WO2023150718A2 - Inhibition par olverembatinib de la régulation à la hausse de cytokines associée au syndrome de libération de cytokines - Google Patents

Inhibition par olverembatinib de la régulation à la hausse de cytokines associée au syndrome de libération de cytokines Download PDF

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WO2023150718A2
WO2023150718A2 PCT/US2023/061990 US2023061990W WO2023150718A2 WO 2023150718 A2 WO2023150718 A2 WO 2023150718A2 US 2023061990 W US2023061990 W US 2023061990W WO 2023150718 A2 WO2023150718 A2 WO 2023150718A2
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kinase
cytokine release
olverembatinib
therapeutically effective
cytokine
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WO2023150718A3 (fr
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Taran GUJRAL
Marina CHAN
Eric Holland
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Fred Hutchinson Cancer Center
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Fred Hutchinson Cancer Center
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • COVID-19 The World Health Organization has declared COVID-19 to be a pandemic. Despite the development of vaccines, COVID-19 continues to be a healthcare burden, especially in persons with a compromised immune system and others who remain unvaccinated. Most COVID-19 patients develop mild to moderate symptoms, while 15- 20% of patients face hyper-inflammation induced by massive cytokine production, called “cytokine storm”, ultimately leading to alveolar damage and respiratory failure.
  • SI subunit of SARS-CoV-2 spike protein causes upregulation and release of a panel of inflammatory molecules such as IL- lb, IL-6, and CCL7 in monocytes and peripheral blood mononuclear cells (PBMCs). Further, it has been shown that stimulation with the N-terminus domain (NTD) of the SI subunit is sufficient to activate monocytes. Consistently, recent studies have identified several C-type lectins and Tweety family member 2 as glycan-dependent binding partners of the NTD of the SARS-CoV-2 spike protein. The engagement of these receptors with the SARS-CoV-2 virus induces robust proinflammatory responses in myeloid cells that correlate with COVID-19 severity.
  • the Omicron (B.1.1.529 / 21K) variant was detected in South Africa and has been associated with rapidly increasing case numbers worldwide.
  • the Omicron variant carries more than 50 mutations, including more than 25 mutations in the Spike protein alone. Of these, -30% of mutations are present in the NTD.
  • the disclosure provides a method to inhibit systemic cytokine release, the method comprising the steps of: (a) identifying a subject in need of inhibiting systemic cytokine release; and (b) administering a therapeutically effective quantity of a multi-specific kinase inhibitor to the subject in need thereof, wherein administering the therapeutically effective quantity of the multi-specific kinase inhibitor reduces systemic cytokine release.
  • the disclosure provides a method to treat moderate to severe COVID-19, the method comprising the steps of: (a) identifying a subject with moderate to severe COVID-19; and (b) administering a therapeutically effective quantity of a multi-specific kinase inhibitor to the subject with moderate to severe COVID-19, wherein administering the therapeutically effective quantity of the multi-specific kinase inhibitor reduces symptoms associated with moderate to severe COVID-19.
  • the systemic cytokine release can be caused by a previously received immune cell-based therapy. In other embodiments, the systemic cytokine release can be caused by an infectious disease. In some embodiments, the subject is infected with a SARS-CoV-2 Omicron variant. In some embodiments, the SARS-CoV-2 Omicron variant-mediated systemic cytokine release is caused by stimulation of peripheral blood mononuclear cells (PBMCs) with the N-terminus domain (NTD) of a spike protein from the Omicron variant. In still other embodiments, the systemic cytokine release can be caused by a disease condition.
  • PBMCs peripheral blood mononuclear cells
  • NTD N-terminus domain
  • the multi-specific kinase inhibitor comprises olverembatinib.
  • the therapeutically effective quantity of olverembatinib provides for a plasma concentration of ⁇ 100 nM olverembatinib.
  • FIGURES 1A through 1C N-terminus domain (NTD) of the SARS-CoV-2 Omicron variant stimulates cytokine release.
  • Figure 1A A schematic showing mutation in the Omicron NTD. Unique mutations found in the Omicron variant are A67V, N211del, L212I, and ins214EPE.
  • Figure IB Comparison of changes in cytokine release in response to the recombinant NTD from Wuhan, Delta, and Omicron variants. Measurement of cytokine release from healthy donor PBMCs treated with PBS or Omicron NTD at 1 pg/ml for 24 h. Cytokines were measured by Luminex multiplex assay.
  • Figure 1C A schematic showing mutation in the Omicron NTD. Unique mutations found in the Omicron variant are A67V, N211del, L212I, and ins214EPE.
  • Figure IB Comparison of changes in cytokine release in response to the recombinant NTD from Wuhan, Delta
  • cytokine release from healthy donor PBMCs treated with Wuhan, Delta, or Omicron NTD at 1 pg/ml for 24 h Cytokine release in the conditioned media was measured by Luminex. Recombinant NTD of different variants were purified from HEK293 cells. Data are shown as the mean of two to three biological replicates. Error bars denote SEM.
  • FIGURES 2A through 2D Olverembatinib is a potent inhibitor of Omicron N- terminus domain (NTD) -mediated cytokine release.
  • Figure 2A Effect of Olverembatinib, Ponatinib, and Baricitinib on Omicron NTD-mediated cytokine release.
  • Figure 2B ECso of Olverembatinib on indicated cytokines.
  • Figure 2C Comparison of kinase inhibition profiles of Olverembatinib, Ponatinib, and Baricitinib.
  • PBMCs Peripheral blood mononuclear cells
  • Omicron NTD Omicron NTD
  • Olverembatinib Olverembatinib
  • Ponatinib Ponatinib
  • Baricitinib Cytokine release in the conditioned media was measured by Luminex. Data are shown as the mean of two biological replicates. Error bars denote SEM.
  • Figure 2D Olverembatinib treatment decreases Omicron-variant-NTD-mediated cytokine release in COVID-19 PBMCs.
  • FIGURES 3A through 3C Comparison of cytokine release in response to SARS-CoV-2 SI spike protein and lipopolysaccharide stimulation of monocytes.
  • Figure 3A Comparison of lipopolysaccharide (LPS) and SI spike protein-mediated changes in cytokine expression in THP1 monocytes.
  • Figure 3B Schematic of experimental strategy to test the role of selected kinases in LPS-mediate cytokine release.
  • Figure 3C A heatmap showing depletion of JAK1, IRAKI, and EPH7 decreases the release of LPS- mediate cytokines, while knockdown of MAP3K2 or scrambled control did not affect cytokine release.
  • the disclosure is based on the inventors’ demonstration that olverembatinib, a clinical-stage multi-kinase inhibitor, potently inhibits Omicron NTD-mediated cytokine release.
  • the inventors have demonstrated that olverembatinib inhibited NTD-mediated release of all seven cytokines measured in a dose-dependent manner. Additionally, olverembatinib inhibited cytokine release even at low nanomolar concentrations.
  • agents e.g., olverembatinib
  • targeting multiple kinases essential for SARS-CoV-2-mediated cytokine release can represent therapeutic options for treating moderate to severe COVID-19.
