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WO2023230593A1 - Inhibiteurs de ptp1b pour traitement d'une lésion pulmonaire - Google Patents

Inhibiteurs de ptp1b pour traitement d'une lésion pulmonaire Download PDF

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Publication number
WO2023230593A1
WO2023230593A1 PCT/US2023/067530 US2023067530W WO2023230593A1 WO 2023230593 A1 WO2023230593 A1 WO 2023230593A1 US 2023067530 W US2023067530 W US 2023067530W WO 2023230593 A1 WO2023230593 A1 WO 2023230593A1
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Prior art keywords
lung injury
msi
pharmaceutically acceptable
acceptable salt
ptp1b inhibitor
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Nicholas Tonks
Dongyan Song
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Cold Spring Harbor Laboratory
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Cold Spring Harbor Laboratory
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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

  • This disclosure relates to Protein-Tyrosine Phosphatase IB (PTP1B) inhibitors and their use in treating lung injury. More specifically, in aspects this disclosure relates to the use of PTP1B inhibitors to treat acute lung injury, such as, antibody-induced lung injury. Even more specifically, in aspects this disclosure relates to the use of PTP1B inhibitors to treat Acute Respiratory Distress Syndromes, including those induced in Coronavirus disease 2019 (COVID- 19).
  • PTP1B Protein-Tyrosine Phosphatase IB
  • ARDS Acute Respiratory Distress Syndrome
  • TRALI Transfusion-Related Acute Lung Injury
  • SARS-CoV-2 Severe Acute Respiratory Syndrome CoronaVirus 2
  • a method of treating lung injury in a subject in need thereof including administering a PTP1B inhibitor to the subject.
  • the lung injury includes one or more of acute lung injury, antibody-induced acute lung injury, acute lung injury associated with inflammation, ARDS, lung injury resulting from sepsis, lung injury resulting from SARS-CoV-2 infection, lung injury resulting from COVID-19, and lung injury resulting from WHIM syndrome.
  • the PTP1B inhibitor is MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof.
  • the PTP1B inhibitor is administered from one to two times a day.
  • administering is accomplished via a route selected from oral, buccal, sublingual, rectal, topical, intranasal, vaginal, or parenteral administration.
  • a method of prophylactically inhibiting symptoms of lung injury in a subject at risk of developing lung injury including administering a PTP1B inhibitor to the subject.
  • the subject is at risk of developing symptoms of lung injury associated with one or more of acute lung injury, antibody-induced acute lung injury, acute lung injury associated with inflammation, ARDS, lung injury resulting from sepsis, lung injury resulting from SARS-CoV-2 infection, lung injury resulting from COVID-19, and lung injury resulting from WHIM syndrome.
  • the PTP1B inhibitor is MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof.
  • the PTP1B inhibitor is administered from one to two times a day.
  • administering is accomplished via a route selected from oral, buccal, sublingual, rectal, topical, intranasal, vaginal, or parenteral administration.
  • a pharmaceutical composition including a PTP1B inhibitor and a carrier, wherein the PTP1B inhibitor is present in an amount sufficient to reduce lung injury in a subject or inhibit symptoms of lung injury in a subject at risk of developing lung injury.
  • the PTP1B inhibitor is MST-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof.
  • the carrier permits administration of the pharmaceutical composition via a route selected from oral, buccal, sublingual, rectal, topical, intranasal, vaginal, or parenteral administration.
  • a method of treating lung injury in a subject in need thereof including administering a PTP1B inhibitor to the subject, wherein the lung injury is at least one of acute lung injury, antibody -induced acute lung injury, acute lung injury associated with inflammation, ARDS, lung injury resulting from sepsis, lung injury resulting from SARS- CoV-2 infection, lung injury resulting from COVID- 19, or lung injury resulting from WHIM syndrome and the PTP1B inhibitor is MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof.
  • the lung injury includes acute lung injury.
  • the lung injury includes antibody-induced acute lung injury.
  • the lung injury includes acute lung injury associated with inflammation.
  • the lung injury includes ARDS. In another example, the lung injury includes lung injury resulting from sepsis. In a further example, the lung injury includes lung injury resulting from SARS- CoV-2 infection. In still a further example, the lung injury results from WHIM syndrome. In another example, the lung injury includes lung injury resulting from sepsis. In still a further example, the lung injury includes lung injury resulting from COVID-19.
