Abstract 4972: Preclinical development of a first-in-class NKp30xBCMA NK cell engager for the treatment of multiple myeloma

Multiple myeloma (MM) is characterized by clonal expansion of malignant plasma cells. Although several new drugs for the treatment of MM have greatly improved survival, many patients are known to relapse and become refractory to all presently available therapies or experience treatment-related toxicities. Therefore, MM remains an unmet medical need and the development of additional novel therapies is required. NK cells play a crucial role in the control of multiple myeloma and accumulating evidence shows the presence of highly cytotoxic NK cells in the bone marrow of MM patients suggesting that targeting NK cells could provide a specific treatment modality to leverage NK cell cytotoxicity in myeloma. Furthermore, NK cells are the first lymphocytes population to reconstitute after autologous stem cell transplant (ASCT) providing an opportunity to target minimal residual disease (MRD) shortly after transplant. B-cell maturation antigen (BCMA) is an excellent target in MM because its restricted expression in normal and malignant plasma cells from untreated and relapsed myeloma patients, but absent in all other main bone marrow cell subsets. Our first-in-class NKp30xBCMA NK cells engager, CTX-4419, binds to BCMA on MM cells and to NKp30 and CD16A (FcγRIIIA) on NK cells, specifically redirecting NK cells towards tumor cells expressing BCMA. We demonstrate here that CTX-4419 retains activity in the presence of high levels of BCMA ligands and serum IgG and induces potent NK cytotoxicity against high and low BCMA expressing cell lines as well as patients (autologous) primary myeloma cells. Moreover, CTX-4419 does not require CD16A binding to kill tumor cells, a unique characteristic that overcomes the reduction or loss of activity of CD16A due to receptor shedding or downregulation in the tumor microenvironment. Furthermore CTX-4419 induces NK proliferation and cytokines/chemokines production by NK cells only in the presence of tumor cells providing sustainable anti-tumor specificity to NK cells. CTX-4419 activates in-vitro cynomolgus NK cells in presence of target cells expressing cynomolgus BCMA and, when given intravenously, CTX-4419 decreases plasma cell counts. CTX-4419 represents a novel class of NK-cell engagers that shows strong potency even in the absence of CD16A engagement and induces NK cell proliferation and lysis of tumor cells expressing low amount of antigen. CTX-4419 has strong activity in an autologous setting when tested in bone marrow samples o