Cel­lec­tis, ris­ing star Al­lo­gene de­sign an 'all-in-one' CAR con­struct with em­bed­ded safe­ty switch as the new part­ners an­gle for the clin­ic

When Arie Bellde­grun and David Chang bagged all of Pfiz­er’s off-the-shelf CAR-T ther­a­pies, they high­light­ed a col­lab­o­ra­tion pro­gram with Cel­lec­tis that po­ten­tial­ly puts Al­lo­gene Ther­a­peu­tics on a path to com­mer­cial­iza­tion. Two months lat­er, the French biotech is fol­low­ing up with a safer, next-gen­er­a­tion chimeric anti­gen re­cep­tor con­struct now po­si­tioned for the clin­ic.

Julien Val­ton

In a pa­per pub­lished in Sci­en­tif­ic Re­ports to­day, Cel­lec­tis re­ports an all-in-one CAR ar­chi­tec­ture that com­bines can­cer-killing po­ten­cy, a “sui­cide switch” for safe­ty, as well as pu­rifi­ca­tion and de­tec­tion ca­pac­i­ties. Dubbed Cu­biCAR, the mol­e­cule was shown to be “ef­fi­cient­ly and ro­bust­ly” de­plet­ed in the pres­ence of Rit­ux­an (rit­ux­imab) both in vit­ro and in vi­vo.

The idea of a sui­cide switch is, of course, not new. CAR-T is a liv­ing drug that could the­o­ret­i­cal­ly stay in­side pa­tients for years, and giv­en the well-known safe­ty con­cerns with CAR-T — such as cy­tokine re­lease syn­drome and neu­ro­tox­i­c­i­ty — an emer­gency switch has been tout­ed as a life­saver.

Cel­lec­tis’ big achieve­ment here, in­no­va­tion team leader Julien Val­ton tells me, is the in­te­gra­tion of both the safe­ty mech­a­nism and oth­er de­sir­able qual­i­ties in one mol­e­cule. That dis­tin­guish­es Cu­biCAR from most of the oth­er sui­cide switch­es in the clin­ic right now, which he says ex­press­es the CAR and the switch in sep­a­rate mol­e­cules — lead­ing to po­ten­tial im­bal­ance be­tween the two.

“Some­times, we have in­stances where the CAR is ex­pressed, and we couldn’t see the sui­cide switch,” he says.

Philippe Duchateau

Pfiz­er had been in­volved in the project since Cel­lec­tis came up with it three years ago, pro­vid­ing Val­ton’s team with a BC­MA-tar­get­ing CAR for mul­ti­ple myelo­ma. That prod­uct now be­longs to Al­lo­gene, which is work­ing with Cel­lec­tis to find clin­i­cal ap­pli­ca­tions for the con­struct. Mean­while, Cel­lec­tis is al­so putting the Cu­biCAR scaf­fold to use in their own CARs hit­ting the CD123, CD22 and oth­er anti­gens.

The part­ners now joins the likes of Bel­licum and Au­to­lus in pur­suit of bet­ter, safer cell ther­a­pies, first for blood can­cer and even­tu­al­ly — ide­al­ly — for sol­id tu­mors.

While Cu­biCAR’s sui­cide switch is ac­ti­vat­ed by an an­ti­body, oth­er com­pa­nies have opt­ed for the small mol­e­cule-me­di­at­ed ap­proach. One of them is Po­sei­da Ther­a­peu­tics, whose CEO Er­ic Os­tertag told C&EN that an­ti­body-me­di­at­ed switch­es can “take days to re­al­ly work.”

There’s no re­al way to mea­sure it un­til the drug is test­ed in hu­mans, but Val­ton tells me that “us­ing Cel­lec­tis’ ex­per­i­men­tal con­di­tions in vit­ro, it takes about 15 min­utes to de­plete the vast ma­jor­i­ty of Safe­guard CAR T-cells with clin­i­cal­ly rel­e­vant dose of [rit­ux­imab]. This ki­net­ic is on par with the da­ta ob­tained with ICas­pase9 and RQR8 sui­cide switch­es doc­u­ment­ed in the lit­er­a­ture.”

Plus, Val­ton says, Cu­biCAR is al­so eas­i­ly de­tect­ed and pu­ri­fied — mean­ing the ac­tive el­e­ments can be ef­fi­cient­ly ex­tract­ed — by the an­ti­body QBEND10.

“Not on­ly is the Cu­biCAR ar­chi­tec­ture an in­te­grat­ed, com­pact safe­guard al­low­ing for the fast and ef­fi­cient de­ple­tion of CAR T-cells, it is al­so com­pat­i­ble with mul­ti­ple scFvs that are de­signed against dif­fer­ent tar­gets, which gives it the unique po­ten­tial to make CAR T-cell im­munother­a­pies safer,” says Cel­lec­tis CSO Philippe Duchateau in a state­ment.

