Reduction of natural killer (NK) cell antibody-dependent cell-mediated cytotoxicity (ADCC) by IgA antibody 3437

Abstract Description ADCC by NK cells is a potent mechanism used to eliminate virally infected cells. It combines the precision of antibody targeting with the immediate cytotoxic power of innate immune cells. ADCC is facilitated by IgG1 antibodies. Viruses, however, induce production of other antibody isotypes, especially IgA during mucosal infections. IgA antibodies are not recognized by the ADCC-mediating NK Fc-gamma-RIII receptor, CD16A. Thus, we aimed to determine if IgA could interfere with ADCC. As a proof of concept, we used commercially available IgG1 and IgA1 rituximab biosimilar mAbs against CD20 (a surface protein of B cells). Cytotoxicity was measured using 51Cr labeled Daudi B cells as targets and NK-92 CD16A WT effector cells. We measured changes in the effective concentration of IgG1 antibody needed for 50% ADCC (EC50s) in the presence of IgA and observed an IgA dose-response reduction of ADCC. The combined concentrations of IgG1 and IgA anti-CD20 were too low to be competitive, as indicated by flow cytometry. Increasing the ratio of NK cells to targets was unable to overcome the IgA’s interference. Consistent with the IgA observations, a separate pair of antibodies that bind or not to CD16A, IgG1 GA101 WT anti-CD20 with engineered Fc LALA-GA101, confirmed that other non-FcR binding antibodies can also impede ADCC. We conclude that the presence of non-CD16A-binding antibodies can reduce ADCC and speculate that this phenomenon might have potential implications for mucosal vaccines. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)