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Matthew J O'Hara, Nathaniel J Murray, Jennifer C Carter, Samuel S Morrison
Zirconium-89 (89 Zr), produced by the (p, n) reaction from naturally monoisotopic yttrium (nat Y), is a promising positron emitting isotope for immunoPET imaging. Its long half-life of 78.4 h is sufficient for evaluating slow physiological processes. A prototype automated fluidic system, coupled to on-line and in-line detectors, has been constructed to facilitate development of new89 Zr purification methodologies. The highly reproducible reagent delivery platform and near-real time monitoring of column effluents allows for efficient method optimization...
February 24, 2018: Journal of Chromatography. A
Lei Kang, Dawei Jiang, Christopher G England, Todd E Barnhart, Bo Yu, Zachary T Rosenkrans, Rongfu Wang, Jonathan W Engle, Xiaojie Xu, Peng Huang, Weibo Cai
PURPOSE: CD38 is considered a potential biomarker for multiple myeloma (MM) and has shown a strong link with chronic lymphocytic leukemia due to high and uniform expression on plasma cells. In vivo evaluation of CD38 expression may provide useful information about lesion detection and prognosis of treatment in MM. In this study, immunoPET imaging with89 Zr-labeled daratumumab was used for differentiation of CD38 expression in murine lymphoma models to provide a potential non-invasive method for monitoring CD38 in the clinic...
February 15, 2018: European Journal of Nuclear Medicine and Molecular Imaging
Sai Kiran Sharma, Andrew Chow, Sebastien Monette, Delphine Vivier, Jacob Pourat, Kimberly J Edwards, Thomas R Dilling, Dalya Abdel-Atti, Brian M Zeglis, J T Poirier, Jason S Lewis
A critical benchmark in the development of antibody-based therapeutics is demonstration of efficacy in preclinical mouse models of human disease, many of which rely on immunodeficient mice. However, relatively little is known about how the biology of various immunodeficient strains impacts the in vivo fate of these drugs. Here we used immunoPET radiotracers prepared from humanized, chimeric and murine monoclonal antibodies against four therapeutic oncologic targets to interrogate their biodistribution in four different strains of immunodeficient mice bearing lung, prostate, and ovarian cancer xenografts...
January 23, 2018: Cancer Research
Pierre Adumeau, Delphine Vivier, Sai Kiran Sharma, Jessica Wang, Terry Zhang, Aimei Chen, Brian J Agnew, Brian M Zeglis
The conjugation of antibodies with cytotoxic drugs can alter their in vivo pharmacokinetics. As a result, the careful assessment of the in vivo behavior and specifically the tumor-targeting properties of antibody-drug conjugates represents a crucial step in their development. In order to facilitate this process, we have created a methodology that facilitates the dual labeling of an antibody with both a toxin and a radionuclide for positron emission tomography (PET). To minimize the impact of these modifications, this chemoenzymatic approach leverages strain-promoted azide-alkyne click chemistry to graft both cargoes to the heavy chain glycans of the immuoglobulin's Fc domain...
January 22, 2018: Molecular Pharmaceutics
Brooke N McKnight, Nerissa T Viola-Villegas
Therapeutic monoclonal antibodies (mAbs) have been used in cancer treatment for 30 years, with around 24 mAb and mAb:drug conjugates approved by the FDA to date. Despite their specificity, efficacy has remained limited, which, in part, derails nascent initiatives towards precision medicine. An image-guided approach to reinforce treatment decisions using immune positron emission tomography (immunoPET) companion diagnostic is warranted. This review provides a general overview of current translational research using Zr-89 immunoPET and opportunities for utilizing and harnessing this tool to its full potential...
January 17, 2018: Journal of Labelled Compounds & Radiopharmaceuticals
Arutselvan Natarajan, Chirag B Patel, Frezghi Habte, Sanjiv S Gambhir
The immune checkpoint programmed death 1 receptor (PD-1) expressed on some tumor-infiltrating lymphocytes, and its ligand (PD-L1) expressed on tumor cells, enable cancers to evade the immune system. Blocking PD-1 with the monoclonal antibody pembrolizumab is a promising immunotherapy strategy. Thus, noninvasively quantifying the presence of PD-1 expression in the tumor microenvironment prior to initiation of immune checkpoint blockade may identify the patients likely to respond to therapy. We have developed a 64Cu-pembrolizumab radiotracer and evaluated human dosimetry...
January 12, 2018: Scientific Reports
Amanda Christine Freise, Kirstin A Zettlitz, Felix Bergara Salazar, Richard Tavaré, Wen-Ting K Tsai, Arion Hadjioannou, Nora Rozengurt, Jonathan Braun, Anna M Wu
Inflammatory bowel diseases (IBD) in humans are characterized in part by aberrant CD4+ T cell responses. Currently, identification of foci of inflammation within the gut requires invasive procedures such as colonoscopy and biopsy. Molecular imaging with antibody fragment probes could be used to noninvasively monitor cell subsets causing intestinal inflammation. Here, GK1.5 cys-diabody (cDb), an anti-mouse CD4 antibody fragment derived from the GK1.5 hybridoma, was used as a positron emission tomography (PET) probe for CD4+ T cells in the dextran sulfate sodium (DSS) mouse model of IBD...
January 11, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Gemma M Dias, Caterina F Ramogida, Julie Rousseau, Nicholas A Zacchia, Cornelia Hoehr, Paul Schaffer, Kuo-Shyan Lin, François Bénard
INTRODUCTION: Zirconium-89 (89Zr, t1/2=78.4h) liquid target (LT) production offers an approach to introduce this positron-emitting isotope to cyclotron centres without the need for a separate solid target (ST) production set up. We compared the production, purification, and antibody radiolabeling yields of 89Zr-(LT) and 89Zr-(ST), and assessed the feasibility of 89Zr-(LT) for preclinical PET/CT. METHODS: 89Zr-(ST) production was performed with an 89Y foil on a TR 19 cyclotron at 13...
November 16, 2017: Nuclear Medicine and Biology
Wim J G Oyen, Chris Jones
No abstract text is available yet for this article.
December 7, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Charles Truillet, Hsueh Ling J Oh, Siok Ping Yeo, Chia-Yin Lee, Loc T Huynh, Junnian Wei, Matthew F L Parker, Collin Blakely, Natalia Sevillano, Yung-Hua Wang, Yuqin S Shen, Victor Olivas, Khaled M Jami, Anna Moroz, Benoit Jego, Emilie Jaumain, Lawrence Fong, Charles S Craik, Albert J Chang, Trever G Bivona, Cheng-I Wang, Michael J Evans
High sensitivity imaging tools could provide a more holistic view of target antigen expression to improve the identification of patients who might benefit from cancer immunotherapy. We developed for immunoPET a novel recombinant human IgG1 (termed C4) that potently binds an extracellular epitope on human and mouse PD-L1 and radiolabeled the antibody with zirconium-89. Small animal PET/CT studies showed that89 Zr-C4 detected antigen levels on a patient derived xenograft (PDX) established from a non-small-cell lung cancer (NSCLC) patient before an 8-month response to anti-PD-1 and anti-CTLA4 therapy...
January 17, 2018: Bioconjugate Chemistry
Kirstin A Zettlitz, Richard Tavaré, Scott M Knowles, Kristopher K Steward, John M Timmerman, Anna M Wu
Purpose: The B-cell antigen CD20 provides a target for antibody-based positron emission tomography (immunoPET). We engineered antibody fragments targeting human CD20 and studied their potential as immunoPET tracers in transgenic mice (huCD20TM) and in a murine lymphoma model expressing human CD20. Experimental Design: Anti-CD20 cys-diabody (cDb) and cys-minibody (cMb) based on rituximab and obinutuzumab (GA101) were radioiodinated and used for immunoPET imaging of a murine lymphoma model. Pairwise comparison of obinutuzumab-based antibody fragments labeled with residualizing (89 Zr) versus non-residualizing (124 I) radionuclides by region of interest analysis of serial PET images was conducted both in the murine lymphoma model and in huCD20TM to assess antigen modulation in vivo Results: 124 I-GAcDb and124 I-GAcMb produced high-contrast immunoPET images of B-cell lymphoma and outperformed the respective rituximab-based tracers...
December 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Zéna Wimana, Geraldine Gebhart, Thomas Guiot, Bruno Vanderlinden, Denis Larsimont, Gilles Doumont, Gaetan Van Simaeys, Serge Goldman, Patrick Flamen, Ghanem Ghanem
Trastuzumab remains an important drug in the management of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer (BC). Several studies reported resistance mechanisms to trastuzumab, including impaired HER2-accessibility caused by mucin 4 (MUC4). Previously, we demonstrated an increase of Zirconium-89-radiolabeled-trastuzumab ((89)Zr-Trastuzumab) accumulation when MUC4-overexpressing BC-cells were challenged with the mucolytic drug N-Acetylcysteine (NAC). Hereby, using the same approach we investigated whether tumor exposure to NAC would also enhance trastuzumab-efficacy...
August 22, 2017: Oncotarget
Genna Davies, Anna-Maria Rolle, Andreas Maurer, Philipp R Spycher, Claudia Schillinger, Djamschid Solouk-Saran, Mike Hasenberg, Juliane Weski, Jesper Fonslet, Adrien Dubois, Frederic Boschetti, Franck Denat, Matthias Gunzer, Martin Eichner, Lauren S Ryder, Mikael Jensen, Roger Schibli, Bernd J Pichler, Stefan Wiehr, Christopher R Thornton
Invasive pulmonary aspergillosis (IPA) is a life-threatening lung disease of hematological malignancy or bone marrow transplant patients caused by the ubiquitous environmental fungus Aspergillus fumigatus. Current diagnostic tests for the disease lack sensitivity as well as specificity, and culture of the fungus from invasive lung biopsy, considered the gold standard for IPA detection, is slow and often not possible in critically ill patients. In a previous study, we reported the development of a novel non-invasive procedure for IPA diagnosis based on antibody-guided positron emission tomography and magnetic resonance imaging (immunoPET/MRI) using a [(64)Cu]DOTA-labeled mouse monoclonal antibody (mAb), mJF5, specific to Aspergillus...
