4.7 Article

Conformation specific antagonistic high affinity antibodies to the RON receptor kinase for imaging and therapy

Journal

SCIENTIFIC REPORTS
Volume 12, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41598-022-26404-7

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Funding

  1. A*STAR

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The RON receptor tyrosine kinase is a promising target for oncology and immunology. The development of potent and selective anti-RON antibodies with high affinity binding has the potential to inhibit tumor growth and enhance tumor immune rejection. These antibodies can also be used for immuno-positron emission tomography imaging and recognize universally exposed RON epitopes on the cell surface.
The RON receptor tyrosine kinase 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 responses 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. We derived cloned and sequenced a new panel of exceptionally avid anti-RON antibodies with picomolar binding affinities that inhibit MSP-induced RON signaling and show remarkable potency in antibody dependent cellular cytotoxicity. Antibody specificity was validated by cloning the antibody genes and creating recombinant antibodies and by the use of RON knock out cell lines. When radiolabeled with 89-Zirconium, the new antibodies 3F8 and 10G1 allow effective immuno-positron emission tomography (immunoPET) imaging of RON-expressing tumors and recognize universally exposed RON epitopes at the cell surface. The 10G1 was further developed into a novel bispecific T cell engager with a 15 pM EC50 in cytotoxic T cell killing assays.

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