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

Area of Science:

• Biochemistry
• Oncology
• Immunology

Background:

• MET receptor tyrosine kinase alterations occur in approximately 6% of non-small cell lung cancers (NSCLC).
• MET overexpression is also observed in NSCLC, highlighting its role in cancer progression.

Purpose of the Study:

• To develop a novel shark-derived single-domain variable new antigen receptor (VNAR) for theranostic applications targeting the MET receptor.
• To evaluate the efficacy of the VNAR-based agent for both imaging and therapeutic intervention in MET-altered NSCLC.

Main Methods:

• Immunization of a nurse shark with human MET extracellular domain to generate VNAR clones.
• Characterization of VNAR for MET selectivity and affinity.
• Development of a bivalent human Fc fusion (vMET1-Fc) for enhanced cellular uptake.
• Radiolabeling with zirconium-89 ([ ⁸⁹ Zr]Zr-vMET1-Fc) for PET/CT imaging.
• Radiolabeling with lutetium-177 ([ ¹⁷⁷ Lu]Lu-vMET1-Fc) for therapeutic evaluation.
• Assessment of biodistribution and safety in non-human primate studies.

Main Results:

• A VNAR clone with high MET selectivity was identified.
• vMET1-Fc demonstrated selective internalization in MET-expressing cell lines and xenografts.
• [ ⁸⁹ Zr]Zr-vMET1-Fc enabled PET/CT detection of MET-positive NSCLC xenografts.
• [ ¹⁷⁷ Lu]Lu-vMET1-Fc delayed tumor growth in MET-mutant and MET-amplified xenografts.
• Non-human primate studies showed favorable biodistribution, predictable clearance, and minimal off-target uptake.

Conclusions:

• vMET1-Fc is a promising theranostic agent for imaging and treating MET-altered NSCLC.
• Shark-derived VNARs represent a viable platform for developing targeted cancer therapies and diagnostics.