Development of [(89)Zr]ZrDFO-amivantamab bispecific to EGFR and c-MET for PET imaging of triple-negative breast cancer.

Article Details

Citation

Copy to clipboard

Cavaliere A, Sun S, Lee S, Bodner J, Li Z, Huang Y, Moores SL, Marquez-Nostra B

Development of [(89)Zr]ZrDFO-amivantamab bispecific to EGFR and c-MET for PET imaging of triple-negative breast cancer.

Eur J Nucl Med Mol Imaging. 2021 Feb;48(2):383-394. doi: 10.1007/s00259-020-04978-6. Epub 2020 Aug 8.

PubMed ID

32770372 [ View in PubMed

]

Abstract

BACKGROUND: Amivantamab is a novel bispecific antibody that simultaneously targets the epidermal growth factor receptor (EGFR) and the hepatocyte growth factor receptor (HGFR/c-MET) that are overexpressed in several types of cancer including triple-negative breast cancer (TNBC). Targeting both receptors simultaneously can overcome resistance to mono-targeted therapy. The purpose of this study is to develop (89)Zr-labeled amivantamab as a potential companion diagnostic imaging agent to amivantamab therapy using various preclinical models of TNBC for evaluation. METHODS: Amivantamab was conjugated to desferrioxamine (DFO) and radiolabeled with (89)Zr to obtain [(89)Zr]ZrDFO-amivantamab. Binding of the bispecific [(89)Zr]ZrDFO-amivantamab as well as its mono-specific "single-arm" antibody controls were determined in vitro and in vivo. Biodistribution studies of [(89)Zr]ZrDFO-amivantamab were performed in MDA-MB-468 xenografts to determine the optimal imaging time point. PET/CT imaging with [(89)Zr]ZrDFO-amivantamab or its isotype control was performed in a panel of TNBC xenografts with varying levels of EGFR and c-MET expression. RESULTS: [(89)Zr]ZrDFO-amivantamab was synthesized with a specific activity of 148 MBq/mg and radiochemical yield of >/= 95%. Radioligand binding studies and western blot confirmed the order of EGFR and c-MET expression levels: HCC827 lung cancer cell (positive control) > MDA-MB-468 > MDA-MB-231 > MDA-MB-453. [(89)Zr]ZrDFO-amivantamab demonstrated bispecific binding in cell lines co-expressed with EGFR and c-MET. PET/CT imaging with [(89)Zr]ZrDFO-amivantamab in TNBC xenografted mice showed standard uptake value (SUVmean) of 6.0 +/- 1.1 in MDA-MB-468, 4.2 +/- 1.4 in MDA-MB-231, and 1.5 +/- 1.4 in MDA-MB-453 tumors, which are consistent with their receptors' expression levels on the cell surface. CONCLUSION: We have successfully prepared a radiolabeled bispecific antibody, [(89)Zr]ZrDFO-amivantamab, and evaluated its pharmacologic and imaging properties in comparison with its single-arm antibodies and non-specific isotype controls. [(89)Zr]ZrDFO-amivantamab demonstrated the greatest uptake in tumors co-expressing EGFR and c-MET.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Amivantamab	Epidermal growth factor receptor	Protein	Humans	Yes	Antibody Downregulator	Details
Amivantamab	Hepatocyte growth factor receptor	Protein	Humans	Yes	Antagonist Antibody	Details