Publications by authors named "Christina Simoglou Karali"

2 Publications

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Selective blood-brain barrier permeabilisation of brain metastases by a type-1 receptor selective tumour necrosis factor mutein.

Neuro Oncol 2021 Jul 23. Epub 2021 Jul 23.

Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.

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 tumour development and heterogeneously permeable at later stages. Intravenous injection of tumour necrosis factor (TNF) selectively induces BBB permeabilisation 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 permeabilisation, whilst minimising potential toxicity.

Methods: A library of human TNF muteins (mutTNF) were generated and assessed for binding specificity to mouse and human TNFR1/2, endothelial permeabilising activity in vitro, potential immunogenicity and circulatory half-life. The permeabilising 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 permeabilisation of an endothelial monolayer. Circulatory half-life was similar to mouse/human TNF and BBB permeabilisation was induced selectively at sites of micrometastases in vivo, with a time window of ≥24h and enabling delivery of agents within a therapeutically-relevant range (0.5-150kDa), including the clinically approved therapy, trastuzumab.

Conclusions: We have developed a clinically-translatable mutTNF that selectively opens the BBB at micrometastatic sites, whilst leaving the rest of the cerebrovasculature intact. This approach will open a window for brain metastasis treatment that currently does not exist.
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http://dx.doi.org/10.1093/neuonc/noab177DOI Listing
July 2021

A novel molecular magnetic resonance imaging agent targeting activated leukocyte cell adhesion molecule as demonstrated in mouse brain metastasis models.

J Cereb Blood Flow Metab 2021 07 5;41(7):1592-1607. Epub 2020 Nov 5.

Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.

Molecular magnetic resonance imaging (MRI) allows visualization of biological processes at the molecular level. Upregulation of endothelial ALCAM (activated leukocyte cell adhesion molecule) is a key element for leukocyte recruitment in neurological disease. The aim of this study, therefore, was to develop a novel molecular MRI contrast agent, by conjugating anti-ALCAM antibodies to microparticles of iron oxide (MPIO), for detection of endothelial ALCAM expression . Binding specificity of ALCAM-MPIO was demonstrated under static and flow conditions. Subsequently, in a proof-of-concept study, mouse models of brain metastasis were induced by intracardial injection of brain-tropic human breast carcinoma, lung adenocarcinoma or melanoma cells to upregulate endothelial ALCAM. At selected time-points, mice were injected intravenously with ALCAM-MPIO, and ALCAM-MPIO induced hypointensities were observed on T*-weighted images in all three models. Post-gadolinium MRI confirmed an intact blood-brain barrier, indicating endoluminal binding. Correlation between endothelial ALCAM expression and ALCAM-MPIO binding was confirmed histologically. Statistical analysis indicated high sensitivity (80-90%) and specificity (79-83%) for detection of endothelial ALCAM with ALCAM-MPIO. Given reports of endothelial ALCAM upregulation in numerous neurological diseases, this advance in our ability to image ALCAM may yield substantial improvements for both diagnosis and targeted therapy.
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http://dx.doi.org/10.1177/0271678X20968943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217895PMC
July 2021
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