WO2020234833A1 - Méthode de traitement, de prévention, d'inhibition ou de réduction de la libération de cytokine - Google Patents

Méthode de traitement, de prévention, d'inhibition ou de réduction de la libération de cytokine Download PDF

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WO2020234833A1
WO2020234833A1 PCT/IB2020/054858 IB2020054858W WO2020234833A1 WO 2020234833 A1 WO2020234833 A1 WO 2020234833A1 IB 2020054858 W IB2020054858 W IB 2020054858W WO 2020234833 A1 WO2020234833 A1 WO 2020234833A1
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syndrome
cytokine
cell
disease
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James C. Costin
Hanns Moehler
Thomas Mueller
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Geistlich Pharma Ag
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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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/463—Cellular immunotherapy characterised by recombinant expression
    • A61K39/4631—Chimeric Antigen Receptors [CAR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/464402—Receptors, cell surface antigens or cell surface determinants
    • A61K39/464411—Immunoglobulin superfamily
    • A61K39/464412—CD19 or B4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
    • A61K2239/48—Blood cells, e.g. leukemia or lymphoma
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • compositions and methods for treating, inhibiting, preventing or reducing cytokine release, cytokine release syndrome (CRS) or a cytokine storm in a subject relate to compositions and methods for treating, inhibiting, preventing or reducing cytokine release, cytokine release syndrome (CRS) or a cytokine storm in a subject.
  • CRS cytokine release syndrome
  • Cytokines are small, secreted proteins necessary for immune cell signaling, activation, and recruitment of other inflammatory cells. Cytokines may be secreted by various types of cells in response to various conditions, diseases, disorders, treatments, and agents. Cytokines are small secreted proteins released by cells have a specific effect on the interactions and
  • Cytokine is a general name; other names include lymphokine (cytokines made by lymphocytes), monokine (cytokines made by monocytes), chemokine (cytokines with chemotactic activities), and interleukin (cytokines made by one leukocyte and acting on other leukocytes). Cytokines may act on the cells that secrete them (autocrine action), on nearby cells (paracrine action), or in some instances on distant cells (endocrine action). There are both pro- inflammatory cytokines and anti-inflammatory cytokines. Certain cytokines/chemokines are involved in various diseases, disorders and conditions.
  • Cytokine release syndrome is a systemic inflammatory response that can be triggered by a variety of factors such as infections and certain drugs.
  • Cancer immunotherapy may include adoptive transfer of T cells with chimeric antigen receptors (CAR) targeting cancer cells (e.g., B cells with antigen CD19 in B cell leukemia), bispecific antibodies targeting cancer cells (e.g., BlinCyto linking CD3 of T-cells with CD19 of B cells for treating B cell leukemia) or high dose IL2 (e.g. for treating melanoma).
  • CAR chimeric antigen receptors
  • bispecific antibodies targeting cancer cells e.g., BlinCyto linking CD3 of T-cells with CD19 of B cells for treating B cell leukemia
  • high dose IL2 e.g. for treating melanoma
  • CRS was observed when the anti-T-cell antibody muromonab- CD3 (OKT3) was introduced into the clinic as an immunosuppressive treatment for solid organ transplantation. Subsequently, CRS has been described after infusion of several antibody-based therapies such as anti-thymocyte globulin (ATG), the CD28 superagonist TGN1412, rituximab, obinutuzumab, alemtuzumab, brentuximab, dacetuzumab, and nivolumab. CRS has also been observed following administration of non-protein-based cancer drugs such as oxaliplatin and lenalidomide. Furthermore, CRS was reported in the setting of haploidentical donor stem cell transplantation, and graft-versus-host disease.
  • AGT anti-thymocyte globulin
  • TGN1412 anti-thymocyte globulin
  • rituximab obinutuzumab
  • alemtuzumab alemtu
  • ACT adoptive cell transfer
  • CAR T- cells chimeric antigen receptor
  • CAR T- cells chimeric antigen receptor
  • T cell-engaging immunotherapies include bispecific antibody constructs and chimeric antigen receptor (CAR) T cell therapies. Both these immunotherapeutic strategies have recently been carried forward into clinical application and have shown impressive therapeutic activity in several hematologic malignancies, such as acute lymphoblastic B cell leukemia (B-ALL), chronic lymphocytic leukemia (CLL), and diffuse large B cell lymphoma (DLBCL).
  • B-ALL acute lymphoblastic B cell leukemia
  • CLL chronic lymphocytic leukemia
  • DLBCL diffuse large B cell lymphoma
  • CRS T cells revealed that CRS is a serious adverse event of these therapies.
  • CRS data is derived from CAR T cell and blinatumomab studies in hematologic malignancies where CRS has been reported in frequencies of up to 100% in CD19-targeted CAR T cell trials, sometimes with fatal outcome.
  • activated T-cells produce a systemic inflammatory response in which there is a rapid and massive release of cytokines into the bloodstream, leading to dangerously low blood pressure, high fever and shivering.
  • cytokine storm a.k.a. cytokine cascade or hypercytokinemia
  • cytokine cascade or hypercytokinemia in which there is a positive feedback loop between cytokines and white blood cells with highly elevated levels of cytokines.
  • This can lead to potentially life- threatening complications including cardiac dysfunction, adult respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, pulmonary edema and disseminated intravascular coagulation.
  • cytokine storms In CRS or a cytokine storm, numerous proinflammatory cytokines, such as interleukin-1 (IL-1), IL-6, gamma interferon (g-IFN, IFN-g or IFN-g), and tumor necrosis factor-a (TNFa), are released, resulting in hypotension, hemorrhage, and, ultimately, multi organ failure.
  • IL-1 interleukin-1
  • g-IFN gamma interferon
  • IFN-g or IFN-g gamma interferon
  • TNFa tumor necrosis factor-a
  • Cytokine release, cytokine storms or CRS may also stem from non-infectious causes, such as acute pancreatitis, severe burns or trauma, or acute respiratory distress syndrome.
  • corticosteroids biological therapies such as anti-IL6 therapies and anti inflammatory drugs are being evaluated to control cytokine release syndrome and cytokine storm in patients administered immunotherapy such as CAR T-cell therapy.
  • CAR T-cell therapy such agents have typically been found to negatively affect response rates to T cell-engaging therapies and eventually lead to relapse.
  • Steroids may effect CAR T-cells' activity and/or proliferation and put the patients in danger of sepsis and opportunistic infections.
  • Anti-inflammatory drugs may not be effective in controlling cytokine release syndromes or cytokine storms, because the cytokine storm includes a very large number of cytokines while there is limited ability to infuse patients with anti
  • tocilizumab (ACTEMRA®) from its original designation of rheumatoid arthritis (RA) treatment to include treating CRS in patients undergoing CAR T treatment.
  • Tocilizumab works by blocking the interleukin-6 (IL-6) receptor, an inflammatory cytokine, but it does not inhibit release of cytokines. As such, tocilizumab provides relief from some symptoms in some subjects but there is much room for improvement.