  • the disclosure provides a method to inhibit systemic cytokine release in a subject in need thereof.
  • the method can comprise the steps of (a) identifying a subject in need of inhibiting systemic cytokine release; and (b) administering a therapeutically effective quantity of a multi-specific kinase inhibitor to the subject in need thereof, wherein administering the therapeutically effective quantity of the multi-specific kinase inhibitor reduces systemic cytokine release.
  • the disclosure provides a method to treat moderate to severe COVID-19.
  • the method can comprise the steps of (a) identifying a subject with moderate to severe COVID-19; and (b) administering a therapeutically effective quantity of a multi-specific kinase inhibitor to the subject with moderate to severe COVID-19, wherein administering the therapeutically effective quantity of the multi-specific kinase inhibitor reduces symptoms associated with moderate to severe COVID-19.
  • systemic cytokine release refers to the conditions known as “cytokine storm”, “cytokine release syndrome”, or “inflammatory cascade”. These conditions describe the dysregulation of proinflammatory cytokines leading to upregulated cytokine release.
  • a “cytokine” refers to one of a class of small soluble signaling proteins that are synthesized and secreted by certain cells of the immune system at variable, and occasionally locally high, concentrations, and by binding to receptors on other cells, send signals to and have an effect on those cells.
  • systemic cytokine release i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade
  • infectious disease refers to a disease caused by bacteria, viruses, or fungi that enter the body to cause an infection.
  • an infectious disease refers to but is not limited to: severe acute respiratory syndrome (SARS), Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), malaria, avian influenza, smallpox, pandemic influenza, adult respiratory distress syndrome (ARDS), Ebola, Marburg, Crimean-Congo hemorrhagic fever (CCHF), South American hemorrhagic fever, dengue, yellow fever, Rift Valley fever, Omsk hemorrhagic fever virus, Kyasanur Forest, Junin, Machupo, Sabia, Guanarito, Garissa, Ilesha, or Lassa fever viruses.
  • SARS severe acute respiratory syndrome
  • SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2
  • malaria avian influenza, smallpox, pandemic influenza, adult respiratory distress syndrome (ARDS), Ebola, Marburg, Crimean-Congo hemorrhagic fever (CCHF), South American hemorrhagic fever, dengue, yellow fever, Rift
  • certain disease conditions that are commonly known to cause cytokine release can cause systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • systemic cytokine release i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade.
  • disease conditions associated with systemic cytokine release refer to those disease conditions that are dependent upon an immune response, and under certain conditions, the immune system can respond too aggressively to the disease condition leading to systemic cytokine release.
  • a disease condition leading to systemic cytokine release refers to but is not limited to: sepsis, systemic inflammatory response syndrome (SIRS), cachexia, septic shock syndrome, traumatic brain injury (e.g., cerebral cytokine storm), or graft versus host disease (GVHD).
  • SIRS systemic inflammatory response syndrome
  • septic shock syndrome e.g., traumatic brain injury
  • traumatic brain injury e.g., cerebral cytokine storm
  • GVHD graft versus host disease
  • systemic cytokine release i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade
  • a “previously received immune cellbased therapy” refers to treating a subject with activated immune cells, wherein the immune cell-based therapy was administered to the subject a certain amount of time before systemic cytokine release.
  • the immune cell-based therapy was administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours before systemic cytokine release.
  • the immune cellbased therapy was administered 1, 2, 3, 4, 5, 6, or 7 days before systemic cytokine release.
  • the immune cell-based therapy was administered 1, 2, 3, or 4 weeks before systemic cytokine release. In still other embodiments, the immune cell-based therapy was administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months before systemic cytokine release. In still other embodiments, the immune cell-based therapy was administered 1, 2, 3, 4, or 5 years before systemic cytokine release. In some embodiments, the immune cell-based therapy can include but is not limited to chimeric antigen receptor (CAR) therapy (e.g., B cell antigen CAR therapy, CD 19 CAR therapy), monoclonal antibodies, or IL-2 activated T cells.
  • CAR chimeric antigen receptor
  • the released cytokines can include but are not limited to granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 1 beta (IL-lb), interleukin 10 (IL- 10), interleukin 6 (IL-6), interleukin 8 (IL-8), chemokine (C-C motif) ligand 2 (CCL-2), tumor necrosis factor alpha (TNFa).
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • IL-lb interleukin 1 beta
  • IL- 10 interleukin 10
  • IL-6 interleukin 6
  • IL-8 interleukin 8
  • CCL-2 tumor necrosis factor alpha
  • SARS- CoV-2 severe Acute Respiratory Syndrome Coronavirus 2
  • ACE2 human host cell receptor angiotensin-converting enzyme 2
  • the SARS-CoV- 2-Spike protein is a 1273 amino acid type I membrane glycoprotein which assembles into trimers that constitute the spikes or peplomers on the surface of the enveloped coronavirus particle.
  • the protein has two essential functions, host receptor binding and membrane fusion, which are attributed to the N-terminal (SI) and C-terminal (S2) halves of the S protein.
  • N-terminus domain refers to the N-terminus of the SI subunit of the SARS-CoV-2 spike protein.
  • the SI subunit comprises an N-terminal domain (14-305 residues) and a receptor-binding domain (RBD, 319-541 residues).
  • a SARS-CoV-2 variant refers to a specific viral genome that contains one or more changes from the original SARS-CoV-2 strain.
  • the SARS- CoV-2 variant is an Omicron strain, which includes several subvariants (i.e., as of this writing) such as B.1.1.529, BA.l, BAL I, BA.2, BA.3, BA.4, BA.5, and BF.7.
  • SARS-CoV-2 variants can also include Delta, Beta, and Alpha strains.
  • infection refers to infections with SARS-CoV-2 and variants of SARS-CoV-2.
  • the term includes coronavirus respiratory tract infections, often in the lower respiratory tract. Symptoms can include high fever, dry cough, shortness of breath, pneumonia, gastro-intestinal symptoms such as diarrhea, organ failure (kidney failure and renal dysfunction), septic shock, and death in severe cases.
  • subjects with moderate to severe COVID-19 have hyperinflammation associated with systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • systemic cytokine release i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade.
  • 15-20% of patients with COVID-19 face hyper-inflammation induced by systemic cytokine release, which can lead to alveolar damage and respiratory failure.
  • the size of the pro-inflammatory response correlates with the severity of COVID-19.
  • less than 50% of subjects infected with SARS-CoV-2 have a robust pro-inflammatory response indicative of moderate to severe COVID-19.
  • less than 40% of subjects infected with SARS-CoV-2 have a robust pro-inflammatory response indicative of moderate to severe COVID-19.
  • less than 30% of subjects infected with SARS-CoV-2 have a robust pro-inflammatory response indicative of moderate to severe COVID-19. In still other embodiments, less than 20% of subjects infected with SARS-CoV-2 have a robust pro-inflammatory response indicative of moderate to severe COVID-19. In still other embodiments, 15-20% of subjects infected with SARS-CoV-2 have a robust pro-inflammatory response indicative of moderate to severe COVID-19.
