NDLI: HER2-specific immunoligands engaging NKp30 or NKp80 trigger NK-cell-mediated lysis of tumor cells and enhance antibody-dependent cell-mediated cytotoxicity

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HER2-specific immunoligands engaging NKp30 or NKp80 trigger NK-cell-mediated lysis of tumor cells and enhance antibody-dependent cell-mediated cytotoxicity

Content Provider	Semantic Scholar
Author	Peipp, Matthias Derer, Stefanie Lohse, Stefan Staudinger, Matthias Klausz, Katja Valerius, Thomas Gramatzki, Martin Kellner, Christian Johannes
Copyright Year	2015
Abstract	NK cells detect tumors through activating surface receptors, which bind self-antigens that are frequently expressed upon malignant transformation. To increase the recognition of tumor cells, the extracellular domains of ligands of the activating NK cell receptors NKp30, NKp80 and DNAM-1 (i.e. B7-H6, AICL and PVR, respectively) were fused to a single-chain fragment variable (scFv) targeting the human epidermal growth factor receptor 2 (HER2), which is displayed by various solid tumors. The resulting immunoligands, designated B7-H6:HER2-scFv, AICL:HER2-scFv, and PVR:HER2-scFv, respectively, bound HER2 and the addressed NK cell receptor. However, whereas B7-H6:HER2-scFv and AICL:HER2-scFv triggered NK cells to kill HER2-positive breast cancer cells at nanomolar concentrations, PVR:HER2-scFv was not efficacious. Moreover, NK cell cytotoxicity was enhanced synergistically when B7-H6:HER2-scFv or AICL:HER2-scFv were applied in combination with another HER2-specific immunoligand engaging the stimulatory receptor NKG2D. In contrast, no improvements were achieved by combining B7-H6:HER2-scFv with AICL:HER2-scFv. Additionally, B7-H6:HER2-scFv and AICL:HER2-scFv enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) by the therapeutic antibodies trastuzumab and cetuximab synergistically, with B7-H6:HER2-scFv exhibiting a higher efficacy. In summary, antibody-derived proteins engaging NKp30 or NKp80 may represent attractive biologics to further enhance anti-tumor NK cell responses and may provide an innovative approach to sensitize tumor cells for antibody-based immunotherapy.
Starting Page	32075
Ending Page	32088
Page Count	14
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://ftp.ncbi.nlm.nih.gov/pub/pmc/ce/8a/oncotarget-06-32075.PMC4741660.pdf
PubMed reference number	4741660
Alternate Webpage(s)	https://doi.org/10.18632/oncotarget.5135
DOI	10.18632/oncotarget.5135
Journal	Oncotarget
Volume Number	6
Language	English
Access Restriction	Open
Subject Keyword	Antibody-Dependent Cellular Cytotoxicity Autoantigens Biological Factors CD226 gene CLEC2B gene Cell-Mediated Cytolysis Exhibits as Topic Growth Factor Receptors Immunotherapy KLRF1 gene Ligands Malignant Childhood Central Nervous System Neoplasm Mammary Neoplasms NCR3 gene NCR3 wt Allele Natural Killer Cells PVR gene Proliferative vitreoretinopathy Receptors, Cell Surface Receptors, Natural Killer Cell cancer cell cellular targeting cetuximab pathologic cytolysis solid tumor trastuzumab
Content Type	Text
Resource Type	Article

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