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Background: CI-8993 is a fully human IgG1κ monoclonal antibody (mAb) that binds specifically to immune checkpoint molecule VISTA (V-domain Ig suppressor of T-cell activation). Phase I safety has been established in patients with advanced cancer (NCT02671955). To determine the pharmacokinetics and biodistribution of CI-8993 in patients, we aimed to develop 89 Zr-labelled CI-8993 and validate PET imaging and quantitation in preclinical models prior to a planned human bioimaging trial., Methods: CI-8993 and human isotype IgG1 control were conjugated to the metal ion chelator p-isothiocyanatobenzyl-desferrioxamine (Df). Quality of conjugates were assessed by SE-HPLC, SDS-PAGE, and FACS. After radiolabelling with zirconium-89 ( 89 Zr), radioconjugates were assessed for radiochemical purity, immunoreactivity, antigen binding affinity, and serum stability in vitro. [ 89 Zr]Zr-Df-CI-8993 alone (1 mg/kg, 4.6 MBq) or in combination with 30 mg/kg unlabelled CI-8993, as well as isotype control [ 89 Zr]Zr-Df-IgG1 (1 mg/kg, 4.6 MBq) were assessed in human VISTA knock-in female (C57BL/6 N-Vsir tm1.1(VSIR)Geno , huVISTA KI) or control C57BL/6 mice bearing syngeneic MB49 bladder cancer tumours; and in BALB/c nu/nu mice bearing pancreatic Capan-2 tumours., Results: Stable constructs with an average chelator-to-antibody ratio of 1.81 were achieved. SDS-PAGE and SE-HPLC showed integrity of CI-8993 was maintained after conjugation; and ELISA indicated no impact of conjugation and radiolabelling on binding to human VISTA. PET imaging and biodistribution in MB49 tumour-bearing huVISTA KI female mice showed specific localisation of [ 89 Zr]Zr-Df-CI-8993 to VISTA in spleen and tumour tissues expressing human VISTA. Specific tumour uptake was also demonstrated in Capan-2 xenografted BALB/c nu/nu mice., Conclusions: We radiolabelled and validated [ 89 Zr]Zr-Df-CI-8993 for specific binding to huVISTA in vivo. Our results demonstrate that 89 Zr-labelled CI-8993 is now suitable for targeting and imaging VISTA expression in human trials., (© 2024. The Author(s).)

Bromodomain and extraterminal (BET) proteins, a family of epigenetic regulators, have emerged as important oncology drug targets. BET proteins have not been targeted for molecular imaging of cancer. Here, we report the development of a novel molecule radiolabelled with positron emitting fluorine-18, [ 18 F]BiPET-2, and its in vitro and preclinical evaluation in glioblastoma models.

Purpose: Τhis study aimed to optimize the 89 Zr-radiolabelling of bintrafusp alfa investigational drug product and controls, and perform the in vitro and in vivo characterization of 89 Zr-Df-bintrafusp alfa and 89 Zr-Df-control radioconjugates., Methods: Bintrafusp alfa (anti-PD-L1 human IgG1 antibody fused to TGF-β receptor II (TGF-βRII), avelumab (anti-PD-L1 human IgG1 control antibody), isotype control (mutated inactive anti-PD-L1 IgG1 control antibody), and trap control (mutated inactive anti-PD-L1 human IgG1 fused to active TGF-βRII) were chelated with p-isothiocyanatobenzyl-desferrioxamine (Df). After radiolabelling with zirconium-89 ( 89 Zr), radioconjugates were assessed for radiochemical purity, immunoreactivity, antigen binding affinity, and serum stability in vitro. In vivo biodistribution and imaging studies were performed with PET/CT to identify and quantitate 89 Zr-Df-bintrafusp alfa tumour uptake in a PD-L1/TGF-β-positive murine breast cancer model (EMT-6). Specificity of 89 Zr-Df-bintrafusp alfa was assessed via a combined biodistribution and imaging experiment in the presence of competing cold bintrafusp alfa (1 mg/kg)., Results: Nanomolar affinities for PD-L1 were achieved with 89 Zr-Df-bintrafusp alfa and 89 Zr-avelumab. Biodistribution and imaging studies in PD-L1- and TGF-β-positive EMT-6 tumour-bearing BALB/c mice demonstrated the biologic similarity of 89 Zr-Df-bintrafusp alfa and 89 Zr-avelumab indicating the in vivo distribution pattern of bintrafusp alfa is driven by its PD-L1 binding arm. Competition study with 1 mg of unlabelled bintrafusp alfa or avelumab co-administered with trace dose of 89 Zr-labelled bintrafusp alfa demonstrated the impact of dose and specificity of PD-L1 targeting in vivo., Conclusion: Molecular imaging of 89 Zr-Df-bintrafusp alfa biodistribution was achievable and allows non-invasive quantitation of tumour uptake of 89 Zr-Df-bintrafusp alfa, suitable for use in bioimaging clinical trials in cancer patients., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Background: Oncrasin-1 is a small molecule which was identified from a screen of KRAS mutant cancer cells and has shown specificity for KRAS mutant cell killing. We aimed to develop a radiolabelled form of Oncrasin-1 to enable in-vivo imaging of mutant KRAS expression in malignant tumours. This work outlines the synthesis of 3 fluorinated derivatives and development of iodonium salt and boronic ester precursors for radiolabelling with the 18 F isotope., Results: In our hands, synthesis of iodonium salts were not easily accessible due to the 3-carbaldehyde indole structure being preferentially oxidized by conditions required for iodonium salt formation, rather than benzyl iodide. Synthesis and radiolabelling of boronic acid pinacol ester precursors were successful, with the products being obtained in yields of 10.76% ± 0.96% (n = 5), 14.7% ±8.58% (n = 3) and 14.92% ±3.9% (n = 3) for 18 F KAM001, 18 F KAM002 and 18 F KAM003 respectively, with radiochemical purity of greater than 99%., Conclusions: The successful synthesis of these tracers has been undertaken utilizing boronic ester radio-fluorination methods and will allow for investigation of Oncrasin based molecules as potential diagnostics for cancers expressing mutant KRAS protein.

