ASH 2025 | A novel CAR T-cell therapy targeting the intracellular protein MZB1 for multiple myeloma

CAR T-cell therapy has become very effective and we utilize cell surface targets to develop CAR T-cells. However, after having a number of studies, now we are running out of cell surface targets. So this particular MZB1-targeting CAR T-cell is a unique CAR T-cell because we are targeting an intracellular protein, in this case MZB1, as a potential target, and what we are utilizing is that intracellular targets are processed and presented in the context of HLA on the cell surface. It’s a nine amino acid sequence for that protein which is presented. So, utilizing this presentation of an intracellular antigen in the context of HLA is what we are utilizing for CAR-T targeting. Normally, the T-cell receptor on T-cells will bind to this and it has the effect. So, we are developing an antibody that looks like the TCR and binds to this HLA target. Now, the HLA we are considering is HLA-A2. So, the MZB1-targeting antibody we have developed is an antibody that recognizes MZB1 expressed in the context of HLA-A2. Using very sophisticated techniques, we have identified an antibody and developed a CAR, which shows that our antibody and CAR bind to myeloma cells, which are HLA-A2 positive and MZB1 positive. It does not bind if either of them is negative or both are negative. The CAR T-cell is able to kill the myeloma cell very effectively, as CAR T-cells are supposed to do, and in an animal model, we have been able to show that the same CAR T-cell is able to eliminate the myeloma. And so, the bottom line is we have a new CAR that’s number one, number two, it’s very effective, and three, this opens up a whole new area where we can begin to have many intracellular targets that we can now utilize for developing cellular therapy.

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