  • the approval of tocilizumab for the treatment of CAR T cell-induced severe or life-threatening CRS in adults and in pediatric patients 2 years of age and older was based on a retrospective data analysis in two cohorts, showing response rates of 53%-69%.
  • tocilizumab is a monoclonal antibody against a single cytokine receptor, IL6, but CRS and cytokine storms involve multiple cytokines including, but not limited to, e.g., TNF-a, Interferon gamma, interleukins, e.g., IL-Ib, IL-2, IL-8, and IL-10 in addition to IL-6.
  • cytokines including, but not limited to, e.g., TNF-a, Interferon gamma, interleukins, e.g., IL-Ib, IL-2, IL-8, and IL-10 in addition to IL-6.
  • the present disclosure provides a method of treating, preventing, inhibiting, or reducing an increase in blood levels of one or more cytokines in a subject in need thereof by administering a composition of the present disclosure to the subject.
  • the present disclosure provides a method of treating, preventing, inhibiting or reducing the incidence of a cytokine release syndrome (CRS) or a cytokine storm in a subject by administering a composition of the present disclosure to the subject.
  • CRS cytokine release syndrome
  • the present disclosure provides a method of treating, preventing, inhibiting or reducing neurotoxicity of a CAR T-cell therapy, antibody therapy, or a bispecific antibody therapy in a subject by administering a composition of the present disclosure to the subject.
  • the present disclosure provides a method of treating, preventing, reducing or inhibiting cytokine production in a subject experiencing cytokine release syndrome or cytokine storm or vulnerable to cytokine release syndrome or cytokine storm by administering a composition of the present disclosure to the subject.
  • the present disclosure provides a method of treating one or more symptoms or adverse reactions triggered by an infectious disease or a disease condition that trigger a widespread release of cytokines in a subject by administering a composition of the present disclosure to the subject.
  • the present disclosure provides a method of increasing the maximum tolerable dose of a T cell-engaging immunotherapeutic drug administered to a subject by administering a composition of the present disclosure to the subject.
  • the present disclosure provides a method of inhibiting, preventing or treating vascular leakage in a subject in need thereof by administering a composition of the present disclosure to the subject.
  • the present disclosure provides a method of treating cardiomyopathy, and/or myocardial dysfunction in a subject at risk thereof due to cytokine release, a cytokine release syndrome, or a cytokine storm by administering a composition of the present disclosure to the subject.
  • the cause of the cytokine release, cytokine release syndrome or cytokine storm may include an infectious stimulus, condition, or syndrome. In some aspects, the cause of the cytokine release, cytokine release syndrome or cytokine storm may include a non- infectious stimulus, condition, or syndrome. In some aspects, the cause of the cytokine
  • cytokine release, cytokine release syndrome or cytokine storm may include a combination of an infectious stimulus, condition, or syndrome and a non-infectious stimulus, condition, or syndrome.
  • the cause of the cytokine release, cytokine release syndrome or cytokine storm may include at least one of viral, bacterial, fungal, helminthic, protozoan, or infectious agent.
  • IL-I b at least one of IL-I b, IL-1RA, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12,
  • FIG. 1 A shows LPS Simulated Human PBMC at 48 hours, IL-Ib.
  • FIG. IB shows
  • FIG. 1C shows EPS Simulated Human PBMC at 48 hours, TNF- a.
  • FIGs. 2A-2C show the results of CD 19 CAR-T co-culture assay with CD- 19 tumor cells (Raji) at 6 hours, CAR-T mediated tumor target cell in the present of increasing concentrations of Taurolidine are shown (E:T ratios of 5: 1, 10: 1, and 20: 1 are shown in FIGs. 2A, 2B, and 2C, respectively).
  • FIGs. 3A-3C show the results of CD19 CAR-T co-culture assay with CD-19 tumor cells (Raji) at 24 hours, CAR-T mediated tumor target cell in the present of increasing
  • FIG. 4 shows the effect of Taurolidine on CD 19 CAR-T cell mediated IF-2 cytokine release across different effector to target ratios.
  • FIG. 5 shows the effect of Taurolidine on CD19 CAR-T cell mediated TNF-a cytokine release across different effector to target ratios.
  • FIG. 6 shows the effect of Taurolidine on CD 19 CAR-T cell mediated IFN-y cytokine release across different effector to target ratios.
  • FIG. 7 shows target cell cytotoxicity of BLINCYTO® in Ramos cells of tested donors.
  • FIG. 8 shows the effect of Taurolidine on BLINCYTO® mediated CD19 + tumor target cell cytotoxicity.
  • FIG. 9A shows the effect of BLINCYTO® on IL-Ib cytokine release in the tested donors.
  • FIG. 9B shows the effect of Taurolidine on BLINCYTO® T-cell mediated IL-Ib cytokine release in the tested donors.
  • FIG. 10A shows the effect of BLINCYTO® on IL-2 cytokine release in the tested donors.
  • FIG. 10B shows the effect of Taurolidine on BLINCYTO® T-cell mediated IL-2 cytokine release in the tested donors.
  • FIG. 11A shows the effect of BLINCYTO® on IL-6 cytokine release in the tested donors.
  • FIG. 1 IB shows the effect of Taurolidine on BLINCYTO® T-cell mediated IL-6 cytokine release in the tested donors.
  • FIG. 12A shows the effect of BLINCYTO® on TNF-a cytokine release in the tested donors.
  • FIG. 12B shows the effect of Taurolidine on BLINCYTO® T-cell mediated TNF-a cytokine release in the tested donors.
  • FIG. 13 A shows the effect of BLINCYTO® on IFN-g cytokine release in the tested donors.
  • FIG. 13B shows the effect of Taurolidine on BLINCYTO® T-cell mediated IFN-g cytokine release in the tested donors.
  • FIG. 14 shows the effect of Taurolidine on tumor target cytotoxicity in the absence of
  • Cytokines are small, secreted proteins necessary for immune cell signaling, activation, and recruitment of other inflammatory cells.
  • Some examples of cytokines include IL-Ib, IL-1RA, IL-2Ra IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, IL-18, IP-10, IFN-a, IFN-g, MCP-3, MCP-1, M-CSF, G-CSF, and TNF-a.
  • Some examples of chemokines include CCL5, CXCL8, CXCL1, CXCL2, CXCL10, CCL2, CCL7, CXCL6, CXCL11, CCL2, CCL3, CCL4, CCL7, CCL8, and CCL20. Certain cytokines/chemokines are involved in various diseases, disorders and conditions.
  • Cytokine release syndrome is a form of systemic inflammatory response syndrome that arises as a complication of some diseases or infections, and is also an adverse effect of some monoclonal antibody drugs, as well as immunotherapies, such as adoptive T-cell therapies.
  • Cytokine release syndrome is a condition that may occur after treatment with some types of immunotherapy, such as monoclonal antibodies and CAR-T cells. Cytokine release syndrome is caused by a large, rapid release of cytokines into the blood from immune cells affected by the immunotherapy. Cytokines are immune substances that have many different actions in the body. Signs and symptoms of cytokine release syndrome include fever, nausea, headache, rash, rapid heartbeat, low blood pressure, and trouble breathing. Most patients have a mild reaction, but sometimes, the reaction may be severe or life threatening.
