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

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, [ 89 Zr]Zr-vMET1-Fc enabled longitudinal PET/CT imaging. High tumor uptake with low background was observed in MET-positive NSCLC xenografts administered [ 89 Zr]Zr-vMET1-Fc. As a targeted beta-particle radiotherapy, [¹⁷⁷Lu]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 ([⁸⁹Zr]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 Significance A shark-derived antibody selectively targeting MET shows preclinical efficacy as a theranostic agent for MET-altered cancer.