  • infection with SARS-CoV-2 causes systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade) in monocytes and peripheral blood mononuclear cells (PCMBs).
  • stimulation with SARS-CoV-2 spike protein causes systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade) in monocytes and PCMBs.
  • stimulation with the SI subunit of the SARS-CoV-2 spike protein causes systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade) in monocytes and PCMBs.
  • stimulation with the N-terminus domain (NTD) of the SI subunit of the SARS-CoV-2 spike protein causes systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade) in monocytes and PCMBs.
  • systemic cytokine release i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade
  • the method of identifying a subject in need of inhibiting systemic cytokine release due to an infectious disease, disease condition, or previously administered immune cell-based therapy can comprise any method well known to those with ordinary skill in the art.
  • the method of identifying a subject with moderate to severe COVID-19 can comprise any method well known to those with ordinary skill in the art.
  • treat refers to the treatment of the conditions mentioned herein, particularly in a subject who demonstrates symptoms of COVID-19.
  • the terms “administration of’ or “administering a” multi-specific kinase inhibitor refers to providing one of the disclosed multi-specific kinase inhibitors to an individual in need of treatment in a form that can be introduced into that individual’s body in a therapeutically useful form and therapeutically useful amount, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as intravenous (IV), intramuscular (IM), or intraperitoneal (IP), and the like; enteral or parenteral, transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories.
  • oral dosage forms such as tablets, capsules, syrups, suspensions, and the like
  • injectable dosage forms such as intravenous (IV), intramuscular (IM), or intraperitoneal (IP), and the like
  • a “multi-specific kinase inhibitor” refers to a molecule that targets and blocks and/or reduces the activity of several kinases.
  • the kinases inhibited by the multi-specific kinase inhibitor include but are not limited to ephrin type- A receptor 7 (EPHA7), mitogen-activated protein kinase 14 (MAPK14), tyrosine protein kinase JAK1 (JAK1), protein tyrosine kinase 5 (PTK5), mitogen- activated protein kinase kinase kinase 3 (MEKK3), mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2), protein tyrosine kinase 2 beta (PTK2B), cAMP- dependent protein kinase catalytic subunit gamma (PKACG), interleukin- 1 receptor- associated
  • a multi-specific kinase inhibitor can include, but is not limited to, olverembatinib, ponatinib, and baricitinib.
  • Olverembatinib (HQP1351; formerly GZD824) is a multi-specific kinase inhibitor with activity against a broad spectrum of BCR-ABL mutants including the T3151 resistance mutation.
  • Ponatinib is a multi-specific kinase inhibitor targeting BCR-ABL, as well as vascular endothelial growth factor receptors (VEGFRs) and fibroblast growth factor receptors (FGFRs).
  • Baricitinib is a multi-specific kinase inhibitor targeting JAK1 and JAK2.
  • a multi-specific kinase inhibitor can be any multi-specific kinase inhibitor well known to one of ordinary skill in the art.
  • a “therapeutically effective amount” of a multi-specific kinase inhibitor is an amount sufficient to provide a therapeutic benefit in the treatment of SARS-CoV-2-mediated systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • a therapeutically effective amount of a multispecific kinase inhibitor means an amount of the molecule, alone or in combination with a second therapeutic agent, which provides a therapeutic benefit in the treatment or management of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • the second therapeutic agent can be a different multi-specific kinase inhibitor.
  • the second therapeutic agent can be an agent known to reduce cytokine release, such as but not limited to, a cytokine inhibitor.
  • cytokine inhibitors can function to decrease the synthesis of cytokines, decrease cytokine concentration in free active form; block cytokine interaction with specific receptors; and interfere with the signaling of cytokine receptors.
  • the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • a therapeutically effective quantity of a multi-specific kinase inhibitor is a quantity that provides for a plasma concentration in the low micromolar range. In some embodiments, a therapeutically effective quantity of a multispecific kinase inhibitor is a quantity that provides for a plasma concentration less than or equal to 10 pM of the multi-specific kinase inhibitor.
  • a therapeutically effective quantity of a multi-specific kinase inhibitor is a quantity that provides for a plasma concentration less than or equal to 10 pM, less than or equal to 9 pM, less than or equal to 8 pM, less than or equal to 7 pM, less than or equal to 6 pM, less than or equal to 5 pM, less than or equal to 4 pM, less than or equal to 3 pM, less than or equal to 2 pM, or less than or equal to 1 pM of the multi-specific kinase inhibitor.
  • a therapeutically effective quantity of a multi-specific kinase inhibitor is a quantity that provides for a plasma concentration in the nanomolar range.
  • a therapeutically effective quantity of a multi-specific kinase inhibitor is a quantity that provides for a plasma concentration less than or equal to 1000 nM of the multi-specific kinase inhibitor. In some embodiments, a therapeutically effective quantity of a multi-specific kinase inhibitor is a quantity that provides for a plasma concentration less than or equal to 1000 nM, less than or equal to 900 nM, less than or equal to 800 nM, less than or equal to 700 nM, less than or equal to 600 nM, less than or equal to 500 nM, less than or equal to 400 nM, less than or equal to 300 nM, less than or equal to 200 nM, or less than or equal to 100 nM of the multi-specific kinase inhibitor.
  • a therapeutically effective quantity of a multispecific kinase inhibitor is a quantity that provides for a plasma concentration in the low nanomolar range. In some embodiments, a therapeutically effective quantity of a multispecific kinase inhibitor is a quantity that provides for a plasma concentration less than or equal to 100 nM of the multi-specific kinase inhibitor.
  • a therapeutically effective quantity of a multi-specific kinase inhibitor is a quantity that provides for a plasma concentration less than or equal to 100 nM, less than or equal to 90 nM, less than or equal to 80 nM, less than or equal to 70 nM, less than or equal to 60 nM, less than or equal to 50 nM, less than or equal to 40 nM, less than or equal to 30 nM, less than or equal to 20 nM, or less than or equal to 10 nM of the multi-specific kinase inhibitor.
  • One of ordinary skill in the art would understand how to prepare a dosage of a multi-specific kinase inhibitor to provide for the preferred plasma concentration.
  • a therapeutically effective quantity of olverembatinib is a quantity that provides for a plasma concentration in the low micromolar range. In some embodiments, a therapeutically effective quantity of olverembatinib is a quantity that provides for a plasma concentration less than or equal to 10 pM of olverembatinib.
  • a therapeutically effective quantity of olverembatinib is a quantity that provides for a plasma concentration less than or equal to 10 pM, less than or equal to 9 pM, less than or equal to 8 pM, less than or equal to 7 pM, less than or equal to 6 pM, less than or equal to 5 pM, less than or equal to 4 pM, less than or equal to 3 pM, less than or equal to 2 pM, or less than or equal to 1 pM of olverembatinib.
  • a therapeutically effective quantity of olverembatinib is a quantity that provides for a plasma concentration in the nanomolar range.
