Non invasive imaging assessment of the biodistribution of GSK2849330, an ADCC and CDC optimized anti HER3 mAb, and its role in tumor macrophage recruitment in human tumor-bearing mice

The purpose of this work was to use various molecular imaging techniques to non-invasively assess GSK2849330 (anti HER3 ADCC and CDC enhanced 'AccretaMab' monoclonal antibody) pharmacokinetics and pharmacodynamics in human xenograft tumor-bearing mice. Immuno-PET biodistribution imaging of...

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Published in:	PloS one Vol. 12; no. 4; p. e0176075
Main Authors:	Alsaid, Hasan, Skedzielewski, Tinamarie, Rambo, Mary V, Hunsinger, Kristen, Hoang, Bao, Fieles, William, Long, Edward R, Tunstead, James, Vugts, Danielle J, Cleveland, Matthew, Clarke, Neil, Matheny, Christopher, Jucker, Beat M
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 27-04-2017 Public Library of Science (PLoS)
Subjects:	Animals Antibodies, Monoclonal - immunology Antibodies, Monoclonal - pharmacokinetics Antibodies, Monoclonal - therapeutic use Antibodies, Monoclonal, Humanized - chemistry Antibodies, Monoclonal, Humanized - pharmacokinetics Antibodies, Monoclonal, Humanized - therapeutic use Bearing Biology and Life Sciences Cell Line, Tumor Coinjection Confocal microscopy Cytotoxicity Dose dependency Drug dosages Epidermal growth factor FDA approval Female Ferrosoferric Oxide - chemistry Gangrene Humans Imaging Imaging techniques Immune response Immune system Immunoglobulins Immunohistochemistry In vivo methods and tests Injection Isotope Labeling Kinases Ligands Macrophages Macrophages - cytology Macrophages - immunology Macrophages - pathology Magnetic resonance imaging Medical imaging Medicine and Health Sciences Mice Mice, Nude Microscopy Monoclonal antibodies Neoplasms - diagnostic imaging Neoplasms - drug therapy Optimization Pharmacodynamics Pharmacokinetics Pharmacology Positron emission Prostate cancer Radioisotopes Radiopharmaceuticals - chemistry Radiopharmaceuticals - pharmacokinetics Radiopharmaceuticals - therapeutic use Receptor, ErbB-3 - immunology Receptor, ErbB-3 - metabolism Research and Analysis Methods Rodents Science Signal to noise ratio Studies Tissue Distribution Tomography Transplantation, Heterologous Tumors Xenografts Zirconium - chemistry United Kingdom > UK United States > US Pennsylvania
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Summary:	The purpose of this work was to use various molecular imaging techniques to non-invasively assess GSK2849330 (anti HER3 ADCC and CDC enhanced 'AccretaMab' monoclonal antibody) pharmacokinetics and pharmacodynamics in human xenograft tumor-bearing mice. Immuno-PET biodistribution imaging of radiolabeled 89Zr-GSK2849330 was assessed in mice with HER3 negative (MIA-PaCa-2) and positive (CHL-1) human xenograft tumors. Dose dependency of GSK2849330 disposition was assessed using varying doses of unlabeled GSK2849330 co-injected with 89Zr-GSK2849330. In-vivo NIRF optical imaging and ex-vivo confocal microscopy were used to assess the biodistribution of GSK2849330 and the HER3 receptor occupancy in HER3 positive xenograft tumors (BxPC3, and CHL-1). Ferumoxytol (USPIO) contrast-enhanced MRI was used to investigate the effects of GSK2849330 on tumor macrophage content in CHL-1 xenograft bearing mice. Immuno-PET imaging was used to monitor the whole body drug biodistribution and CHL-1 xenograft tumor uptake up to 144 hours post injection of 89Zr-GSK2849330. Both hepatic and tumor uptake were dose dependent and saturable. The optical imaging data in the BxPC3 xenograft tumor confirmed the tumor dose response finding in the Immuno-PET study. Confocal microscopy showed a distinguished cytoplasmic punctate staining pattern within individual CHL-1 cells. GSK2849330 inhibited tumor growth and this was associated with a significant decrease in MRI signal to noise ratio after USPIO injection and with a significant increase in tumor macrophages as confirmed by a quantitative immunohistochemistry analysis. By providing both dose response and time course data from both 89Zr and fluorescently labeled GSK2849330, complementary imaging studies were used to characterize GSK2849330 biodistribution and tumor uptake in vivo. Ferumoxytol-enhanced MRI was used to monitor aspects of the immune system response to GSK2849330. Together these approaches potentially provide clinically translatable, non-invasive techniques to support dose optimization, and assess immune activation and anti-tumor responses.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceptualization: HA BMJ.Formal analysis: HA TS MVR KH BH WF ERL JT DJV.Investigation: HA TS MVR KH BH WF ERL JT DJV.Methodology: HA BH WF ERL JT DJV.Project administration: HA BMJ.Resources: HA ERL JT DJV MC NC CM BMJ.Supervision: HA JT DJV MC NC CM BMJ.Validation: HA JT DJV BMJ.Visualization: HA KH BH WF ERL JT.Writing – original draft: HA KH BH WF ERL JT DJV NC CM BMJ.Writing – review & editing: HA CM BMJ. Competing Interests: The authors receive funding, or own shares from GlaxoSmithKline. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0176075