Abstract
Antibody-dependent cell-mediated cytotoxicity (ADCC) mediated through the IgG Fc receptor FcγRIIIa represents a major effector function of many therapeutic antibodies. In an attempt to further enhance natural killer (NK) cell-mediated ADCC, we combined therapeutic antibodies against CD20 and CD38 with recombinant immunoligands against the stimulatory NK cell receptors NKG2D or NKp30. These immunoligands, respectively designated as ULBP2:7D8 and B7-H6:7D8, contained the CD20 scFv 7D8 as a targeting moiety and a cognate ligand for either NKG2D or NKp30 (i.e. ULBP2 and B7-H6, respectively). Both the immunoligands synergistically augmented ADCC in combination with the CD20 antibody rituximab and the CD38 antibody daratumumab. Combinations with ULBP2:7D8 resulted in higher cytotoxicity compared to combinations with B7-H6:7D8, suggesting that coligation of FcγRIIIa with NKG2D triggered NK cells more efficiently than with NKp30. Addition of B7-H6:7D8 to ULBP2:7D8 and rituximab in a triple combination did not further increase the extent of tumor cell lysis. Importantly, immunoligand-mediated enhancement of ADCC was also observed for tumor cells and autologous NK cells from patients with hematologic malignancies, in which, again, ULBP2:7D8 was particularly active. In summary, co-targeting of NKG2D was more effective in promoting rituximab or daratumumab-mediated ADCC by NK cells than co-ligation of NKp30. The observed increase in the ADCC activity of these therapeutic antibodies suggests promise for a ‘dual-dual-targeting’ approach in which tumor cell surface antigens are targeted in concert with two distinct activating NK cell receptors (i.e. FcγRIIIa and NKG2D or B7-H6).
Highlights
The introduction of antibodies into standard treatment regimens has improved the outcome of lymphoma and leukemia patients significantly.[1,2] despite the success, certain subgroups of patients and those with advanced disease stages are often refractory to immuno-chemotherapy
Simultaneous binding of both rituximab and the immunoligands to individual lymphoma cells was detected (Fig. 1A), albeit at reduced levels as compared to single agents (Figs. 1B, C). This became obvious when rituximab was combined with B7 homolog 6 (B7-H6):7D8, which was employed at higher concentrations than UL-16 binding protein 2 (ULBP2):7D8 to compensate for its previously observed lower cytotoxic capacity.[29]
Both ULBP2:7D8 and B7-H6:7D8 promoted Antibody-dependent cell-mediated cytotoxicity (ADCC) by the therapeutic antibodies rituximab and daratumumab synergistically, indicating that natural killer (NK) cell cytotoxicity was enhanced by simultaneous engagement of FcgRIIIa and either natural killer group 2 member D (NKG2D) or NKp30
Summary
The introduction of antibodies into standard treatment regimens has improved the outcome of lymphoma and leukemia patients significantly.[1,2] despite the success, certain subgroups of patients and those with advanced disease stages are often refractory to immuno-chemotherapy. Improving antibody therapy remains a major effort in translational research. Various mechanisms of action are discussed to contribute to the efficacy of therapeutic antibodies in patients, including induction of apoptosis, complement-dependent cytotoxicity, ADCC, phagocytosis and T cell-based immune responses.[2]. The relative contribution of individual mechanisms is not fully understood and may vary for different antibodies and tumor entities. Results from several animal models suggested that recruitment of effector cells by engagement of FcgR expressed by various effector cells and induction of cellmediated cytotoxicity are important antibody functions in vivo.[3,4,5,6] The importance of Fc receptor engagement by therapeutic antibodies is evidenced by clinical observations.
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