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Emily B Ehlerding, Christopher G England, Rebecca L Majewski, Hector F Valdovinos, Dawei Jiang, Glenn Liu, Douglas G McNeel, Robert J Nickles, Weibo Cai
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is expressed on the surface of activated T cells and some tumor cells, and is the target of the clinically approved monoclonal antibody ipilimumab. In this study, we investigate specific binding of radiolabeled ipilimumab to CTLA-4 expressed by human non-small cell lung cancer cells in vivo using positron emission tomography (PET). Ipilimumab was radiolabeled with (64)Cu (t1/2 = 12.7 h) through the use of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to formulate (64)Cu-DOTA-ipilimumab...
April 12, 2017: Molecular Pharmaceutics
Haiming Luo, Christopher G England, Shreya Goel, Stephen A Graves, Fanrong Ai, Bai Liu, Charles P Theuer, Hing C Wong, Robert J Nickles, Weibo Cai
Dual-targeted imaging agents have shown improved targeting efficiencies in comparison to single-targeted entities. The purpose of this study was to quantitatively assess the tumor accumulation of a dual-labeled heterobifunctional imaging agent, targeting two overexpressed biomarkers in pancreatic cancer, using positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging modalities. A bispecific immunoconjugate (heterodimer) of CD105 and tissue factor (TF) Fab' antibody fragments was developed using click chemistry...
March 24, 2017: Molecular Pharmaceutics
Dawei Jiang, Hyung-Jun Im, Haiyan Sun, Hector F Valdovinos, Christopher G England, Emily B Ehlerding, Robert J Nickles, Dong Soo Lee, Steve Y Cho, Peng Huang, Weibo Cai
PURPOSE: Human epidermal growth factor receptor 2 (HER2) is over-expressed in over 30% of ovarian cancer cases, playing an essential role in tumorigenesis and metastasis. Non-invasive imaging of HER2 is of great interest for physicians as a mean to better detect and monitor the progression of ovarian cancer. In this study, HER2 was assessed as a biomarker for ovarian cancer imaging using (64)Cu-labeled pertuzumab for immunoPET imaging. METHODS: HER2 expression and binding were examined in three ovarian cancer cell lines (SKOV3, OVCAR3, Caov3) using in vitro techniques, including western blot and saturation binding assays...
March 6, 2017: European Journal of Nuclear Medicine and Molecular Imaging
Arutselvan Natarajan, Aaron T Mayer, Robert E Reeves, Claude M Nagamine, Sanjiv Sam Gambhir
PURPOSE: It is well known that cancers exploit immune checkpoints (programmed death 1 receptor (PD-1) and its ligand (PD-L1)) to evade anti-tumor immune responses. Although immune checkpoint (IC) blockade is a promising approach, not all patients respond. Hence, imaging of tumor-infiltrating lymphocytes (TILs) is of high specific interest, as they are known to express PD-1 during activation and subsequent exhaustion in the tumor microenvironment and are thought to be potentially predictive of therapeutic responses to IC blockade...
February 28, 2017: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
Aaron T Mayer, Arutselvan Natarajan, Sydney R Gordon, Roy L Maute, Melissa N McCracken, Aaron M Ring, Irving L Weissman, Sanjiv S Gambhir
Immune checkpoint blockade has emerged as a promising cancer treatment paradigm. Unfortunately, there are still a large number of patients and malignancies that do not respond to therapy. A major barrier to validating biomarkers for the prediction and monitoring of responders to clinical checkpoint blockade has been the lack of imaging tools to accurately assess dynamic immune checkpoint expression. Here, we sought to optimize noninvasive immuno-PET imaging of human programmed death-ligand 1 (PD-L1) expression, in a preclinical model, using a small high-affinity engineered protein scaffold (HAC-PD1)...
April 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Amanda C Freise, Kirstin A Zettlitz, Felix B Salazar, Xiang Lu, Richard Tavaré, Anna M Wu
PURPOSE: Molecular imaging of CD4(+) T cells throughout the body has implications for monitoring autoimmune disease and immunotherapy of cancer. Given the key role of these cells in regulating immunity, it is important to develop a biologically inert probe. GK1.5 cys-diabody (cDb), a previously developed anti-mouse CD4 antibody fragment, was tested at different doses to assess its effects on positron emission tomography (PET) imaging and CD4(+) T cell viability, proliferation, CD4 expression, and function...
December 13, 2016: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
Christopher G England, Lixin Rui, Weibo Cai
Lymphoma is a complex disease that arises from cells of the immune system with an intricate pathology. While lymphoma may be classified as Hodgkin or non-Hodgkin, each type of tumor is genetically and phenotypically different and highly invasive tissue biopsies are the only method to investigate these differences. Noninvasive imaging strategies, such as immunoPET, can provide a vital insight into disease staging, monitoring treatment response in patients, and dose planning in radioimmunotherapy. ImmunoPET imaging with radiolabeled antibody-based tracers may also assist physicians in optimizing treatment strategies and enhancing patient stratification...