  • a therapeutically effective quantity of olverembatinib is a quantity that provides for a plasma concentration less than or equal to 1000 nM of olverembatinib. In some embodiments, a therapeutically effective quantity of olverembatinib is a quantity that provides for a plasma concentration less than or equal to 1000 nM, less than or equal to 900 nM, less than or equal to 800 nM, less than or equal to 700 nM, less than or equal to 600 nM, less than or equal to 500 nM, less than or equal to 400 nM, less than or equal to 300 nM, less than or equal to 200 nM, or less than or equal to 100 nM of olverembatinib.
  • a therapeutically effective quantity of olverembatinib is a quantity that provides for a plasma concentration in the low nanomolar range. In some embodiments, a therapeutically effective quantity of olverembatinib is a quantity that provides for a plasma concentration less than or equal to 100 nM of olverembatinib.
  • a therapeutically effective quantity of olverembatinib is a quantity that provides for a plasma concentration less than or equal to 100 nM, less than or equal to 90 nM, less than or equal to 80 nM, less than or equal to 70 nM, less than or equal to 60 nM, less than or equal to 50 nM, less than or equal to 40 nM, less than or equal to 30 nM, less than or equal to 20 nM, or less than or equal to 10 nM of olverembatinib.
  • a therapeutically effective quantity of ponatinib is a quantity that provides for a plasma concentration in the low micromolar range. In some embodiments, a therapeutically effective quantity of ponatinib is a quantity that provides for a plasma concentration less than or equal to 10 pM of ponatinib.
  • a therapeutically effective quantity of ponatinib is a quantity that provides for a plasma concentration less than or equal to 10 pM, less than or equal to 9 pM, less than or equal to 8 pM, less than or equal to 7 pM, less than or equal to 6 pM, less than or equal to 5 pM, less than or equal to 4 pM, less than or equal to 3 pM, less than or equal to 2 pM, or less than or equal to 1 pM of ponatinib.
  • a therapeutically effective quantity of ponatinib is a quantity that provides for a plasma concentration in the nanomolar range.
  • a therapeutically effective quantity of ponatinib is a quantity that provides for a plasma concentration less than or equal to 1000 nM of ponatinib. In some embodiments, a therapeutically effective quantity of ponatinib is a quantity that provides for a plasma concentration less than or equal to 1000 nM, less than or equal to 900 nM, less than or equal to 800 nM, less than or equal to 700 nM, less than or equal to 600 nM, less than or equal to 500 nM, less than or equal to 400 nM, less than or equal to 300 nM, less than or equal to 200 nM, or less than or equal to 100 nM of ponatinib.
  • a therapeutically effective quantity of ponatinib is a quantity that provides for a plasma concentration in the low nanomolar range. In some embodiments, a therapeutically effective quantity of ponatinib is a quantity that provides for a plasma concentration less than or equal to 100 nM of ponatinib.
  • a therapeutically effective quantity of ponatinib is a quantity that provides for a plasma concentration less than or equal to 100 nM, less than or equal to 90 nM, less than or equal to 80 nM, less than or equal to 70 nM, less than or equal to 60 nM, less than or equal to 50 nM, less than or equal to 40 nM, less than or equal to 30 nM, less than or equal to 20 nM, or less than or equal to 10 nM of ponatinib.
  • a therapeutically effective quantity of the combination of olverembatinib and ponatinib is a quantity that provides for a plasma concentration in the low micromolar range. In some embodiments, a therapeutically effective quantity of the combination of olverembatinib and ponatinib is a quantity that provides for a plasma concentration less than or equal to 10 pM of the combination of olverembatinib and ponatinib.
  • a therapeutically effective quantity of the combination of olverembatinib and ponatinib is a quantity that provides for a plasma concentration less than or equal to 10 pM, less than or equal to 9 pM, less than or equal to 8 pM, less than or equal to 7 pM, less than or equal to 6 pM, less than or equal to 5 pM, less than or equal to 4 pM, less than or equal to 3 pM, less than or equal to 2 pM, or less than or equal to 1 pM of the combination of olverembatinib and ponatinib.
  • a therapeutically effective quantity of the combination of olverembatinib and ponatinib is a quantity that provides for a plasma concentration in the nanomolar range. In some embodiments, a therapeutically effective quantity of the combination of olverembatinib and ponatinib is a quantity that provides for a plasma concentration less than or equal to 1000 nM of the combination of olverembatinib and ponatinib.
  • a therapeutically effective quantity of the combination of olverembatinib and ponatinib is a quantity that provides for a plasma concentration less than or equal to 1000 nM, less than or equal to 900 nM, less than or equal to 800 nM, less than or equal to 700 nM, less than or equal to 600 nM, less than or equal to 500 nM, less than or equal to 400 nM, less than or equal to 300 nM, less than or equal to 200 nM, or less than or equal to 100 nM of the combination of olverembatinib and ponatinib.
  • a therapeutically effective quantity of the combination of olverembatinib and ponatinib is a quantity that provides for a plasma concentration in the low nanomolar range. In some embodiments, a therapeutically effective quantity of the combination of olverembatinib and ponatinib is a quantity that provides for a plasma concentration less than or equal to 100 nM of the combination of olverembatinib and ponatinib.
  • a therapeutically effective quantity of the combination of olverembatinib and ponatinib is a quantity that provides for a plasma concentration less than or equal to 100 nM, less than or equal to 90 nM, less than or equal to 80 nM, less than or equal to 70 nM, less than or equal to 60 nM, less than or equal to 50 nM, less than or equal to 40 nM, less than or equal to 30 nM, less than or equal to 20 nM, or less than or equal to 10 nM of the combination of olverembatinib and ponatinib.
  • cytokine release refers to a multi-specific kinase inhibitor’s ability to block or inhibit the number of cytokines released from peripheral blood mononuclear cells (PBMCs) as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • PBMCs peripheral blood mononuclear cells
  • cytokines released from PBMCs include but are not limited to granulocytemacrophage colony-stimulating factor (GM-CSF), interleukin 1 beta (IL- lb), interleukin 10 (IL- 10), interleukin 6 (IL-6), interleukin 8 (IL-8), chemokine (C-C motif) ligand 2 (CCL-2), tumor necrosis factor alpha (TNFa).
  • GM-CSF granulocytemacrophage colony-stimulating factor
  • IL- lb interleukin 10
  • IL-6 interleukin 6
  • IL-8 interleukin 8
  • chemokine (C-C motif) ligand 2 CCL-2
  • TNFa tumor necrosis factor alpha
  • the multi-specific kinase inhibitor can reduce release of at least 50% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release
  • the multi-specific kinase inhibitor can reduce release of at least 60% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In other embodiments, the multi-specific kinase inhibitor can reduce release of at least 70% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • the multi-specific kinase inhibitor can reduce release of at least 80% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In other embodiments, the multispecific kinase inhibitor can reduce release of at least 90% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • the multi-specific kinase inhibitor can reduce release of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In some embodiments, the multi-specific kinase inhibitor can reduce release of 100% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • olverembatinib can reduce release of cytokines from PBMCs that include but are not limited to granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 1 beta (IL-lb), interleukin 10 (IL-10), interleukin 6 (IL-6), interleukin 8 (IL-8), chemokine (C-C motif) ligand 2 (CCL-2), tumor necrosis factor alpha (TNFa).
