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Enhanced anti-metastatic bioactivity of an IGF-TRAP re-engineered to improve physicochemical properties.

ABSTRACT: The insulin-like growth factor (IGF) axis has been implicated in the progression of malignant disease and identified as a clinically important therapeutic target. Several IGF-1 receptor (IGF-1R) targeting drugs including humanized monoclonal antibodies have advanced to phase II/III clinical trials, but to date, have not progressed to clinical use, due, at least in part, to interference with insulin receptor signalling. We previously reported on the production of a soluble fusion protein consisting of the extracellular domain of human IGF-1R fused to the Fc portion of human IgG1 (first generation IGF-TRAP) that bound human IGF-1 and IGF-2 with a 3?log higher affinity than insulin. We showed that the IGF-TRAP had potent anti-cancer activity in several pre-clinical models of aggressive carcinomas. Here we report on the re-engineering of the IGF-TRAP with the aim of improving physicochemical properties and suitability for clinical applications. We show that cysteine-serine substitutions in the Fc hinge region of IGF-TRAP eliminated high-molecular-weight oligomerized species, while a further addition of a flexible linker, not only improved the pharmacokinetic profile, but also enhanced the therapeutic profile of the IGF-TRAP, as evaluated in an experimental colon carcinoma metastasis model. Dose-response profiles of the modified IGF-TRAPs correlated with their bio-availability profiles, as measured by the IGF kinase-receptor-activation (KIRA) assay, providing a novel, surrogate biomarker for drug efficacy. This study provides a compelling example of structure-based re-engineering of Fc-fusion-based biologics for better manufacturability that also significantly improved pharmacological parameters. It identifies the re-engineered IGF-TRAP as a potent anti-cancer therapeutic.

SUBMITTER: Vaniotis G

PROVIDER: S-EPMC6255772 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Enhanced anti-metastatic bioactivity of an IGF-TRAP re-engineered to improve physicochemical properties.

Vaniotis George G Moffett Serge S Sulea Traian T Wang Ni N Elahi S Mehdy SM Lessard Etienne E Baardsnes Jason J Perrino Stephanie S Durocher Yves Y Frystyk Jan J Massie Bernard B Brodt Pnina P

Scientific reports 20181126 1

The insulin-like growth factor (IGF) axis has been implicated in the progression of malignant disease and identified as a clinically important therapeutic target. Several IGF-1 receptor (IGF-1R) targeting drugs including humanized monoclonal antibodies have advanced to phase II/III clinical trials, but to date, have not progressed to clinical use, due, at least in part, to interference with insulin receptor signalling. We previously reported on the production of a soluble fusion protein consisti ...[more]

PMID: 30478273

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Project description:ObjectiveThis study evaluated the bioactivity and physicochemical properties of three commercial calcium silicate-based endodontic materials (MTA, EndoSequence Root Repair Material putty, and Biodentine™). Material and Methods. Horizontal sections of 3 mm thickness from 18 root canals of human teeth were subjected to biomechanical preparation with WaveOne Gold large rotary instruments. The twelve specimens were filled with three tested materials (MM-MTA, EndoSequence Root Repair Material putty, and Biodentine™) and immersed in phosphate-buffered saline for 7 and 30 days. After this period of time, each specimen of each material was processed for morphological observation, surface precipitates, and interfacial dentin using SEM. In addition, the surface morphology of the set materials, without soaking in phosphate-buffered solution after one day and after 28 days stored in phosphate-buffered saline, was evaluated using SEM; also, the pH of the soaking water and the amount of calcium ions released from the test materials were measured by using an inductively coupled plasma-optical emission spectroscopy test. Data obtained were analyzed using one-way analysis of variance and Tukey's honest significant difference test with a significance level of 5%.ResultThe formation of precipitates was observed on the surfaces of all materials at 1 week and increased substantially over time. Interfacial layers in some areas of the dentin-cement interface were found from one week of immersion. All the analyzed materials showed alkaline pH and capacity to release calcium ions; however, the concentrations of released calcium ions were significantly more in Biodentine and ESRRM putty than MM-MTA (P < 0.05). ESRRM putty maintained a pH of around 11 after 28 days.ConclusionCompared with MM-MTA, Biodentine and ESRRM putty showed significantly more calcium ion release. However, exposure of three tested cements to phosphate-buffered solution resulted in precipitation of apatite crystalline structures over both cement and dentin that increased over time. This suggests that the tested materials are bioactive.

Project description:BackgroundSome polymer-functionalized AgNPs (P-AgNPs) have been developed to optimize the biological properties of AgNPs. However, there are no studies in the literature comparing the differences in physicochemical and biological properties of AgNPs caused by various polymer-functionalizations and providing evidence for the selection of polymers to optimize AgNPs.MethodsTwo AgNPs with similar nano-size and opposite surface charges were synthesized and functionalized by seven polymers. Their physicochemical properties were evaluated by UV-Visible absorption, dynamic light scattering, transmission electron microscopy and inductively coupled plasma optical emission spectroscopy. Their biological properties against Porphyromonas gingivalis and human gingival fibroblast were investigated by MIC determination, time-dependent antibacterial assay, antibiofilm activity and cell viability assay. Silver diamine fluoride, AgNO3 and metronidazole were used as positive controls.ResultsComparative analysis found that there were no significant differences between P-AgNPs and AgNPs in nano-size and in surface charge. Raman spectroscopy analysis provided evidence about the attachment of polymers on AgNPs. For antibacterial property, among the negatively charged AgNPs, only polyvinylpyrrolidone (PVP)-functionalized AgNPs-1 showed a significant lower MIC value than AgNPs-1 (0.79 vs. 4.72 μg/ml). Among the positively charged AgNPs, the MIC values of all P-AgNPs (0.34-4.37 μg/ml) were lower than that of AgNPs-2 (13.89 μg/ml), especially PVP- and Pluronic127-AgNPs-2 (1.75 and 0.34 μg/ml). For antibiofilm property, PVP-AgNPs-1 (7.86 μg/ml, P = 0.002) and all P-AgNPs-2 (3.42-31.14 μg/ml, P < 0.001) showed great antibiofilm effect against P. gingivalis biofilm at 5* to 10*MIC level. For cytotoxicity, all negatively charged AgNPs and PVP-AgNPs-2 showed no cytotoxicity at MIC level, but significant cytotoxicity was detected at 2.5* to 10*MIC levels.ConclusionAmong the polymers studied, polymer functionalization does not significantly alter the physical properties of AgNPs, but modifies their surface chemical property. These modifications, especially the functionalization of PVP, contribute to optimize the antibacterial and antibiofilm properties of AgNPs, while not causing cytotoxicity at the MIC level.

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Enhanced anti-metastatic bioactivity of an IGF-TRAP re-engineered to improve physicochemical properties.

Publications

Enhanced anti-metastatic bioactivity of an IGF-TRAP re-engineered to improve physicochemical properties.

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