March 2017: European Journal of Nuclear Medicine and Molecular Imaging
Anton G T Terwisscha van Scheltinga, Annie Ogasawara, Glenn Pacheco, Alexander N Vanderbilt, Jeff N Tinianow, Nidhi Gupta, Dongwei Li, Ron Firestein, Jan Marik, Suzie J Scales, Simon-Peter Williams
Antibody-drug conjugates (ADC) use monoclonal antibodies (mAb) as vehicles to deliver potent cytotoxic drugs selectively to tumor cells expressing the target. Molecular imaging with zirconium-89 ((89)Zr)-labeled mAbs recapitulates similar targeting biology and might help predict the efficacy of these ADCs. An anti-mesothelin antibody (AMA, MMOT0530A) was used to make comparisons between its efficacy as an ADC and its tumor uptake as measured by (89)Zr immunoPET imaging. Mesothelin-targeted tumor growth inhibition by monomethyl auristatin E (MMAE), ADC AMA-MMAE (DMOT4039A), was measured in mice bearing xenografts of ovarian cancer OVCAR-3×2...
January 2017: Molecular Cancer Therapeutics
Reinier Hernandez, Haiyan Sun, Christopher G England, Hector F Valdovinos, Emily B Ehlerding, Todd E Barnhart, Yunan Yang, Weibo Cai
Overexpression of CD146 has been correlated with aggressiveness, recurrence rate, and poor overall survival in hepatocellular carcinoma (HCC) patients. In this study, we set out to develop a CD146-targeting probe for high-contrast noninvasive in vivo positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging of HCCs. YY146, an anti-CD146 monoclonal antibody, was employed as a targeting molecule to which we conjugated the zwitterionic near-infrared fluorescence (NIRF) dye ZW800-1 and the chelator deferoxamine (Df)...
2016: Theranostics
Françoise Kraeber-Bodere, Clément Bailly, Michel Chérel, Jean-François Chatal
No abstract text is available yet for this article.
November 2016: European Journal of Nuclear Medicine and Molecular Imaging
A G de Lucas, A J Schuhmacher, M Oteo, E Romero, J A Cámara, A de Martino, A G Arroyo, M Á Morcillo, M Squatrito, J L Martinez-Torrecuadrada, F Mulero
BACKGROUND: A critical challenge in the management of Glioblastoma Multiforme (GBM) tumors is the accurate diagnosis and assessment of tumor progression in a noninvasive manner. We have identified Membrane-type 1 matrix metalloproteinase (MT1-MMP) as an attractive biomarker for GBM imaging since this protein is actively involved in tumor growth and progression, correlates with tumor grade and is closely associated with poor prognosis in GBM patients. Here, we report the development of an immunoPET tracer for effective detection of MT1-MMP in GBM models...
2016: PloS One
Michael Hettich, Friederike Braun, Mark D Bartholomä, Reinhold Schirmbeck, Gabriele Niedermann
Checkpoint-blocking antibodies like those targeting the PD-1/PD-L1 pathway have revolutionized oncology. We developed radiotracers based on therapeutic checkpoint-blocking antibodies permitting sensitive and high-resolution PET imaging of both PD-1 and PD-L1 in immunocompetent mice. ImmunoPET of naive mice revealed similar overall expression patterns for PD-1 and PD-L1 in secondary lymphoid organs (spleen and lymph nodes). Interestingly, PD-L1 was also detected in brown adipose tissue (BAT), confirming the notion that BAT is immunologically relevant...
2016: Theranostics
Haiyan Sun, Christopher G England, Reinier Hernandez, Stephen A Graves, Rebecca L Majewski, Anyanee Kamkaew, Dawei Jiang, Todd E Barnhart, Yunan Yang, Weibo Cai
PURPOSE: Overexpression of CD146 in solid tumors has been linked to disease progression, invasion, and metastasis. We describe the generation of a (64)Cu-labeled CD146-specific antibody and its use for quantitative immunoPET imaging of CD146 expression in six lung cancer models. METHODS: The anti-CD146 antibody (YY146) was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA) and radiolabeled with (64)Cu. CD146 expression was evaluated in six human lung cancer cell lines (A549, NCI-H358, NCI-H522, HCC4006, H23, and NCI-H460) by flow cytometry and quantitative western blot studies...
November 2016: European Journal of Nuclear Medicine and Molecular Imaging
Reinier Hernandez, Haiyan Sun, Christopher G England, Hector F Valdovinos, Todd E Barnhart, Yunan Yang, Weibo Cai
Recently, the overexpression of CD146 and its potential as a therapeutic target in high-grade gliomas, the most lethal type of brain cancer, was uncovered. In this study, we describe the generation of (89)Zr-Df-YY146, a novel (89)Zr-labeled monoclonal antibody (mAb) for the targeting and quantification of CD146 expression in a mouse model of glioblastoma, using noninvasive immunoPET imaging. YY146, a high affinity anti-CD146 mAb, was conjugated to deferoxamine (Df) for labeling with the long-lived positron emitter (89)Zr (t1/2: 78...