The detection of network motifs has recently become an important part of network analysis across all disciplines. In this work, we detected and analyzed network motifs from undirected and directed networks of several different disciplines, including biological network, social network, ecological network, as well as other networks such as airlines, power grid, and co-purchase of political books networks. Our analysis revealed that undirected networks are similar at the basic three and four nodes, while the analysis of directed networks revealed the distinction between networks of different disciplines. The study showed that larger motifs contained the three-node motif as a subgraph. Topological analysis revealed that similar networks have similar small motifs, but as the motif size increases, differences arise. Pearson correlation coefficient showed strong positive relationship between some undirected networks but inverse relationship between some directed networks. The study suggests that the three-node motif is a building block of larger motifs. It also suggests that undirected networks share similar low-level structures. Moreover, similar networks share similar small motifs, but larger motifs define the unique structure of individuals. Pearson correlation coefficient suggests that protein structure networks, dolphin social network, and co-authorships in network science belong to a superfamily. In addition, yeast protein-protein interaction network, primary school contact network, Zachary's karate club network, and co-purchase of political books network can be classified into a superfamily.

To model the transport of electrons through material requires knowledge of how the electrons lose energy and scatter. Theoretical models are used to describe electron energy loss and scatter and these models are supported by a limited amount of measured data. The purpose of this work was to obtain additional data that can be used to test models of electron scattering. Measurements were carried out using 13 and 20 MeV pencil beams of electrons produced by the National Research Council of Canada research accelerator. The electron fluence was measured at several angular positions from 0 degree to 90 degrees for scattering foils of different thicknesses and with atomic numbers ranging from 4 to 79. The angle, theta 1/e at which the fluence has decreased to 1/e of its value on the central axis was used to characterize the distributions. Measured values of theta 1/e ranged from 1.5 degrees to 8 degrees with a typical uncertainty of about 1%. Distributions calculated using the EGSnrc Monte Carlo code were compared to the measured distributions. In general, the calculated distributions are narrower than the measured ones. Typically, the difference between the measured and calculated values of theta 1/e is about 1.5%, with the maximum difference being 4%. The measured and calculated distributions are related through a simple scaling of the angle, indicating that they have the same shape. No significant trends with atomic number were observed.

Background: Asthmatic patients taking low to moderate doses of inhaled topical corticosteroids have been shown to have lower bone density than those taking bronchodilators only. There is little information on bone density in asthmatic patients taking high dose inhaled corticosteroids., Methods: Bone mass was studied in three age matched groups of asthmatic patients. These comprised: 17 asthmatic patients who had never taken inhaled or systemic corticosteroids (group 1); 20 patients who had taken beclomethasone diproprionate in a dosage of 1000-2000 micrograms daily for at least a year, who had also received courses of systemic corticosteroids in the past (group 2); and 20 patients who were taking both high dose inhaled corticosteroids and regular low dose prednisolone, at a median dose of 7 mg daily (group 3). Vertebral bone density was measured by quantitative computed tomography. Biochemical indices of bone formation and resorption were also measured., Results: Mean bone density in group 2 (127.5(22.6) mg/ml) was similar to that in group 3 (114.5 (36.0) mg/ml). Bone density was significantly lower in both of these groups than in group 1 (160.4 (27.4) mg/ml). There were no significant differences between groups for any of the markers of bone formation and resorption., Conclusions: Asthmatic patients receiving high dose inhaled beclomethasone and intermittent courses of systemic corticosteroids have reduced vertebral bone density. The bone loss is similar in degree to that seen in patients taking high dose inhaled topical corticosteroids and continuous low dose systemic corticosteroids.

The findings on gallium-67 scans were compared with the findings of standard techniques (X-ray chest, lymphangiography, clinical examination, and laparotomy findings) in patients with lymphoma, mainly at presentation, but sometimes on follow-up. The objective was to ascertain the reliability of this non-invasive technique in detecting lymphomatous deposits, and to assess its place in the battery of investigations which may be used in clinical staging of lymphomas. One hundred and sixty-six patients were studied, in whom 198 gallium-67 scans were performed. The results indicated that detection of mediastinal and upper para-aortic node involvement was the most significant function, and such detection might alter clinical staging, and, therefore, therapy. Gallium-67 was unhelpful in splenic scanning, being positive usually only in cases which had clinically detectable involvement. Unsuspected lung and bone lesions were found occasionally, and this was of considerable importance. Gallium-67 scanning is regarded as an important, non-traumatic additional investigation, clinically useful in staging lymphomas.