Arcellx On Designing A Dynamic CAR-T
By Tyler Menichiello, contributing editor
The advent of CAR-T marks an inflection point in the history of medicine. This modality, which used to resemble science fiction more than reality, has exploded into a multibillion-dollar market. The result is a space bursting with innovation at every turn. Hundreds of companies are working (and in many cases, competing) to develop next-generation CAR-T therapies and inventing unique ways to overcome the modality’s inherent challenges.
D-Domain Design: Enabling Simpler and More Stable CAR-T Constructs
The D-Domain is made up of three alpha helices bundled together, which makes it easier for cells to express, Heery explains, because there are less opportunities for misfolding to happen. Their hydrophobic cores keep the helices attracted to each other. This attraction helps ensure structural integrity across a wide range of temperatures and pH conditions and makes the D-Domain “extremely stable,” he tells me.
Advancing CAR-T Utility Through The ARC-SparX Platform
The D-Domain is integral to the company’s ARC-SparX platform, which uses specially designed adaptor proteins (aka SparX proteins) to direct ARC-T cells (ddCAR T cells designed to bind with the TAG domain on the SparX protein) to their targets — similar to antibody-mediated CAR-T platforms. This approach allows for a dose-dependent CAR-T response (by adjusting the SparX protein dose), as well as the option to target multiple antigens without remaking the CAR T cells (by swapping out the SparX protein).
“While in lymphoma and multiple myeloma you can get really good results with one single target, in most cancers, you cannot,” Heery explains. “That has become one of the big limitations of CAR T cells.”
Heery thinks the next generation of CAR-Ts need to overcome this “heterogeneity of expression” to treat more complicated, multi-target cancers, and he believes ARC-SparX has this potential.
CMC Challenges For Unique Platform Technologies
The tradeoff for a platform as dynamic as ARC-SparX is the additional work to validate it (i.e., its respective parts) and demonstrate its safety to regulators. “From a clinical development standpoint, you have more variables,” Heery says. For example, accounting for the pharmacology of the SparX proteins and comparing this to a traditional CAR-T approach. Not that accounting for these additional variables is hard, Heery says, it’s just more work.
“It’s not as simple as just making the cells, putting them in, and hoping for the best,” he explains. Questions need to be answered — questions like, “Can we control how well they interact? Can we control safety? Can we control efficacy in a different way by changing the dosing strategy?”
With platform technology like ARC-SparX, there is always a question of what regulatory requirements subsequent products will need to meet. When the company designs a new SparX protein to target a different antigen, will it need to be reviewed as a new investigational therapy or simply validated under the existing product?
That’s a question that will warrant more conversations with the FDA, say Heery and Singh. While they may not have a hard answer yet, Singh has faith in regulators’ common sense. “There’s a lot of innovation here, and the regulatory agencies in cell therapy are more and more open to understanding the complexity of these therapies and accommodating where you can make the right case,” he says.
“If the universal cell product and vector are the same and you have established safety, you should be able to use that data for humans from one indication to another,” Singh says. Though there may be caveats from one disease to another, these can be understood through a simpler bridging study with a small number of patients, he tells me.
Arcellx’s Strategic Partnership With Kite, A “Win-Win”
Arcellx and Kite are working together to develop anito-cel, which is currently in Phase 3 to evaluate its benefit for patients with relapsed or refractory multiple myeloma. Heery explains the genesis of this relationship quite simply. “We needed infrastructure without having to build it all, and they needed a great product to put into an infrastructure that had already been built,” he says.
“So, win-win!”
This partnership is both collaborative and mutually beneficial, Heery tells me. “Sometimes we’re driving things, and sometimes they’re driving things,” he says. In such partnerships, “big companies have more systematic approaches to things and more approval processes, while smaller companies tend to be a bit more nimble.”
These organizational differences amount to complementary teamwork and a balanced approach to development. Similar partnerships have resulted in successful CAR-T product approvals in the past (e.g., Bristol Myers Squibb and Bluebird Bio collaborating on Abecma).
Arcellx’s singular focus right now is to continue towards the commercial approval and launch of anito-cel, leveraging its own strengths and capabilities with Kite’s. The biggest challenge ahead of the company lies in the execution at this point, Singh tells me. “Doing what we say we are doing and making sure it gets done within the timelines,” he says. Between its technology and partnership with Kite, Arcellx is positioned to significantly advance the field of CAR-T.