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • IL-lb interleukin 1 beta
  • IL-10 interleukin 10
  • IL-6 interleukin 6
  • IL-8 interleukin 8
  • CCL-2 tumor necrosis factor alpha
  • olverembatinib can reduce release of at least 50% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In other embodiments, olverembatinib can reduce release of at least 60% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • olverembatinib can reduce release of at least 70% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In other embodiments, olverembatinib can reduce release of at least 80% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • olverembatinib can reduce release of at least 90% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In some embodiments, olverembatinib can reduce release of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • olverembatinib can reduce release of 100% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • ponatinib can reduce release of cytokines from PBMCs that include but are not limited to granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 1 beta (IL-lb), interleukin 10 (IL- 10), interleukin 6 (IL-6), interleukin 8 (IL-8), chemokine (C-C motif) ligand 2 (CCL-2), tumor necrosis factor alpha (TNFa).
  • ponatinib can reduce release of at least 50% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • ponatinib can reduce release of at least 60% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In other embodiments, ponatinib can reduce release of at least 70% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • ponatinib can reduce release of at least 80% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In other embodiments, ponatinib can reduce release of at least 90% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • ponatinib can reduce release of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In some embodiments, ponatinib can reduce release of 100% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • the combination of olverembatinib and ponatinib can reduce release of cytokines from PBMCs that include but are not limited to granulocytemacrophage colony-stimulating factor (GM-CSF), interleukin 1 beta (IL- lb), interleukin 10 (IL- 10), interleukin 6 (IL-6), interleukin 8 (IL-8), chemokine (C-C motif) ligand 2 (CCL-2), tumor necrosis factor alpha (TNFa).
  • GM-CSF granulocytemacrophage colony-stimulating factor
  • IL- lb interleukin 1 beta
  • IL- 10 interleukin 10
  • IL-6 interleukin 6
  • IL-8 interleukin 8
  • CCL-2 tumor necrosis factor alpha
  • the combination of olverembatinib and ponatinib can reduce release of at least 50% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In other embodiments, the combination of olverembatinib and ponatinib can reduce release of at least 60% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • the combination of olverembatinib and ponatinib can reduce release of at least 70% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In other embodiments, the combination of olverembatinib and ponatinib can reduce release of at least 80% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • the combination of olverembatinib and ponatinib can reduce release of at least 90% of cytokines released from PBMCs as part of a cytokine storm. In some embodiments, the combination of olverembatinib and ponatinib can reduce release of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • systemic cytokine release i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade.
  • the combination of olverembatinib and ponatinib can reduce release of 100% of cytokines released from PBMCs as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • a multi-specific kinase inhibitor s ability block or inhibit the number of cytokines released from peripheral blood mononuclear cells (PBMCs) as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade) is dependent upon kinase inhibition.
  • PBMCs peripheral blood mononuclear cells
  • the kinases inhibited by the multi-specific kinase inhibitor include but are not limited to ephrin type- A receptor 7 (EPHA7), mitogen-activated protein kinase 14 (MAPK14), tyrosine protein kinase JAK1 (JAK1), protein tyrosine kinase 5 (PTK5), mitogen- activated protein kinase kinase kinase 3 (MEKK3), mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2), protein tyrosine kinase 2 beta (PTK2B), cAMP- dependent protein kinase catalytic subunit gamma (PKACG), interleukin- 1 receptor- associated kinase 1 (IRAKI), calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2), mitogen-activated protein kina
  • the multi-specific kinase inhibitor can inhibit 100% of the kinase activity in at least 50% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In some embodiments, the multi-specific kinase inhibitor can inhibit 100% of the kinase activity in at least 60% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • the multi-specific kinase inhibitor can inhibit 100% of the kinase activity in at least 70% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In some embodiments, the multi-specific kinase inhibitor can inhibit 100% of the kinase activity in at least 80% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • the multi-specific kinase inhibitor can inhibit 100% of the kinase activity in at least 90% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In some embodiments, the multi-specific kinase inhibitor can inhibit 100% of the kinase activity in at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • the multi-specific kinase inhibitor can inhibit 100% of the kinase activity in 100% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • olverembatinib ability block or inhibit the number of cytokines released from peripheral blood mononuclear cells (PBMCs) as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade) is dependent upon kinase inhibition.
  • PBMCs peripheral blood mononuclear cells
  • the kinases inhibited by olverembatinib include but are not limited to ephrin type-A receptor 7 (EPHA7), mitogen-activated protein kinase 14 (MAPK14), tyrosine protein kinase JAK1 (JAK1), protein tyrosine kinase 5 (PTK5), mitogen-activated protein kinase kinase kinase 3 (MEKK3), mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2), protein tyrosine kinase 2 beta (PTK2B), cAMP-dependent protein kinase catalytic subunit gamma (PKACG), interleukin- 1 receptor-associated kinase 1 (IRAKI), calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2), mitogen-activated protein kina
  • olverembatinib can inhibit 100% of the kinase activity in at least 50% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In some embodiments, olverembatinib can inhibit 100% of the kinase activity in at least 60% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • olverembatinib can inhibit 100% of the kinase activity in at least 70% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In some embodiments, olverembatinib can inhibit 100% of the kinase activity in at least 80% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • olverembatinib can inhibit 100% of the kinase activity in at least 90% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In some embodiments, olverembatinib can inhibit 100% of the kinase activity in at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • olverembatinib can inhibit 100% of the kinase activity in 100% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • ponatinib ability block or inhibit the number of cytokines released from peripheral blood mononuclear cells (PBMCs) as part of systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade) is dependent upon kinase inhibition.
  • PBMCs peripheral blood mononuclear cells
  • the kinases inhibited by ponatinib include but are not limited to ephrin type-A receptor 7 (EPHA7), mitogen- activated protein kinase 14 (MAPK14), tyrosine protein kinase JAK1 (JAK1), protein tyrosine kinase 5 (PTK5), mitogen-activated protein kinase kinase kinase 3 (MEKK3), mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2), protein tyrosine kinase 2 beta (PTK2B), cAMP-dependent protein kinase catalytic subunit gamma (PKACG), interleukin-1 receptor-associated kinase 1 (IRAKI), calcium/calmodulin- dependent protein kinase kinase 2 (CAMKK2), mitogen-activated protein kinase 12 (MAPAACG),
  • ponatinib can inhibit 100% of the kinase activity in at least 50% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In some embodiments, ponatinib can inhibit 100% of the kinase activity in at least 60% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • ponatinib can inhibit 100% of the kinase activity in at least 70% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In some embodiments, ponatinib can inhibit 100% of the kinase activity in at least 80% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • ponatinib can inhibit 100% of the kinase activity in at least 90% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In some embodiments, ponatinib can inhibit 100% of the kinase activity in at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • ponatinib can inhibit 100% of the kinase activity in 100% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • the combination of olverembatinib and ponatinib to block or inhibit the number of cytokines released from peripheral blood mononuclear cells (PBMCs) as part of systemic cytokine release is dependent upon kinase inhibition.
