流式细胞术
癌症研究
抗体
化学
单域抗体
免疫荧光
体内
分子生物学
生物
免疫学
遗传学
作者
Ningning Luo,Rachel Minne,Joseph P. Gallant,Gihan S. Gunaratne,Jonathan West,Saahil Javeri,Austin J. Robertson,Eric W. Lake,Jonathan W. Engle,Jason C. Mixdorf,Eduardo Aluicio‐Sarduy,K.P. Nickel,Reinier Hernandez,Randall J. Kimple,Andrew M. Baschnagel,Aaron M. LeBeau
标识
DOI:10.1021/acs.bioconjchem.4c00019
摘要
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.
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