title: Enhancing natural killer cell-mediated lysis of lymphoma cells by combining therapeutic antibodies with CD20-specific immunoligands engaging NKG2D or NKp30.
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).
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine; Christian-Albrechts-University Kiel; Kiel, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kellner
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine; Christian-Albrechts-University Kiel; Kiel, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Günther
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine; Christian-Albrechts-University Kiel; Kiel, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Humpe
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine; Christian-Albrechts-University Kiel; Kiel, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Repp
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine; Christian-Albrechts-University Kiel; Kiel, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Klausz
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine; Christian-Albrechts-University Kiel; Kiel, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Derer
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine; Christian-Albrechts-University Kiel; Kiel, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Valerius
authors.affiliation: 2nd Department of Medicine; Christian-Albrechts-University Kiel ; Kiel, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ritgen
authors.affiliation: 2nd Department of Medicine; Christian-Albrechts-University Kiel ; Kiel, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Brüggemann
authors.affiliation: Genmab; Utrecht, the Netherlands; Department of Immunology; University Medical Center Utrecht; Utrecht, the Netherlands.
authors.forename: Jan Gj
authors.initials: JG
authors.lastname: van de Winkel
authors.affiliation: Genmab; Utrecht, the Netherlands; Department of Cancer and Inflammation Research; Institute of Molecular Medicine; University of Southern Denmark; Odense, Denmark; Department of Immunohematology and Blood Transfusion; Leiden University Medical Center; Leiden, the Netherlands.
authors.forename: Paul Whi
authors.initials: PW
authors.lastname: Parren
authors.affiliation: 2nd Department of Medicine; Christian-Albrechts-University Kiel ; Kiel, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kneba
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine; Christian-Albrechts-University Kiel; Kiel, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Gramatzki
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine; Christian-Albrechts-University Kiel; Kiel, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Peipp
keywords: ADCC; CD20; NK cells; NKG2D; NKp30; antibody