Preventing cancer and metastasis
Our researchers have developed a novel therapeutic strategy targeting EMMPRIN (CD147)—a key protein involved in cancer progression and metastasis. The approach includes both an active vaccine and a monoclonal antibody, each designed to target a newly discovered epitope on EMMPRIN that regulates angiogenesis and tumor invasiveness. In multiple animal models of colon, prostate, renal, and breast cancer, both treatments significantly reduced tumor growth, prevented metastasis, and even induced long-term immune memory to protect against recurrence. The therapies not only inhibited tumor proliferation and angiogenesis, but also reprogrammed the tumor microenvironment, enhancing immune cell infiltration and shifting it from immunosuppressive to immune-permissive. Importantly, these treatments selectively target cancer cells without affecting healthy tissues, offering a powerful and specific tool in cancer immunotherapy with potential to improve outcomes in combination with other treatments.
Inventors
Prof Michal Rahat, Carmel Medical Center
Contact info
Sari Prutchi Sagiv PhD Director of Pharma and Diagnostics
For further information please contact:
sari@mor-research.comThe multifunctional CD147/EMMPRIN protein (Extracellular Matrix MetalloPRoteinase Inducer) is overexpressed in cancer cells and particularly in metastatic cells. It participates in processes that are crucial for cancer progression and metastasis, including angiogenesis, lactate clearance, leukocyte recruitment to the microenvironment, epithelial-to-mesenchymal transition (EMT) and exit from dormancy. This places CD147/EMMPRIN as an attractive candidate for targeting.
We have identified a previously unknown epitope in the EMMPRIN protein sequence that affects the induction of MMP-9 and VEGF, two key factors in angiogenesis (the formation of new blood vessels from pre-existing vessels). Then, we have taken two approaches for the targeting of EMMPRIN: an approach of active vaccination using a modified peptide derived from the protein sequence (161-MAP), and an approach of passive immunization with a newly developed monoclonal antibody directed against the same epitope (hMR18-mAb).
We have shown in three mouse models of colon, prostate and renal carcinomas, that the active vaccine can attenuate (and sometimes even regress) primary tumors, and significantly reduce metastasis. The long-term memory that was generated prevented tumor relapse. Similarly, the passive immunization with hMR18-mAb reduced tumor progression in two mouse models of colon and mammary carcinomas, and significantly reduced metastasis. The two forms of vaccines shared similar mechanisms of action and could reduce angiogenesis and proliferation of tumor cells. Moreover, we demonstrated that by targeting EMMPRIN with either the peptide or the antibody, the tumor cells were killed by necroptosis, released dsRNA that was taken up by nearby macrophages, changed their mode of activation and shifted the tumor microenvironment from immunosuppressive to immune permissive that recruited more effector cytotoxic T cells and macrophages. Moreover, the vaccines inhibited the process of EMT and pushed metastatic cells towards dormancy. Importantly, both vaccines specifically recognize EMMPRIN in tumor cells but not in normal tissues.
The ability of our two EMMPRIN-specific reagents to target a key molecule involved in so many processes that promote tumor growth and metastasis suggests that they may improve the efficacy of other treatment modalities, and offer a new hope for a treatment that blocks the metastatic disease and prevent metastatic relapse, the most urgent need in cancer treatment.