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Emilie Billaud, Sarah Belderbos, Frederik Cleeren, Wim Maes, Marlies Van de Wouwer, Michel Koole, Alfons Verbruggen, Uwe Himmelreich, Nick Geukens, Guy Bormans
In cancer research, pretargeted positron emission tomography (PET) imaging has emerged as an effective two-step approach that combines the excellent target affinity and selectivity of antibodies with the advantages of using short-lived radionuclides such as fluorine-18. One possible approach is based on the bioorthogonal inverse-electron-demand Diels-Alder (IEDDA) reaction between tetrazines and trans-cyclooctene (TCO) derivatives. Here, we report the first successful use of an 18F-labeled small TCO compound, [18F]1 recently developed in our laboratory, to perform pretargeted immuno-PET imaging...
November 30, 2017: Bioconjugate Chemistry
In Ho Song, Youn Noh, Junhye Kwon, Jae Ho Jung, Byung Chul Lee, Kwang Il Kim, Yong Jin Lee, Joo Hyun Kang, Chae Seo Rhee, Chul Hee Lee, Tae Sup Lee, Ik Joon Choi
The epidermal growth factor receptor (EGFR) is one of the most comprehensively studied molecular targets in head and neck squamous cell carcinoma (HNSCC). However, inherent and acquired resistance are serious problems and are responsible for limited clinical efficacy and tumor recurrence. In this study, we evaluated the feasibility of immuno-positron emission tomography (PET) imaging and radioimmunotherapy (RIT) with 64Cu-/177Lu-PCTA-cetuximab in cetuximab-resistant SNU-1066 HNSCC xenografted model. The cellular uptake of 64Cu/177Lu-3,6,9,15-tetraazabicyclo[9...
November 3, 2017: Oncotarget
Feifei Teng, Xiangjiao Meng, Li Kong, Jinming Yu
Despite the marked success of applications of PD-1/PD-L1 checkpoint blockades in clinical, the efficacy and responsiveness of these agents varies greatly among different tumor types and across individual patients. Therefore, establishment of predictive biomarkers for checkpoint blockades is of the most importance to maximize the therapeutic benefits. In this review, we discuss the current progress and challenges of developing predictive biomarkers of immunotherapy responsiveness, aiming to provide some directions for future studies...
November 16, 2017: Cancer Letters
Liza Lindenberg, Stephen Adler, Ismail B Turkbey, Francesca Mertan, Anita Ton, Khanh Do, Shivaani Kummar, Esther Mena Gonzalez, Sibaprasad Bhattacharyya, Paula M Jacobs, Peter Choyke
(89)Zr-panitumumab is a novel immuno-PET radiotracer. A fully humanized IgG2 antibody, panitumumab binds with high affinity to the extracellular ligand binding domain of EGFR. Immuno-PET with radiolabeled panitumumab is a non-invasive method that could characterize EGFR expression in tumors and metastatic lesions. It might also assist in selecting patients likely to benefit from targeted therapy as well as monitor response and drug biodistribution for dosing guidance. Our objective was to calculate the maximum dosing for effective imaging with minimal radiation exposure in a small subset...
2017: American Journal of Nuclear Medicine and Molecular Imaging
Nahid Yusufi, Sabine Mall, Henrique de Oliveira Bianchi, Katja Steiger, Sybille Reder, Richard Klar, Stefan Audehm, Mona Mustafa, Stephan Nekolla, Christian Peschel, Markus Schwaiger, Angela M Krackhardt, Calogero D'Alessandria
A number of different technologies have been developed to monitor in vivo the distribution of gene-modified T cells used in immunotherapy. Nevertheless, in-depth characterization of novel approaches with respect to sensitivity and clinical applicability are so far missing. We have previously described a novel method to track engineered human T cells in tumors using (89)Zr-Df-aTCRmu-F(ab')2 targeting the murinized part of the TCR beta domain (TCRmu) of a transgenic TCR. Here, we performed an in-depth in vitro characterization of the tracer in terms of antigen affinity, immunoreactivity, influence on T-cell functionality and stability in vitro and in vivo...
2017: Theranostics
L Allott, C Da Pieve, J Meyers, T Spinks, D M Ciobota, G Kramer-Marek, G Smith
The future of (89)Zr-based immuno-PET is reliant upon the development of new chelators with improved stability compared to the currently used deferoxamine (DFO). Herein, we report the evaluation of the octadentate molecule DFO-HOPO (3) as a suitable chelator for (89)Zr and a more stable alternative to DFO. The molecule showed good potential for the future development of a DFO-HOPO-based bifunctional chelator (BFC) for the radiolabelling of biomolecules with (89)Zr. This work broadens the selection of available chelators for (89)Zr in search of improved successors to DFO for clinical (89)Zr-immuno-PET...
July 27, 2017: Chemical Communications: Chem Comm
Mohammad Rashidian, Jessica R Ingram, Michael Dougan, Anushka Dongre, Katherine A Whang, Camille LeGall, Juan J Cragnolini, Brian Bierie, Monica Gostissa, James Gorman, Gijsbert M Grotenbreg, Atul Bhan, Robert A Weinberg, Hidde L Ploegh
Immunotherapy using checkpoint-blocking antibodies against targets such as CTLA-4 and PD-1 can cure melanoma and non-small cell lung cancer in a subset of patients. The presence of CD8 T cells in the tumor correlates with improved survival. We show that immuno-positron emission tomography (immuno-PET) can visualize tumors by detecting infiltrating lymphocytes and, through longitudinal observation of individual animals, distinguish responding tumors from those that do not respond to therapy. We used 89Zr-labeled PEGylated single-domain antibody fragments (VHHs) specific for CD8 to track the presence of intratumoral CD8+ T cells in the immunotherapy-susceptible B16 melanoma model in response to checkpoint blockade...