  • symptomatic treatment e.g., antihistamines, NSAIDS, narcotics, IV fluids
  • prophylactic medications indicated for ⁇ 24 hrs
  • Grade 3 Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae (e.g., renal impairment, pulmonary infiltrates); Grade
  • Grade 1 includes fever and constitutional symptoms
  • Grade 2 includes hypotension responding to fluids/low dose vasopressors and Grade 2 organ toxicities
  • Grade 3 includes shock requiring high dose/multiple vasopressors
  • Grade 4 includes the need for mechanical ventilation and Grade 4 organ toxicities.
  • cytokine storm refers to the dysregulation of pro- inflammatory cytokines leading to adverse events, toxicity and disease and has been referred to as a “cytokine storm,”“cytokine release syndrome” or“inflammatory cascade”. Often,
  • a cytokine storm or cascade is referred to as being part of a sequence because one cytokine typically leads to the production of multiple other cytokines that can reinforce and amplify the immune response.
  • these pro-inflammatory mediators have been divided into two subgroups: early mediators and late mediators.
  • Early mediators such as e.g., tumor-necrosis factor, interleukin- 1, interleukin-6, are not sufficient therapeutic targets for re-establishing homeostatic balance because they are resolved within the time frame of a patient's travel to a clinic to receive medical attention.
  • the so-called“late mediators” have been targeted because it is during this later “inflammatory cascade” that the patient realizes that he or she has fallen ill.
  • infectious diseases commonly associated with a“cytokine storm” include but at not limited to, malaria, avian influenza, smallpox, pandemic influenza, adult respiratory distress syndrome (ARDS), a severe acute respiratory syndrome (SARS).
  • Certain specific infectious agents include but are not limited to: infectious diseases is selected from at least one of 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.
  • Disease conditions commonly associated with a“cytokine storm” include but are not limited to: sepsis, systemic inflammatory response syndrome (SIRS), cachexia, septic shock syndrome, traumatic brain injury (e.g., cerebral cytokine storm), graft versus host disease (GVHD), or the result of treatment with immune therapy, e.g., activated immune cells, IL-2 activated T cells, T cells activated with anti-CD 19 Chimeric Antigen Receptor (CAR) T cells.
  • SIRS systemic inflammatory response syndrome
  • cachexia e.g., cerebral cytokine storm
  • GVHD graft versus host disease
  • immune therapy e.g., activated immune cells, IL-2 activated T cells, T cells activated with anti-CD 19 Chimeric Antigen Receptor (CAR) T cells.
  • CAR Chimeric Antigen Receptor
  • a cytokine storm is a healthy systemic expression of a vigorous immune system.
  • the present invention can, inter alia, be used to treat, prevent, inhibit, reduce or eliminate some or most of an exaggerated immune response caused by, e.g., rapidly proliferating and highly activated T-cells or natural killer (NK) cells that results in the release of the“cytokine storm” that can include more than 150 inflammatory mediators (cytokines, oxygen free radicals, and coagulation factors). Both pro-inflammatory cytokines (such as Tumor Necrosis Factor-a,
  • Interleukin- 1, and Interkeukin-6) and anti-inflammatory cytokines become greatly elevated in, e.g., serum, before or during a cytokine storm. It is this excessive release of inflammatory mediators that triggers the “cytokine storm.”
  • a cytokine storm can result in permanent lung damage and, in many cases, death.
  • the end stage symptoms of the cytokine storm include but are not limited to: hypotension; tachycardia; dyspnea; fever; ischemia or insufficient tissue perfusion; uncontrollable hemorrhage; severe metabolism dysregulation; and multisystem organ failure.
  • Deaths from infectious diseases such as Ebola virus infection are not caused by the virus itself, but rather, the cytokine storm that causes uncontrollable hemorrhaging; severe metabolism dysregulation; hypotension; tachycardia; dyspnea; fever; ischemia or insufficient tissue perfusion; and multisystem organ failure.
  • cytokine release syndrome refers to a subject that has come into contact with, is coming into contact with, or will come into contact with one or more environmental agents, pollutants, chemicals, drugs, foods, diseases, treatment regimens, disorders, and conditions that induce undesired cytokine release, cytokine release syndrome, or cytokine storm in the subject.
  • the terms“substantially” and“substantial” refer to a considerable degree or extent. When used in conjunction with, for example, an event, circumstance,
  • the terms can refer to instances in which the event, circumstance, characteristic, or property occurs precisely as well as instances in which the event, circumstance, characteristic, or property occurs to a close approximation, such as accounting for typical tolerance levels or variability of the examples described herein.
  • the term“about” is used to provide flexibility to a numerical range endpoint by providing that a given value may be“a little above” or“a little below” the endpoint.
  • the degree of flexibility of this term can be dictated by the particular variable and would be within the knowledge of those skilled in the art to determine based on experience and the associated description herein.
  • the degree of flexibility can be within about ⁇ 10% of the numerical value.
  • the degree of flexibility can be within about ⁇ 5% of the numerical value.
  • the degree of flexibility can be within about ⁇ 2%, ⁇ 1%, or ⁇ 0.05%, of the numerical value.
  • the compounds of the invention may be useful in a free acid form, a free base form, in the form of pharmaceutically acceptable salts, pharmaceutically acceptable hydrates,
  • “Pharmaceutically acceptable salt”,“hydrate”,“ester” or“solvate” refers to a salt, hydrate, ester, or solvate of the inventive compounds which possesses the desired
  • Organic acids can be used to produce salts, hydrates, esters, or solvates such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, p-toluenesulfonate, bisulfate, sulfamate, sulfate, naphthylate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate heptanoate, hexanoate, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, tosy
  • pharmaceutically acceptable salts include, but are not limited to, hydrochloride, hydrobromide, sulphate, phosphate, tartrate, fumarate, maleate, oxalate, acetate, propionate, succinate, mandelate, mesylate, besylate and tosylate.
  • salts, hydrates, esters, or solvates may also be formed with organic bases.
  • Pharmaceutically acceptable base addition salts of acidic compounds may be formed with organic and inorganic bases by conventional methods.
  • alkali metal and alkaline earth metal hydroxides, carbonates and bicarbonates such as sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, sodium bicarbonate, magnesium carbonate and the like, ammonia, primary, secondary and tertiary amines and the like.
  • aluminum salts of the instant compounds may be obtained by treating the corresponding sodium salt with an appropriate aluminum complex such as, for example, aluminum chloride hexahydrate, and the like.
  • Non-toxic organic bases include, but are not limited to, triethylamine, butylamine, piperazine, and
  • Suitable base salts, hydrates, esters, or solvates include hydroxides, carbonates, and bicarbonates of ammonia, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, and zinc salts.
  • Organic bases suitable for the formation include hydroxides, carbonates, and bicarbonates of ammonia, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, and zinc salts.
  • the class of such organic bases may include mono-, di-, and trialkylamines, such as methylamine, dimethylamine, triethylamine and dicyclohexylamine; mono-, di- or trihydroxyalkylamines, such as mono-, di-, and triethanolamine; amino acids, such as arginine and lysine; guanidine; N-methyl-glucosamine; N-methyl-glucamine; L-glutamine; N- methyl-piperazine; morpholine; ethylenediamine; N-benzyl-phenethylamine; (trihydroxy- methyl)aminoethane; and the like.
  • mono-, di-, and trialkylamines such as methylamine, dimethylamine, triethylamine and dicyclohexylamine
  • mono-, di- or trihydroxyalkylamines such as mono-, di-, and triethanolamine
  • amino acids such as arginine and lysine
  • basic nitrogen-containing groups can be quaternized with agents including: lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides such as benzyl and phenethyl bromides.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyl, lauryl, myristyl and stearyl
  • the salts, hydrates, esters, or solvates of the basic compounds may be prepared either by dissolving the free base of compound of a compound of the present disclosure in an aqueous solution or an, aqueous alcohol solution or other suitable solvent containing the appropriate acid, and isolating the salt by evaporating the solution.
  • the free base of a compound of the present disclosure may be reacted with an acid, as well as reacting the compound of the present disclosure having an acid group thereon with a base, such that the reactions are in an organic solvent, in which case the salt separates directly or can be obtained by concentrating the solution.
  • “Pharmaceutically acceptable prodrug” refers to a derivative of the inventive compounds which undergoes biotransformation prior to exhibiting its pharmacological effect(s).
  • the prodrug is formulated with the objective(s) of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity).
  • the prodrug can be readily prepared from the inventive compounds using methods known in the art, such as those described by Burger's Medicinal Chemistry and Drug
  • inventive compounds can be transformed into prodrugs by converting one or more of the hydroxy or carboxy groups into esters.
  • N-protected versions of the inventive compounds are also included as non-limiting examples of pharmaceutically acceptable prodrugs of the inventive compounds.
  • “Pharmaceutically acceptable metabolite” refers to drugs that have undergone a metabolic transformation. After entry into the body, most drugs are substrates for chemical reactions that may change their physical properties and biologic effects. These metabolic conversions, which usually affect the polarity of the compound, alter the way in which drugs are distributed in and excreted from the body. However, in some cases, metabolism of a drug is required for therapeutic effect. For example, anti cancer drugs of the antimetabolite class must be converted to their active forms after they have been transported into a cancer cell. Since must drugs undergo metabolic transformation of some kind, the biochemical reactions that play a role in drug metabolism may be numerous and diverse. The main site of drug metabolism is the liver, although other tissues may also participate.
  • compositions, concentrations, dosage regimens, dosage amounts, syndromes or conditions, steps, or the like may be discussed in the context of one specific aspect. It is understood that this is merely for convenience, and such disclosure is equally applicable to other aspects found herein. For example, a list of method steps, active agents, kits or
  • compositions described with respect to a method of treating CRS or cytokine storm would find direct support for aspects related to method steps, active agents, kits or compositions of, e.g., the following: inhibiting or reducing neurotoxicity; decreasing or inhibiting cytokine production;
  • beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilizing (i.e. not worsening) the state of disease, delaying or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable.“Treating” and“treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • the methods described herein may be useful for the prevention or prophylaxis of disease.
  • the term“treating” refers to any administration of a compound of the present invention and includes: (i) preventing or inhibiting the disease in a mammal, e.g., a human, that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology); or (ii) ameliorating the disease in a mammal, e.g., a human that is experiencing or displaying the pathology or symptomatology of the disease (i.e., reversing the pathology and/or symptomatology).
  • the term“controlling” includes preventing, treating, eradicating, ameliorating or otherwise reducing the severity of the condition being controlled.
  • any one of these transition terms i.e.“comprising,”“consisting,” or“consisting essentially”
  • the present disclosure relates to using an "N-methylol transfer agent” and“N- methylol donating compound,” collectively referred to as“N-methylol transfer agent” or “compounds of the present disclosure.”
  • the terms "N-methylol transfer agent” and“N-methylol donating compound” and cognates thereof indicate a compound which contains or is capable of producing a methylol molecule under physiological conditions.
  • N-methylol transfer agents include compounds such as Taurolidine and Taurultam, and their derivatives, including taurinamide and urea derivatives.
  • the compounds Taurolidine and Taurultam are disclosed in U.S. Patent No. 5,210,083, which is incorporated herein by reference, and are structurally depicted as follows:
  • Certain N-methylol transfer agents are Taurolidine, Taurultam, and mixtures thereof.
  • N-methylol-containing compounds include taurinamide derivatives and urea derivatives, examples of which are identified herein and shown in the Figures.
  • Examples of specific derivatives of Taurolidine, Taurultam, taurinamide and urea which may be useful in the present invention also can be found in WO 01/39763 A2, the disclosures of which are hereby incorporated by reference.
  • A“derivative” of Taurolidine or Taurultam refers to a sulfonamide compound which possesses at least 10% of the neoplastic activity of Taurolidine or Taurultam, respectively.
  • Some examples of such compounds include but are not limited to l,3,-dimethylol-5,5-dimethylhydantoin, hexamethylene tetramine, or noxythiolin.
  • Other N-methylol transfer agents contemplated for use with the invention include cyclotaurolidine or N-methyltaurinamide and compounds disclosed in U.S. Pat. No. 9,028,866, which is incorporated herein by reference in its entirety.
  • the invention also relates to compositions, e.g., pharmaceutical composition containing the compounds described herein, including pharmaceutically acceptable solutions of said compounds, as well as orally administrable compositions such as capsules and tablets containing said compositions.
  • compositions e.g., pharmaceutical composition containing the compounds described herein, including pharmaceutically acceptable solutions of said compounds, as well as orally administrable compositions such as capsules and tablets containing said compositions.
  • the terms“effective amount” or“therapeutically effective amount” described herein means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the therapeutically effective amount comprises about 0.0001 to about 10,000 mg/kg, about 0.001 mg/kg to about 5,000 mg/kg, about 0.01 mg/kg to about 1,000 mg/kg, about 0.05 mg/kg to about 750 mg/kg, about 0.1 mg/kg to about 600 mg/kg, about 1 mg/kg to about 500 mg/kg, about 10 mg/kg to about 400 mg/kg, about 20 mg/kg to about 300 mg/kg, about 200 mg/kg to about 500 mg/kg, about 300 mg/kg to about 400 mg/kg, about 250 mg/kg, 300 mg/kg, 400 mg/kg, 420 mg/kg, 450 mg/kg, about 500 mg/kg, or an dosage amount or range within any of the disclosed ranges of body weight of the subject.
  • administration of’ or“administering a” compound as used herein should be understood to mean providing a compound of the invention to the individual in need of treatment in a form that can be introduced into that individual's body, e.g., intravenously, subcutaneously, intramuscularly, topically, orally, intraperitoneally, intrathecally, intranasally, intrapulmonary, transdermally, intraocularly, by inhalation, transtracheally, intravitreally, or a combination thereof.
  • a compound of the invention may be administered 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), intranasal, 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), intranasal, 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
  • compositions well known in the art may be used. These include solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances.
  • Optional pharmaceutically active materials may be included, which do not substantially interfere with the activity of the one or more compounds of the present disclosure.
  • intravenous administration includes injection, infusion, and other modes of intravenous administration.
  • conditions mediated by cytokine release additionally include and are not limited to condition selected from the group consisting of appendicitis, peptic, gastric and duodenal ulcers, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute and ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, Crohn's disease, enteritis, Whipple's disease, asthma, allergy, anaphylactic shock, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, e
  • the present disclosure provides a method for treating a neuromyelitis optica spectrum disorder (NMSOD), which is a rare relapsing autoimmune disease of the central nervous system.
  • NMSOD neuromyelitis optica spectrum disorder
  • IL-6 signaling is implicated in playing a key role in the inflammation that occurs in NMSOD, in particular in triggering relapse.
  • the compounds of the present disclosure inhibit the production of inflammatory cytokines including IL-6 so as to treat patients suffering from or at risk of developing a NMSOD.
  • the present disclosure includes monitoring the subject for fever as a clinical sign of impending cytokine release, CRS or cytokine storm in patients at risk of undesired cytokine release or in need of control or down-regulation of cytokine release and administering one or more compounds of the present disclosure within about 24 hours, e.g., within about 1, 2, 3, 4, 5,
  • the patient may be receiving
  • the present disclosure includes monitoring the subject for one or more biomarkers indicative of impending cytokine release, CRS or cytokine storm in patients receiving T cell-engaging therapies and administering one or more compounds of the present disclosure within about 24 hours, e.g., within about 1, 2, 3, 4, 5, 6, 8, 10, or 12 hours of detection of the one or more biomarkers.
  • serum, blood or tissue levels of one or more of IL-I b, IL-1RA, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IP-10, IFN-a, IFN-g, G-CSF, and TNF-a of the subject receiving T cell-engaging therapies are monitored and one or more compounds of the present disclosure are administered within about 6 hours, e.g., within about 0.5, 1, 2, 3, 4, 5, 6 hours of detection of an increase in the serum, blood or tissue levels of one or more of IL-I b, IL-IRA, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IP- 10, IFN-a, IFN-g, G-CSF, and TNF-a above a threshold level or percentage above a baseline.
  • CD4+ and CD8+ T cell levels and ratios of the subject are monitored and one or more oxathiazin-like compounds of the present disclosure are administered within about 6 hours, e.g., within about 0.5, 1, 2, 3, 4, 5, 6 hours of detection of an increase in the serum, blood or tissue levels of one or more of CD4+ or CD4/CD8 ratio above a threshold level or percentage above a baseline.
  • the present disclosure includes monitoring the subject using a
  • the present disclosure includes monitoring the subject using a whole blood (WB) assay.
  • WB whole blood
  • the present disclosure includes preventing, inhibiting or reducing cytokine release including, but not limited to release of IL-Ib, IL-IRA, IL-2Ra, IL-2, IL-4, IL-6, IL- 8, IL-10, IL-12, IL-17, IL-18, IP- 10, IFN-a, IFN-g, MCP-3, MCP-1, M-CSF, G-CSF, MIP-la, TNF- a, CCL5, CXCL8, CXCL1, CXCL2, CXCL10, CCL2, CCL7, CXCL6, CXCL11, CCL2, CCL3, CCL4, CCL7, CCL8, and CCL20 in subjects before, during or after the onset of cytokine release, e.g., before, during or after treatment with, e.g., immunotherapeutics, e.g., T-cell engaging therapeutics.
  • cytokine release including, but not limited to release of IL-Ib, IL-IRA,
  • the present disclosure includes inhibiting, reducing or preventing release of IFN-g.
  • Secreted IFN-g induces activation of other immune cells, most importantly macrophages.
  • the activated macrophages produce excessive amounts of additional cytokines such as IL-6, TNF-a, and IL-10.
  • TNF-a elicits flu-like symptoms similar to IFN-g with fever, general malaise, and fatigue but furthermore is responsible for watery diarrhea, vascular leakage, cardiomyopathy, lung injury, and the synthesis of acute phase proteins.
  • Various therapeutic drugs including anti-cancer therapies and interferon drugs are known in the art to induce flu-like symptoms in patients.
  • the present disclosure includes treating, inhibiting, reducing or preventing drug-induced flu-like symptoms in a subject at risk thereof by administering one or more compounds to a subject.
  • IL-6 contributes to many of the key symptoms of CRS and cytokine storm. Via trans signaling, IL-6 leads to characteristic symptoms of severe CRS and cytokine storm, i.e., vascular leakage, and activation of the complement and coagulation cascade inducing disseminated intravascular coagulation (DIC). In addition, IL-6 likely contributes to cardiomyopathy that is often observed in patients with CRS and cytokine storm by promoting myocardial dysfunction.
  • DIC disseminated intravascular coagulation
  • the present disclosure includes inhibiting, preventing, reducing or treating vascular leakage, activation of the complement and coagulation cascade inducing disseminated intravascular coagulation (DIC), cardiomyopathy, and/or myocardial dysfunction in a subject at risk thereof by administering one or more compounds to a subject in need thereof.
  • Inflammatory signals such as LPS trigger the release of inflammatory cytokines by activating the transcription factor NFkB (NF kappa B).
  • NFkB transcription factor NFkB
  • NFkB transcription factor NF kappa B
  • the patient is treated with one or more compounds, or a combination thereof, administered intravenously, orally or a combination thereof.
  • the patient is treated with taurolidine administered intravenously, orally or a combination thereof.
  • the administration of the composition occurs prior to, concurrent with, or following therapy, e.g., immunotherapy, T cell engaging therapy, CAR T-cell therapy, and antibody therapy, e.g., monoclonal antibody therapy) and/or bispecific antibody therapy.
  • the patient is administered one or more compounds of the present disclosure in a combination therapy with one or more anti-neoplastic drugs such as nucleoside analogues, antifolates, antimetabolites, topoisomerase I inhibitors, anthracyclines, podophyllotoxins, taxanes, vinca alkaloids, alkylating agents, platinum compounds, antibodies, tyrosine kinase inhibitors, mTOR inhibitors, retinoids, immunomodulatory agents, histone deacetylase inhibitors, plant alkaloids, and antitumor antibiotics.
  • anti-neoplastic drugs such as nucleoside analogues, antifolates, antimetabolites, topoisomerase I inhibitors, anthracyclines, podophyllotoxins, taxanes, vinca alkaloids, alkylating agents, platinum compounds, antibodies, tyrosine kinase inhibitors, mTOR inhibitors, retinoids, immunomodulatory agents, histone deacety
  • the patient may be administered one or more compounds of the present disclosure in combination with non-protein-based cancer drugs such as oxaliplatin and lenalidomide.
