Journal
MEDCHEMCOMM
Volume 9, Issue 5, Pages 783-788Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c8md00010g
Keywords
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Funding
- MEXT, Japan [17K19204]
- JSPS [17J05032]
- Grants-in-Aid for Scientific Research [17K19204, 17J05032] Funding Source: KAKEN
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Antibody-dependent cell-mediated cytotoxicity (ADCC) is caused by natural killer (NK) cells upon recognition of antigen-bound IgG via Fc gamma RIIIa. This mechanism is crucial for cytolysis of pathogen-infected cells and monoclonal antibody (mAb)-mediated elimination of cancer cells. However, there is concern that mAb-based cancer therapy induces ADCC against non-target cells expressing antigens. To date, no strategy has been reported to enhance the selectivity of ADCC to protect non-target cells expressing antigens. Here, we introduce a model inhibitor which specifically blocks ADCC of anti-EGFR mAbs towards EGFR/folate receptor alpha (FR alpha) double positive cells. This inhibitor recruits mAbs on the FRa of the cell surface independent of Fab antigen recognition. The resulting ternary and/or quaternary complexes formed on the cell surface suppress signal transduction of Fc gamma RIIIa in NK cells, consequently leading to more specific ADCC.
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