title: Molecular Imaging and Quantitation of EphA2 Expression in Xenograft Models with 89Zr-DS-8895a.
abstract: Subtype A2 of the erythropoietin-producing hepatocellular tyrosine kinase (EphA2) cell surface receptor is expressed in a range of epithelial cancers. This study evaluated the molecular imaging of EphA2 expression in vivo in mouse tumor models using SPECT/MR and PET/MR and a humanized anti-EphA2 antibody, DS-8895a.
  
  
  
  DS-8895a was labeled with (111)In, (125)I, and (89)Zr and assessed for radiochemical purity, immunoreactivity (Lindmo analysis), antigen-binding affinity (Scatchard analysis), and serum stability in vitro. In vivo biodistribution, imaging, and pharmacokinetic studies were performed with SPECT/MR and PET/MR. A dose-escalation study was also performed to determine EphA2 receptor saturability through tissue and imaging quantitative analysis.
  
  
  
  All conjugates demonstrated good serum stability and specific binding to EphA2-expressing cells in vitro. In vivo biodistribution studies showed high uptake of (111)In-CHX-A″-DTPA-DS-8895a and (89)Zr-Df-Bz-NCS-DS-8895a in EphA2-expressing xenograft models, with no specific uptake in normal tissues. In comparison, retention of (125)I-DS-8895a in tumors was lower because of internalization of the radioconjugate and dehalogenation. These results were confirmed by SPECT/MR and PET/MR. EphA2 receptor saturation was observed at the 30 mg/kg dose.
  
  
  
  Molecular imaging of tumor uptake of DS-8895a allows noninvasive measurement of EphA2 expression in tumors in vivo and determination of receptor saturation. (89)Zr-Df-Bz-NCS-DS-8895a is suited for human bioimaging trials on the basis of superior imaging characteristics and will inform DS-8895a dose assessment and patient response evaluation in clinical trials.
authors.affiliation: Tumour Targeting Laboratory, Ludwig Institute for Cancer Research and Olivia Newton-John Cancer Research Institute, Melbourne, Australia School of Cancer Medicine, La Trobe University, Melbourne, Australia.
authors.forename: Ingrid J G
authors.initials: IJ
authors.lastname: Burvenich
authors.affiliation: Tumour Targeting Laboratory, Ludwig Institute for Cancer Research and Olivia Newton-John Cancer Research Institute, Melbourne, Australia School of Cancer Medicine, La Trobe University, Melbourne, Australia Department of Medical Oncology, Austin Health, Heidelberg, Melbourne, Australia.
authors.forename: Sagun
authors.initials: S
authors.lastname: Parakh
authors.affiliation: Tumour Targeting Laboratory, Ludwig Institute for Cancer Research and Olivia Newton-John Cancer Research Institute, Melbourne, Australia School of Cancer Medicine, La Trobe University, Melbourne, Australia Department of Medical Oncology, Austin Health, Heidelberg, Melbourne, Australia.
authors.forename: Hui K
authors.initials: HK
authors.lastname: Gan
authors.affiliation: Tumour Targeting Laboratory, Ludwig Institute for Cancer Research and Olivia Newton-John Cancer Research Institute, Melbourne, Australia.
authors.forename: Fook-Thean
authors.initials: FT
authors.lastname: Lee
authors.affiliation: Tumour Targeting Laboratory, Ludwig Institute for Cancer Research and Olivia Newton-John Cancer Research Institute, Melbourne, Australia.
authors.forename: Nancy
authors.initials: N
authors.lastname: Guo
authors.affiliation: Tumour Targeting Laboratory, Ludwig Institute for Cancer Research and Olivia Newton-John Cancer Research Institute, Melbourne, Australia.
authors.forename: Angela
authors.initials: A
authors.lastname: Rigopoulos
authors.affiliation: Tumour Targeting Laboratory, Ludwig Institute for Cancer Research and Olivia Newton-John Cancer Research Institute, Melbourne, Australia Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia.
authors.forename: Sze-Ting
authors.initials: ST
authors.lastname: Lee
authors.affiliation: Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Gong
authors.affiliation: Department of Medical Oncology, Austin Health, Heidelberg, Melbourne, Australia Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia.
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: O'Keefe
authors.affiliation: Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia.
authors.forename: Henri
authors.initials: H
authors.lastname: Tochon-Danguy
authors.affiliation: Translational Medicine and Clinical Pharmacology Department, Daiichi-Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Kotsuma
authors.affiliation: Biologics Pharmacology Research Laboratories, Daiichi-Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Hasegawa
authors.affiliation: Department of Translational Medicine and Clinical Pharmacology, Daiichi-Sankyo Pharma Development, Edison, New Jersey; and.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Senaldi
authors.affiliation: Tumour Targeting Laboratory, Ludwig Institute for Cancer Research and Olivia Newton-John Cancer Research Institute, Melbourne, Australia Department of Medical Oncology, Austin Health, Heidelberg, Melbourne, Australia Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia Department of Medicine, University of Melbourne, Melbourne, Australia andrew.scott@onjcri.org.au.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry* / Q000276:immunology / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003676:Deferoxamine / Q000031:analogs & derivatives / Q000737:chemistry; D005260:Female; D006801:Humans; D017879:Isothiocyanates / Q000737:chemistry; D051379:Mice; D004369:Pentetic Acid / Q000737:chemistry; D049268:Positron-Emission Tomography / Q000379:methods*; D011786:Quality Control; D011868:Radioisotopes; D036104:Receptor, EphA2 / Q000276:immunology / Q000378:metabolism*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D015040:Zirconium / Q000737:chemistry*
chemical_list: C549125:4-isothiocyanatobenzyl-desferrioxamine; D061067:Antibodies, Monoclonal, Humanized; D017879:Isothiocyanates; D011868:Radioisotopes; D004369:Pentetic Acid; D015040:Zirconium; D036104:Receptor, EphA2; D003676:Deferoxamine
keywords: 89Zr; DS-8895a; EphA2; bioimaging; cancer