IMMUNOTHERAPY TARGETING RON IN CANCER

Abstract

Recepteur d'origine nantais (RON) receptor tyrosine kinase (RTK) and its ligand, macrophage-stimulating protein (MSP), are vital players in cell proliferation, inflammation, epithelial to mesenchymal transition during carcinogenesis, as well as migration and invasion, angiogenesis and chemoresistance. Overexpression of RON in various tumours and can¬cer cells dependent on RON signalling for tumour growth, metastasis and prolonged survival provide the rationale to target RON for cancer therapy. This study describes the development of monoclonal antibodies against RON as therapeutic molecules in cancer treatment/diagnostics. A panel of RON monoclonal antibodies (mAbs) was developed and characterised by Western blotting, immunofluorescence staining, ability to recognize native RON protein and be endocytosed into live cancer cell, ability to inhibit tumour growth and wound healing in vitro, and diagnostic ability and therapeutic efficacy in HT29 xenografted mice. Our two lead antibodies 6D4 and 7G8 bound strongly to native RON and were endocytosed in¬¬¬to cancer cells. The antibodies reduced HCT116 and HT29 cell growth and caused cellular death in the presence of secondary antibody drug conjugates. In addition, 6D4 and 7G8 proved to be effective in correctly diagnosing and inhibiting RON mediated tumours in a mouse model.