Journal Article

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

Barrett, Kendall E, Luo, Natalie Y, LeBeau, Aaron M, Bunker, Brittany, Mixdorf, Jason C, Engle, Jonathan W, Bednarz, Bryan, Hernandez, Reinier, Teague, Jordan, West, Jayden L, Gunaratne, Gihan S, Wopat, Madalynn R, Lopez, Loren D Rivera, Minne, Rachel L, Zitzer, Nina C, Phillips, Jessica M, Toscano, Will A, Idrissou, Malick Bio, Mork, Caroline M, Aluicio-Sarduy, Eduardo, Kimple, Randall J, Rojas, Hansel Comas, Javeri, Saahil, Nickel, Kwangok P, Baschnagel, Andrew M, Kwon, Ohyun, Ott, Kendahl L, Gallant, Joseph P

2026

Overview

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 ( ) 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, [ Zr]Zr-vMET1-Fc enabled longitudinal PET/CT imaging. High tumor uptake with low background was observed in MET-positive NSCLC xenografts administered [ Zr]Zr-vMET1-Fc. As a targeted beta-particle radiotherapy, [ 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.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory Preprints
• Subject: Antigens / c-Met protein / Ginglymostoma cirratum / Immunization / Juveniles / Non-small cell lung carcinoma / Protein-tyrosine kinase receptors / Small cell lung carcinoma / Xenografts