Drug regimen for treatment of cerebral ischemia
Inventors
Kauvar, Lawrence M. • Janigro, Damir
Assignees
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Publication Number
US-10617756-B2
Publication Date
2020-04-14
Expiration Date
Abstract
Treatment of subjects experiencing cerebral ischemia is improved when the treatment employs a thrombolytic and an inhibitor against vascular endothelial growth factor receptor signal transduction (VEGF-RST) at a reduced, low dosage compared to that used to treat cancer patients. The treatment is also improved to permit point-of-care use by formulating protein drugs for long term stability at room temperature, providing doses appropriate for the method, and by combining the therapeutic agents with a point-of-care diagnostic for blood brain barrier integrity.
Core Innovation
The invention provides a method of treatment to reduce neuronal damage caused by a cerebral ischemic event in a human patient. The method includes administering an effective amount of a thrombolytic and an effective amount of an inhibitor of vascular endothelial growth factor (VEGF) receptor-mediated signal transduction (VEGF-RST). The VEGF-RST inhibitor is bevacizumab or an antigen-binding fragment thereof, and it provides inhibition of >50% of VEGF-RST activity over 24 hours while the serum concentration level is reduced below the pharmacologically active level at least by 48 hours after administration.
The described approach also addresses treatment in which neuronal damage is reduced by controlling VEGF-RST activity for a limited period after a cerebral ischemic event. The treatment pairs VEGF-RST inhibition with either pharmacologic thrombolysis or mechanical removal of a blood clot associated with the ischemic event. In the mechanical-removal embodiment, an inhibitor of VEGF-RST is administered in association with the mechanical removal, with the same time-limited inhibition and serum concentration features.
The described methods include embodiments that use blood biomarker measurement to support patient selection and timing related to blood-brain barrier (BBB) integrity. The biomarker framing is tied to assessing BBB integrity loss caused by the ischemic event, including assay formats that measure total S100B and/or S100BB homodimer in blood, and also mentions UCHL-1 as an alternative.
Claims Coverage
The partial content contains two independent claims directed to methods for reducing neuronal damage after a cerebral ischemic event using (i) a thrombolytic plus a VEGF-RST inhibitor under time-limited VEGF-RST activity suppression, and (ii) mechanical clot removal combined with a time-limited VEGF-RST inhibitor administration. Across the claims, the inventive requirements emphasize >50% VEGF-RST inhibition over 24 hours and reduction of inhibitor serum concentration below pharmacologically active level by at least 48 hours, using bevacizumab (or an antigen-binding fragment) as the VEGF-RST inhibitor.
Thrombolytic plus VEGF-RST inhibitor with limited activity window
Administering to a human patient an effective amount of a thrombolytic and an effective amount of an inhibitor of vascular endothelial growth factor (VEGF) receptor-mediated signal transduction (VEGF-RST), wherein the effective amount of said inhibitor provides inhibition of >50% of said VEGF-RST activity over 24 hours and wherein the serum concentration level of said inhibitor is reduced below this pharmacologically active level at least by 48 hours after administration.
Bevacizumab VEGF-RST inhibition agent
Wherein said inhibitor is bevacizumab or an antigen-binding fragment thereof.
Mechanical removal of clot with VEGF-RST inhibitor dosing
Mechanically removing a blood clot associated with said cerebral ischemic event and administering in association with said removing a measured dose of an inhibitor of VEGF-RST effective to inhibit >50% of signal transduction over 24 hours and wherein the serum concentration level of said inhibitor is reduced below this pharmacologically active level at least by 48 hours after administration.
Bevacizumab VEGF-RST inhibitor for mechanical removal method
Wherein the inhibitor of VEGF-RST is bevacizumab or antigen-binding fragment thereof.
Across the independent claims, the inventive concept is treatment of cerebral ischemia with VEGF-RST inhibition that is limited in duration and pharmacologically active serum exposure, achieved using bevacizumab (or an antigen-binding fragment), with pairing to either thrombolysis or mechanical clot removal.
Stated Advantages
Reduce neuronal damage caused by a cerebral ischemic event in a human patient.
Inhibit >50% of VEGF-RST activity over 24 hours while reducing the serum concentration level of the inhibitor below the pharmacologically active level at least by 48 hours after administration.
Documented Applications
Treatment of cerebral ischemia in a human patient to reduce neuronal damage.
Treatment that includes pharmacologic thrombolysis in combination with VEGF-RST inhibition to reduce neuronal damage after a cerebral ischemic event.
Treatment that includes mechanical removal of a blood clot associated with cerebral ischemic event combined with VEGF-RST inhibition to reduce neuronal damage.
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