A MET-Targeted Variable New Antigen Receptor Theranostic for Non-Small Cell Lung Cancer

LeBeau, A.; Minne, R.; West, J.; Luo, N.; Nickel, K.; Gunaratne, G.; Ott, K.; Gallant, J.; Barrett, K.; Mork, C.; Wopat, M.; Zitzer, N.; Javeri, S.; Lopez, L.; Toscano, W.; Kwon, O.; Teague, J.; Bunker, B.; Phillips, J.; Idrissou, M.; Mixdorf, J.; Rojas, H.; Alucio-Sarduy, E.; Engle, J.; Bednarz, B.; Hernandez, R. T.; Kimple, R.; Baschnagel, A.

doi:10.64898/2026.01.30.702875

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bioRxiv · 10.64898/2026.01.30.702875

A MET-Targeted Variable New Antigen Receptor Theranostic for Non-Small Cell Lung Cancer

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Abstract

The MET receptor tyrosine kinase is mutated or amplified in [~]6% of non-small cell lung cancer (NSCLC) and overexpressed in [~]80% of all NSCLC cases. A theranostic agent that can both see and treat MET-altered NSCLC has never been described before in the literature. Here, we report a shark-derived single-domain variable new antigen receptor (VNAR) for MET with theranostic applications. Following the immunization of a juvenile nurse shark (Ginglymostoma cirratum) with the extracellular domain of human MET, we identified a VNAR clone that specifically engaged MET with high affinity. Engineering the lead VNAR into a bivalent human Fc, vMET1-Fc, yielded a construct that selectively targeted and was internalized by MET-positive cells without affecting cell viability or downstream MET signaling. When radiolabeled with the positron emitting isotope Zr-89, [89Zr]Zr-vMET1-Fc enabled longitudinal PET/CT imaging. High tumor uptake with low background was observed in MET-positive NSCLC xenografts administered [89Zr]Zr-vMET1-Fc. As a targeted beta-particle radiotherapy, [{superscript 1}Lu]Lu-vMET1-Fc resulted in marked tumor-growth delay and exhibited a favorable toxicity profile, collectively improving progression-free survival in NSCLC mouse models. Non-human primate PET/CT imaging studies with ([Zr]Zr-vMET1-Fc in healthy rhesus macaques confirmed favorable biodistribution and dosimetry, predictable clearance, and minimal off-target uptake. Additional blood chemistry analysis found no significant immune response or cytotoxicity. Together, these findings establish vMET1-Fc as a theranostic agent for imaging and treating MET-altered NSCLC. Statement of SignificanceA shark-derived antibody selectively targeting MET shows preclinical efficacy as a theranostic agent for MET-altered cancer.

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LeBeau, A., Minne, R., West, J., Luo, N., Nickel, K., Gunaratne, G., Ott, K., Gallant, J., Barrett, K., Mork, C., Wopat, M., Zitzer, N., Javeri, S., Lopez, L., Toscano, W., Kwon, O., Teague, J., Bunker, B., Phillips, J., Idrissou, M., Mixdorf, J., Rojas, H., Alucio-Sarduy, E., Engle, J., Bednarz, B., Hernandez, R. T., Kimple, R., Baschnagel, A.. 2026-02-02. A MET-Targeted Variable New Antigen Receptor Theranostic for Non-Small Cell Lung Cancer. https://doi.org/10.64898/2026.01.30.702875

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