Recepteur d'origine nantais (RON)
receptor tyrosine kinase (RTK) and its
ligand, serum
macrophage-stimulating protein (MSP), are well-established oncogenic drivers for
tumorigenesis and
metastasis. RON is often found to be alternatively spliced resulting in various
isoforms that are constitutively active. RON is therefore an attractive target for
cancer therapeutics, including small molecular inhibitors and
monoclonal antibodies. While small molecule inhibitors of RON may inhibit other
protein kinases including the highly similar MET
kinase,
monoclonal antibodies targeting RON are more specific, potentially inducing fewer side effects. Although anti-RON
monoclonal antibody therapies have been developed and tested in clinical trials, they were met with limited success.
Cancer cells have been associated with aberrant glycosylation mechanisms. Notably for RON, the loss of N-bisected glycosylation is a direct cause for
tumorigenesis and poorer prognosis in
cancer patients. Particularly in
gastric cancer, aberrant RON glycosylation augments RON activation. Here, we present a novel panel of
monoclonal antibodies which potentially widens the specific targeting of not only the glycosylated RON, but also unglycosylated and aberrantly glycosylated RON. Our
antibodies can bind strongly to deglycosylated RON from
tunicamycin treated cells, recognise RON in IHC/IF and possess superior therapeutic efficacy in RON expressing xenograft tumours. Our most potent antibody in xenograft assays, is directed to the RON alpha chain and targets a sulfhydryl bond constrained
epitope that appears to be cryptic in the crystal structure. This establishes the paradigm that such constrained and cryptic
epitopes represent good targets for therapeutic
antibodies.