title: In vivo imaging of therapy response to a novel pan-HER antibody mixture using FDG and FLT positron emission tomography.
abstract: OBJECTIVE
  Overexpression of the human epidermal growth factor receptor (HER) family and their ligands plays an important role in many cancers. Targeting multiple members of the HER family simultaneously may increase the therapeutic efficacy. Here, we report the ability to image the therapeutic response obtained by targeting HER family members individually or simultaneously using the novel monoclonal antibody (mAb) mixture Pan-HER.
  
  
  RESULTS
  Mice with subcutaneous BxPC-3 pancreatic adenocarcinomas were divided into five groups receiving vehicle or mAb mixtures directed against either EGFR (HER1), HER2, HER3 or all three receptors combined by Pan-HER. Small animal positron emission tomography/computed tomography (PET/CT) with 2'-deoxy-2'-[(18)F]fluoro-D-glucose (FDG) and 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) was performed at baseline and at day 1 or 2 after initiation of therapy. Changes in tumor uptake of tracers were quantified and compared to reduction in tumor size. Imaging results were further validated by immunohistochemistry and qPCR. Mean FDG and FLT uptake in the Pan-HER treated group decreased by 19 ± 4.3% and 24 ± 3.1%, respectively. The early change in FDG and FLT uptake correlated with tumor growth at day 23 relative to day 0. Ex vivo molecular analyses of markers associated with the mechanisms of FDG and FLT uptake confirmed the in vivo imaging results.
  
  
  CONCLUSIONS
  Taken together, the study supports the use of FDG and FLT as imaging biomarkers of early response to Pan-HER therapy. FDG and FLT PET/CT imaging should be considered as imaging biomarkers in clinical evaluation of the Pan-HER mAb mixture.
authors.affiliation: Minerva Imaging ApS, Copenhagen, Denmark.|Department of Clinical Physiology, Nuclear Medicine and PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors.forename: Carsten H
authors.initials: CH
authors.lastname: Nielsen
authors.affiliation: Minerva Imaging ApS, Copenhagen, Denmark.|Department of Clinical Physiology, Nuclear Medicine and PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mette M
authors.initials: MM
authors.lastname: Jensen
authors.affiliation: Minerva Imaging ApS, Copenhagen, Denmark.|Department of Clinical Physiology, Nuclear Medicine and PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lotte K
authors.initials: LK
authors.lastname: Kristensen
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Anna
authors.initials: A
authors.lastname: Dahlman
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Camilla
authors.initials: C
authors.lastname: Fröhlich
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Helle J
authors.initials: HJ
authors.lastname: Jacobsen
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Poulsen
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Johan
authors.initials: J
authors.lastname: Lantto
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Ivan D
authors.initials: ID
authors.lastname: Horak
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Kragh
authors.affiliation: Minerva Imaging ApS, Copenhagen, Denmark.|Department of Clinical Physiology, Nuclear Medicine and PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kjaer
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015224:Dideoxynucleosides / Q000008:administration & dosage*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008819:Mice, Nude; D064847:Multimodal Imaging; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D049268:Positron-Emission Tomography / Q000379:methods*; D011237:Predictive Value of Tests; D019275:Radiopharmaceuticals / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000276:immunology; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D055114:X-Ray Microtomography; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D015224:Dideoxynucleosides; D066246:ErbB Receptors; D019788:Fluorodeoxyglucose F18; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; C002854:alovudine
keywords: FDG and FLT; HER family; PET/CT; antibody therapy; pancreatic cancer