July 5, 2016: Molecular Pharmaceutics
Maurizio Conti, Lars Eriksson
With the increased interest in new PET tracers, gene-targeted therapy, immunoPET, and theranostics, other radioisotopes will be increasingly used in clinical PET scanners, in addition to (18)F. Some of the most interesting radioisotopes with prospective use in the new fields are not pure short-range β(+) emitters but can be associated with gamma emissions in coincidence with the annihilation radiation (prompt gamma), gamma-gamma cascades, intense Bremsstrahlung radiation, high-energy positrons that may escape out of the patient skin, and high-energy gamma rays that result in some e (+)/e (-) pair production...
December 2016: EJNMMI Physics
Calogero D'Alessandria, Sten Braesch-Andersen, Kristel Bejo, Sybille Reder, Birgit Blechert, Markus Schwaiger, Armando Bartolazzi
The high prevalence of thyroid nodules in the adult population and the relatively low incidence of thyroid cancer make the preoperative identification of malignant lesions challenging. The β-galactoside-binding protein galectin-3 is widely expressed in well-differentiated thyroid carcinomas, but not in normal thyrocytes and benign thyroid nodules. This molecule offers a candidate biomarker to improve thyroid cancer diagnosis. Here we report the development of an immunoPET approach for noninvasive imaging of thyroid cancer...
June 15, 2016: Cancer Research
Jorge A Carrasquillo, Patrick G Morris, John L Humm, Peter M Smith-Jones, Volkan Beylergil, Timothy Akhurst, Joseph A O'Donoghue, Shutian Ruan, Shanu Modi, Clifford A Hudis, Steven M Larson
BACKGROUND: The current study aims to assess the safety, pharmacokinetics, feasibility, and reproducibility of immunoPET imaging with copper-64 (64Cu)-trastuzumab. METHODS: An i.v. injection of 296-370MBq/5mg 64Cu-trastuzumab was administered between 1 to 4 h after routine trastuzumab treatment. Whole-body PET scans were performed immediately post-injection and at 24 h post-injection. Serial pharmacokinetics were performed. Of 11 patients (median age of 52; range of 31-61), 8 underwent a repeat study with 64Cu-trastuzumab to assess image and pharmacokinetic reproducibility...
May 12, 2016: Quarterly Journal of Nuclear Medicine and Molecular Imaging
Dean O Campbell, Akihiro Noda, Alla Verlinsky, Josh Snyder, Yuji Fujita, Yoshihiro Murakami, Hiroshi Fushiki, Sosuke Miyoshi, Sergio Lacayo, Edward Cabral, Peng Yang, David R Stover, Ingrid B J K Joseph
PURPOSE: Nectin-4 is selectively overexpressed in a variety of cancers and is currently under clinical investigation as a therapeutic target. A monoclonal antibody against nectin-4 (AGS-22M6) was evaluated as an Immuno-positron emission tomography (ImmunoPET) reagent. Its ability to assay nectin-4 expression as well as detect nectin-4 positive tumors in the liver and bone was evaluated using mouse models. PROCEDURES: The biodistribution of [(89)Zr]AGS-22M6 was evaluated in mice bearing tumors with varying levels of nectin-4 expression...
October 2016: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
Christopher G England, Anyanee Kamkaew, Hyung-Jun Im, Hector F Valdovinos, Haiyan Sun, Reinier Hernandez, Steve Y Cho, Edward J Dunphy, Dong Soo Lee, Todd E Barnhart, Weibo Cai
The role of insulin-like growth factor-1 receptor (IGF-1R) in cancer tumorigenesis was established decades ago, yet there are limited studies evaluating the imaging and therapeutic properties of anti-IGF-1R antibodies. Noninvasive imaging of IGF-1R may allow for optimized patient stratification and monitoring of therapeutic response in patients. Herein, this study reports the development of a Zirconium-89 ((89)Zr)-labeled anti-IGF-1R antibody ((89)Zr-Df-1A2G11) for PET imaging of pancreatic cancer. Successful chelation and radiolabeling of the antibody resulted in a highly stable construct that could be used for imaging IGF-1R expressing tumors in vivo...
June 6, 2016: Molecular Pharmaceutics
Simon-Peter Williams, Annie Ogasawara, Jeff N Tinianow, Judith E Flores, David Kan, Jeffrey Lau, MaryAnn Go, Alexander N Vanderbilt, Herman S Gill, Li Miao, Joshua Goldsmith, Bonnee Rubinfeld, Weiguang Mao, Ron Firestein, Shang-Fan Yu, Jan Marik, Anton G T Terwisscha van Scheltinga
The efficacy of antibody-drug conjugates (ADCs) targeted to solid tumors depends on biological processes that are hard to monitor in vivo. 89Zr-immunoPET of the ADC antibodies could help understand the performance of ADCs in the clinic by confirming the necessary penetration, binding, and internalization. This work studied monomethyl auristatin E (MMAE) ADCs against two targets in metastatic castration-resistant prostate cancer, TENB2 and STEAP1, in four patient-derived tumor models (LuCaP35V, LuCaP70, LuCaP77, LuCaP96...
May 3, 2016: Oncotarget
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