A common feature of human
IgG1 antibodies used for
cancer treatment is that their anti-tumour efficacy requires high serum trough levels and continued
therapy for several months. Treatment cycles, thereby, consume several grams of
IgG1 translating into significant
drug needs and costs. The basis for the low in vivo efficacy, which is in contrast to high in vitro antibody-dependent cellular cytotoxicity (ADCC), is not well understood. Here, we have explored factors contributing to this discrepancy using
adecatumumab (MT201), a fully human monoclonal
IgG1 against
epithelial cell adhesion molecule (
Ep-CAM) and
trastuzumab (
Herceptin), a humanized
IgG1 with specificity for the human epithelial
growth factor receptor type 2 (HER-2)
antigen. We found that physiological levels of human sera strongly inhibited ADCC of both
IgG1 antibodies. Effects showed some dependence on the density of
Ep-CAM and HER-2 targets, the tumour cell line tested and on effector cell and serum donors. Removal of
IgG by affinity chromatography abolished the inhibitory effect of a serum pool. Inhibition of ADCC was fully restored by adding back the
IgG fraction or by an equal amount of
IgG from a commercial source. We further demonstrate that CD56-positive lymphocytes within human PBMC contributed >90% to ADCC and that normal serum levels of
IgG effectively competed for in vitro binding of an
IgG1 antibody to low-affinity Fcgamma receptor type III (CD16), as is present on natural killer (NK) cells. Competition of serum
IgG for binding of therapeutic
IgG1 to NK cell may be one important reason why high antibody doses are required in the clinic for treatment of
cancer by an ADCC-based mechanism.