posted on 2024-03-12, 16:46authored byNatalie
Y. Luo, Rachel L. Minne, Joseph P. Gallant, Gihan S. Gunaratne, Jayden L. West, Saahil Javeri, Austin J. Robertson, Eric W. Lake, Jonathan W. Engle, Jason C. Mixdorf, Eduardo Aluicio-Sarduy, Kwang P. Nickel, Reinier Hernandez, Randall J. Kimple, Andrew M. Baschnagel, Aaron M. LeBeau
The Mesenchymal Epithelial Transition (MET) receptor
tyrosine kinase
is upregulated or mutated in 5% of non-small-cell lung cancer (NSCLC)
patients and overexpressed in multiple other cancers. We sought to
develop a novel single-domain camelid antibody with high affinity
for MET that could be used to deliver conjugated payloads to MET expressing
cancers. From a naïve camelid variable-heavy-heavy (VHH) domain
phage display library, we identified a VHH clone termed 1E7 that displayed
high affinity for human MET and was cross-reactive with MET across
multiple species. When expressed as a bivalent human Fc fusion protein,
1E7-Fc was found to selectively bind to EBC-1 (MET amplified) and
UW-Lung 21 (MET exon 14 mutated) cell lines by flow cytometry and
immunofluorescence imaging. Next, we investigated the ability of [89Zr]Zr-1E7-Fc to detect MET expression in vivo by PET/CT imaging. [89Zr]Zr-1E7-Fc demonstrated rapid
localization and high tumor uptake in both xenografts with a %ID/g
of 6.4 and 5.8 for EBC-1 and UW-Lung 21 at 24 h, respectively. At
the 24 h time point, clearance from secondary and nontarget tissues
was also observed. Altogether, our data suggest that 1E7-Fc represents
a platform technology that can be employed to potentially both image
and treat MET-altered NSCLC.