title: Expression and targeting of human fibroblast activation protein in a human skin/severe combined immunodeficient mouse breast cancer xenograft model.
abstract: Antigens and receptors that are highly expressed on tumor stromal cells, such as fibroblast activation protein (FAP), are attractive targets for antibody-based therapies because the supporting stroma and vessel network is essential for a solid neoplasm to grow beyond a size of 1-2 mm. The in vivo characterization of antibodies targeting human stromal or vessel antigens is hindered by the lack of an appropriate mouse model system because xenografts in standard mouse models express stromal and vessels elements of murine origin. This limitation may be overcome by the development of a human skin/mouse chimeric model, which is established by transplanting human foreskin on to the lateral flank of severe combined immunodeficient mice. The subsequent inoculation of breast carcinoma MCF-7 cells within the dermis of the transplanted human skin resulted in the production of xenografts expressing stromal and vessel elements of human origin. Widespread expression of human FAP-positive reactive stromal fibroblasts within xenografts was seen up to 2 months posttransplantation and postinjection of cells. Human blood vessel antigen expression also persisted at 2 months posttransplantation and postinjection of cells with murine vessels coexisting with the human vascular supply. The model was subsequently used to evaluate the biodistribution properties of an iodine-131-labeled humanized anti-FAP monoclonal antibody (BIBH-7). The results showed high specific targeting of the stromal compartment of the xenograft, indicating that the model provides a useful and novel approach for the in vivo assessment of the immunotherapeutic potential of molecules targeting human stroma and angiogenic systems.
authors.affiliation: Tumour Targeting Program, Ludwig Institute for Cancer Research, Melbourne Branch, Austin, Victoria 3084, Australia.
authors.forename: Kiki
authors.initials: K
authors.lastname: Tahtis
authors.forename: Fook-Thean
authors.initials: FT
authors.lastname: Lee
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Wheatley
authors.forename: Pilar
authors.initials: P
authors.lastname: Garin-Chesa
authors.forename: John E
authors.initials: JE
authors.lastname: Park
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Smyth
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Obata
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Stockert
authors.forename: Cathrine M
authors.initials: CM
authors.lastname: Hall
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.forename: Wolfgang J
authors.initials: WJ
authors.lastname: Rettig
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm / Q000032:analysis* / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D010450:Endopeptidases; D018093:Gelatinases; D018390:Gene Targeting; D006183:H-2 Antigens / Q000378:metabolism; D015234:HLA-A Antigens / Q000032:analysis; D015235:HLA-B Antigens / Q000032:analysis; D015236:HLA-C Antigens / Q000032:analysis / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D016513:Mice, SCID; D023421:Models, Animal; D009368:Neoplasm Transplantation; D012697:Serine Endopeptidases / Q000032:analysis*; D012867:Skin / Q000737:chemistry; D016038:Skin Transplantation; D017154:Stromal Cells / Q000201:enzymology; D014183:Transplantation, Heterologous; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D010450:Endopeptidases; D018093:Gelatinases; D006183:H-2 Antigens; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha