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Sitah F Alanazi, Khalid S Alzimami, Magdy M Ghannam, Ibrahim J Aljammaz, Faisal Alrumayan, Salem A Sassi
PURPOSE: Interest in PET imaging using zirconium-89 (Zr) (t1/2=78.41 h)-labeled tracers for the tracking and quantification of monoclonal antibodies (mAbs) is growing, mainly because of its well-matched physical half-life with the biological half-life of intact mAbs. This study aims to evaluate the imaging characteristics of Zr-PET in comparison with those obtained using fluorine-18 fluorodeoxyglucose (F-FDG) PET (gold standard tracer in PET imaging) using a Time-Of-Flight (TOF) PET/computed tomography (CT) scanner...
October 4, 2016: Nuclear Medicine Communications
Danielle J Vugts, Chris Klaver, Claudia Sewing, Alex J Poot, Kevin Adamzek, Seraina Huegli, Cristina Mari, Gerard W M Visser, Ibai E Valverde, Gilles Gasser, Thomas L Mindt, Guus A M S van Dongen
PURPOSE: All clinical (89)Zr-immuno-PET studies are currently performed with the chelator desferrioxamine (DFO). This chelator provides hexadentate coordination to zirconium, leaving two coordination sites available for coordination with, e.g., water molecules, which are relatively labile ligands. The unsaturated coordination of DFO to zirconium has been suggested to result in impaired stability of the complex in vivo and consequently in unwanted bone uptake of (89)Zr. Aiming at clinical improvements, we report here on a bifunctional isothiocyanate variant of the octadentate chelator DFO* and the in vitro and in vivo comparison of its (89)Zr-DFO*-mAb complex with (89)Zr-DFO-mAb...
August 30, 2016: European Journal of Nuclear Medicine and Molecular Imaging
Fook T Lee, Ingrid J G Burvenich, Nancy Guo, Pece Kocovski, Henri Tochon-Danguy, Uwe Ackermann, Graeme J O'Keefe, Sylvia Gong, Angela Rigopoulos, Zhanqi Liu, Hui K Gan, Andrew M Scott
PURPOSE: The aims of the study were to develop and evaluate a novel residualizing peptide for labeling internalizing antibodies with (124)I to support clinical development using immuno-positron emission tomography (PET). METHODS: The anti-epidermal growth factor receptor antibody ch806 was radiolabeled directly or indirectly with isotopes and various residualizing peptides. Azido-derivatized radiolabeled peptides were conjugated to dibenzylcyclooctyne-derivatized ch806 antibody via click chemistry...
2016: Molecular Imaging
Sabine Mall, Nahid Yusufi, Ricarda Wagner, Richard Klar, Henrique Bianchi, Katja Steiger, Melanie Straub, Stefan Audehm, Iina Laitinen, Michaela Aichler, Christian Peschel, Sibylle Ziegler, Mona Mustafa, Markus Schwaiger, Calogero D'Alessandria, Angela M Krackhardt
Sensitive in vivo imaging technologies applicable to the clinical setting are still lacking for adoptive T-cell-based immunotherapies, an important gap to fill if mechanisms of tumor rejection or escape are to be understood. Here, we propose a highly sensitive imaging technology to track human TCR-transgenic T cells in vivo by directly targeting the murinized constant TCR beta domain (TCRmu) with a zirconium-89 ((89)Zr)-labeled anti-TCRmu-F(ab')2 fragment. Binding of the labeled or unlabeled F(ab')2 fragment did not impair functionality of transgenic T cells in vitro and in vivo Using a murine xenograft model of human myeloid sarcoma, we monitored by Immuno-PET imaging human central memory T cells (TCM), which were transgenic for a myeloid peroxidase (MPO)-specific TCR...
July 15, 2016: Cancer Research
Marc H A Jansen, Tonny Lagerweij, A Charlotte P Sewing, Danielle J Vugts, Dannis G van Vuurden, Carla F M Molthoff, Viola Caretti, Susanna J E Veringa, Naomi Petersen, Angel M Carcaboso, David P Noske, W Peter Vandertop, Pieter Wesseling, Guus A M S van Dongen, Gertjan J L Kaspers, Esther Hulleman
The role of the VEGF inhibitor bevacizumab in the treatment of diffuse intrinsic pontine glioma (DIPG) is unclear. We aim to study the biodistribution and uptake of zirconium-89 ((89)Zr)-labeled bevacizumab in DIPG mouse models. Human E98-FM, U251-FM glioma cells, and HSJD-DIPG-007-FLUC primary DIPG cells were injected into the subcutis, pons, or striatum of nude mice. Tumor growth was monitored by bioluminescence imaging (BLI) and visualized by MRI. Seventy-two to 96 hours after (89)Zr-bevacizumab injections, mice were imaged by positron emission tomography (PET), and biodistribution was analyzed ex vivo High VEGF expression in human DIPG was confirmed in a publically available mRNA database, but no significant (89)Zr-bevacizumab uptake could be detected in xenografts located in the pons and striatum at an early or late stage of the disease...
September 2016: Molecular Cancer Therapeutics
I Bahce, M Yaqub, E F Smit, A A Lammertsma, G A M S van Dongen, N H Hendrikse
Non-small cell lung cancer (NSCLC) therapy has entered a rapidly advancing era of precision medicine with an ever increasing number of drugs directed against a variety of specific tumor targets. Amongst these new agents, tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) are most frequently used. However, as only a sensitive subgroup of patients benefits from targeting drugs, predictive biomarkers are needed. Positron emission tomography (PET) may offer such a biomarker for predicting therapy efficacy...
May 31, 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Jin Su Kim
Monoclonal antibodies (mAbs), which play a prominent role in cancer therapy, can interact with specific antigens on cancer cells, thereby enhancing the patient's immune response via various mechanisms, or mAbs can act against cell growth factors and, thereby, arrest the proliferation of tumor cells. Radionuclide-labeled mAbs, which are used in radioimmunotherapy (RIT), are effective for cancer treatment because tumor associated-mAbs linked to cytotoxic radionuclides can selectively bind to tumor antigens and release targeted cytotoxic radiation...
June 2016: Nuclear Medicine and Molecular Imaging
Yvonne W S Jauw, C Willemien Menke-van der Houven van Oordt, Otto S Hoekstra, N Harry Hendrikse, Danielle J Vugts, Josée M Zijlstra, Marc C Huisman, Guus A M S van Dongen
Selection of the right drug for the right patient is a promising approach to increase clinical benefit of targeted therapy with monoclonal antibodies (mAbs). Assessment of in vivo biodistribution and tumor targeting of mAbs to predict toxicity and efficacy is expected to guide individualized treatment and drug development. Molecular imaging with positron emission tomography (PET) using zirconium-89 ((89)Zr)-labeled monoclonal antibodies also known as (89)Zr-immuno-PET, visualizes and quantifies uptake of radiolabeled mAbs...
2016: Frontiers in Pharmacology
Caroline Bodet-Milin, Alain Faivre-Chauvet, Thomas Carlier, Aurore Rauscher, Mickael Bourgeois, Evelyne Cerato, Vincent Rohmer, Olivier Couturier, Delphine Drui, David M Goldenberg, Robert M Sharkey, Jacques Barbet, Francoise Kraeber-Bodéré
: Earlier clinical studies reported a high sensitivity of pretargeted immunoscintigraphy using murine or chimeric anti-carcinoembryonic antigen (CEA) bispecific antibody (BsMAb) and peptides labeled with (111)In or (131)I in medullary thyroid carcinoma (MTC). Preclinical studies showed that new generation humanized recombinant anti-CEA x anti-histamine-succinyl-glycine (HSG) trivalent BsMAb TF2 and radiolabeled HSG peptide (IMP288) present good features for PET. This study aimed at optimizing molar doses and pretargeting interval of TF2 and (68)Ga-labeled IMP288 for immuno-PET in relapsed MTC patients with calcitonin serum levels > 150 pg/ml...
