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Tumour Targeting Program, Ludwig Institute for Cancer Research, Melbourne Branch, Austin and Repatriation Medical Centre, Victoria 3084, Australia [K. T., F-T. L., J. M. W., F. E. S., C. M. H., A. M. S.]; Department of Surgery, Austin and Repatriation Medical Centre, Victoria 3084, Australia [J. M. W.]; RIKEN Bioresource Centre, Tsukuba Institute, Tsubuka 305-0074, Japan [Y. O.]; Ludwig Institute for Cancer Research, New York Branch, Memorial Sloan Kettering Cancer Center, New York, New York 10021 [E. S., L. J. O.]; and Department of Oncology Research, Boehringer Ingelheim Pharma KG, 88397 Biberach, Germany [P. G-C., J. E. P., W. J. R.]

¹ To whom requests for reprints should be addressed, at Ludwig Institute for Cancer Research, Austin and Repatriation Medical Centre, Heidelberg, Victoria 3084, Australia. Phone: 613-9496-5876; Fax: 613-9496-5892; E-mail: ams{at}austin.unimelb.edu.au

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.

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