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

How to col­lect and sub­mit RWD to win ap­proval for a new drug in­di­ca­tion: FDA spells it out in a long-await­ed guid­ance

Real-world data is messy. There can be differences in the standards used to collect different types of data, differences in terminologies and curation strategies, and even in the way data is exchanged.

While acknowledging this somewhat controlled chaos, the FDA is now explaining how biopharma companies can submit study data derived from real-world data (RWD) sources in applicable regulatory submissions, including new drug indications.

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David Lockhart, ReCode Therapeutics CEO

Pfiz­er throws its weight be­hind LNP play­er eye­ing mR­NA treat­ments for CF, PCD

David Lockhart did not see the meteoric rise of messenger RNA and lipid nanoparticles coming.

Thanks to the worldwide fight against Covid-19, mRNA — the genetic code that can be engineered to turn the body into a mini protein factory — and LNPs, those tiny bubbles of fat carrying those instructions, have found their way into hundreds of millions of people. Within the biotech world, pioneers like Alnylam and Intellia have demonstrated just how versatile LNPs can be as a delivery vehicle for anything from siRNA to CRISPR/Cas9.

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Sur­geons suc­cess­ful­ly at­tach pig kid­ney to a hu­man for the first time, us­ing tech from Unit­ed's Re­vivi­cor

In a first, researchers reportedly successfully transplanted a pig kidney into a human without triggering an immediate immune response this week. And the technology came from the biotech United Therapeutics.

Surgeons spent three days attaching the kidney to the patient’s blood vessels, but when all was said and done, the kidney appeared to be functioning normally in early testing, Reuters and the New York Times were among those to report. The kidney came from a genetically altered pig developed through United’s Revivicor unit.

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Leen Kawas (L) has resigned as CEO of Athira and will be replaced by COO Mark Litton

Ex­clu­sive: Athi­ra CEO Leen Kawas re­signs af­ter in­ves­ti­ga­tion finds she ma­nip­u­lat­ed da­ta

Leen Kawas, CEO and founder of the Alzheimer’s upstart Athira Pharma, has resigned after an internal investigation found she altered images in her doctoral thesis and four other papers that were foundational to establishing the company.

Mark Litton, the company’s COO since June 2019 and a longtime biotech executive, has been named full-time CEO. Kawas, meanwhile, will no longer have ties to the company except for owning a few hundred thousand shares.

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Sen. Richard Durbin (D-IL, foreground) and Sen. Richard Blumenthal (D-CT) (Patrick Semansky/AP Images)

Sen­a­tors back FDA's plan to re­quire manda­to­ry pre­scriber ed­u­ca­tion for opi­oids

Three Senate Democrats are backing an FDA plan to require mandatory prescriber education for opioids as overdose deaths have risen sharply over the past decade, with almost 97,000 American opioid-related overdose deaths in the past year alone.

While acknowledging a decline in overall opioid analgesic dispensing in recent years, the FDA said it’s reconsidering the need for mandatory prescriber training through a REMS given the current situation with overdoses, and is seeking input on the aspects of the opioid crisis that mandatory training could potentially mitigate.

Bris­tol My­ers pledges to sell its Ac­celeron shares as ac­tivist in­vestors cir­cle Mer­ck­'s $11.5B buy­out — re­port

Just as Avoro Capital’s campaign to derail Merck’s proposed $11.5 billion buyout of Acceleron gains steam, Bristol Myers Squibb is leaning in with some hefty counterweight.

The pharma giant is planning to tender its Acceleron shares, Bloomberg reported, which add up to a sizable 11.5% stake. Based on the offer price, the sale would net Bristol Myers around $1.3 billion.

To complete its deal, Merck needs a majority of shareholders to agree to sell their shares.

Boost­er bo­nan­za: FDA en­dors­es 'mix-and-match' scheme, and Mod­er­na and J&J too

The FDA late Wednesday signed off on authorizing the use of heterologous — or what FDA calls a “mix and match” of a primary vaccine series and different booster doses — for all currently available Covid-19 vaccines, in addition to separately authorizing Moderna and J&J boosters.

On the mix-and-match approach, which FDA officials insisted isn’t too confusing in a press conference, the agency offered the example of an 18-year-old who received the J&J shot at least two months ago and may now receive a single booster of the J&J, a half dose of the Moderna, or the Pfizer-BioNTech booster.

David Livingston (Credit: Michael Sazel for CeMM)

Renowned Dana-Far­ber sci­en­tist, men­tor and bio­phar­ma ad­vi­sor David Liv­ingston has died

David Livingston, the Dana-Farber/Harvard Med scientist who helped shine a light on some of the key molecular drivers of breast and ovarian cancer, died unexpectedly last Sunday.

One of the senior leaders at Dana-Farber during his nearly half century of work there, Livingston was credited with shedding light on the genes that regulate cell growth, with insights into inherited BRCA1 and BRCA2 mutations that helped lay the scientific foundation for targeted therapies and earlier detection that have transformed the field.