  • the patient is administered one or more compounds of the present disclosure in combination with antibody-based therapies such as anti-thymocyte globulin (ATG), the CD28 superagonist TGN1412, rituximab, obinutuzumab, alemtuzumab, brentuximab, dacetuzumab, and nivolumab.
  • AGT anti-thymocyte globulin
  • rituximab obinutuzumab
  • alemtuzumab alemtuzumab
  • brentuximab dacetuzumab
  • nivolumab nivolumab
  • the patient is administered one or more compounds of the present disclosure in combination with immunotherapies such as T-cell engaging therapy and antibodies.
  • the patient is administered one or more compounds of the present disclosure or a combination thereof in combination with donor stem cell transplantation.
  • the patient is administered one or more compounds of the present disclosure or a combination thereof in combination with an interferon-containing drug product, e.g., interferon alpha, interferon beta, or interferon gamma, or an interleukin-containing drug product.
  • an interferon-containing drug product e.g., interferon alpha, interferon beta, or interferon gamma, or an interleukin-containing drug product.
  • the patient is administered one or more compounds of the present disclosure or a combination thereof in combination with an erythropoietin, a granulocyte colony- stimulating factor, or a bone morphogenetic protein.
  • the present disclosure includes administering one or more compounds of the present disclosure in combination with one or more of tocilizumab,
  • antihistamines include antihistamines, antipyretics, anti-inflammatory compounds, corticosteroids, glucocorticoids, TNF- inhibitors (e.g., etanercept), siltuximab, T cell-depleting antibody therapies such as alemtuzumab and antithymocyte globulins (ATG), IL-lR-based inhibitors (anakinra), ibrutinib and cyclophosphamide.
  • TNF- inhibitors e.g., etanercept
  • siltuximab T cell-depleting antibody therapies such as alemtuzumab and antithymocyte globulins (ATG), IL-lR-based inhibitors (anakinra), ibrutinib and cyclophosphamide.
  • Compounds according to the invention can be administered by any suitable method.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the provided composition is mixed with at least one inert, pharmaceutically acceptable excipient and/or fillers or extenders (e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid), binders (e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia), humectants (e.g., glycerol), disintegrating agents (e.g., agar, calcium carbonate, potato starch, tapioca starch, alginic acid, certain silicates, and sodium carbonate), solution retarding agents (e.g., paraffin), absorption accelerators (e.g., quaternary ammonium compounds), wetting agents (e.g., cetyl alcohol and glycerol monostearate), absorbents (e.g.,
  • Solid compositions of a similar type may be employed as fillers in soft and/or hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the provided composition(s) only in, or targeting, a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • capsules may contain an excipient formulation containing one or more of hydroxypropyl methylcellulose (HPMC), gelatin, and fish gelatin.
  • HPMC hydroxypropyl methylcellulose
  • the capsule may optionally further contain one or more of lycopene, ellagic acid (polyphenol), curcumin, piperine, delphinidin, resveratrol, isothiocyanates such as sulforaphane, capsaicin, and piperlongumine.
  • concentration of the agent into the bloodstream of the subject of at least about 2 pg/mL, at least about 4 pg/mL, at least about 5 pg/mL, at least about 10 pg/mL, at least about 20 pg/mL, up to about 80 pg/mL.
  • Certain embodiments can introduce a concentration of the agent into the bloodstream of the subject within a range of about 2 pg/mL to about 80 pg/mL, about 2 pg/mL to about 40 pg/mL, about 2 pg/mL to about 30 pg/mL, about 2 pg/mL to about 20 pg/mL, about 4 pg/mL to about 80 pg/mL, about 4 pg/mL to about 40 pg/mL, about 4 pg/mL to about 30 pg/mL, about 4 pg/mL to about 20 pg/mL, about 5 pg/mL to about 80 pg/mL, about 5 pg/mL to about 40 pg/mL, about 5 pg/mL to about 30 pg/mL, about 5 pg/mL to about 20 pg/mL, about 10 pg/mL to about 80 pg/
  • Embodiments of the invention also provide uses of the N-methylol transfer agents in the manufacture of an oral medicament to produce an efficacious serum or plasma level of the agent in the body. Also included are methods of treating a disease or introducing a pharmaceutical agent into the bloodstream of a subject, comprising oral administration of one or more of the oral compositions described above to the subject.
  • the disease can be a neoplastic disease.
  • the agent is an N-methylol transfer agent, such as Taurobdine, Taurultam, 1183B (cyclo- taurobdine), N-methylol taurinamide, l,3,-dimethylol-5,5-dimethylhydantoin, hexamethylene tetramine, or noxythiobn, N-methyltaurinamide, a substance which forms N-methylol taurinamide, or any combination thereof.
  • the agent is Taurobdine, Taurultam, or a combination thereof.
  • Embodiments of the invention provide use of an agent in the manufacture of a medicament for treating a disease, e.g., a neoplastic or infectious disease, wherein the medicament is formulated to provide release of the agent in the duodenum or jejunum of a patient or to release the agent at a pH of about 5.4 to about 6.5, e.g., about pH 5.5 or higher.
  • a disease e.g., a neoplastic or infectious disease
  • the medicament is formulated to provide release of the agent in the duodenum or jejunum of a patient or to release the agent at a pH of about 5.4 to about 6.5, e.g., about pH 5.5 or higher.
  • the agent is an N-methylol transfer agent such as Taurolidine, Taurultam, 1183B (cyclo-taurolidine), N-methylol taurinamide, l,3,-dimethylol-5,5-dimethylhydantoin, hexamethylene tetramine, or noxythiolin, N- methyltaurinamide, a substance which forms N-methylol taurinamide, or any combination thereof.
  • N-methylol transfer agent such as Taurolidine, Taurultam, 1183B (cyclo-taurolidine), N-methylol taurinamide, l,3,-dimethylol-5,5-dimethylhydantoin, hexamethylene tetramine, or noxythiolin, N- methyltaurinamide, a substance which forms N-methylol taurinamide, or any combination thereof.
  • FIG. 10 Further embodiments of the invention also provide a method of introducing an agent into a subject’s bloodstream, comprising orally administering the agent to the subject in combination with a pharmaceutically acceptable targeted release carrier, wherein, upon oral administration, the carrier (a) carries the agent through the subject’s stomach and releases the agent into the subject’s duodenum or jejunum so as to permit the agent to enter the subject’s bloodstream through the duodenum or jejunum, (b) releases the agent at a pH of about 5.4 to about 6.5, or (c) both.
  • a pharmaceutically acceptable targeted release carrier wherein, upon oral administration, the carrier (a) carries the agent through the subject’s stomach and releases the agent into the subject’s duodenum or jejunum so as to permit the agent to enter the subject’s bloodstream through the duodenum or jejunum, (b) releases the agent at a pH of about 5.4 to about 6.5, or (c) both.
