Generation of human tumor specific antibodies in humanized tumor mice (HTM)

Breast cancer is a highly inter- and intra-individual heterogeneous disease that comprises a number of subtypes for which no therapeutic antibodies are available yet. Hence we utilized the Humanized Tumor Mouse (HTM) model and evaluated its capability to generate tumor cell specific human antibodies directed against BC cells. HTM were generated by the co-transplantation of human hematopoietic stem cells and human Her2-positive breast cancer cells into neonatal NSG mice. These mice develop a human immune system in combination with human breast cancer growth. Due to the concurrent transplantation the transfer of MHC-mismatched tumor cells causes an activation of a variety of immune (CD4+, NK, myeloid) cells 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 enabling an MHC-dependent interaction and thereby the generation of T-cell dependent antibody production by B-cells. Overall, HTM were able to generate human tumor-specific antibodies which dose dependently inhibited tumor outgrowth. Western blot analyses revealed that the tumor-specific antibodies generated in HTM recognized antigens which were different from Her2. In conclusion, HTM offer a novel approach to generate complete human monoclonal antibodies that do not require further genetic manipulation (e. g. "humanization"). This might be of particular interest for cancer subtypes with no currently available antibody therapy.