Enhancing Immune Surveillance: Antibody-based Strategies for the Activation and Expansion of Natural Killer (NK) Cells and γδ T cells

Natural Killer cells (NK cells) continuously screen surrounding cells and differentiate between “self” and “missing-self” as well as healthy or stressed/malignant. The activity of NK cells and the corresponding immune response is regulated by a complex interplay of activating and inhibiting receptors and the respective ligands. However, recognition of malignant cells can become difficult when the cells shed the respective signals from the cell surface and thus make themselves invisible to NK cells. In order to restore the recognition of malignant cells and consequently redirect NK cells against malignant cells, antibodies can be used that bind the antigen on tumor cells and activate NK cells by binding to the FcγRIIIa or an activating receptor on NK cells. In the context of this work, novel NK cell engagers (NKCEs) were produced and tested that bridge the epidermal growth factor receptor (EGFR) on tumor cells to NKp30 on NK cells. Once it was established that the bound epitope played a decisive role in the effectiveness of the NKCEs, further attributes of the antibodies were modified to investigate the respective effect of the modification. In addition to the lack of recognition by NK cells, selected patients show a reduced number of effector cells, as well as a certain dysfunction of these. Therefore, an adoptive cell transfer (ACT) of cytotoxic NK cells represents a promising approach to treat these patients. However, the expansion of cytotoxic NK cells is not trivial and often requires the use of genetically modified feeder cells. In this work, a novel technology for the ex vivo expansion of NK cells was established that obviates the need of genetically modified feeder cells and achieved high numbers of cytotoxic NK cells which are well suited for the development of therapies based on ACT.

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