Genetic variants of IgG1 antibodies and FcγRIIIa receptors influence the magnitude of antibody-dependent cell-mediated cytotoxicity against prostate cancer cells

Antibody-dependent, cell-mediated cytotoxicity (ADCC) is one of the major mechanisms underlying the clinical efficacy of anticancer monoclonal antibodies (mAbs), such as the mucin 1 (MUC1)-targeting molecule HuHMFG1. IgG antibodies trigger ADCC upon interaction with Fcγ receptors (FcγRs) expressed on the surface of immune effector cells. Polymorphisms affecting FcγRs are known to influence the magnitude of ADCC, but the impact of natural genetic variations in the Fc-coding sequence, γ marker (GM) allotypes, has not been adequately investigated. Using an ADCC inhibition assay, we demonstrate that IgG1 antibodies of the 3+, 1−, 2− GM allotype block almost all valine-containing FcγRIIIa receptors expressed by natural killer (NK) cells, inhibiting by 93% their ability to mediate HuHMFG1-dependent ADCC against DU145 prostate cancer cells. Of note, the ADCC-inhibitory effect of the same IgG1 molecules was significantly reduced when NK cells expressed phenylalanine-containing FcγRIIIa (93% vs. 50%; P = 0.0000005). These and other findings presented here have important therapeutic implications for the use of anti-MUC1 mAbs in patients with prostate cancer and other MUC1-overexpressing adenocarcinomas.