Journal
ONCOIMMUNOLOGY
Volume 5, Issue 1, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2015.1058459
Keywords
ADCC; antibody; CD20; NK cells; NKp30; NKG2D
Categories
Funding
- Deutsche Krebshilfe e.V., Bonn, Germany [110951]
- Wilhelm Sander Stiftung, Neustadt, Germany [2007.065.2]
- Werner und Lara Kreitz Stiftung (Bad Segeberg, Germany)
- Christian-Albrechts-University Kiel
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Antibody-dependent cell-mediated cytotoxicity (ADCC) mediated through the IgG Fc receptor Fc gamma RIIIa 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 Fc gamma RIIIa 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. Fc gamma RIIIa and NKG2D or B7-H6).
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