title: Immuno-PET Imaging of HER3 in a Model in which HER3 Signaling Plays a Critical Role.
abstract: HER3 is overexpressed in various carcinomas including colorectal cancer (CRC), which is associated with poor prognosis, and is involved in the development of therapy resistance. Thus, an in vivo imaging technique is needed to evaluate the expression of HER3, an important therapeutic and diagnostic target. Here, we report successful HER3 PET imaging using a newly generated anti-human HER3 monoclonal antibody, Mab#58, and a mouse model of a HER3-overexpressing xenograft tumor. Furthermore, we assessed the role of HER3 signaling in CRC cancer tissue-originated spheroid (CTOS) and applied HER3 imaging to detect endogenous HER3 in CTOS-derived xenografts. Cell binding assays of 89Zr-labeled Mab#58 using the HER3-overexpressing cell line HER3/RH7777 demonstrated that [89Zr]Mab#58 specifically bound to HER3/RH7777 cells (Kd = 2.7 nM). In vivo biodistribution study in mice bearing HER3/RH7777 and its parent cell xenografts showed that tumor accumulation of [89Zr]Mab#58 in HER3/RH7777 xenografts was significantly higher than that in the control from day 1 to day 4, tending to increase from day 1 to day 4 and reaching 12.2 ± 4.5%ID/g. Radioactivity in other tissues, including the control xenograft, decreased or remained unchanged from day 1 to day 6. Positron emission tomography (PET) in the same model enabled clear visualization of HER3/RH7777 xenografts but not of RH7777 xenografts. CTOS growth assay and signaling assay revealed that CRC CTOS were dependent on HER3 signaling for their growth. In PET studies of mice bearing a CRC CTOS xenograft, the tumor was clearly visualized with [89Zr]Mab#58 but not with the 89Zr-labeled control antibody. Thus, tumor expression of HER3 was successfully visualized by PET with 89Zr-labeled anti-HER3 antibody in CTOS xenograft-bearing mice, a model that retains the properties of the patient tumor. Non-invasive targeting of HER3 by antibodies is feasible, and it is expected to be useful for cancer diagnosis and treatment.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Furukawa
authors.affiliation: Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tashiro
authors.affiliation: Cell Biology Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, Kinki University, Higashi Osaka, Japan.|Carna Biosciences Inc., Kobe, Japan.
authors.forename: Kouki
authors.initials: K
authors.lastname: Okita
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Jin
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Winn
authors.initials: W
authors.lastname: Aung
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Sugyo
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Nagatsu
authors.affiliation: Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Endo
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Atsushi B
authors.initials: AB
authors.lastname: Tsuji
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.affiliation: Cell Biology Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, Kinki University, Higashi Osaka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Masuko
authors.affiliation: Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fujibayashi
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Saga
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D015200:Fluoroimmunoassay; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009928:Organ Specificity; D049268:Positron-Emission Tomography / Q000379:methods; D051381:Rats; D020893:Receptor, ErbB-3 / Q000502:physiology*; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000378:metabolism
chemical_list: C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3