Engaging the NKG2D Receptor with a Novel Bispecific Protein (ULBP2-antiCD138) Activates NK Cells and Has Potent Antitumor Activity Against Human Multiple Myeloma.

NK cells, a component of the innate immune system, attack virus-infected and malignant cells without prior antigen stimulation, mediate cellular cytotoxicity and produce cytokines such as interferon gamma (IFN-gamma) upon stimulation. There is growing evidence that NK cells also participate directly in adaptive immune responses, mainly by cross-talk with dendritic cells. One key factor responsible for the activation of innate and adaptive immune responses is NKG2D, a stimulatory receptor expressed on natural killer cells that binds to cellular ligands on malignant cells. Therefore we designed a recombinant NK receptor ligand (ULBP2) fused to an antibody (BB4) detecting the tumor antigen CD138 which is overexpressed on a variety of malignancies including multiple myeloma (MM). The major findings were that (1) ULBP2-BB4 bound both NK cells and tumor cells, (2) triggered NK-mediated cell lysis of CD138+ malignant cell lines and primary MM cells in the allogenic and autologous setting, (3) activated IFN-gamma secretion of NK cells exposed to immobilized protein, and (4) the co-therapy with ULBP-BB4 and human peripheral blood lymphocytes abrogated the tumor growth in a nude mouse model with subcutaneously growing MM cells. This is the first report on the design, expression, purification and functional pre-clinical investigation of a recombinant NKG2D ligand. The results suggest not only a potential clinical use of this novel construct in patients with MM, but might also offer an innovative therapy approach which is based on NKG2D engagement transferable to other malignancies.