Development of [(89)Zr]ZrDFO-amivantamab bispecific to EGFR and c-MET for PET imaging of triple-negative breast cancer.
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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 YesAntibodyDownregulatorDetails Amivantamab Hepatocyte growth factor receptor Protein Humans YesAntagonistAntibodyDetails