  • Certain methods of this type employ a targeted release carrier which comprises an enteric coating. Certain methods use a targeted release carrier that releases said agent into said subject’s duodenum or jejunum (e.g., upper jejunum). Certain methods also employ an agent which is a N-methylol transfer agent, such as Taurolidine, Taurultam, 1183B (cyclo-taurolidine), N- methylol taurinamide or any combination thereof.
  • a targeted release carrier which comprises an enteric coating.
  • Certain methods use a targeted release carrier that releases said agent into said subject’s duodenum or jejunum (e.g., upper jejunum).
  • Certain methods also employ an agent which is a N-methylol transfer agent, such as Taurolidine, Taurultam, 1183B (cyclo-taurolidine), N- methylol taurinamide or any combination thereof.
  • the composition introduces a concentration of the agent into the bloodstream of the subject of at least about 2 pg/mL, at least about 4 pg/niL, at least about 5 pg/mL, at least about 10 pg/mL, at least about 20 pg/mL, up to about 80 pg/mL.
  • the composition may introduce a concentration of the agent into the bloodstream of said subject within a range of about 2 pg/mL to about 80 pg/mL, about 2 pg/mL to about 40 pg/mL, about 2 pg/mL to about 30 pg/mL, about 2 mg/nlL to about 20 gg/mL, about 4 gg/mL to about 80 gg/mL, about 4 gg/mL to about 40 gg/mL, about 4 gg/mL to about 30 gg/mL, about 4 gg/mL to about 20 gg/mL, about 5 gg/mL to about 80 gg/mL, about 5 gg/mL to about 40 gg/mL, about 5 gg/mL to about 30 gg/mL, about 5 gg/mL to about 20 gg/mL, about 10 gg/mL to about 80 gg/mL, about 10 gg/mL to about 40 gg/mL, about 10
  • compositions also provide oral compositions and uses thereof wherein the composition contains a corticosteroid.
  • exemplary compositions include combinations of an agent, e.g. an N-methylol transfer agent such as Taurolidine and/or Taurultam, and a corticosteroid.
  • compositions for introducing an agent into the bloodstream of a subject or of treating a disease comprising administering these compositions also are provided.
  • a compound of the present disclosure is provided in a composition at a concentration of about 0.01 to about 500 gg/ml. In some aspects, a compound of the present disclosure is provided in a composition at a concentration of about 0.1 to about 100 gg/ml. In some aspects, a compound of the present disclosure is provided in a composition at a concentration of about 10 to about 50 gg/ml.
  • a compound of the present disclosure is provided in a composition at a concentration of about 0.001 to about 5 wt. %, about 0.01 to about 3.5 wt.%, about 0.1 to about 3 wt.%, about 0.5 to about 2.5 wt.%, or about 1 to about 2 wt.% . In some aspects, a compound of the present disclosure is provided in a composition at a concentration of about 0.01 to about 1.5%. In some aspects, a compound of the present disclosure is provided in a composition at a concentration of about 0.1% to about 1%.
  • a compound of the present disclosure is provided in a composition at a concentration of about 100 to about 5000 gM, about 250 to about 2500 gM, about 500 to about 2000 gM, about 750 to about 1500 gM, about 1000 to about 1250 gM, or any other concentration within the recited ranges.
  • a compound of the present disclosure is provided in a composition in a unit dosage form.
  • a“unit dosage form” is a composition containing an amount of a compound of the present disclosure that is suitable for administration to an animal, such as a mammal, e.g., a human subject, in a single dose, according to a good medical practice.
  • These compositions may contain from about 0.1 mg (milligrams) to about 500 mg, for example from about 5 mg to about 350 mg of a compound of the present disclosure.
  • the frequency of treatment with the composition of the invention may be changed to achieve and maintain the desired target plasma level.
  • treatment schedules include daily, twice daily, three times daily, weekly, biweekly, monthly, and combinations thereof.
  • the composition of the invention may also be administered as a continuous infusion.
  • one or more compounds of the present disclosure are administered to a subject prior to administration of a therapeutic that is expected to lead to cytokine release in the subject.
  • the one or more compounds of the present disclosure are administered about 12 to 96, e.g., 24, 48 or 72, hours prior to administration of a therapeutic that is expected to lead to cytokine release in the subject.
  • the one or more compounds of the present disclosure are administered in one or multiple doses prior to administration of a therapeutic that is expected to lead to cytokine release in the subject.
  • one or more compounds of the present disclosure are administered to a subject concurrently with a therapeutic that is expected to lead to cytokine release in the subject.
  • a compound of the present disclosure is administered to the subject within about 1 to about 24 hours, about 2 to about 18 hours, about 6 to about 15 hours, about 4 to about 12 hours, or any range of time in the disclosed ranges after administration to the subject of a therapeutic that is expected to lead to cytokine release in the subject.
  • one or more compounds of the present disclosure are administered according to a regimen during a period when CRS or cytokine storm is expected to occur.
  • the one or more compounds of the present disclosure are administered daily, every other day, biweekly, or weekly for a 3 to 10 week period, a 4 to 8 week period, or a 4 to 6 week period, before, during, and/or after administration of a therapeutic that is expected to lead to cytokine release in the subject, e.g., a T-cell engaging therapy.
  • one or more compounds of the present disclosure prophy tactically prior to initiation of the therapy.
  • CRS or cytokine storm from bispecific antibody therapy is often observed within minutes to hours of administration of the bispecific antibody and thus it is particularly advantageous to administer the cytokine release- inhibiting compounds of the present disclosure prior to administration of the bispecific antibody therapy.
  • a compound of the present disclosure is provided in a composition and is administered to a subject in need thereof at a total daily dosage may be about 0.001 g to about 1000 g, e.g., about 0.01 g to about 500 g, 0.1 to 300 g, 0.5 to 200 g, 1 g to 100 g, or any amount within the recited range.
  • the daily dosage may be administered in the form of an orally
  • the daily dosage may be administered in the form of a capsule, a tablet, or a pharmaceutically acceptable solution.
  • the daily dosage may be administered in a form that contains compounds of the present disclosure, e.g., taurolidine, at a concentration of about 0.01 to about 3% w/v.
  • the daily dosage may be administered in a form that contains compound taurolidine at a concentration of about 0.01 pg/ml to about 1000 pg/ml.
  • the daily dosage may be administered in a form that contains one or more solubilizing agents, e.g., polyols.
  • Effective dosage amounts of a compound of the present disclosure are provided in a composition may include dosage units containing about 0.01-500 mg/kg, about 1-100 mg/kg per day, or about 5-50 mg/kg per day of the compound of the present disclosure. In some aspects, dosage units are administered every other day, biweekly, or weekly.
  • the specific effective dose for any particular patient will depend on a variety of factors including the severity or likelihood of the cytokine release, cytokine release syndrome (CRS) or cytokine storm; activity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the preparation of the specific compound; the time and route of administration; the duration of administration; therapeutic agents used in combination or coinciding with the specific compound employed; and like factors known in the medical arts.
  • the effective dose may also change over time as the cytokine release syndromes or storms worsen or improve. For chronic conditions, subjects may receive effective doses for a plurality of days, weeks, or months. The number of and frequency of administrations or co-administrations may vary depending upon the likelihood or severity of the cytokine release, CRS and cytokine storm, and the patient specific response to the particular compound administered and/or the second therapeutically active agent administered.
