Vyas, Maulik (2016). Development of novel trispecific immunoligands (triplebodies) to retarget natural killer cells against chronic lymphocytic leukemia. PhD thesis, Universität zu Köln.

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Abstract

Chronic lymphocytic leukemia of B cells (B-CLL or CLL) involves malignant transformation of mature B lymphocytes and is characterized by accumulation of CD19+ CD5+ monoclonal B cells. Chemo-immunotherapy and recently approved kinase inhibitors are currently used for the treatment of CLL patients. Despite significant advances in the field, many patients relapse and CLL remains an incurable disease. Natural Killer (NK) cells in CLL patients are intrinsically potent but fail to be activated against malignant B cells. Soluble ligands for the Natural-killer group 2 member D (NKG2D), an activating receptor on NK cells, are one of the main players in inhibiting NK cell activity in CLL. To this end, novel immunotherapies that can harness NK cells to kill CLL cells are warranted. Here, I developed recombinant trispecific immunoligands (triplebodies) in three different formats but with a common aim to retarget NK cells against CLL. A mono-targeting triplebody ULBP2-aCD19-aCD19 utilized an NKG2D ligand ULBP2 to successfully retarget NK cells against CD19+ CLL cell line and primary tumor cells in both, allogeneic and autologous settings. Further, significant in vivo potency of this triplebody was observed in immunodeficient (NSG) mouse model. A dual-targeting triplebody ULBP2-aCD19-aCD33 was specifically generated to target antigen loss variants in cancer. Dual specificity of this triplebody was functional and could eliminate CD19+CD33+ tumor cells as well as CD19loss and CD33loss tumor variants. Finally, the third format a dual activating triplebody ULBP2-aCD19-aNKR was developed to enhance the activation of NK cells. NKR is another major activating receptor on NK cells and stimulation of this receptor by the triplebody greatly improved the NK cell effector functions. Clinical implications and foreseeable challenges for all three triplebodies are discussed in the context of CLL.

Item Type: Thesis (PhD thesis)
Creators:
CreatorsEmailORCID
Vyas, Maulikmaulikkvyas@gmail.comUNSPECIFIED
URN: urn:nbn:de:hbz:38-77343
Subjects: Natural sciences and mathematics
Medical sciences Medicine
Uncontrolled Keywords:
KeywordsLanguage
ImmunoligandsEnglish
Natural Killer cellsEnglish
Cancer ImmunotherapyEnglish
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences
Language: English
Date: 15 October 2016
Date of oral exam: 30 November 2016
Referee:
NameAcademic Title
Nürnberg, PeterProf. Dr.
Pogge von Strandmann, ElkeProf. Dr.
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/7734

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