Diagnostic marker for treatment of cerebral ischemia
Inventors
Kauvar, Lawrence M. • Janigro, Damir
Assignees
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Publication Number
US-9913899-B2
Publication Date
2018-03-13
Expiration Date
Abstract
Identification of candidates for treatment and treatment of subjects experiencing cerebral ischemia wherein the treatment employs a thrombolytic or thrombectomy agent and an inhibitor of vascular endothelial growth factor (VEGF) receptor-mediated signal transduction are determined by testing the blood of a patient for total S-100B or for S-100BB as a marker of blood brain barrier integrity.
Core Innovation
The invention relates to using peripheral blood levels of total S-100B and/or the S-100BB homodimer as markers of blood-brain barrier integrity loss in a human patient with a cerebral ischemic event. The disclosed approach measures the level of total S-100B or of S-100BB in the peripheral blood and compares the measured level to a threshold level of 0.12 b5g/mL.
When the level of total S-100B or of S-100BB is above the threshold, the method administers an effective amount of a thrombolytic agent or performs a thrombectomy intervention to remove a thrombus. The method further administers an effective amount of an inhibitor of VEGF-R-mediated signal transduction to the patient, where the inhibitor is an antibody or antigen-binding fragment thereof that specifically binds to VEGF or binds to VEGF-R and is antagonistic thereto.
The disclosure also frames the measurement-based approach as enabling decision-making during BBB integrity loss by defining an appropriate treatment window, including optional repeated measurements to confirm rising marker levels consistent with loss of blood-brain barrier integrity. The described support includes prior-art discussion of S-100B/BBB permeability assays and experimental examples including a rat ischemia model and a human thrombus study.
Claims Coverage
The partial content identifies one independent claim (clm-00001). Across this claim, the inventive coverage comprises a total S-100B/S-100BB threshold measurement in peripheral blood, followed by thrombus-removal (thrombolytic agent and/or thrombectomy) combined with an inhibitor of VEGF-R-mediated signal transduction, with the inhibitor defined by binding specificity and antagonistic properties or by membership in specified VEGF-R/VEGF-targeted agents.
Peripheral blood S-100B/S-100BB threshold selection for BBB integrity loss
A method measuring the level of total S-100B or of S-100BB in the peripheral blood of a human patient, and where, if a level of total S-100B or of S-100BB above a threshold level of 0.12 b5g/ml is found, the subsequent treatment steps are triggered.
Combined thrombus removal and VEGF-R signal transduction inhibition
Administering an effective amount of a thrombolytic agent or performing a thrombectomy intervention to remove a thrombus, and administering an effective amount of an inhibitor of VEGF-R-mediated signal transduction to the patient where the inhibitor is an antibody or antigen-binding fragment thereof that specifically binds to vascular endothelial growth factor (VEGF) or binds to VEGF-R and is antagonistic thereto.
VEGF-R-mediated signal transduction inhibitor defined by antagonistic antibody binding or specified agent set
The inhibitor of VEGF-R mediated signal transduction is an antibody or antigen-binding fragment thereof that specifically binds to VEGF or binds to VEGF-R and is antagonistic thereto or is selected from the group consisting of SU1498, SU5416, cediranib (AZD2171), sunitinib (SU11248), vatalanib (PTK787/ZK222584), sorafenib, and pazopanib (GW786034B).
The independent claim requires using peripheral blood total S-100B or S-100BB above a threshold of 0.12 b5g/mL as a trigger, then combining thrombus removal (thrombolytic agent or thrombectomy) with VEGF-R-mediated signal transduction inhibition using a VEGF/VEGF-R antagonistic antibody/antigen-binding fragment or one of the specified inhibitors.
Stated Advantages
Enables identifying cerebral ischemia/stroke patients likely to benefit from combined thrombolytic or mechanical thrombectomy plus an inhibitor of VEGF-R-mediated signal transduction based on BBB integrity loss marker levels.
Defines an appropriate treatment window during BBB integrity loss.
Documented Applications
Use in a method to reduce neuronal damage caused by a cerebral ischemic event in a human patient by using peripheral blood total S-100B or S-100BB measurements to guide administration of thrombolytic/thrombectomy intervention together with an inhibitor of VEGF-R-mediated signal transduction.
In a rat ischemia model, the disclosure reports that an anti-VEGF antibody reduces serum S-100B.
In human stroke thrombus samples, the disclosure reports correlations between thrombus S-100B and VEGF and links of VEGF to MRI-defined stroke severity.
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