AACR: Bay Area biotech bets on an­ti­bod­ies armed with im­muno-stim­u­lant to fight check­point-re­sis­tant can­cers

The sci­en­tist be­hind the first prostate can­cer vac­cine Provenge — once cel­e­brat­ed as a his­toric break­through, but now a fad­ing star — has de­vised a type of armed an­ti­body — loaded with an im­muno-stim­u­lant rather than a cy­to­tox­ic pay­load — to fight can­cers re­sis­tant to the army of ex­ist­ing check­point in­hibitors.

Ed En­gle­man

The re­searcher, Stan­ford’s Ed En­gle­man, has built on his re­search in­to den­drit­ic cells — which are con­sid­ered ‘sen­tinels’ of the im­mune sys­tem as they are re­spon­si­ble for in­duc­ing im­mune T-cell re­spons­es — to de­vel­op this Im­mune-Stim­u­lat­ing An­ti­body Con­ju­gate (ISAC) tech­nol­o­gy, which was un­veiled by ex­clu­sive li­censee Bolt Bio­ther­a­peu­tics at the Amer­i­can As­so­ci­a­tion for Can­cer Re­search (AACR) Con­fer­ence on Mon­day.

“What Bolt has come up with is to wake up den­drit­ic cells with­in the (tu­mor) mi­croen­vi­ron­ment, and we were able to do this in a tar­get­ed way,” said David Dor­nan, se­nior VP of re­search, in an in­ter­view with End­points News ahead of the con­fer­ence.

Many pa­tients are re­frac­to­ry to check­point in­hibitors be­cause there are a num­ber of im­muno­sup­pres­sive fac­tors present in their tu­mor mi­croen­vi­ron­ment, and so re­searchers have been try­ing to har­ness dif­fer­ent mol­e­cules to stim­u­late the im­mune sys­tem, one of which are toll-like re­cep­tor (TLR) ag­o­nists — spe­cial­ized pro­teins that ini­ti­ate an im­mune re­sponse to for­eign pathogens or, in this case, can­cer cells.

David Dor­nan

But the chal­lenge of de­liv­er­ing these ad­ju­vants is that they must be de­liv­ered in­tra­tu­moral­ly, be­cause if they were ad­min­is­tered sys­tem­i­cal­ly — say oral­ly or in­tra­venous­ly — they can be­come tox­ic as im­mune cells across the body are ac­ti­vat­ed and the im­pact is not tar­get­ed, Dor­nan em­pha­sized.

Bolt’s ISAC tech­nol­o­gy is there­fore tar­get­ed — it con­ju­gates an ad­ju­vant on to a tu­mor tar­get­ing an­ti­body in or­der to de­liv­er this im­mune ag­o­nist di­rect­ly to the tu­mor.

Grant Yone­hi­ro

This is a log­i­cal evo­lu­tion — orig­i­nal­ly, re­searchers were tar­get­ing the tu­mor with chemother­a­peu­tics or an­ti­body drug con­ju­gates, then came the check­point in­hibitors that were de­signed to prime the im­mune sys­tem to at­tack the tu­mor, Bolt’s chief op­er­at­ing of­fi­cer Grant Yone­hi­ro said. “We do both, we’re tar­get­ing the tu­mor with our an­ti­body, but we’re al­so turn­ing on the im­mune sys­tem in the tu­mor.”

But it’s still ear­ly days. Bolt has so far con­duct­ed pre­clin­i­cal stud­ies.

The da­ta sug­gest that the tech can “rein­vig­o­rate the im­mune sys­tem to an ex­tent that if the can­cer came back you have a reper­toire of T-cells that can find, start pro­lif­er­at­ing and then start to kill the can­cer cells,” Dor­nan said.

“We see pro­found tu­mor shrink­age in pre­clin­i­cal mod­els, we see im­muno­log­i­cal mem­o­ry — the abil­i­ty for once when you clear a tu­mor, that if the can­cer comes back — if we give the mouse the can­cer cells, we don’t have re-ad­min­is­ter any ther­a­py — the mouse’s T-cells rec­og­nize the tu­mor and erad­i­cate it. We’ve done these mod­els in can­cers that are large­ly re­frac­to­ry to stan­dard-of-care ther­a­pies.”

With the ad­di­tion of a cy­to­tox­ic pay­load, the du­ra­tion of re­sponse is the main hur­dle — but adding on an im­muno-stim­u­lant can cir­cum­vent that, the ex­ec­u­tives un­der­scored. Bolt’s pre­clin­i­cal da­ta has shown that the ISAC ap­proach is arm­ing the body with a reper­toire of T-cells that even if the can­cer tries to mu­tate around it, the pa­tient has a fight­ing chance.

Bolt has sev­er­al pro­grams in its ar­se­nal, and its lead pro­gram is like­ly go­ing to be de­vel­oped for use in breast can­cer, gas­tric can­cer and blad­der can­cer, Dor­nan said.

The 30-em­ploy­ee Bay Area com­pa­ny has raised $72 mil­lion so far, and hopes to be in the clin­ic by 2020. An IPO is al­so on the cards. “We’re still a lit­tle ear­ly for that, but we think there’s a lot of po­ten­tial for an IPO down the line,” Yone­hi­ro said.

