Can we freeze them? Yes we can, says Nkarta

The company is now in the clinic, claiming to have cleared one of the biggest hurdles blocking development of an NK cell therapy.

Paul Hastings, chief executive of Nkarta, is not shy about his company’s achievement. “We have mastered cryopreservation,” he tells Evaluate Vantage.

And with that the company might have solved the biggest problem to have held back development of NK cell therapeutics: normally the cells cannot be frozen without risking changing their phenotype. Nkarta also reckons to have cracked another problem, transducing NK cells with a retrovirus, and its optimism matches the market mood of resurgent enthusiasm for these therapies.

That enthusiasm for NK cells took off at last year’s Ash meeting, and Nkarta, along with Gamida Cell, Fate Therapeutics and Nantkwest, celebrated surging stock prices. Remarkably, Nkarta presented no clinical data at the conference, though it has since started trials of its first Car-NK therapy, NKX101, targeting NKG2D ligands.

What do we want?

“One of the things we defined right up front was what we wanted from a product,” Mr Hastings says. “Until we got that we weren’t going to try and move these things into the clinic.”

For Nkarta a product must be off the shelf and cryopreserved – though just how this is achieved is a proprietary secret – and it must come in a vial, not a bag, so it can be multiple-dosed easily. The aim is to ship Car-NK cells just like an antibody directly to a doctor.

Thus affordability, a thorny issue for cell therapies, is at the core of Nkarta’s thinking. Mr Hastings reckons cost of manufacturing can be limited to $2,000 per vial of a billion NK cells; and, as each dosing cycle comprises three lots of 100 million cells, each vial could give up to three cycles.

As for supply, Nkarta sources NK cells from healthy donors, in contrast to Fate, which uses induced pluripotent stem cells (iPSCs). Mr Hastings says each healthy donor can yield 500 doses, and manufacturing, including standard viral transduction, takes 14 days, with the inclusion of membrane-bound IL-15 improving persistence and reducing exhaustion, ensuring that cells are maximally potent when delivered.

The iPSC approach is seen as more advanced, but is complex as desired characteristics need to be engineered in. Mr Hastings says with donor-derived cells “you start with a large number of cells, and they’re actually NK cells”, though he does not rule out looking at iPSCs in future.

“We’re all placing bets, and this is our bet,” adds James Trager, Nkarta’s chief scientific officer. And he denies that donor-derived cells lack flexibility, saying the donor pool is very diverse: “There are a fair number of donors walking around who have NK cells with pretty exceptional properties.”

For now, however, Nkarta is not looking at donors with NK cells expressing high-affinity CD16; Fate, for instance, engineers this into most of its projects to improve antibody-dependent killing.

Clinical data

Investors do not have long to wait for the first evidence of NKX101’s clinical activity. Mr Hastings says Nkarta expects interim results from a handful of patients “at a medical meeting – not by press release” – towards the end of 2021.

And an IND filing for the group’s second asset, a CD19-targeting Car-NK coded NKX019, is due in the current quarter. This gives Nkarta’s pipeline a mix of proven (CD19) and high-risk (NKG2D ligands) approaches, and final proof-of-concept data for both are due in the first half of 2023; current cash, meanwhile, takes Nkarta to the second half of that year.

On a design level both therapies differ from current Car-T approaches in using as the co-stimulatory domain not 4-1BB or CD28 but Ox40, which Mr Trager says gives NK cells the best serial killing activity.

Even though the CD19 space is extremely crowded, unlike many other cell therapy players Nkarta is not using a CD19 approach just to test its tech. “We absolutely believe that a CD19 programme that’s allogeneic, cryopreserved in a vial is going to be very competitive,” stresses Mr Hastings.

And the group’s next project will target solid tumours, but for now remains under wraps. “The way we’ll disclose targets is when we have a clinical candidate,” says the chief exec.

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