Backed by five pharma giants and a crew of Penn superstars, a startup uses mRNA to create in vivo CAR-T — with a pro at the helm

Earlier this year, Jonathan Epstein and other scientists at Penn published a paper in Science that spelled out the intriguing results of a mouse study. Using CD-5 targeted lipid nanoparticles, the tiny vehicles used to carry messenger RNA, they were able to reprogram T lymphocytes into CAR-Ts in vivo, in the body. Trained to recognize fibrotic cells specifically in the heart, the scientists involved were able to restore cardiac function in mice.

Jonathan Epstein

While still very much at the preclinical stage, the tech comes with some disruptive potential applications in oncology and fibrosis — plus some — and a group of experienced biotech investors has crafted a biotech startup designed to pilot it into the clinic. After VCs planted the initial $63 million seed round, a group of Big Pharmas has come in to help with a $102 million Series A. And they’ve recruited a high-profile CEO to captain the venture, plucking her off the beach shortly after her last effort recently sank beneath the waves of a storm-tossed Nasdaq.

This new enterprise, dubbed Capstan, is the brainchild of some of the world’s top cell therapy and mRNA specialists at Penn. The biotech has gathered a who’s who in these fields to help godfather the venture, including:

• Carl June and Bruce Levine, two cell engineering experts who played a big role in developing Novartis’ gen-1 CAR-T.
• Drew Weissman and Hamideh Parhiz, who have been working on mRNA and lipid tech.
• Jonathan Epstein, chief scientific officer for Penn Medicine and author of the mouse study in Science, and Haig Aghajanian, now VP of research at Capstan.
• Ellen Puré and Steven Albelda are focusing on immunology and fibrosis.

Laura Shawver has jumped aboard as CEO, just weeks after her last biotech — Silverback — was relegated to reverse-merger material when the pipeline imploded at a time the markets are ruthless when it comes to R&D failure. And she’s skippering a crew that is after another white whale.

“To me,” Shawver tells me, “it’s as if the Covid-19 vaccine and cell therapy had a baby and this is what they produced.”

“Covid-19 vaccine taught us you could deliver a messenger RNA payload in a lipid nanoparticle. It would be translated into a protein that had a biological consequence,” she adds. “And cell therapy has taught us that if you can ex vivo activate T cells to recognize a tumor antigen and put them back that you can cure some people with certain cancers. Really just marrying the two together makes all the sense. It’s a huge opportunity for patients to have a more convenient treatment. And the breadth of the platform is quite broad.”

With a scientific foundation like Capstan’s, money has not been a major issue. Novartis Venture Fund, OrbiMed, RA Capital and Vida Ventures put up the $63 million stealth round last fall. Then Pfizer Ventures led the $102 million A round with Leaps by Bayer (seemingly game for anything likely to inspire a tech revolution), Eli Lilly, Bristol Myers Squibb, Polaris Partners and Alexandria Venture Investments jumping in alongside the seed crowd for the launch money.

Silverback may have proved to be a bust, but in this business, if you survive long enough, there are plenty of thrills and spills in line for everyone. Before Silverback, Shawver’s recent track record also includes Synthorx, the IL-2 play that Sanofi snapped up for $2.5 billion, though that’s proved troublesome. And along the way, Shawver has earned a rep for an upbeat even-handedness in just about any situation.

Rajul Jain

“She’s a very steady hand,” says Rajul Jain, the managing director of Vida and part of the former Kite CAR-T crew that helped create the venture outfit, which has been a key player in the cell therapy 2.0 field. And Jain believes Shawver’s broad experience in launching a biotech will be essential in the years to come.

Capstan originally got started as Teefib, a very low-profile June (et al) spinout initially focused on CAR-T for fibrosis, which Jain and the Vida crew watched from the sidelines for a couple of years. Then the scope and tech broadened. Vida came in on the seed round in late 2021, knowing that there are some major challenges ahead as Capstan works on payloads and targeting.

Getting the right payload, in sufficient size, and then steering it to the right cell in humans, represents a major challenge for Capstan, Jain notes.

“The biggest technological barrier will be around the RNA itself,” he says. “It’s going to be getting enough of the RNA into the T cell when we give this ultimately in human. When we describe what is the problem we hope that Capstan is on a path to solving, the hardest problem would probably be that one.”

Adrian Bot

Shawver will start out in her new gig with 45 staffers, including Adrian Bot, the former CSO at CAR-T pioneer Kite, along with chief technology officer Priya Karmali, who’s worked for years in the lipid nanoparticle field. They initially got started primarily in Philadelphia, close to Penn, then added a San Diego facility.

They’ll be focused on what could be considered the third generation of cell therapies with a second-gen mRNA strategy. Along the way from the birth of these technologies, there have been some huge challenges.

Priya Karmali

“People have been trying to do this for a very long time,” Shawver says. And there’s still a long way to go.

“How do you get RNA into the right cells?” Shawver asks. “You have to change the structure of RNA, you have to code it into a lipid nanoparticle. Of course we also decorate that lipid nanoparticle with a targeting moiety or antibodies to get it to specific cell types.”

But Capstan’s founding scientists were the leaders in making it all work, initially. And now they’ll help lead the charge for something new and better — provided it works. And that fits neatly into Shawver’s life’s work.

“Whatever I’ve chosen to do throughout my career, whether it worked or hasn’t worked, has been to always make meaningful differences for patients with serious diseases,” says Shawver.

Whether it was the early days of precision medicine, novel targets, I/O, “the goal has been the same.” And now the opportunities to do something big are better than ever.

“Everybody can see the stage has been set, the field is moving, the innovation is here to bring what cell therapy brought to people,” says Shawver. “But more broadly in a more convenient way in a cost that is more accessible and bring them to patients who can’t access these things today. So I’m certainly excited about this opportunity.”

Long sabbaticals just aren’t her style.

“I would be bored,” she said with a laugh. “If I took time off, in two days’ time I’d say, oh my gosh, why am I doing this?”

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