Vyas, Maulik ORCID: 0000-0003-2996-4682, Schneider, Ann-Charlott, Shatnyeva, Olga, Reiners, Katrin S., Tawadros, Samir, Kloess, Stephan, Koehl, Ulrike, Hallek, Michael, Hansen, Hinrich P. and von Strandmann, Elke Pogge (2016). Mono- and dual-targeting triplebodies activate natural killer cells and have anti-tumor activity in vitro and in vivo against chronic lymphocytic leukemia. OncoImmunology, 5 (9). PHILADELPHIA: TAYLOR & FRANCIS INC. ISSN 2162-402X

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Abstract

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia that affects B lymphocytes in adults. Natural killer (NK) cells in CLL patients are intrinsically potent but display poor in situ effector functions. NKG2D is an activating receptor found on NK and CD8(+) T cells and plays a role in immunosurveillance of CLL. In this study, we developed mono- and dual-targeting triplebodies utilizing a natural ligand for human NKG2D receptor (ULBP2) to retarget NK cells against tumor cells. Triplebodies in both formats showed better ability to induce NK-cell-dependent killing of target cells compared to bispecific counterparts. A mono-targeting triplebody ULBP2-aCD19-aCD19 successfully triggered NK cell effector functions against CLL cell line MEC1 and primary tumor cells in allogenic and autologous settings. Additionally, a dual-targeting triplebody ULBP2-aCD19-aCD33 specific for two distinct tumor-associated antigens was developed to target antigen loss variants, such as mixed lineage leukemia (MLL). Of note, this triplebody exhibited cytotoxic activity against CD19/CD33 double positive cells and retained its binding features even in the absence of one of the tumor antigens. Further, ULBP2-aCD19-aCD19 showed significant in vivo activity in immune-deficient (NSG) mouse model transplanted with CLL cell line as target cells and human immune cells as an effector population providing a proof-of-principle for this therapeutic concept.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Vyas, MaulikUNSPECIFIEDorcid.org/0000-0003-2996-4682UNSPECIFIED
Schneider, Ann-CharlottUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shatnyeva, OlgaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reiners, Katrin S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tawadros, SamirUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kloess, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koehl, UlrikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hansen, Hinrich P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Strandmann, Elke PoggeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-288950
DOI: 10.1080/2162402X.2016.1211220
Journal or Publication Title: OncoImmunology
Volume: 5
Number: 9
Date: 2016
Publisher: TAYLOR & FRANCIS INC
Place of Publication: PHILADELPHIA
ISSN: 2162-402X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
T-CELLS; NKG2D RECEPTOR; TUMOR-CELLS; NK CELLS; MULTIPLE-MYELOMA; ANTIGEN; GAMMA; CYTOTOXICITY; LIGANDS; LYSISMultiple languages
Oncology; ImmunologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/28895

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