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Eur J Immunol. 2019 Feb;49(2):228-241. doi: 10.1002/eji.201847611. Epub 2018 Dec 17.

Human anti-NKp46 antibody for studies of NKp46-dependent NK cell function and its applications for type 1 diabetes and cancer research.

Author information

1
The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, The BioMedical Research Institute Israel Canada of the Faculty of Medicine (IMRIC), The Hebrew University Hadassah Medical School, Jerusalem, Israel.
2
Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
3
Core Research Facility, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
4
Chromatography Unit, Scientific Equipment Center, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
5
The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
6
Department of Histology and Embryology and Center for Proteomics, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.

Abstract

Natural killer (NK) cells are innate lymphocytes that efficiently eliminate cancerous and infected cells. NKp46 is an important NK activating receptor shown to participate in recognition and activation of NK cells against pathogens, tumor cells, virally infected cells, and self-cells in autoimmune conditions, including type I and II diabetes. However, some of the NKp46 ligands are unknown and therefore investigating human NKp46 activity and its critical role in NK cell biology is problematic. We developed a unique anti-human NKp46 monocloncal antibody, denoted hNKp46.02 (02). The 02 mAb can induce receptor internalization and degradation. By binding to a unique epitope on a particular domain of NKp46, 02 lead NKp46 to lysosomal degradation. This downregulation therefore enables the investigation of all NKp46 activities. Indeed, using the 02 mAb we determined NK cell targets which are critically dependent on NKp46 activity, including certain tumor cells lines and human pancreatic beta cells. Most importantly, we showed that a toxin-conjugated 02 inhibits the growth of NKp46-positive cells; thus, exemplifying the potential of 02 in becoming an immunotherapeutic drug to treat NKp46-dependent diseases, such as, type I diabetes and NK and T cell related malignancies.

KEYWORDS:

NK cells; NKp46; antibody; cancer; type 1 diabetes

PMID:
30536875
DOI:
10.1002/eji.201847611

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