  • PBMCs peripheral blood mononuclear cells
  • the kinases inhibited by the combination of olverembatinib and ponatinib can include but are not limited to ephrin type-A receptor 7 (EPHA7), mitogen-activated protein kinase 14 (MAPK14), tyrosine protein kinase JAK1 (JAK1), protein tyrosine kinase 5 (PTK5), mitogen-activated protein kinase kinase kinase 3 (MEKK3), mitogen- activated protein kinase kinase kinase kinase 2 (MAP4K2), protein tyrosine kinase 2 beta (PTK2B), cAMP-dependent protein kinase catalytic subunit gamma (PKACG), interleukin-1 receptor-associated kinase 1 (IRAKI), calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2)
  • the combination olverembatinib and ponatinib can inhibit 100% of the kinase activity in at least 50% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In some embodiments, the combination of olverembatinib and ponatinib can inhibit 100% of the kinase activity in at least 60% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • the combination of olverembatinib and ponatinib can inhibit 100% of the kinase activity in at least 70% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade). In some embodiments, the combination of olverembatinib and ponatinib can inhibit 100% of the kinase activity in at least 80% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • the combination of olverembatinib and ponatinib can inhibit 100% of the kinase activity in at least 90% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • the combination of olverembatinib and ponatinib can inhibit 100% of the kinase activity in at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • systemic cytokine release i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade.
  • the combination of olverembatinib and ponatinib can inhibit 100% of the kinase activity in 100% of the kinases required for cytokine release from PBMCs in systemic cytokine release (i.e., cytokine storm, cytokine release syndrome, or inflammatory cascade).
  • the multi-specific kinase inhibitor is administered as part of a pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective quantity of the multi-specific kinase inhibitor combined with a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable is used herein to describe a carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the multi-specific kinase inhibitor can include, but is not limited to, olverembatinib and ponatinib.
  • compositions suitable for oral or nasal administration can consist of liquid solutions, such as an effective amount of the composition dissolved in a diluent (e.g., water or saline), capsules, sachets, tablets, or gels, each containing a predetermined amount of the multi-specific kinase inhibitor.
  • a diluent e.g., water or saline
  • the composition can also be an aerosol formulation for inhalation, for example, to the bronchial passageways. Aerosol formulations can be mixed with pressurized, pharmaceutically acceptable propellants (e.g., dichlorodifluoromethane, propane, or nitrogen).
  • the composition can be administered after a subject has been administered a cell-based therapy, diagnosed with a viral infection, or diagnosed with a disease condition that causes systemic cytokine release (hereinafter cause of systemic cytokine release).
  • the composition can be administered, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 20, 24, 48, or 72 hours, 2, 3, 5, or 7 days, 2, 4, 6 or 8 weeks, 3, 4, 6, or 9 months, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 years following the cause of systemic cytokine release.
  • the composition can be administered to the subject either before the occurrence of symptoms or a definitive diagnosis or after diagnosis or symptoms become evident.
  • the composition can be administered immediately after diagnosis or the clinical recognition of symptoms or 2, 4, 6, 10, 15, or 24 hours, 2, 3, 5, or 7 days after diagnosis or detection of symptoms.
  • One or more doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses) of the composition can be administered to a subject in need thereof.
  • a subject is administered at least one dose.
  • a subject is administered at least two doses.
  • multiple doses are administered on the same day.
  • doses are administered on different days (i.e., one dose per day).
  • one or more doses of the composition can be administered with one or more additional therapeutic agents either sequentially or simultaneously.
  • the additional therapeutic agents can inhibit kinase activity associate with systemic cytokine release. In still other embodiments, the additional therapeutic agents can inhibit cytokine release.
  • the dose of the composition or the number of treatments using the composition can be increased or decreased based on the severity of, occurrence of, or progression of, cytokine release.
  • the dosage administered depends on the subject to be treated (e.g., the age, body weight, capacity of the immune system, and general health of the subject being treated), the form of administration (e.g., as a solid or liquid), and the manner of administration (e.g., by injection, inhalation, or dry powder propellant).
  • the words “comprise,” “comprising,” and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to indicate, in the sense of “including, but not limited to.” Words using the singular or plural number also include the plural and singular number, respectively. Additionally, the words “herein,” “above,” and “below,” and words of similar import, when used in this application, shall refer to this application as a whole and not to any particular portions of the application.
  • the word “about” indicates a number within range of minor variation above or below the stated reference number. For example, “about” can refer to a number within a range of 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% above or below the indicated reference number.
  • Embodiment 1 A method to inhibit systemic cytokine release in a subject in need thereof, the method comprising the steps of: (a) identifying a subject in need of inhibiting systemic cytokine release; and (b) administering a therapeutically effective quantity of a multi-specific kinase inhibitor to the subject in need thereof, wherein administering the therapeutically effective quantity of the multi-specific kinase inhibitor reduces systemic cytokine release.
  • Embodiment 2 The method of embodiment 1, wherein the multi-specific kinase inhibitor comprises olverembatinib.
  • Embodiment 3 The method of embodiment 2, wherein the therapeutically effective quantity of olverembatinib provides for a plasma concentration of ⁇ 100 nM olverembatinib.
  • Embodiment 4 The method as in any preceding embodiment, wherein the systemic cytokine release is caused by a previously received immune cell-based therapy.
  • Embodiment 5 The method as in any preceding embodiment, wherein the systemic cytokine release is caused by an infectious disease.
  • Embodiment 6 The method as in any preceding embodiment, wherein the systemic cytokine release is caused by a disease condition.
  • Embodiment 7 The method as in any preceding embodiment, wherein the infections disease is a SARS-CoV-2 Omicron variant.
  • Embodiment 8 The method of any preceding embodiment, wherein the SARS- CoV-2 Omicron variant-mediated systemic cytokine release is caused by stimulation of peripheral blood mononuclear cells (PBMCs) with an N-terminus domain (NTD) of a spike protein from the Omicron variant.
  • PBMCs peripheral blood mononuclear cells
  • NTD N-terminus domain
  • Embodiment 9 The method of any preceding embodiment, wherein the N- terminus domain (NTD) mediated systemic cytokine release is dependent upon activity of at least one of the following kinases ephrin type-A receptor 7 (EPHA7), mitogen- activated protein kinase 14 (MAPK14), tyrosine protein kinase JAK1 (JAK1), protein tyrosine kinase 5 (PTK5), mitogen-activated protein kinase kinase kinase 3 (MEKK3), mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2), protein tyrosine kinase 2 beta (PTK2B), cAMP-dependent protein kinase catalytic subunit gamma (PKACG), interleukin-1 receptor-associated kinase 1 (IRAKI), calcium/calmodulin- dependent protein kinase
  • Embodiment 10 The method of any preceding embodiment, wherein SARS-CoV- 2-mediated systemic cytokine release results in the release of at least one of the following cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 1 beta (IL-lb), interleukin 10 (IL-10), interleukin 6 (IL-6), interleukin 8 (IL-8), chemokine (C-C motif) ligand 2 (CCL2), or tumor necrosis factor alpha (TNFa).
