Arcellx emerged from stealth with over $85 million in series B funding and a team of CAR T veterans to develop the latest iteration of a CAR T adaptor platform that balances safety and efficacy by carefully tuning adaptor protein half life. The team believes its platform can treat refractory cancers and move into non-oncology indications.
The series B round was led by new investors Aju IB Investment and Quan Capital.
The CAR T adaptor concept involves creating T cells with CARs that target an intermediary adaptor protein designed to bind a tumor antigen, rather than targeting the tumor antigen directly.
The idea is that the CARs will only be active when the adaptor is present, making them easier to control than the standard CAR T construct.
The CAR T cell adaptor constructs can also be more easily adapted for new targets, as it’s the adaptor protein rather than the T cell that needs to be modified, said Arcellx Inc. President and CEO David Hilbert.
Arcellx’s version of the platform involves CAR T cells dubbed Antigen Receptor Complex T (ARC-T) cells that are designed to bind a tag not expressed on any human cells, plus the soluble protein antigen-receptor X-linker (sparX) adaptor protein. The sparX adaptor is made up of one or more tumor-binding domains fused to the tag.
Other companies such as Unum Therapeutics Inc. (NASDAQ:UMRX) are using antibodies as the adaptor, which have longer half lives than the proteins. That means toxicity issues would not resolve as quickly, said Hilbert. Antibodies also have their own inherent biological activity and toxicity, which can be difficult to sort out from that of the T cells, he added.
Unum’s lead program, ACTR707, targets CD20 for non-Hodgkin lymphoma and is in Phase I testing. FDA placed a second clinical hold on Unum’s other Phase I therapy, ACTR087, in the indication in July following a report that a patient experienced grade 3 neurotoxicity and cytomegalovirus infection, as well as grade 4 respiratory distress.
On the other end of the spectrum, companies such as Senti Biosciences Inc. have preclinical adaptive molecules with very short half lives, said Hilbert, meaning it can be hard for the drug to find all tumor cells in the complex tumor environment.
“We’ve designed the half lives to be between the two extremes: long enough to get in, and short enough that toxicity will resolve quickly,” said Hilbert.
Arcellx submitted an IND for its lead candidate targeting BCMA for multiple myeloma in September, and expects to begin clinical testing this year. The company’s second program targets CD123 for acute myelogenous leukemia (AML).
“We chose these to derisk the platform with targets already understood in CAR T therapy, and then plan to expand and validate other targets from there,” Hilbert said.
CMO Angela Shen added, “We’re focusing on AML and myeloma because those are two indications notorious for relapse and refractory disease. We envision coming back with a second sparX with different specificity to change targets as tumors evolve.”
Shen is one of two Arcellx executives with a hand in developing one of the first two approved CAR T cell therapies. She previously served as the first global clinical program head for CAR T at Novartis AG (NYSE:NVS; SWX:NOVN), where she helped develop Kymriah tisagenlecleucel.
Marianna Sabatino, VP of cell product sciences, was senior director of product sciences at Kite Pharma Inc., where her work supported the BLA filing of approved CAR T therapy Yescarta axicabtagene ciloleucel.
Further down the pipeline, Arcellx plans to target solid tumors, move into non-oncology indications and explore allogeneic therapies.
For solid tumors, sparX delivery can be spatially restricted, and they can be designed with multi-antigen specificity to act as AND gated CARs, which are activated only when both targets are bound. That allows some flexibility for hitting solid tumor antigens not exclusively expressed on cancer cells.
Beyond cancer, Hilbert thinks the safety checks built into the adaptor complex make Arcellx’s CAR Ts well suited for indications with different risk-benefit requirements.
The company is exploring transplant and autoimmune disease indications with effector CAR T cells, but said the ARC-T construct could be dropped into other cell types such as Tregs, NK cells or iPS cells in the future.
While the company’s first generation candidates are autologous, Hilbert said Arcellx is following the allogeneic CAR T cell race and plans to position its ARC-T platform as a universal construct that can go into the winning allogeneic cells.
Han Lee, CBO and head of finance, said the series B round should fund Arcellx through clinical proof of concept for its first two programs while advancing its preclinical programs in solid tumors and non-oncology indications.
Other new investors in the series B included Mirae Asset Venture Investment, Mirae Asset Capital, LG Technology Ventures, JVC Investment Partners and funds managed by Clough Capital Partners. Existing investors Novo Holdings A/S, SR One, NEA and Takeda Ventures also participated.
Targets: BCMA (TNFRSF17; CD269) - Tumor necrosis factor superfamily member 17; CD123 - Interleukin-3 receptor α