  • PBMCs peripheral blood mononuclear cells
  • LPS Lipopolysaccharide
  • Cryopreserved PBMCs from five healthy human donors were thawed and cultured in RPMI 1640 medium (Gibco RPMI-1640 Medium (ATCC, Catalog #30-2001) supplemented with 10% FCS, 2 mM L-glutamine, 100 IU/mL penicillin, 100 pg/mL streptomycin, 1 mM sodium pyruvate (all from ThermoFisher) with viability >85% as determined automated cell counter (Countess II FL Automated Cell Counter; ThermoFisher; Catalog #AMQAF1000) prior to experiments.
  • RPMI 1640 medium Gibco RPMI-1640 Medium (ATCC, Catalog #30-2001) supplemented with 10% FCS, 2 mM L-glutamine, 100 IU/mL penicillin, 100 pg/mL streptomycin, 1 mM sodium pyruvate (all from ThermoFisher) with viability >85% as determined automated cell counter (Countess
  • a 73 mM stock was prepared by adding 208 mg Taurolidine into 10 mL 5% polyvinyl pyrrolidone (PVP) in water and heating to 60°C and then cooling to 20°C and adjusting the pH to 7.6. Prior to use in the assay, the pH of the solution was adjusted to 7.0. 100 m ⁇ of PBMCs at 1.0 x 10 7 cells/mL were washed and re-suspended in tissue culture medium containing a fixed concentration (1 ng/ml) of LPS from E. coli, serotype 0111 :B4. LPS stimulation was performed for 48 hours at 37°C, 5% CO2 prior to harvesting tissue culture supernatant for cytokine analysis. Taurolidine was used at 200, 400, and 800 mM concentrations.
  • PVP polyvinyl pyrrolidone
  • FIG. 1A results for IL-Ib, IL-6, and TNF-a are summarized in FIGs. 1A, IB, and 1C.
  • FIG. 1A results for IL-Ib, IL-6, and TNF-a are summarized in FIGs. 1A, IB, and 1C.
  • FIG. 1A shows LPS Simulated Human PBMC at 48 hours, IL-I b (LLD 0.62 pg/ml; ULD 15,228 pg/ml).
  • FIG. IB shows LPS Simulated Human PBMC at 48 hours, IL-6 (LLD 1.0 pg/ml; ULD 19,360 pg/ml).
  • FIG. 1C shows LPS Simulated Human PBMC at 48 hours, TNF- a (LLD 0.39 pg/ml; ULD 10,000 pg/ml).
  • Each symbol represents the mean value of triplicate analysis of a single donor.
  • Each bar per treatment group represents the mean value of all donors where the triplicate value of each donor is averaged.
  • Human CD 19 specific CAR-T effector cells from a donor were co-cultured with Raji, a human CD 19 expressing target B cell line at different effector to target cell ratios of 5: 1, 10: 1, and 20: 1 in the presence of Taurolidine.
  • Co-culture was performed for 6 hours or 24 hours at 37°C, 5% CO2 prior to harvesting cells for CAR-T mediated target cell lysis or tissue culture supernatant for cytokine analysis.
  • Taurolidine was used at 200, 400, and 800 mM concentrations and was allowed to pre-incubate with CAR-T cells prior to addition of tumor target cells.
  • FIGs. 2A-2C show the results of CD 19 CAR-T co-culture assay with CD- 19 tumor cells (Raji) at 6 hours, CAR-T mediated tumor target cell in the present of increasing concentrations of Taurolidineare shown (E:T ratios of 5: 1, 10: 1, and 20: 1 are shown in FIGs. 2A, 2B, and 2C, respectively).
  • FIGs. 3A-3C show the results of CD19 CAR-T co-culture assay with CD-19 tumor cells (Raji) at 24 hours, CAR-T mediated tumor target cell in the present of increasing
  • FIG. 4 shows that Taurolidinereduces CD19 CAR-T cell mediated IL-2 cytokine release across different effector to target ratios.
  • FIG. 5 shows that Taurolidinereduces CD 19 CAR-T cell mediated TNF-a cytokine release across different effector to target ratios.
  • FIG. 6 shows that Taurolidinereduces CD 19 CAR-T cell mediated IFN-y cytokine release across different effector to target ratios.
  • Taurolidinedoes not abrograte CD 19 CAR-T mediated CD19 + tumor target cell cytotoxicity at different effector to target cell ratios at 6 hours or 24 hours. Taurolidineshuts down cytokine release (including IL-Ib, IL-6, TNF-a, and IFN-y cytokines).
  • Co-culture was performed for 24 hours at 37°C, 5% CO2, prior to harvesting cells or tissue culture supernatant for analysis.
  • Taurolidine was used at 200, 400, and 800 mM concentrations and was allowed to pre-incubate with T cells prior to addition of BLINCYTO®.
  • FIG. 7 shows that BLINCYTO® increased target cell cytotoxicity in Ramos cells of all tested donors.
  • FIG. 8 shows that Taurolidinedid not reduce BLINCYTO® mediated CD 19 + tumor target cell cytotoxicity.
  • FIG. 9A shows the effect of BLINCYTO® on IL-Ib cytokine release in the tested donors.
  • FIG. 9B shows that Taurolidine reduced BLINCYTO® T-cell mediated IL-Ib cytokine release in the tested donors.
  • FIG. 10A shows the effect of BLINCYTO® on IL-2 cytokine release in the tested donors.
  • FIG. 10B shows that Taurolidine reduced BLINCYTO® T-cell mediated IL-2 cytokine release in the tested donors.
  • FIG. 11A shows the effect of BLINCYTO® on IL-6 cytokine release in the tested donors.
  • FIG. 1 IB shows that Taurolidine reduced BLINCYTO® T-cell mediated IL-6 cytokine release in the tested donors.
  • FIG. 12A shows the effect of BLINCYTO® on TNF-a cytokine release in the tested donors.
  • FIG. 12B shows that Taurolidine reduced BLINCYTO® T-cell mediated TNF-a cytokine release in the tested donors.
  • FIG. 13A shows the effect of BLINCYTO® on IFN-g cytokine release in the tested donors.
  • FIG. 13B shows that Taurolidine reduced BLINCYTO® T-cell mediated IFN-g cytokine release in the tested donors.
  • FIG. 14 shows that Taurolidine increased tumor target cytotoxicity in the absence of BLINCYTO®.

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Abstract

L'invention concerne une méthode de prévention, d'inhibition ou de réduction de la libération de cytokine et de l'incidence d'un syndrome de libération de cytokine (CRS) ou d'une hypercytokinémie chez un sujet au moyen de certains agents de transfert de type N-méthylol et/ou des composés apparentés.
PCT/IB2020/054858 2019-05-22 2020-05-21 Méthode de traitement, de prévention, d'inhibition ou de réduction de la libération de cytokine WO2020234833A1 (fr)

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