title: High concentrations of therapeutic IgG1 antibodies are needed to compensate for inhibition of antibody-dependent cellular cytotoxicity by excess endogenous immunoglobulin G.
abstract: 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.
authors.affiliation: Micromet AG, Staffelseestrasse 2, 81477 Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Preithner
authors.forename: Stefanie
authors.initials: S
authors.lastname: Elm
authors.forename: Sandra
authors.initials: S
authors.lastname: Lippold
authors.forename: Mathias
authors.initials: M
authors.lastname: Locher
authors.forename: Andreas
authors.initials: A
authors.lastname: Wolf
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: da Silva
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Baeuerle
authors.forename: Nadja S
authors.initials: NS
authors.lastname: Prang
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000918:Antibody Specificity; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects* / Q000276:immunology*; D001667:Binding, Competitive / Q000187:drug effects; D001782:Blood Donors; D019002:CD56 Antigen / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology*; D017452:Receptors, IgG / Q000378:metabolism; D044967:Serum; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019002:CD56 Antigen; D015815:Cell Adhesion Molecules; D007074:Immunoglobulin G; D017452:Receptors, IgG; C460839:adecatumumab; D000068878:Trastuzumab