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • IL-lb interleukin 1 beta
  • IL-10 interleukin 10
  • IL-6 interleukin 6
  • IL-8 interleukin 8
  • CCL2 tumor necrosis factor alpha
  • Embodiment 11 The method of any preceding embodiment, wherein the subject is co-administered an agent to inhibit kinase activity associated with systemic cytokine release.
  • Embodiment 12 The method of any preceding embodiment, wherein the subject is co-administered an agent to reduce cytokine release associated with systemic cytokine release.
  • Embodiment 13 The method of any preceding embodiment, wherein the multispecific kinase inhibitor is administered as part of a pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective quantity of the multi-specific kinase inhibitor combined with a pharmaceutically acceptable carrier.
  • Embodiment 14 The method of any preceding embodiment, wherein the multispecific kinase inhibitor comprises a therapeutically effective quantity of olverembatinib.
  • Embodiment 15 The method of any preceding embodiment, wherein the therapeutically effective quantity of olverembatinib provides for a plasma concentration of ⁇ 100 nM olverembatinib.
  • Embodiment 16 A method to inhibit cytokine release in a subjected infected by a Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the method comprising the steps of: (a) identifying a subject with SARS-CoV-2-mediated cytokine storm; and (b) administering a therapeutically effective quantity of a multi-specific kinase inhibitor to the subject with SARS-CoV-2-mediated cytokine storm, wherein administering the therapeutically effective quantity of the multi-specific kinase inhibitor reduces cytokine release associated with SARS-CoV-2-mediated cytokine storm.
  • SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2
  • Embodiment 17 The method of embodiment 16, wherein the multi-specific kinase inhibitor comprises olverembatinib.
  • Embodiment 18 The method of embodiment 16 or embodiment 17, wherein the therapeutically effective quantity of olverembatinib provides for a plasma concentration of ⁇ 100 nM olverembatinib.
  • Embodiment 19 The method of any one of embodiments 16-18, wherein the subject is infected with a SARS-CoV-2 Omicron variant.
  • Embodiment 20 The method of any one of embodiments 16-19, wherein the SARS-CoV-2 Omicron variant-mediated cytokine storm is caused by stimulation of peripheral blood mononuclear cells (PBMCs) with an N-terminus domain (NTD) of a spike protein from the Omicron variant.
  • PBMCs peripheral blood mononuclear cells
  • NTD N-terminus domain
  • Embodiment 21 The method of any one of embodiments 16-20, wherein the N- terminus domain (NTD) mediated cytokine storm is dependent upon activity of at least one of the following kinases ephrin type-A receptor 7 (EPHA7), mitogen-activated protein kinase 14 (MAPK14), tyrosine protein kinase JAK1 (JAK1), protein tyrosine kinase 5 (PTK5), mitogen-activated protein kinase kinase kinase 3 (MEKK3), mitogen- activated protein kinase kinase kinase kinase 2 (MAP4K2), protein tyrosine kinase 2 beta (PTK2B), cAMP-dependent protein kinase catalytic subunit gamma (PKACG), interleukin-1 receptor-associated kinase 1 (IRAKI), calcium/calmodulin-dependent protein kinase
  • Embodiment 22 The method of any one of embodiments 16-21, wherein SARS- CoV-2-mediated cytokine storm results in the release of at least one of the following cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 1 beta (IL-lb), interleukin 10 (IL-10), interleukin 6 (IL-6), interleukin 8 (IL-8), chemokine (C-C motif) ligand 2 (CCL2), or tumor necrosis factor alpha (TNFa).
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • IL-lb interleukin 1 beta
  • IL-10 interleukin 10
  • IL-6 interleukin 6
  • IL-8 interleukin 8
  • CCL2 tumor necrosis factor alpha
  • Embodiment 23 The method of any one of embodiments 16-22, wherein the subject is co-administered an agent to inhibit kinase activity associated with SARS-CoV- 2 mediated cytokine storm.
  • Embodiment 24 The method of any one of embodiments 16-23, wherein the subject is co-administered an agent to reduce cytokine storm associated with SARS-CoV- 2 infection.
  • Embodiment 25 The method of any one of embodiments 16-24, wherein the multi-specific kinase inhibitor is administered as part of a pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective quantity of the multi-specific kinase inhibitor combined with a pharmaceutically acceptable carrier.
  • Embodiment 26 The method of any one of embodiments 16-25, wherein the multi-specific kinase inhibitor comprises a therapeutically effective quantity of olverembatinib.
  • Embodiment 27 The method of any one of embodiments 16-26, wherein the therapeutically effective quantity of olverembatinib provides for a plasma concentration of ⁇ 100 nM olverembatinib.
  • Embodiment 28 A method to treat moderate to severe COVID-19, the method comprising the steps of: (a) identifying a subject with moderate to severe COVID-19; and (b) administering a therapeutically effective quantity of a multi-specific kinase inhibitor to the subject with moderate to severe COVID-19, wherein administering the therapeutically effective quantity of the multi-specific kinase inhibitor reduces symptoms associated with moderate to severe COVID-19.
  • Embodiment 29 The method of embodiment 28, wherein the multi-specific kinase inhibitor comprises olverembatinib.
  • Embodiment 30 The method of embodiment 28 or embodiment 29, wherein the therapeutically effective quantity of olverembatinib provides for a plasma concentration of ⁇ 100 nM olverembatinib.
  • Embodiment 31 The method of any one of embodiments 28-30, wherein the moderate to severe COVID-19 is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Omicron variant.
  • SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2
  • Embodiment 32 The method of any one of embodiments 28-31, wherein the moderate to severe COVID-19 results in a cytokine storm.
  • Embodiment 33 The method of any one of embodiments 28-32, wherein the cytokine storm is caused by activation of at least one of the following kinases ephrin type- A receptor 7 (EPHA7), mitogen-activated protein kinase 14 (MAPK14), tyrosine protein kinase JAK1 (JAK1), protein tyrosine kinase 5 (PTK5), mitogen-activated protein kinase kinase kinase 3 (MEKK3), mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2), protein tyrosine kinase 2 beta (PTK2B), cAMP-dependent protein kinase catalytic subunit gamma (PKACG), interleukin- 1 receptor-associated kinase 1 (IRAKI), calcium/calmodulin-dependent protein kinase kinase 2 (CAM
  • Embodiment 34 The method of any one of embodiments 28-33, wherein the cytokine storm results in release of at least one of the following cytokines granulocytemacrophage colony-stimulating factor (GM-CSF), interleukin 1 beta (IL- lb), interleukin 10 (IL- 10), interleukin 6 (IL-6), interleukin 8 (IL-8), chemokine (C-C motif) ligand 2 (CCL2), or tumor necrosis factor alpha (TNFa).
