title: An epitope-specific novel anti-EMMPRIN polyclonal antibody inhibits tumor progression.
abstract: Extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) mediates tumor cell-macrophage interactions, and has been shown to induce both matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF). However, the epitope responsible for MMP induction is controversial, and the epitope responsible for VEGF induction is yet unknown. We generated a novel anti-EMMPRIN antibody directed against a specific epitope that successfully inhibited the production of both MMP-9 and VEGF in tumor cell-macrophagein vitroco-culture systems, exhibiting a U-shaped dose response. Furthermore, this antibody efficiently inhibitedin vivotumor progression in both the RENCA renal cell carcinoma and CT26 colon carcinoma subcutaneous tumor models, and reduced tumor size and number of metastatic foci in the 4T1 orthotopic model. This was achieved by inhibiting angiogenesis as assessed by immunohistochemical staining for the endothelial marker CD31, by inhibiting tumor cell proliferation as assessed by the staining for Ki-67, and by enhancing tumor cell apoptosis as assessed in the TUNEL assay. Moreover, administration of the antibody recruited more macrophages into the tumor, and skewed the tumor microenvironment for macrophages from TGFβ-dominated anti-inflammatory microenvironment, to a less immunosuppressive one. The antibody improved the ability of stimulated macrophages to perform antibody-dependent cell cytotoxicity (ADCC) and kill tumor cells. Thus, our new antibody maps the epitope capable of inducing both MMPs and VEGF, and places EMMPRIN as a good target for cancer therapy.
authors.affiliation: Immunology Research Unit, Carmel Medical Center , Haifa, Israel.
authors.forename: Miriam
authors.initials: M
authors.lastname: Walter
authors.affiliation: Immunology Research Unit, Carmel Medical Center , Haifa, Israel.
authors.forename: Elina
authors.initials: E
authors.lastname: Simanovich
authors.affiliation: Ischemia-shock Research Laboratory, Carmel Medical Center, The Ruth and Bruce Rappaport Faculty of Medicine , Technion, Haifa, Israel.
authors.forename: Vera
authors.initials: V
authors.lastname: Brod
authors.affiliation: Immunology Research Unit, Carmel Medical Center , Haifa, Israel.
authors.forename: Nitza
authors.initials: N
authors.lastname: Lahat
authors.affiliation: Ischemia-shock Research Laboratory, Carmel Medical Center, The Ruth and Bruce Rappaport Faculty of Medicine , Technion, Haifa, Israel.
authors.forename: Haim
authors.initials: H
authors.lastname: Bitterman
authors.affiliation: Immunology Research Unit, Carmel Medical Center , Haifa, Israel.
authors.forename: Michal A
authors.initials: MA
authors.lastname: Rahat
keywords: ADCC; MMP-9; VEGF; angiogenesis; anti-EMMPRIN/CD147; apoptosis; tumor cell–macrophage interactions; tumor microenvironment