Extracellular histones as biomarkers for prognosis and molecular targets for therapy
Inventors
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Assignees
Member
Oklahoma Medical Research FoundationFounded in 1946, this independent nonprofit biomedical research institute conducts basic, translational, and clinical research in critical areas such as heart disease, cancer, autoimmune, and neurodegenerative diseases. Its mission focuses on understanding biological mechanisms and advancing diagnostics and therapeutics. Activities include conducting clinical trials, managing a patent portfolio, commercializing biotechnologies, and supporting the biotech community. Research efforts are funded by grants and philanthropy, and the institute hosts advanced facilities, interdisciplinary research teams, and collaborations with academia and industry.
Founded in 1946, this independent nonprofit biomedical research institute conducts basic, translational, and clinical research in critical areas such as heart disease, cancer, autoimmune, and neurodegenerative diseases. Its mission focuses on understanding biological mechanisms and advancing diagnostics and therapeutics. Activities include conducting clinical trials, managing a patent portfolio, commercializing biotechnologies, and supporting the biotech community. Research efforts are funded by grants and philanthropy, and the institute hosts advanced facilities, interdisciplinary research teams, and collaborations with academia and industry.
Publication Number
US-10350261-B2
Publication Date
2019-07-16
Expiration Date
Abstract
Hyper-inflammatory responses can lead to a variety of diseases including sepsis. It is now shown that extracellular histones released in response to inflammatory challenge are mediators contributing to endothelial dysfunction, organ failure and death during sepsis. As such, they can be targeted pharmacologically by inhibitors, as well as used as biomarkers for prognosis of sepsis and other diseases.
Core Innovation
The invention identifies extracellular histones, particularly histone H3 and histone H4, as cytotoxic mediators in hyper-inflammatory states and as prognostic biomarkers and therapeutic targets. It discloses compositions and methods comprising anti-histone antibodies (notably anti-H4), histone-derived peptides and fragments including an H4 peptide (SEQ ID NO:19, H4P39), histone-cleaving enzymes such as activated protein C, and combinations or cocktails of peptides and antibodies for therapy and diagnosis by ELISA or Western blot.
The disclosure addresses medical conditions driven by extracellular histone cytotoxicity by inhibiting histone-mediated endothelial cytotoxicity, pro-inflammatory cytokine production, and increased endothelial permeability. It specifically claims methods to inhibit such pathology in severe acute pancreatitis and ischemia reperfusion injury and describes that activated protein C cleaves H4 and reduces histone cytotoxicity, that APC-generated H4 fragments retain bactericidal activity with reduced cytotoxicity, and that anti-H4 antibodies or APC protect animal models challenged with LPS or E. coli.
Claims Coverage
Overview: This section identifies 2 inventive features derived from the independent claims.
Anti-H3 or anti-H4 antibody administration
Administering at least a first anti-histone antibody selected from an anti-H3 antibody or an anti-H4 antibody to inhibit a medical condition involving extracellular histone cytotoxicity, wherein the medical condition is severe acute pancreatitis or ischemia reperfusion injury; the administration inhibits pro-inflammatory cytokine production by endothelial cells and reduces endothelial permeability.
H4 peptide fragment (SEQ ID NO:19) administration
Administering to a subject a first inhibitor of cytotoxic activity comprising an H4 histone peptide fragment comprising SEQ ID NO:19 to inhibit a medical condition involving extracellular histone cytotoxicity, wherein the medical condition is severe acute pancreatitis or ischemia reperfusion injury; the administration inhibits pro-inflammatory cytokine production by endothelial cells and reduces endothelial permeability.
The independent claims principally claim two therapeutic modalities: administration of anti-H3 or anti-H4 antibodies and administration of an H4 peptide fragment (SEQ ID NO:19), each directed to inhibiting extracellular histone cytotoxicity, inhibiting endothelial pro-inflammatory cytokine production, and reducing endothelial permeability, specifically for severe acute pancreatitis and ischemia reperfusion injury.
Stated Advantages
Extracellular histones, especially H3 and H4, serve as prognostic biomarkers in blood or plasma.
Activated protein C cleaves histone H4 and reduces histone cytotoxicity.
APC-generated H4 fragments retain bactericidal activity while exhibiting reduced cytotoxic activity.
An H4 peptide (SEQ ID NO:19 / H4P39) retains bactericidal activity with reduced endothelial cytotoxicity.
Anti-H4 monoclonal antibody and activated protein C protect in animal models (LPS-challenged mice and baboon E. coli model).
Documented Applications
Sepsis (detection of extracellular histones in septic baboon plasma and therapeutic targeting).
Severe acute pancreatitis (therapeutic methods administering anti-histone antibodies or H4 peptide fragment).
Ischemia reperfusion injury (therapeutic methods administering anti-histone antibodies or H4 peptide fragment).
Acute respiratory distress syndrome (ARDS) as a listed disease indication.
Cardiovascular and autoimmune diseases as listed disease indications.
Trauma and burns as listed disease indications.
Diagnostic detection and prognosis of extracellular histones in blood or plasma using ELISA or Western blot.
Therapeutic approaches and combinations including anti-histone antibodies, histone-derived peptides/fragments, histone-cleaving enzymes (e.g., activated protein C, granzymes, plasmin), and peptide/antibody cocktails.
Demonstrated protection in animal models including LPS-challenged mice and a baboon E. coli model.
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