May 26, 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Valery Radchenko, Penelope Bouziotis, Theodoros Tsotakos, Mari Paravatou-Petsotas, Ana de la Fuente, George Loudos, Adrian L Harris, Stavros Xanthopoulos, Dmitry Filosofov, Harald Hauser, Michael Eisenhut, Bernard Ponsard, Frank Roesch
The application of radionuclide-labeled biomolecules such as monoclonal antibodies or antibody fragments for imaging purposes is called immunoscintigraphy. More specifically, when the nuclides used are positron emitters, such as zirconium-89, the technique is referred to as immuno-PET. Currently, there is an urgent need for radionuclides with a half-life which correlates well with the biological kinetics of the biomolecules under question and which can be attached to the proteins by robust labeling chemistry...
May 2016: Nuclear Medicine and Biology
James C Knight, Stephen J Paisey, Adam M Dabkowski, Cristina Marculescu, Anwen S Williams, Christopher Marshall, Bart Cornelissen
The most widely cited procedures for radiolabeling antibodies with zirconium-89 for immuno-PET require multi-milligram amounts of antibody which can be cost-prohibitive, particularly during the research and development process. We therefore sought to develop a reliable (89)Zr-radiolabeling procedure that provides high radiochemical yields at the microgram scale.
April 21, 2016: Dalton Transactions: An International Journal of Inorganic Chemistry
Mohammad Rashidian, Edmund Keliher, Michael Dougan, Patrick K Juras, Marco Cavallari, Gregory R Wojtkiewicz, Johanne Jacobsen, Jerre G Edens, Jeroen M G Tas, Gabriel Victora, Ralph Weissleder, Hidde Ploegh
We generated (18)F-labeled antibody fragments for PET imaging using a sortase-mediated reaction to install a transcyclooctene (TCO)-functionalized short peptide onto proteins of interest, followed by reaction with a tetrazine-labeled-(18)F-2-deoxyfluoroglucose (FDG). The method is rapid, robust, and site-specific (radiochemical yields >25%, not decay corrected). The availability of (18)F-2-deoxyfluoroglucose avoids the need for more complicated chemistries used to generate carbon-fluorine bonds. We demonstrate the utility of the method by detecting heterotopic pancreatic tumors in mice by PET, using anti-Class II MHC single domain antibodies...
June 24, 2015: ACS Central Science
In Ho Song, Tae Sup Lee, Yong Serk Park, Jin Sook Lee, Byung Chul Lee, Byung Seok Moon, Gwang Il An, Hae Won Lee, Kwang Il Kim, Yong Jin Lee, Joo Hyun Kang, Sang Moo Lim
UNLABELLED: Immuno-PET provides valuable information about tumor location, phenotype, susceptibility to therapy, and treatment response, especially to targeted radioimmunotherapy. In this study, we prepared antiepidermal growth factor receptor (EGFR) antibody via identical chelator, 3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-trience-3,6,9,-triacetic acid (PCTA), labeled with (64)Cu or (177)Lu to evaluate the EGFR expression levels using immuno-PET and the feasibility of radioimmunotherapy in an esophageal squamous cell carcinoma (ESCC) model...
July 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Jens Fissers, Ann-Marie Waldron, Thomas De Vijlder, Bianca Van Broeck, Darrel J Pemberton, Marc Mercken, Pieter Van Der Veken, Jurgen Joossens, Koen Augustyns, Stefanie Dedeurwaerdere, Sigrid Stroobants, Steven Staelens, Leonie Wyffels
PURPOSE: The aim of this study was to evaluate the in vitro and in vivo characteristics of [(89)Zr]JRF/AβN/25, a radiolabeled monoclonal antibody directed against amyloid-β (Aβ). PROCEDURES: JRF/AβN/25 was labeled with (89)Zr following modification with desferal. The affinity of the tracer for Aβ1-40 was determined in a saturation binding assay. In vitro stability was evaluated, and in vivo plasma stability and biodistribution of [(89)Zr]Df-Bz-JRF/AβN/25 were determined in wild-type mice...