2017: Theranostics
M Moreau, S Poty, J-M Vrigneaud, P Walker, M Guillemin, O Raguin, A Oudot, C Bernhard, C Goze, F Boschetti, B Collin, F Brunotte, F Denat
Improved bifunctional chelating agents (BFC) are required for copper-64 radiolabelling of monoclonal antibodies (mAbs) under mild conditions to yield stable, target-specific imaging agents. Four different bifunctional chelating agents (BFC) were evaluated for Fab (Fragment antigen binding) conjugation and radiolabelling with copper-64. Two DOTA- (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and two NOTA- (1,4,7-triazacyclononane-1,4,7-triacetic acid) derivatives bearing a p-benzyl-isothiocyanate group were conjugated to Fab-trastuzumab - which targets the HER2/neu receptor - and the average number of chelators attached ranged from 2...
October 31, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
Reinier Hernandez, Christopher G England, Yunan Yang, Hector F Valdovinos, Bai Liu, Hing C Wong, Todd E Barnhart, Weibo Cai
Overexpression of tissue factor (TF) has been associated with increased tumor growth, tumor angiogenesis, and metastatic potential in many malignancies, including pancreatic cancer. Additionally, high TF expression was shown to strongly correlate with poor prognoses and decreased survival in pancreatic cancer patients. Herein, we exploited the potential targeting of TF for positron emission tomography (PET) imaging of pancreatic cancer. The TF-targeted tracer was developed through radiolabeling of the anti-human TF monoclonal antibody (ALT-836) with (89)Zr...
October 28, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
Christopher G England, Dawei Jiang, Reinier Hernandez, Haiyan Sun, Hector F Valdovinos, Emily B Ehlerding, Jonathan W Engle, Yunan Yang, Peng Huang, Weibo Cai
CD146 has been identified as an excellent biomarker for lung cancer as its overexpression in solid tumors has been linked to disease progression, invasion, and metastasis. Previously, our group described a positive correlation between (64)Cu-labeled YY146 uptake and increased expression of CD146 in six human lung cancer cell lines using subcutaneous tumor models. In this study, we investigate a monoclonal antibody called YY146 for immunoPET imaging of CD146 in two intrapulmonary metastasis models of non-small cell lung cancer (NSCLC)...
October 2, 2017: Molecular Pharmaceutics
Masahiro Kikuchi, David A Clump, Raghvendra M Srivastava, Lingyi Sun, Dexing Zeng, Julio A Diaz-Perez, Carolyn J Anderson, W Barry Edwards, Robert L Ferris
Radiation therapy (RT) can induce upregulation of programmed death ligand 1 (PD-L1) on tumor cells or myeloid cells, which may affect response to PD-1-based immunotherapy. PD-L1 upregulation during RT is a dynamic process that has been difficult to monitor during treatment. The aim of this study was to evaluate the RT-induced PD-L1 upregulation in the tumor and its microenvironment using immunoPET/CT imaging of two syngeneic murine tumor models (HPV+ head and neck squamous cell carcinoma (HNSCC) or B16F10 melanoma)...
2017: Oncoimmunology
Sandra Heskamp, René Raavé, Otto Boerman, Mark Rijpkema, Victor Goncalves, Franck Denat
Immuno-positron emission tomography (immunoPET) with (89)Zr-labeled antibodies has shown great potential in cancer imaging. It can provide important information about the pharmacokinetics and tumor-targeting properties of monoclonal antibodies and may help in anticipating on toxicity. Furthermore, it allows accurate dose planning for individualized radioimmunotherapy and may aid in patient selection and early-response monitoring for targeted therapies. The most commonly used chelator for (89)Zr is desferrioxamine (DFO)...
September 20, 2017: Bioconjugate Chemistry
(no author information available yet)
No abstract text is available yet for this article.
August 1, 2017: Cancer Research
Christian Buchwalder, Cristina Rodríguez-Rodríguez, Paul Schaffer, Stoyan K Karagiozov, Katayoun Saatchi, Urs O Häfeli
Zirconium-89 ((89)Zr) is an ideal radiometal isotope for antibody-based positron emission tomography (immunoPET) as its physical half-life (3.27 days) is a good match with the biological half-life of larger molecular weight targeting molecules, such as antibodies (3-4 days), and its positron emission (BR = 100% EC/β(+), Eβ(+),avg = 395.5 keV) is suited for high resolution PET imaging. Concerns over the in vivo stability of the most commonly used (89)Zr-chelator, desferrioxamine B (DFO), have spurred efforts into the development of alternative (89)Zr-chelators that withstand the release of osteophilic (89)Zr(4+)...
July 25, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
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