Abstract B026: Development of a novel theranostic agent targeting MET in lung and head and neck cancer
Authors: Minne Rachel L. , Luo Natalie Y. , Mork Caroline M. , Wopat Madalynn R. , West Jayden L. , Griffin Jessica E. , Esbona Karla , Javeri Saahil , Nickel Kwangok P. , Hernandez Reinier , LeBeau Aaron M. , Kimple Randall J. , Baschnagel Andrew M. 
Published: January 2025

Background: The mesenchymal transcript factors is a receptor tyrosine kinase that when dysregulated or overexpressed can stimulate oncogenesis. Alterations in MET are found in 5% of non-small cell lung cancer but are also found in head and neck cancer and in cancers resistant to tyrosine kinase inhibitors targeting other oncogenic drivers. Our objective is to evaluate a novel, camelid-derived, MET binding antibody as a potential theranostic agent used in MET expressing cancers. Methods: The anti-MET VHH camelid antibody, 1E7-Fc, was identified from a phage display library. Binding to human MET was assessed via serially diluted ELISA analysis and bio-Layer interferometry. Western blot and qRT-PCR analysis was used to assess MET and p-MET expression in established multiple lung cancer (EBC-1 and UW-Lung-21) and head and neck cancer (Detroit 562, UM-SCC47, and UPCI:SCC90) cell lines where inhibition was compared to treatment with the MET inhibitor, capmatinib. Binding affinity and internalization of 1E7-Fc to these cell lines was assessed via flow cytometry and immunofluorescence. EC50 assays were performed to measure the effects of 1E7-Fc on cell viability. Bioconjugation of 89Zr and 177Lu enabled tumor uptake imaging in xenograft models using PET/CT and SPECT imaging, respectively. The efficacy of [89Zr]Zr-1E7-Fc as an imaging agent targeting MET expression in vivo was investigated through PET/CT imaging, region of interest (ROI) image analysis, and ex vivo activity. Results: 1E7-Fc demonstrates a high binding affinity for human MET. Binding to MET expressing cell lines correlated to levels of MET expression and was seen even in cells resistant to MET inhibitor capmatinib. 1E7-Fc did not cause disrupt MET signaling and did not impair cell proliferation. [89Zr]Zr-1E7-Fc demonstrated rapid localization and high tumor uptake in EBC-1, UW-Lung-21, and Detroit 562 xenografts with rapid clearance from circulatory systems as tumor to blood ratios were 2.7, 2.5, and 1.8 forty-eight hours post injection, respectively.1E7-Fc was successfully labeled with 177Lu and imaged by SPECT. Conclusions: Our preclinical findings indicate that the camelid antibody MET-1E7-Fc has potential as an imaging agent for high MET-expressing cancers. Further studies are needed to assess the therapeutic response to 177Lu-conjugated antibodies and to translate these results to patients.

Citation Format: Rachel L. Minne, Natalie Y. Luo, Caroline M. Mork, Madalynn R. Wopat, Jayden L. West, Jessica E. Griffin, Karla Esbona, Saahil Javeri, Kwangok P. Nickel, Reinier Hernandez, Aaron M. LeBeau, Randall J. Kimple, Andrew M. Baschnagel. Development of a novel theranostic agent targeting MET in lung and head and neck cancer. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B026.