August 7, 2017: Journal of Experimental Medicine
Nikunj B Bhatt, Darpan N Pandya, Jide Xu, David Tatum, Darren Magda, Thaddeus J Wadas
The development of bifunctional chelators (BFCs) for zirconium-89 immuno-PET applications is an area of active research. Herein we report the synthesis and evaluation of octadentate hydroxyisophthalamide ligands (1 and 2) as zirconium-89 chelators. While both radiometal complexes could be prepared quantitatively and with excellent specific activity, preparation of 89Zr-1 required elevated temperature and an increased reaction time. 89Zr-1 was more stable than 89Zr-2 when challenged in vitro by excess DTPA or serum proteins and in vivo during acute biodistribution studies...
2017: PloS One
Darpan N Pandya, Nikunj Bhatt, Hong Yuan, Cynthia S Day, Brandie M Ehrmann, Marcus Wright, Ulrich Bierbach, Thaddeus J Wadas
We report our initial investigations into the use of tetraazamacrocycles as zirconium-89 chelators. We describe the synthesis and complete characterization of several Zr tetraazamacrocycle complexes, and definitively describe the first crystal structure of zirconium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Zr-DOTA) using single crystal X-ray diffraction analysis. After evaluating several radioactive analogs, we found that (89)Zr-DOTA is superior to (89)Zr-DFO, the only (89)Zr-complex to be used clinically in (89)Zr-radiopharmaceutical applications...
March 1, 2017: Chemical Science
Hasan Alsaid, Tinamarie Skedzielewski, Mary V Rambo, Kristen Hunsinger, Bao Hoang, William Fieles, Edward R Long, James Tunstead, Danielle J Vugts, Matthew Cleveland, Neil Clarke, Christopher Matheny, Beat M Jucker
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...
2017: PloS One
Catharina H M J Van Elssen, Mohammad Rashidian, Vladimir Vrbanac, Kai W Wucherpfennig, Zeina El Habre, Jana Sticht, Christian Freund, Johanne T Jacobsen, Juanjo Cragnolini, Jessica Ingram, Loes Plaisier, Eric Spierings, Andrew M Tager, Hidde L Ploegh
The immune system plays a crucial role in many diseases. Activation or suppression of immunity is often related to clinical outcome. Methods to explore the dynamics of immune responses are important to elucidate their role in conditions characterized by inflammation, such as infectious disease, cancer, or autoimmunity. Immuno-PET is a noninvasive method by which disease and immune cell infiltration can be explored simultaneously. Using radiolabeled antibodies or fragments derived from them, it is possible to image disease-specific antigens and immune cell subsets...
June 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Milos Petrik, Chuangyan Zhai, Hubertus Haas, Clemens Decristoforo
This review covers publications on siderophores applied for molecular imaging applications, mainly for radionuclide-based imaging. Siderophores are low molecular weight chelators produced by bacteria and fungi to scavenge essential iron. Research on these molecules has a continuing history over the past 50 years. Many biomedical applications have been developed, most prominently the use of the siderophore desferrioxamine (DFO) to tackle iron overload related diseases. Recent research described the upregulation of siderophore production and transport systems during infection...
2017: Clinical and Translational Imaging: Reviews in Nuclear Medicine and Molecular Imaging
Yvonne W S Jauw, Josée M Zijlstra, Daphne de Jong, Danielle J Vugts, Sonja Zweegman, Otto S Hoekstra, Guus A M S van Dongen, Marc C Huisman
PURPOSE: Treatment of patients with diffuse large B cell lymphoma (DLBCL) includes rituximab, an anti-CD20 monoclonal antibody (mAb). Insufficient tumor targeting might cause therapy failure. Tumor uptake of 89Zirconium (89Zr)-mAb is a potential imaging biomarker for tumor targeting, since it depends on target antigen expression and accessibility. The aim of this pilot study was to describe the performance of 89Zr-labeled-rituximab-PET to assess CD20 targeting in patients with relapsed/refractory DLBCL...
2017: PloS One
Clément Bailly, Pierre-François Cléry, Alain Faivre-Chauvet, Mickael Bourgeois, François Guérard, Ferid Haddad, Jacques Barbet, Michel Chérel, Françoise Kraeber-Bodéré, Thomas Carlier, Caroline Bodet-Milin
Recent advances in molecular characterization of tumors have allowed identification of new molecular targets on tumor cells or biomarkers. In medical practice, the identification of these biomarkers slowly but surely becomes a prerequisite before any treatment decision, leading to the concept of personalized medicine. Immuno-positron emission tomography (PET) fits perfectly with this approach. Indeed, monoclonal antibodies (mAbs) labelled with radionuclides represent promising probes for theranostic approaches, offering a non-invasive solution to assess in vivo target expression and distribution...
December 28, 2016: International Journal of Molecular Sciences
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...
December 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...
February 2017: 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 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
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