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Nikunj B Bhatt, Darpan N Pandya, Thaddeus J Wadas
The interest in zirconium-89 (89 Zr) as a positron-emitting radionuclide has grown considerably over the last decade due to its standardized production, long half-life of 78.2 h, favorable decay characteristics for positron emission tomography (PET) imaging and its successful use in a variety of clinical and preclinical applications. However, to be utilized effectively in PET applications it must be stably bound to a targeting ligand, and the most successfully used89 Zr chelator is desferrioxamine B (DFO), which is commercially available as the iron chelator Desferal® ...
March 12, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Denis R Beckford Vera, Christof C Smith, Lisa M Bixby, Dylan M Glatt, Stuart S Dunn, Ryoichi Saito, William Y Kim, Jonathan S Serody, Benjamin G Vincent, Matthew C Parrott
The ability to non-invasively monitor tumor-infiltrating T cells in vivo could provide a powerful tool to visualize and quantify tumor immune infiltrates. For non-invasive evaluations in vivo, an anti-CD3 mAb was modified with desferrioxamine (DFO) and radiolabeled with zirconium-89 (Zr-89 or 89Zr). Radiolabeled 89Zr-DFO-anti-CD3 was tested for T cell detection using positron emission tomography (PET) in both healthy mice and mice bearing syngeneic bladder cancer BBN975. In vivo PET/CT and ex vivo biodistribution demonstrated preferential accumulation and visualization of tracer in the spleen, thymus, lymph nodes, and bone marrow...
2018: PloS One
Freddy E Escorcia, Jeffrey M Steckler, Dalya Abdel-Atti, Eric W Price, Sean D Carlin, Wolfgang W Scholz, Jason S Lewis, Jacob L Houghton
PURPOSE: Tumor-specific molecular imaging is an important tool for assessing disease burden and treatment response. CA19.9 is an important tumor-specific marker in several malignancies, including urothelial carcinoma. [89 Zr]DFO-HuMab-5B1 (MVT-2163) is a CA19.9-specific antibody-based construct that has been validated in preclinical animal models of lung, colorectal, and pancreatic malignancies for positron emission tomography (PET) imaging and is currently in a phase I trial for pancreatic cancer (NCT02687230)...
March 5, 2018: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
Clément Bailly, Sébastien Gouard, Marie Lacombe, Patricia Remaud-Le Saëc, Benjamin Chalopin, Mickaël Bourgeois, Nicolas Chouin, Raphaël Tripier, Zakaria Halime, Ferid Haddad, Alain Faivre-Chauvet, Françoise Kraeber-Bodéré, Michel Chérel, Caroline Bodet-Milin
Purpose: Although recent data from the literature suggest that PET imaging with [18]-Fluorodeoxyglucose (18 F-FDG) is a promising technique in multiple myeloma (MM), the development of other radiopharmaceuticals seems relevant. CD138 is currently used as a standard marker in many laboratories for the identification and purification of myeloma cells, and could be used in phenotype tumor imaging. In this study, we evaluated a64 Cu-labeled anti-CD138 murine antibody (64 Cu-TE2A-9E7.4) and a metabolic tracer (64 CuCl2 ) for PET imaging in a MM syngeneic mouse model...
February 6, 2018: Oncotarget
Dan Li, Siyuan Cheng, Sijuan Zou, Dongling Zhu, Tinghui Zhu, Pilin Wang, Xiaohua Zhu
Recently, various immuno-PET tracers based on monoclonal antibodies (mAbs), engineered scaffold proteins and peptides were developed to target either programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1), showing promise in assessment of immune checkpoints. We sought to develop an immunotherapeutic agent-based PET probe that enable real-time assessment of PD-L1 expression and evaluation of antibody drug biodistribution to select eligible candidates for anti-PD-1/PD-L1 immunotherapies...
