Harnessing NKp30xBCMA Engagers: A Novel Approach to Multiple Myeloma Therapy

Multiple myeloma is a malignant condition marked by the proliferation of abnormal plasma cells. Despite advancements in drug therapies that have enhanced patient survival rates, challenges such as relapse, resistance to treatments, and side effects persist. There is a pressing need for innovative treatment options. Natural killer (NK) cells are pivotal in controlling myeloma, and studies indicate that these cells, particularly those with high cytotoxicity, are present in the bone marrow of affected individuals. This suggests that therapies targeting NK cells could be a specialized approach to utilize their cytotoxic capabilities against myeloma.

Post autologous stem cell transplantation, NK cells are among the first lymphocytes to reestablish, presenting an opportunity to address minimal residual disease. B-cell maturation antigen (BCMA) is identified as a prime target due to its limited expression in both healthy and cancerous plasma cells, and its absence in other bone marrow cells. A pioneering NKp30xBCMA NK cell engager, CTX-4419, has been developed. It targets BCMA on myeloma cells and NKp30 and CD16A on NK cells, effectively directing NK cells to BCMA-expressing tumor cells.

The study shows that CTX-4419 is effective even in environments with elevated BCMA ligands and serum IgG levels, and it triggers potent cytotoxic responses from NK cells against both high and low BCMA-expressing cell lines and primary myeloma cells from patients. Notably, CTX-4419 can eliminate tumor cells without relying on CD16A binding, a distinctive feature that addresses the issue of CD16A activity reduction due to receptor loss or downregulation in the tumor environment.

Moreover, CTX-4419 stimulates NK cell proliferation and the production of cytokines and chemokines by NK cells in the presence of tumor cells, ensuring sustained anti-tumor specificity. In vitro, it activates cynomolgus NK cells in the presence of target cells expressing the relevant BCMA, and when administered intravenously, it reduces plasma cell counts.

CTX-4419 is a novel NK-cell engager that exhibits significant potency without the need for CD16A engagement. It promotes NK cell proliferation and the destruction of tumor cells that express low levels of antigen. Demonstrating robust activity in patient bone marrow samples and showing efficacy in a non-human primate model, CTX-4419 stands out from conventional therapeutic antibodies. It is a promising candidate for myeloma treatment, with the potential for use as a standalone therapy or in conjunction with NK cell transfer and other immunotherapies.