Development of an Engineered Single-Domain Antibody for Targeting MET in Non-Small Cell Lung Cancer.

Autor: Luo NY; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States.; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States., Minne RL; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States.; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States., Gallant JP; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States.; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States.; Molecular and Cellular Pharmacology Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States., Gunaratne GS; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States.; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States., West JL; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States.; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States.; Molecular and Cellular Pharmacology Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States., Javeri S; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States., Robertson AJ; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States.; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States.; Molecular and Cellular Pharmacology Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States., Lake EW; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States.; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States., Engle JW; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States.; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States., Mixdorf JC; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States., Aluicio-Sarduy E; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States., Nickel KP; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States.; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States., Hernandez R; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States.; Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States., Kimple RJ; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States.; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States., Baschnagel AM; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States.; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States., LeBeau AM; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States.; University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States.; Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, United States.
Jazyk: angličtina
Zdroj: Bioconjugate chemistry [Bioconjug Chem] 2024 Mar 20; Vol. 35 (3), pp. 389-399. Date of Electronic Publication: 2024 Mar 12.
DOI: 10.1021/acs.bioconjchem.4c00019
Abstrakt: 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 [ 89 Zr]Zr-1E7-Fc to detect MET expression in vivo by PET/CT imaging. [ 89 Zr]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.
Databáze: MEDLINE
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