Picomolar Binding Selective Human Ron Inhibitory Antibodies Directed to Surface Displayed Conformational Epitopes for Imaging and Therapy  

Abstract

BackgroundThe RON protein is an exceptionally interesting target in oncology and immunology. It is not only overexpressed in a wide variety of tumors but also has been shown to be expressed on myeloid cells associated with tumor infiltration, where it serves to dampen tumour immune response and reduce the efficacy of anti-CTLA4 therapy. Potent and selective inhibitory antibodies to RON might therefore both inhibit tumor cell growth and stimulate immune rejection of tumors. MethodsWe derived a new panel of exceptionally avid anti-RON antibodies with using traditional hybridoma technologies with picomolar binding affinities that inhibit MSP-induced RON signaling and show remarkable potency in antibody dependent cellular cytotoxicity (ADCC). ResultsWhen radiolabeled with 89-Zirconium, the new antibodies 3F8 and 10G1 also allow effective immuno-positron emission tomography (immunoPET) imaging of RON-expressing tumors and recognize universally exposed RON epitopes at the cell surface. Conclusion In addition to their development as anti-RON cancer therapeutics, the new antibodies have great potential to be developed for tracking RON expressing tumours and metastases in cancer patients as diagnostic PET imaging agents, either as whole IgG or as a minibody.