mune sys­tem.”

Last sum­mer In­sil­i­co part­nered with Glax­o­SmithK­line on their maid­en ef­fort on AI and ma­chine learn­ing in drug de­vel­op­ment. And Zha­voronkov has been backed by UK bil­lion­aire Jim Mel­lon, who helped found the start­up Ju­ve­nes­cence, which is mak­ing ag­ing re­search its cen­tral fo­cus, at a time most of the play­ers in R&D are just get­ting their feet wet with this tech­nol­o­gy.

The next step at Y-Traps Inc is to move past the seed fund­ing and raise a ven­ture round to cre­ate a full-fledged plat­form biotech that can move to file an IND and then start hu­man stud­ies in I/O, where the tech­nol­o­gy can ad­dress the most ob­vi­ous chal­lenges well rec­og­nized in the field. Then they can start branch­ing out, ex­plor­ing in­dus­try part­ner­ships to lever­age more work in the field.

That all fits with a key trend in on­col­o­gy re­search. As a tsuna­mi of check­points promis­es to com­modi­tize the first gen­er­a­tion of check­points, the em­pha­sis now is on the next-gen in­no­va­tions that can main­tain a prod­uct’s unique sta­tus. And Be­di is bet­ting that Y-traps can play a big role in that.

We’ll keep you post­ed on that.


Il­lus­tra­tion: In­sil­i­co Med­i­cine

Health­care Dis­par­i­ties and Sick­le Cell Dis­ease

In the complicated U.S. healthcare system, navigating a serious illness such as cancer or heart disease can be remarkably challenging for patients and caregivers. When that illness is classified as a rare disease, those challenges can become even more acute. And when that rare disease occurs in a population that experiences health disparities, such as people with sickle cell disease (SCD) who are primarily Black and Latino, challenges can become almost insurmountable.

The End­points 11: They've got mad mon­ey and huge am­bi­tions. It's time to go big or go home

These days, selecting a group of private biotechs for the Endpoints 11 spotlight begins with a sprint to get ahead of IPOs and the M&A teams at Big Pharma. I’ve had a couple of faceplants earlier this year, watching some of the biotechs on my short list choose a quick leap onto Nasdaq or into the arms of a buyer.

Vividion, you would have been a great pick for the Endpoints 11. I’m sorry I missed you.

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Dave Lennon, former president of Novartis Gene Therapies

So what hap­pened with No­var­tis Gene Ther­a­pies? Here's your an­swer

Over the last couple of days it’s become clear that the gene therapy division at Novartis has quietly undergone a major reorganization. We learned on Monday that Dave Lennon, who had pursued a high-profile role as president of the unit with 1,500 people, had left the pharma giant to take over as CEO of a startup.

Like a lot of the majors, Novartis is an open highway for head hunters, or anyone looking to staff a startup. So that was news but not completely unexpected.

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Jacob Van Naarden (Eli Lilly)

Ex­clu­sives: Eli Lil­ly out to crash the megablock­buster PD-(L)1 par­ty with 'dis­rup­tive' pric­ing; re­veals can­cer biotech buy­out

It’s taken 7 years, but Eli Lilly is promising to finally start hammering the small and affluent PD-(L)1 club with a “disruptive” pricing strategy for their checkpoint therapy allied with China’s Innovent.

Lilly in-licensed global rights to sintilimab a year ago, building on the China alliance they have with Innovent. That cost the pharma giant $200 million in cash upfront, which they plan to capitalize on now with a long-awaited plan to bust up the high-price market in lung cancer and other cancers that have created a market worth tens of billions of dollars.

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Who are the women su­per­charg­ing bio­phar­ma R&D? Nom­i­nate them for this year's spe­cial re­port

The biotech industry has faced repeated calls to diversify its workforce — and in the last year, those calls got a lot louder. Though women account for just under half of all biotech employees around the world, they occupy very few places in C-suites, and even fewer make it to the helm.

Some companies are listening, according to a recent BIO survey which showed that this year’s companies were 2.5 times more likely to have a diversity and inclusion program compared to last year’s sample. But we still have a long way to go. Women represent just 31% of biotech executives, BIO reported. And those numbers are even more stark for women of color.

FDA+ roundup: Bs­U­FA III ready for show­time, court tells FDA to re-work com­pound­ing plan, new guid­ance up­dates and more

The FDA has now spelled out what exactly will be included in the third iteration of Biosimilar User Fee Act (BsUFA) from 2023 through 2027, which similarly to the prescription drug deal, sets fees that industry has to pay for submitting applications, in exchange for firm timelines that the agency must meet.

This latest deal includes several sweeteners for the biosimilar industry, which has yet to make great strides in the US market, with shorter review timelines for safety labeling updates and updates to add or remove an indication that does not contain efficacy data.

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Jean Bennett (Brent N. Clarke/Invision/AP Images)

Lux­tur­na in­ven­tor Jean Ben­nett starts a new gene ther­a­py com­pa­ny to tack­le rare dis­eases left be­hind by phar­ma, VCs

A few years ago Jean Bennett found herself in a surprising place for a woman who invented the first gene therapy ever approved in the United States: No one, it seemed, wanted her work.

Bennett, who designed and co-developed Luxturna, approved in 2018 for a rare form of blindness, had kept building new gene therapies for eye diseases at her University of Pennsylvania lab. But although the results in animals looked promising, pharma companies and investors kept turning down the pedigreed ophthalmology professor.

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David Meek, new Mirati CEO (Marlene Awaad/Bloomberg via Getty Images)

Fresh off Fer­Gene's melt­down, David Meek takes over at Mi­rati with lead KRAS drug rac­ing to an ap­proval

In the insular world of biotech, a spectacular failure can sometimes stay on any executive’s record for a long time. But for David Meek, the man at the helm of FerGene’s recent implosion, two questionable exits made way for what could be an excellent rebound.

Meek, most recently FerGene’s CEO and a past head at Ipsen, has become CEO at Mirati Therapeutics, taking the reins from founding CEO Charles Baum, who will step over into the role of president and head of R&D, according to a release.

Maureen Hillenmeyer, Hexagon Bio CEO

Hexa­gon Bio rais­es $61M to con­tin­ue ef­forts to turn fun­gi in­to drugs

A year after raising a $47 million launch round, the fungi-loving drug hunters at Hexagon Bio have more than doubled their coffers.

Hexagon announced today that it raised another $61 million for its efforts to design cancer and infectious disease drugs based on insights mined from the DNA in millions of species of fungi. The new financing brings Hexagon’s committed funding to over $108 million.