title: Exchanging human Fcgamma1 with murine Fcgamma2a highly potentiates anti-tumor activity of anti-EpCAM antibody adecatumumab in a syngeneic mouse lung metastasis model.
abstract: An important mode of action shared by human IgG1 antibody therapies is antibody-dependent cellular cytotoxicity (ADCC). ADCC relies on the interaction of the antibody's Fc portion with Fc-gama receptors (FcgammaR) on immune effector cells. The anti-tumor activity of human IgG1 antibodies is frequently assessed in mouse models. Binding of human IgG1 to murine FcgammaRs is however of reduced affinity. We here show that ADCC of adecatumumab (MT201), a fully human IgG1 antibody specific for epithelial cell adhesion molecule (EpCAM/CD326), is drastically lower if human peripheral blood mononuclear cells are replaced by murine splenocytes as effector cells. When the variable domains of adecatumumab were genetically fused to a murine IgG2a backbone (yielding mu-adecatumumab), ADCC with murine effector cells was much improved, but at the same time significantly reduced with human effector cells. The serum half-lives of adecatumumab and mu-adecatumumab were determined in mice and dosing schedules established that gave similar serum trough levels during a 4-week antibody treatment. The anti-tumor activities of adecatumumab and mu-adecatumumab were then compared side-by-side in a lung metastasis mouse model established with a syngeneic B16 melanoma line expressing human EpCAM at physiologically relevant levels. Treatment of mice with mu-adecatumumab led to an almost complete prevention of lung metastases, while the human version of the antibody was much less active. This shows that adecatumumab has high anti-tumor activity when tested in a form that is better compatible with the species' immune system. Moreover, our data suggest to routinely compare in mouse models human IgG1 and murine IgG2a versions of antibodies to properly assess the contribution of ADCC to overall anti-tumor activity.
authors.affiliation: Micromet AG, Staffelseestr. 2, 81477 Munich, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Lutterbuese
authors.forename: Klaus
authors.initials: K
authors.lastname: Brischwein
authors.forename: Robert
authors.initials: R
authors.lastname: Hofmeister
authors.forename: Sandrine
authors.initials: S
authors.lastname: Crommer
authors.forename: Grit
authors.initials: G
authors.lastname: Lorenczewski
authors.forename: Laetitia
authors.initials: L
authors.lastname: Petersen
authors.forename: Sandra
authors.initials: S
authors.lastname: Lippold
authors.forename: Antonio
authors.initials: A
authors.lastname: da Silva
authors.forename: Mathias
authors.initials: M
authors.lastname: Locher
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Baeuerle
authors.forename: Bernd
authors.initials: B
authors.lastname: Schlereth
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity; D015703:Antigens, CD / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D000071858:Epithelial Cell Adhesion Molecule; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D009362:Neoplasm Metastasis / Q000188:drug therapy; D017452:Receptors, IgG / Q000276:immunology*; D013045:Species Specificity; D014185:Transplantation, Isogeneic
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C489017:FCGR1A protein, human; C080568:Fc gamma receptor IIA; D017452:Receptors, IgG; C460839:adecatumumab