biostudies-literatureUnknown5(1)Schanin JMast cells (MC) are key drivers of allergic and inflammatory diseases. Sialic acid-binding immunoglobulin-like lectin (Siglec)-6 is an immunoregulatory receptor found on MCs. While it is recognized that engaging Siglecs with antibodies mediates inhibition across immune cells, the mechanisms that govern this agonism are not understood. Here we generated Siglec-6 mAb clones (AK01 to AK18) to better understand Siglec-6-mediated agonism. Siglec-6 mAbs displayed epitope-dependent receptor internalization and inhibitory activity. We identified a Siglec-6 mAb (AK04) that required Fc-mediated interaction for receptor internalization and induced inhibition and antibody-dependent cellular phagocytosis against MCs. AK04-mediated MC inhibition required Siglec-6 immunoreceptor tyrosine-based inhibitoryCommunications biology1226https://www.ebi.ac.uk/biostudies/studies/S-EPMC9652399biostudies-literatureDiscovery of an agonistic Siglec-6 antibody that inhibits and reduces human mast cells.PMC9652399De Freitas NChang KBrehm MAYoungblood BASchanin JLuu TBenet ZLeung JKorver WBrock ECXu AWong ALuehrsen KfalseDiscovery of an agonistic Siglec-6 antibody that inhibits and reduces human mast cells.Mast cells (MC) are key drivers of allergic and inflammatory diseases. Sialic acid-binding immunoglobulin-like lectin (Siglec)-6 is an immunoregulatory receptor found on MCs. While it is recognized that engaging Siglecs with antibodies mediates inhibition across immune cells, the mechanisms that govern this agonism are not understood. Here we generated Siglec-6 mAb clones (AK01 to AK18) to better understand Siglec-6-mediated agonism. Siglec-6 mAbs displayed epitope-dependent receptor internalization and inhibitory activity. We identified a Siglec-6 mAb (AK04) that required Fc-mediated interaction for receptor internalization and induced inhibition and antibody-dependent cellular phagocytosis against MCs. AK04-mediated MC inhibition required Siglec-6 immunoreceptor tyrosine-based inhibitory2022-01-01T00:00:00Z2022 Nov2026-07-14T15:49:51.494Z2025-04-06T02:39:00.154ZS-EPMC96523993636935810.1038/s42003-022-04207-w