Tumor cell lysis and synergistically enhanced antibody-dependent cell-mediated cytotoxicity by NKG2D engagement with a bispecific immunoligand targeting the HER2 antigen
Kellner, Christian; Lutz, Sebastian; Oberg, Hans-Heinrich; Wesch, Daniela; Otte, Anna; Diemer, Katarina J; Wilcken, Hauke; Bauerschlag, Dirk; Glüer, Claus-Christian; Wichmann, Christian; Kabelitz, Dieter; Leusen, Jeanette H W; Klausz, Katja; Humpe, Andreas; Gramatzki, Martin; Peipp, Matthias
(2022) Biological Chemistry, volume 403, issue 5-6, pp. 545 - 556
(Article)
Abstract
Natural killer group 2 member D (NKG2D) plays an important role in the regulation of natural killer (NK) cell cytotoxicity in cancer immune surveillance. With the aim of redirecting NK cell cytotoxicity against tumors, the NKG2D ligand UL-16 binding protein 2 (ULBP2) was fused to a single-chain fragment variable (scFv)
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targeting the human epidermal growth factor receptor 2 (HER2). The resulting bispecific immunoligand ULBP2:HER2-scFv triggered NK cell-mediated killing of HER2-positive breast cancer cells in an antigen-dependent manner and required concomitant interaction with NKG2D and HER2 as revealed in antigen blocking experiments. The immunoligand induced tumor cell lysis dose-dependently and was effective at nanomolar concentrations. Of note, ULBP2:HER2-scFv sensitized tumor cells for antibody-dependent cell-mediated cytotoxicity (ADCC). In particular, the immunoligand enhanced ADCC by cetuximab, a therapeutic antibody targeting the epidermal growth factor receptor (EGFR) synergistically. No significant improvements were obtained by combining cetuximab and anti-HER2 antibody trastuzumab. In conclusion, dual-dual targeting by combining IgG1 antibodies with antibody constructs targeting another tumor associated antigen and engaging NKG2D as a second NK cell trigger molecule may be promising. Thus, the immunoligand ULBP2:HER2-scFv may represent an attractive biological molecule to promote NK cell cytotoxicity against tumors and to boost ADCC.
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Keywords: ADCC, antibody therapy, EGFR, HER2, NK cells, NKG2D, Molecular Biology, Biochemistry, Clinical Biochemistry, Journal Article
ISSN: 1431-6730
Publisher: Walter de Gruyter GmbH & Co. KG
Note: Funding Information: Research funding: This study was supported by intramural funding from the Christian-Albrechts-University of Kiel (to C.K.) and research grant 2014.134.1 by the Wilhelm Sander Foundation (to C.K. and M.P.) and the German Cancer Aid (Mildred-Scheel-Professorship program to M.P.). Publisher Copyright: © 2021 Walter de Gruyter GmbH, Berlin/Boston.
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