  • GM-CSF granulocytemacrophage colony-stimulating factor
  • IL- 10 interleukin 1 beta
  • IL-6 interleukin 6
  • IL-8 interleukin 8
  • CCL2 tumor necrosis factor alpha
  • Embodiment 35 The method of any one of embodiments 28-34, wherein the subject is co-administered an agent to inhibit kinase activity associated with SARS-CoV- 2 mediated cytokine storm.
  • Embodiment 36 The method of any one of embodiments 28-35, wherein the subject is co-administered an agent to reduce cytokine storm associated with SARS-CoV- 2 infection.
  • Embodiment 37 The method of any one of embodiments 28-36, wherein the multi-specific kinase inhibitor is administered as part of a pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective quantity of the multi-specific kinase inhibitor combined with a pharmaceutically acceptable carrier.
  • Embodiment 38 The method of any one of embodiments 28-37, wherein the multi-specific kinase inhibitor comprises a therapeutically effective quantity of olverembatinib.
  • Embodiment 39 The method of any one of embodiments 28-38, wherein the therapeutically effective quantity of olverembatinib provides for a plasma concentration of ⁇ 100 nM olverembatinib.
  • This Example describes that multi-specific kinase inhibitors (e.g., olverembatinib and ponatinib) targeting multiple kinases essential for SARS-CoV-2-mediated cytokine release can represent a therapeutic option for treating moderate to severe COVID-19.
  • pooled PBMCs were stimulated with mammalian cell (HEK293)-derived NTD (Ipg/mL) of the Omicron variant.
  • PBMCs from healthy donors spanning various age groups were obtained from Bloodworks NW, Seattle, Washington.
  • a robust (>100- fold) increase in the release of interleukins including IL- 10, IL-6, and tumor necrosis factor (TNFa) Fig.
  • Ponatinib an FDA-approved drug for chronic myelogenous leukemia, as a potent inhibitor of SI protein-mediated cytokine release in PBMCs (Chan M et al., (2021) Machine learning identifies molecular regulators and therapeutics for targeting SARS-CoV2-induced cytokine release. Molecular systems biology 17: el0426).
  • the inventors determined whether Ponatinib treatment could also inhibit cytokine release mediated by the NTD from the Omicron variant.
  • the kinase activity profile of Olverembatinib showed that this drug inhibits 11 out of 13 kinases predicted to be essential for the NTD-mediated chemokine and cytokine release (e.g., RPHA7, MAPK14, JAK1, PTK5, MEKK3, MAP4K2, PTK2B, PKACG, IRAKI, CAMKK2, and MAPK12) (Fig 2C). Similar to olverembatinib, the kinase activity profile of ponatinib showed that this drug inhibits 11 out of 13 kinases predicted to be essential for the NTD-mediated chemokine and cytokine release.
  • agents targeting multiple kinases essential for SARS-CoV-2- mediated cytokine release can represent a therapeutic option for treating moderate to severe COVID-19.
  • This Example discloses SARS-CoV-2 SI spike protein and lipopolysaccharide (LPS) stimulation of THP1 monocytes increase expression of all measured cytokines.
  • LPS lipopolysaccharide
  • SI spike protein I pg/mL
  • LPS LPS
  • cytokines e.g., CXCL10, IL- lb, IL-8, IL-6, CCL2, and TNFa
  • cytokines e.g., CXCL10, IL- lb, IL-8, IL-6, CCL2, and TNFa
  • FIG. 3B illustrates the schematic of the experimental strategy to test the role of selected kinases in LPS-mediated cytokine release, the results for which are illustrated in Figure 3C.
  • depletion of kinases JAK1, IRAKI, and EPHA7 decreased LPS-mediated release of cytokines (e.g., GMCSF, IL-lb, IL-6, IL- 8, CCL2, and TNFa).
  • cytokines e.g., GMCSF, IL-lb, IL-6, IL- 8, CCL2, and TNFa.
  • TNFa is less than 20% of control following depletion of either JAK1 or IRAKI.
  • depletion of the kinase MAP3K3, or scrambled control did not affect cytokine release.
  • release of any one of GMCSF, IL-lb, IL-6, IL-8, CCL2, and TNFa is at least 100% of control following depletion of MAP3K3.
  • multi-specific kinase inhibitors such as olverembatinib or ponatinib, would effectively inhibit systemic cytokine release caused by a broad variety of stimulates (i.e., not limited to SARS-CoV-2 or LPS).
  • This Example discloses administering a multi-specific kinase inhibitor to a subject with SARS-CoV-2-mediated cytokine storm.
  • a subject with systemic cytokine release caused by a previously received cellbased therapy, an infectious disease, or a disease condition, or otherwise having moderate to severe COVID-19, will first be identified.
  • the multi-specific kinase inhibitor or a pharmaceutical composition comprising a multi-specific kinase inhibitor e.g., olverembatinib or ponatinib
  • a multi-specific kinase inhibitor e.g., olverembatinib or ponatinib
  • administering the multi-specific kinase inhibitor will inhibit release of cytokines including but not limited to: granulocytemacrophage colony-stimulating factor (GM-CSF), interleukin 1 beta (IL- lb), interleukin 10 (IL- 10), interleukin 6 (IL-6), interleukin 8 (IL-8), chemokine (C-C motif) ligand 2 (CCL2), or tumor necrosis factor alpha (TNFa), which are associated with systemic cytokine release.
  • cytokines including but not limited to: granulocytemacrophage colony-stimulating factor (GM-CSF), interleukin 1 beta (IL- lb), interleukin 10 (IL- 10), interleukin 6 (IL-6), interleukin 8 (IL-8), chemokine (C-C motif) ligand 2 (CCL2), or tumor necrosis factor alpha (TNFa), which are associated with systemic cytokine release.
  • Inhibiting release of the above-identified cytokines will reduce the subject’s hyper-inflammation, treating/ameliorating the symptoms associated with systemic cytokine release caused by a previously received cell-based therapy, an infectious disease, or a disease condition, or otherwise having moderate to severe COVID-19.

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Abstract

Des modes de réalisation de la présente divulgation concernent une méthode d'inhibition de la libération systémique de cytokines chez un sujet en dont l'état le nécessite. La méthode peut comprendre les étapes consistant à (a) identifier un sujet dont 'état nécessite l'inhibition de la libération de cytokine systémique ; et (b) à administrer une quantité thérapeutiquement efficace d'un inhibiteur de kinase multi-spécifique au sujet en dont l'état le nécessite, l'administration de la quantité thérapeutiquement efficace de l'inhibiteur de kinase multi-spécifique réduisant la libération de cytokine systémique.
PCT/US2023/061990 2022-02-04 2023-02-03 Inhibition par olverembatinib de la régulation à la hausse de cytokines associée au syndrome de libération de cytokines Ceased WO2023150718A2 (fr)

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