Universität zu Köln

Kloess, Stephan, da Silva, Alessa Ede Valverde, Oberschmidt, Olaf, Gardlowski, Tanja, Matthies, Nadine, Vyas, Maulik, Arseniev, Lubomir, Heuser, Michael ORCID: 0000-0001-5318-9044, von Strandmann, Elke Pogge and Koehl, Ulrike (2017). Triplebody Mediates Increased Anti-Leukemic Reactivity of IL-2 Activated Donor Natural Killer (NK) Cells and Impairs Viability of Their CD33-Expressing NK Subset. Front. Immunol., 8. LAUSANNE: FRONTIERS MEDIA SA. ISSN 1664-3224

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Abstract

Natural killer cells (NK) are essential for the elimination of resistant acute myeloid and acute lymphoblastic leukemia (AML and ALL) cells. NK cell-based immunotherapies have already successfully entered for clinical trials, but limitations due to immune escape mechanisms were identified. Therefore, we extended our established NK cell protocol by integration of the previously investigated powerful trispecific immunoligand ULBP2-aCD19-aCD33 [the so-called triplebodies (TBs)] to improve the anti-leukemic specificity of activated NK cells. IL-2-driven expansion led to strongly elevated natural killer group 2 member D (NKG2D) expressions on donor NK cells which promote the binding to ULBP2(+) TBs. Similarly, CD33 expression on these NK cells could be detected. Dual-specific targeting and elimination were investigated against the B-cell precursor leukemia cell line BV-173 and patient blasts, which were positive for myeloid marker CD33 and B lymphoid marker CD19 exclusively presented on biphenotypic B/myeloid leukemia's. Cytotoxicity assays demonstrated improved killing properties of NK cells pre-coated with TBs compared to untreated controls. Specific NKG2D blocking on those NK cells in response to TBs diminished this killing activity. On the contrary, the observed upregulation of surface CD33 on about 28.0% of the NK cells decreased their viability in response to TBs during cytotoxic interaction of effector and target cells. Similar side effects were also detected against CD33(+) T- and wCD19(+) B-cells. Very preliminary proof of principle results showed promising effects using NK cells and TBs against primary leukemic cells. In summary, we demonstrated a promising strategy for redirecting primary human NK cells in response to TBs against leukemia, which may lead to a future progress in NK cell-based immunotherapies.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kloess, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED da Silva, Alessa Ede Valverde UNSPECIFIED UNSPECIFIED UNSPECIFIED Oberschmidt, Olaf UNSPECIFIED UNSPECIFIED UNSPECIFIED Gardlowski, Tanja UNSPECIFIED UNSPECIFIED UNSPECIFIED Matthies, Nadine UNSPECIFIED UNSPECIFIED UNSPECIFIED Vyas, Maulik UNSPECIFIED UNSPECIFIED UNSPECIFIED Arseniev, Lubomir UNSPECIFIED UNSPECIFIED UNSPECIFIED Heuser, Michael UNSPECIFIED orcid.org/0000-0001-5318-9044 UNSPECIFIED von Strandmann, Elke Pogge UNSPECIFIED UNSPECIFIED UNSPECIFIED Koehl, Ulrike UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-217974
DOI:	10.3389/fimmu.2017.01100
Journal or Publication Title:	Front. Immunol.
Volume:	8
Date:	2017
Publisher:	FRONTIERS MEDIA SA
Place of Publication:	LAUSANNE
ISSN:	1664-3224
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language POTENT ANTITUMOR-ACTIVITY; ACUTE MYELOID-LEUKEMIA; IN-VIVO EXPANSION; MONOCLONAL-ANTIBODY; NKG2D RECEPTOR; EXPRESSION; LIGANDS; CD33; RITUXIMAB; CANCER Multiple languages Immunology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21797