title: Human Epidermal Growth Factor Receptor 3-Specific Tumor Uptake and Biodistribution of89Zr-MSB0010853 Visualized by Real-Time and Noninvasive PET Imaging.
abstract: The human epidermal growth factor receptor 3 (HER3) is an interesting target for antitumor therapy. For optimal HER3 signaling inhibition, a biparatopic Nanobody construct (MSB0010853) was developed that binds 2 different HER3 epitopes. In addition, MSB0010853 contains a third HER3 epitope that binds albumin to extend its circulation time. MSB0010853 is cross-reactive with HER3 and albumin of mouse origin. We aimed to gain insight into MSB0010853 biodistribution and tumor uptake by radiolabeling the Nanobody construct with89Zr.Methods:MSB0010853 was radiolabeled with89Zr. Dose- and time-dependent tumor uptake was studied in nude BALB/c mice bearing a subcutaneous HER3 overexpressing H441 non-small cell lung cancer xenograft. Dose-dependent biodistribution of89Zr-MSB0010853 was assessed ex vivo at 24 h after intravenous injection. Protein doses of 5, 10, 25, 100, and 1,000 μg were used. Time-dependent biodistribution of MSB0010853 was analyzed ex vivo at 3, 6, 24, and 96 h after intravenous administration of 25 μg of89Zr-MSB0010853. PET imaging and biodistribution were performed 24 h after administration of 25 μg of89Zr-MSB0010853 to mice bearing human H441, FaDu (high HER3 expression), or Calu-1 (no HER3 expression) tumor xenografts.Results:Radiolabeling of MSB0010853 with89Zr was performed with a radiochemical purity of greater than 95%. Ex vivo biodistribution showed protein dose- and time-dependent distribution of89Zr-MSB0010853 in all organs. Uptake of89Zr-MSB0010853 in H441 tumors was only time-dependent. Tumor could be visualized up to at least 96 h after injection. The highest mean SUV of 0.6 ± 0.2 was observed at 24 h after injection of 25 μg of89Zr-MSB0010853.89Zr-MSB0010853 tumor uptake correlated with HER3 expression and was highest in H441 (6.2 ± 1.1 percentage injected dose per gram [%ID/g]) and lowest in Calu-1 (2.3 ± 0.3 %ID/g) xenografts.Conclusion:89Zr-MSB0010853 organ distribution and tumor uptake in mice are time-dependent, and tumor uptake correlates with HER3 expression. In contrast to tumor uptake except for kidney uptake, organ distribution of89Zr-MSB0010853 is protein dose-dependent for the tested doses.89Zr-MSB0010853 PET imaging gives insight into the in vivo behavior of MSB0010853.
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Warnders
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Anton G T
authors.initials: AGT
authors.lastname: Terwisscha van Scheltinga
authors.affiliation: Merck, Biopharma Global R&D, Darmstadt, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Knuehl
authors.affiliation: Ablynx N.V., Ghent, Belgium.
authors.forename: Maarten
authors.initials: M
authors.lastname: van Roy
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Erik F J
authors.initials: EFJ
authors.lastname: de Vries
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, The Netherlands.|Unit PharmacoTherapy, Epidemiology and Economy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands; and.
authors.forename: Jos G W
authors.initials: JGW
authors.lastname: Kosterink
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Elisabeth G E
authors.initials: EGE
authors.lastname: de Vries
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands m.n.de.hooge@umcg.nl.|Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Marjolijn N
authors.initials: MN
authors.lastname: Lub-de Hooge
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008175:Lung Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D057127:Single-Chain Antibodies / Q000378:metabolism* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: C000622062:89Zr-MSB0010853; D057127:Single-Chain Antibodies; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3
keywords: 89Zr; HER3; Nanobody; albumin; imaging