The Fac­tors Dri­ving a Rapid Evo­lu­tion of Gene & Cell Ther­a­py and CAR-T Clin­i­cal Re­search in APAC

APAC is the fastest growing region globally for cell & gene therapy trials representing more than a third of all cell & gene studies globally, with China leading in the region. 

APAC is the leading location globally for CAR-T trials with China attracting ~60% of all CAR-T trials globally between 2015-2022. The number of CAR-T trials initiated by Western companies has rapidly increased in recent years (current CAGR of about 60%), with multiple targets being explored including CD19, CD20, CD22, BCMA, CD30, CD123, CD33, CD38, and CD138.

The End­points 11; blue­bird's $3M gene ther­a­py; Bio­gen tout new neu­ro da­ta; Harsh re­views for can­cer drugs; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

Reading about John Carroll’s pick of biotech’s most promising startups has become a treasured tradition. If you ever get curious about previous classes of the Endpoints 11, you can find all of them (plus a number of our other regular specials) here.

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EMA warns of short­ages of two Boehringer heart drugs due to a spike in de­mand

The EMA is putting EU member states on alert over the shortage of two drugs that counter heart attacks due to an uptick in demand.

On Friday, the EMA sent out a warning that two Boehringer Ingelheim drugs are experiencing a shortage: Actilyse and Metalyse. The drugs are used as emergency treatments for adults experiencing acute myocardial infarction, or a heart attack, by dissolving blood clots that have formed in the blood vessels.

The End­points 11: The top pri­vate biotechs in pur­suit of new drugs. Push­ing the en­ve­lope with pow­er­ful new tech­nolo­gies

Right around the beginning of the year, we got a close-up look at what happens after a boom ripples through biotech. The crash of life sciences stocks in Q1 was heard around the world.

In the months since, we’ve seen the natural Darwinian down cycle take effect. Reverse mergers made a comeback, with more burned out shells to go public at a time IPOs and road shows are out of favor. And no doubt some of the more recent arrivals on the investing side of the business are finding greener pastures.

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Jim Wells (UCSF)

An­ti­bod­ies once act­ed on­ly as pro­tein block­ers. Now, sci­en­tists are find­ing new ways to make them pro­tein de­stroy­ers

The first lab-made antibody medicine was approved in 1986 — it bound to an antigen known as CD3 on T cells and was meant to prevent kidney transplant rejection. While antibody technology improved, most antibodies were made as blocking agents, neutering clamps that attacked cells and proteins.

But then scientists got creative with their engineering. They made antibody-drug conjugates, or ADCs for short, which attached toxins or drugs to the antibodies, enabling them to kill cells. Then they made CAR-T therapies, which attached a patient’s T cell to the targeting fragment of an antibody, to destroy cancer cells.

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As­traZeneca, Mer­ck cull one Lyn­parza in­di­ca­tion in heav­i­ly pre­treat­ed ovar­i­an can­cer pa­tients

Just one day after blockbuster Lynparza got access to another indication in China, its Big Pharma owners have decided to withdraw it in certain patients after reviewing Phase III data.

The two companies that work together on Lynparza decided to recall one of the indications several weeks ago in a specific type of ovarian cancer, Lynparza’s first indication when it was first FDA-approved in 2014. Initial data showed that rates of overall survival in patients with at least three rounds of chemo before getting on the PARP inhibitor were lower than in patients with less previous chemo treatment.

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Fu­ji­film con­tin­ues CD­MO ex­pan­sion, break­ing ground on $435M UK site

Fujifilm’s CDMO arm, Fujifilm Diosynth, has been on a roll this month as the company has recently broken ground on a major project in Europe and it appears to be keeping up the momentum.

Fujifilm Diosynth announced that it has kicked off an expansion project for its microbial manufacturing facility at its campus in the town of Billingham, UK, in the northeast of England.

The 20,000 square-foot, £400 million ($435 million) expansion will add clean rooms, purification suites and a packing area along with more space for the manufacturing itself.

An­oth­er Cipla site lands a Form 483 over clean­ing is­sues and QC con­trols

A Cipla drug manufacturing site in India has once again landed in the crosshairs of FDA inspectors.

The facility in question is Cipla’s drug manufacturing facility in the village of Verna, in the state of Goa in India’s southwest. In a sign that foreign inspections might ramp up again, the FDA’s visit from Aug. 16 to Aug. 22 uncovered six observations.

The 11-page report noted that environmental monitoring at the site did not properly ensure that microbial contaminants were not making any impact in the aseptic filling areas. It also found that procedures meant to stop microbial contamination were not adequately conducted in aseptic areas of the facility.

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Solicitor General Elizabeth Prelogar

Should SCO­TUS hear Am­gen's Repatha case? So­lic­i­tor gen­er­al says no

Back in April, Amgen said it was encouraged by the solicitor general’s anticipated review of its Supreme Court petition to rehear a Repatha patent case. They’re likely much less optimistic about the outcome now.

Solicitor General Elizabeth Prelogar wrote in a recent 27-page brief that Amgen’s arguments “lack merit and further review is not warranted.”

The case traces back to a suit filed in 2014 against Sanofi and Regeneron’s Praluent, which ended up beating Amgen’s PCSK9 blockbuster Repatha to market by a month just a year later.