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Updated: Aug 15, 2025
Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
Conformation specific antagonistic high affinity antibodies to the RON receptor kinase for imaging and therapy
Xin Yu Koh1, Xiao Hui Koh2, Diana Spiegelberg3,4
1Disease Intervention Technology Lab, Institute of Molecular Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-06, Neuros/Immunos, Singapore, 138648, Singapore.
Abstract:
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.
Insights
Researchers developed novel, high-affinity anti-RON antibodies that inhibit tumor growth and enhance immune response. These antibodies also enable precise imaging of RON-expressing tumors using immunoPET and can be engineered into T cell engagers for cancer therapy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- The RON receptor tyrosine kinase is overexpressed in various tumors.
- RON is expressed on myeloid cells, dampening anti-tumor immune responses and reducing immunotherapy efficacy.
- Targeting RON presents a dual approach to inhibit tumor growth and stimulate immune rejection.
Purpose of the Study:
- To develop potent and selective inhibitory antibodies against RON.
- To evaluate the therapeutic potential of these antibodies in cancer treatment.
- To explore their utility in diagnostic imaging and as T cell engagers.
Main Methods:
- Derivation, cloning, and sequencing of high-affinity anti-RON antibodies.
- Assessment of antibody inhibition of MSP-induced RON signaling and antibody-dependent cellular cytotoxicity (ADCC).
- Validation of antibody specificity using recombinant antibodies and RON knockout cell lines.
- Radiolabeling antibodies with 89-Zirconium for immuno-PET imaging.
- Development of a bispecific T cell engager from an anti-RON antibody.
Main Results:
- A panel of highly avid anti-RON antibodies with picomolar binding affinities was generated.
- These antibodies effectively inhibited RON signaling and demonstrated potent ADCC.
- Antibody specificity was confirmed through genetic engineering and functional assays.
- 89-Zirconium-labeled antibodies enabled effective immuno-PET imaging of RON-expressing tumors.
- A bispecific T cell engager exhibited potent cytotoxic T cell killing with a 15 pM EC50.
Conclusions:
- Novel anti-RON antibodies offer a promising strategy for cancer therapy by inhibiting tumor growth and enhancing immune responses.
- These antibodies serve as effective tools for immuno-PET imaging of RON-positive tumors.
- The development of a bispecific T cell engager highlights the versatility of anti-RON antibodies in advanced cancer treatment modalities.
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