March 5, 2018: Molecular Pharmaceutics
Armando Bartolazzi, Salvatore Sciacchitano, Calogero D'Alessandria
Galectins (S-type lectins) are an evolutionarily-conserved family of lectin molecules, which can be expressed intracellularly and in the extracellular matrix, as well. Galectins bind β-galactose-containing glycoconjugates and are functionally active in converting glycan-related information into cell biological programs. Altered glycosylation notably occurring in cancer cells and expression of specific galectins provide, indeed, a fashionable mechanism of molecular interactions able to regulate several tumor relevant functions, among which are cell adhesion and migration, cell differentiation, gene transcription and RNA splicing, cell cycle and apoptosis...
February 2, 2018: International Journal of Molecular Sciences
Michael Wagner, Melinda Wuest, Ingrit Hamann, Ana Lopez-Campistrous, Todd P W McMullen, Frank Wuest
INTRODUCTION: Receptor tyrosine kinase (RTK) platelet-derived growth factor receptor-alpha (PDGFRα) was recently identified as a molecular switch for dedifferentiation in thyroid cancer that predicts resistance to therapy as well as recurrence of disease in papillary thyroid cancer. Here we describe the radiolabeling and functional characterization of an imaging probe based on a PDGFRα-specific monoclonal antibody (mAb) for immuno-PET imaging of PDGFRα in papillary thyroid cancer. METHODS: Antibody D13C6 (Cell Signaling) was decorated with chelator NOTA using bioconjugation reaction with 2-(p-NCS-Bz)-NOTA...
December 27, 2017: Nuclear Medicine and Biology
Yvonne W S Jauw, Marc C Huisman, Tapan K Nayak, Danielle J Vugts, Randolph Christen, Valerie Meresse Naegelen, Dominik Ruettinger, Florian Heil, Adriaan A Lammertsma, Henk M W Verheul, Otto S Hoekstra, Guus A M S van Dongen, C Willemien Menke-van der Houven van Oordt
BACKGROUND: Ideally, monoclonal antibodies provide selective treatment by targeting the tumour, without affecting normal tissues. Therefore, antibody imaging is of interest, preferably in early stages of drug development. However, the imaging signal consists of specific, as well as non-specific, uptake. The aim of this study was to assess specific, target-mediated uptake in normal tissues, with immuno-PET in a phase I dose escalation study, using the anti-CD44 antibody RG7356 as example...
January 22, 2018: EJNMMI Research
Aaron T Mayer, Sanjiv S Gambhir
No abstract text is available yet for this article.
January 18, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
P J Santangelo, C Cicala, S N Byrareddy, K T Ortiz, D Little, K E Lindsay, S Gumber, J J Hong, K Jelicic, K A Rogers, C Zurla, F Villinger, A A Ansari, A S Fauci, J Arthos
Integrin α4β7 mediates the trafficking of leukocytes, including CD4+ T cells, to lymphoid tissues in the gut. Virus mediated damage to the gut is implicated in HIV and SIV mediated chronic immune activation and leads to irreversible damage to the immune system. We employed an immuno-PET/CT imaging technique to evaluate the impact of an anti-integrin α4β7 mAb alone or in combination with ART, on the distribution of both SIV infected cells and CD4+ cells in rhesus macaques infected with SIV. We determined that α4β7 mAb reduced viral antigen in an array of tissues of the lung, spleen, axillary, and inguinal lymph nodes...
December 20, 2017: Mucosal Immunology
Xudong Shi, Kai Gao, Hao Huang, Ran Gao
Pretargeted immuno-PET imaging based on the bioorthogonal chemistry between 18F-labeled Reppe anhydride derivatives and tetrazine conjugates of the EGFR-specific monoclonal antibodies cetuximab and panitumumab was performed. This pretargeting approach yielded high target-to-nontarget ratios. Furthermore, due to the fast clearance rate of the PET probe, the overall radiation burden to nontarget tissues was also substantially decreased.
January 16, 2018: Bioconjugate Chemistry
Emilie M F 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 an18 F-labeled small TCO compound, [18 F]1 recently developed in our laboratory, to perform pretargeted immuno-PET imaging...
December 20, 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) with64 Cu-/177 Lu-PCTA-cetuximab in cetuximab-resistant SNU-1066 HNSCC xenografted model. The cellular uptake of64 Cu/177 Lu-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...
February 1, 2018: 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
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