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Enhancement of NK Cell Antitumor Effector Functions Using a Bispecific Single Domain Antibody Targeting CD16 and the
Elisa C Toffoli1, Abdolkarim Sheikhi1,2, Roeland Lameris1
1Amsterdam Infection and Immunity Institute, Cancer Center Amsterdam, Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
Abstract:
The ability to kill tumor cells while maintaining an acceptable safety profile makes Natural Killer (NK) cells promising assets for cancer therapy. Strategies to enhance the preferential accumulation and activation of NK cells in the tumor microenvironment can be expected to increase the efficacy of NK cell-based therapies. In this study, we show binding of a novel bispecific single domain antibody (VHH) to both CD16 (FcRγIII) on NK cells and the epidermal growth factor receptor (EGFR) on tumor cells of epithelial origin. The bispecific VHH triggered CD16- and EGFR-dependent activation of NK cells and subsequent lysis of tumor cells, regardless of the KRAS mutational status of the tumor. Enhancement of NK cell activation by the bispecific VHH was also observed when NK cells of colorectal cancer (CRC) patients were co-cultured with EGFR expressing tumor cells. Finally, higher levels of cytotoxicity were found against patient-derived metastatic CRC cells in the presence of the bispecific VHH and autologous peripheral blood mononuclear cells or allogeneic CD16 expressing NK cells. The anticancer activity of CD16-EGFR bispecific VHHs reported here merits further exploration to assess its potential therapeutic activity either alone or in combination with adoptive NK cell-based therapeutic approaches.
Insights
A novel bispecific antibody targets Natural Killer (NK) cells and tumor cells, enhancing NK cell cancer-killing activity. This approach shows promise for improving cancer immunotherapies, particularly for colorectal cancer (CRC).
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Natural Killer (NK) cells are crucial for cancer therapy due to their tumor-killing ability and safety profile.
- Enhancing NK cell activity within the tumor microenvironment is key to improving cancer treatment efficacy.
Purpose of the Study:
- To investigate a novel bispecific single domain antibody (VHH) targeting CD16 on NK cells and epidermal growth factor receptor (EGFR) on tumor cells.
- To evaluate the VHH's ability to activate NK cells and induce tumor cell lysis.
Main Methods:
- Developed a bispecific VHH antibody binding to CD16 (FcγIII) on NK cells and EGFR on epithelial tumor cells.
- Assessed NK cell activation and tumor cell lysis in vitro using co-culture systems with tumor cells and NK cells from healthy donors and colorectal cancer (CRC) patients.
- Evaluated cytotoxicity against patient-derived metastatic CRC cells.
Main Results:
- The bispecific VHH successfully triggered CD16- and EGFR-dependent NK cell activation and tumor cell lysis, irrespective of KRAS mutation status.
- Enhanced NK cell activation was observed in CRC patient-derived NK cells co-cultured with EGFR-expressing tumor cells.
- Increased cytotoxicity was demonstrated against metastatic CRC cells using the bispecific VHH with autologous or allogeneic NK cells.
Conclusions:
- The novel CD16-EGFR bispecific VHH demonstrates potent anticancer activity by enhancing NK cell-mediated tumor cell killing.
- This approach holds therapeutic potential as a standalone treatment or in combination with adoptive NK cell therapies for epithelial cancers, including CRC.
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