دورية أكاديمية
Selective blood-brain barrier permeabilization of brain metastases by a type 1 receptor-selective tumor necrosis factor mutein.
| العنوان: | Selective blood-brain barrier permeabilization of brain metastases by a type 1 receptor-selective tumor necrosis factor mutein. |
|---|---|
| المؤلفون: | Munoz Pinto MF; Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal., Campbell SJ; Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK., Simoglou Karali C; Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.; MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK., Johanssen VA; Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK., Bristow C; Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK., Cheng VWT; Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.; Leeds Institute of Medical Research, University of Leeds, Leeds, UK., Zarghami N; Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK., Larkin JR; Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK., Pannell M; Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.; OxSonics Ltd., The Magdalen Centre, Oxford Science Park, Oxford, UK., Hearn A; Abzena Ltd., Babraham Research Campus, Babraham, Cambridge, UK., Chui C; Abzena Ltd., Babraham Research Campus, Babraham, Cambridge, UK., Brinquis Nunez B; Abzena Ltd., Babraham Research Campus, Babraham, Cambridge, UK., Bokma E; Abzena Ltd., Babraham Research Campus, Babraham, Cambridge, UK., Holgate R; Abzena Ltd., Babraham Research Campus, Babraham, Cambridge, UK., Anthony DC; Department of Pharmacology, University of Oxford, Oxford, UK., Sibson NR; Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK. |
| المصدر: | Neuro-oncology [Neuro Oncol] 2022 Jan 05; Vol. 24 (1), pp. 52-63. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: England NLM ID: 100887420 Publication Model: Print Cited Medium: Internet ISSN: 1523-5866 (Electronic) Linking ISSN: 15228517 NLM ISO Abbreviation: Neuro Oncol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2010- : Oxford : Oxford University Press Original Publication: 1999-<2002> : Charlottesville, VA : Carden Jennings Pub., |
| مواضيع طبية MeSH: | Blood-Brain Barrier*/metabolism , Brain Neoplasms*/drug therapy, Animals ; Brain/metabolism ; Mice ; Trastuzumab ; Tumor Necrosis Factor-alpha/metabolism |
| مستخلص: | Background: Metastasis to the brain is a major challenge with poor prognosis. The blood-brain barrier (BBB) is a significant impediment to effective treatment, being intact during the early stages of tumor development and heterogeneously permeable at later stages. Intravenous injection of tumor necrosis factor (TNF) selectively induces BBB permeabilization at sites of brain micrometastasis, in a TNF type 1 receptor (TNFR1)-dependent manner. Here, to enable clinical translation, we have developed a TNFR1-selective agonist variant of human TNF that induces BBB permeabilization, while minimizing potential toxicity. Methods: A library of human TNF muteins (mutTNF) was generated and assessed for binding specificity to mouse and human TNFR1/2, endothelial permeabilizing activity in vitro, potential immunogenicity, and circulatory half-life. The permeabilizing ability of the most promising variant was assessed in vivo in a model of brain metastasis. Results: The primary mutTNF variant showed similar affinity for human TNFR1 than wild-type human TNF, similar affinity for mouse TNFR1 as wild-type mouse TNF, undetectable binding to human/mouse TNFR2, low potential immunogenicity, and permeabilization of an endothelial monolayer. Circulatory half-life was similar to mouse/human TNF and BBB permeabilization was induced selectively at sites of micrometastases in vivo, with a time window of ≥24 hours and enabling delivery of agents within a therapeutically relevant range (0.5-150 kDa), including the clinically approved therapy, trastuzumab. Conclusions: We have developed a clinically translatable mutTNF that selectively opens the BBB at micrometastatic sites, while leaving the rest of the cerebrovasculature intact. This approach will open a window for brain metastasis treatment that currently does not exist. (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.) |
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| معلومات مُعتمدة: | 16945 United Kingdom CRUK_ Cancer Research UK; C5255/A15935 United Kingdom CRUK_ Cancer Research UK; MR/V005995/1 United Kingdom MRC_ Medical Research Council; MR/N028031/1 United Kingdom MRC_ Medical Research Council; C5255/A16466 United Kingdom CRUK_ Cancer Research UK |
| فهرسة مساهمة: | Keywords: blood-brain barrier; brain metastasis; mutein; permeabilization; tumor necrosis factor |
| المشرفين على المادة: | 0 (Tumor Necrosis Factor-alpha) P188ANX8CK (Trastuzumab) |
| تواريخ الأحداث: | Date Created: 20210723 Date Completed: 20220119 Latest Revision: 20240405 |
| رمز التحديث: | 20240405 |
| مُعرف محوري في PubMed: | PMC8730757 |
| DOI: | 10.1093/neuonc/noab177 |
| PMID: | 34297105 |
| قاعدة البيانات: | MEDLINE |
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