August 2016: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
Roy L Maute, Sydney R Gordon, Aaron T Mayer, Melissa N McCracken, Arutselvan Natarajan, Nan Guo Ring, Richard Kimura, Jonathan M Tsai, Aashish Manglik, Andrew C Kruse, Sanjiv S Gambhir, Irving L Weissman, Aaron M Ring
Signaling through the immune checkpoint programmed cell death protein-1 (PD-1) enables tumor progression by dampening antitumor immune responses. Therapeutic blockade of the signaling axis between PD-1 and its ligand programmed cell death ligand-1 (PD-L1) with monoclonal antibodies has shown remarkable clinical success in the treatment of cancer. However, antibodies have inherent limitations that can curtail their efficacy in this setting, including poor tissue/tumor penetrance and detrimental Fc-effector functions that deplete immune cells...
November 24, 2015: Proceedings of the National Academy of Sciences of the United States of America
Mai Lin, Uday Mukhopadhyay, Gregory J Waligorski, Julius A Balatoni, Carlos González-Lepera
Interest in using (89)Zr is rapidly increasing for immuno-PET applications due to its unique characteristics and increased availability. The focus of this study was to develop an optimized semi-automated methodology for producing (89)Zr-oxalate/(89)Zr-chloride, and evaluate the potential application of (89)Zr-chloride for radiopharmaceutical compounding. The data presented herein will be useful for the production of (89)Zr-labeled radiopharmaceuticals and their compliance with regulatory issues for both preclinical and clinical use...
January 2016: Applied Radiation and Isotopes
Richard Tavaré, Helena Escuin-Ordinas, Stephen Mok, Melissa N McCracken, Kirstin A Zettlitz, Felix B Salazar, Owen N Witte, Antoni Ribas, Anna M Wu
The rapidly advancing field of cancer immunotherapy is currently limited by the scarcity of noninvasive and quantitative technologies capable of monitoring the presence and abundance of CD8(+) T cells and other immune cell subsets. In this study, we describe the generation of (89)Zr-desferrioxamine-labeled anti-CD8 cys-diabody ((89)Zr-malDFO-169 cDb) for noninvasive immuno-PET tracking of endogenous CD8(+) T cells. We demonstrate that anti-CD8 immuno-PET is a sensitive tool for detecting changes in systemic and tumor-infiltrating CD8 expression in preclinical syngeneic tumor immunotherapy models including antigen-specific adoptive T-cell transfer, agonistic antibody therapy (anti-CD137/4-1BB), and checkpoint blockade antibody therapy (anti-PD-L1)...
January 1, 2016: Cancer Research
Qinghua Yuan, Takako Furukawa, Takahiro Tashiro, Kouki Okita, Zhao-Hui Jin, Winn Aung, Aya Sugyo, Kotaro Nagatsu, Hiroko Endo, Atsushi B Tsuji, Ming-Rong Zhang, Takashi Masuko, Masahiro Inoue, Yasuhisa Fujibayashi, Tsuneo Saga
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...
2015: PloS One
Noriyuki Kasai, Maiko Adachi, Kazuya Yamano
PURPOSE: Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family and is an important therapeutic target in some types of human cancers. KHK2866 is a humanized anti-HB-EGF monoclonal antibody IgG that neutralizes HB-EGF activity by inhibiting the binding of HB-EGF to its receptors. The phase I study of KHK2866 was discontinued because of neuropsychiatric toxicity. In this study, the pharmacokinetics of KHK2866 was evaluated by (89)Zr-immuno-PET study and the determination of drug concentrations in serum and cerebrospinal fluid using cynomolgus monkeys was performed in order to predict neurotoxicity in a reverse-translational manner...
February 2016: Pharmaceutical Research
Arutselvan Natarajan, Aaron T Mayer, Lingyun Xu, Robert E Reeves, Jacob Gano, Sanjiv S Gambhir
Immune checkpoint signaling through the programmed death 1 (PD-1) axis to its ligand (PD-L1) significantly dampens anti-tumor immune responses. Cancer patients treated with checkpoint inhibitors that block this suppressive signaling have exhibited objective response rates of 20-40% for advanced solid tumors, lymphomas, and malignant melanomas. This represents a tremendous advance in cancer treatment. Unfortunately, all patients do not respond to immune checkpoint blockade. Recent findings suggest that patients with tumor infiltrating lymphocytes (TILs) expressing PD-1 may be most likely to respond to αPD-1/PD-L1 checkpoint inhibitors...
October 21, 2015: Bioconjugate Chemistry
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