title: Co-transplantation of human hematopoietic stem cells and human breast cancer cells in NSG mice: a novel approach to generate tumor cell specific human antibodies.
abstract: Humanized tumor mice (HTM) were generated by the co-transplantation of human hematopoietic stem cells and human breast cancer cells overexpressing HER2 into neonatal NOD-scid IL2Rγ(null) (NSG) mice. These mice are characterized by the development of a human immune system in combination with human breast cancer growth. Due to concurrent transplantation into newborn mice, transfer of MHC-mismatched tumor cells resulted in solid coexistence and immune cell activation (CD4(+) T cells, natural killer cells, and myeloid cells), but without evidence for rejection. Histological staining of the spleen of HTM revealed co-localization of human antigen-presenting cells together with human T and B cells allowing MHC-dependent interaction, and thereby the generation of T cell-dependent antibody production. Here, we investigated the capability of these mice to generate human tumor-specific antibodies and correlated immunoglobulin titers with tumor outgrowth. We found detectable IgM and also IgG amounts in the serum of HTM, which apparently controlled tumor development when IgG serum concentrations were above 10 µg/ml. Western blot analyses revealed that the tumor-specific antibodies generated in HTM did not recognize HER2/neu antigens, but different, possibly relevant antigens for breast cancer therapy. In conclusion, HTM offer a novel approach to generate complete human monoclonal antibodies that do not require further genetic manipulation (e. g., humanization) for a potential application in humans. In addition, efficacy and safety of the generated antibodies can be tested in the same mouse model under human-like conditions. This might be of particular interest for cancer subtypes with no currently available antibody therapy.
authors.affiliation: Department of Gynecology and Obstetrics; University Medical Center Regensburg; Regensburg, Germany.
authors.forename: Anja K
authors.initials: AK
authors.lastname: Wege
authors.affiliation: Department of Obstetrics and Gynecology; University Hospital; Mainz, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Department of Cell Engineering/GLP; Fraunhofer Institute for Cell Therapy and Immunology; Leipzig, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Ueberham
authors.affiliation: Department of Gynecology and Obstetrics; University Medical Center Regensburg; Regensburg, Germany.
authors.forename: Marvin
authors.initials: M
authors.lastname: Ponnath
authors.affiliation: Department of Gynecology and Obstetrics; University Medical Center Regensburg; Regensburg, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Ortmann
authors.affiliation: Department of Gynecology and Obstetrics; University Medical Center Regensburg; Regensburg, Germany.
authors.forename: Gero
authors.initials: G
authors.lastname: Brockhoff
authors.affiliation: Department of Cell Engineering/GLP; Fraunhofer Institute for Cell Therapy and Immunology; Leipzig, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Lehmann
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology*; D001943:Breast Neoplasms / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D064593:Heterografts; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation
chemical_list: D000912:Antibodies, Neoplasm; D007074:Immunoglobulin G; D007075:Immunoglobulin M
keywords: IgG; IgM; breast cancer; humanized tumor mice (HTM); tumor-specific antibodies