Immunotherapeutic Development of a Tri-Specific NK Cell Engager Recognizing BCMA.

Simple Summary: Chemotherapy-refractive multiple myeloma (MM) is serious and life-threatening, and better treatments are urgently needed. BCMA is a cell surface protein known to be expressed on MM and therefore an accepted target for antibody therapy, but progress has been slow. Natural killer (NK) cells normally fend off cancer cells, but many cancers override them. Using a more aggressive strategy, we bioengineer a tri-specific biological drug containing an antibody fragment that binds BCMA, an antibody fragment that binds NK cells, as well as an NK-enhancing cytokine. Together, this complex triggers a more robust NK response. Studies in test tubes show that the hybrid drug enhances NK expansion, priming, and activity against MM cell lines. Importantly, studies in special immunosuppressed mice receiving lethal doses of human MM cells show anti-cancer activity. Studies indicate that the drug should be considered further for clinical development. Chemotherapy-refractive multiple myeloma (MM) is serious and life-threatening, and better treatments are urgently needed. BCMA is a prominent marker on the cell surface of MM cells, rendering it an accepted target for antibody therapy. Considering that MM is a liquid tumor and immunotherapy has enjoyed success against leukemia, we devise an approach designed to enhance NK cell activity against MM. Ordinarily, NK cells function to naturally survey the body and eliminate malignant cells. Our platform approach is designed to enhance NK function. A tri-specific immune-engaging TriKE is manufactured, consisting of a camelid nanobody VHH antibody fragment recognizing CD16 expressed on NK cells and an scFv antibody fragment specifically recognizing BCMA. These two fragments are crosslinked by the human cytokine interleukin-15 (IL-15) known to have prominent activating effects on NK cells. The molecule, when tested by flow cytometry, shows activation of NK cells in their numbers and activity. Additionally, the molecule demonstrates anti-cancer effects in an in vivo xenograft model of human MM. We believe that the drug will have the capability of enhancing NK cells at the site of the immune synapse, i.e., the effector:target cell interface, and this will promote cancer remissions. [ABSTRACT FROM AUTHOR]