  • the lung injury includes acute lung injury and the PTP1B inhibitor is MSI-1436 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes acute lung injury and the PTP1B inhibitor is DPM-1003 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes antibody-induced acute lung injury and the PTP1B inhibitor is MSI-1436 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes antibody-induced acute lung injury and the PTP1B inhibitor is DPM-1003 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes acute lung injury associated with inflammation and the PTP1B inhibitor is MSI-1436 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes acute lung injury associated with inflammation and the PTP1B inhibitor is DPM-1003 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes ARDS and the PTP1B inhibitor is MSI-1436 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes ARDS and the PTP1B inhibitor is DPM-1003 or a pharm ceutically acceptable salt thereof.
  • the lung injury includes lung injury resulting from SARS-CoV-2 infection and the PTP1B inhibitor is MSI-1436 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes lung injury resulting from SARS-CoV-2 infection and the PTP1B inhibitor is DPM- 1003 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes lung injury resulting from sepsis and the PTP1B inhibitor is MSI-1436 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes lung injury resulting from sepsis and the PTP1B inhibitor is DPM-1003 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes lung injury resulting from COVID- 19 and the PTP1B inhibitor is MSI-1436 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes lung injury resulting from COVID- 19 and the PTP1B inhibitor is DPM-1003 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes lung injury resulting from WHIM syndrome and the PTP1B inhibitor is MSI-1436 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes lung injury resulting from WHIM syndrome and the PTP1B inhibitor is DPM-1003 or a pharmaceutically acceptable salt thereof.
  • a method of prophylactically inhibiting symptoms of lung injury in a subject at risk of developing lung injury including administering a PTP1B inhibitor to the subject, wherein the subject is at risk of developing symptoms of lung injury associated with one or more of acute lung injury, antibody-induced acute lung injury, acute lung injury associated with inflammation, ARDS, lung injury resulting from sepsis, lung injury resulting from SARS-CoV-2 infection, lung injury resulting from COVID- 19, and lung injury associated with WHIM syndrome and the PTP1B inhibitor is MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof.
  • the lung injury includes acute lung injury.
  • the lung injury includes antibody-induced acute lung injury.
  • the lung injury includes acute lung injury associated with inflammation.
  • the lung injury includes ARDS.
  • the lung injury includes lung injury resulting from sepsis.
  • the lung injury includes lung injury resulting from SARS-CoV-2 infection.
  • the lung injury includes lung injury resulting from sepsis.
  • the lung injury includes lung injury resulting from COVTD-19.
  • the lung injury includes lung injury resulting from WHIM syndrome.
  • the lung injury includes acute lung injury and the PTP1B inhibitor is MSI-1436 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes acute lung injury and the PTP1B inhibitor is DPM-1003 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes antibody-induced acute lung injury and the PTP1B inhibitor is MSI-1436 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes antibody-induced acute lung injury and the PTP1B inhibitor is DPM-1003 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes acute lung injury associated with inflammation and the PTP1B inhibitor is MSI-1436 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes acute lung injury associated with inflammation and the PTP1B inhibitor is DPM-1003 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes ARDS and the PTP1B inhibitor is MSI-1436 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes ARDS and the PTP1B inhibitor is DPM-1003 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes lung injury resulting from SARS-CoV-2 infection and the PTP1B inhibitor is MSI-1436 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes lung injury resulting from SARS-CoV-2 infection and the PTP1B inhibitor is DPM- 1003 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes lung injury resulting from sepsis and the PTP1B inhibitor is MSI-1436 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes lung injury resulting from sepsis and the PTP1B inhibitor is DPM-1003 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes lung injury resulting from COVID- 19 and the PTPIB inhibitor is MSI-1436 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes lung injury resulting from COVID- 19 and the PTPIB inhibitor is DPM-1003 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes lung injury resulting from WHIM syndrome and the PTPIB inhibitor is MSI-1436 or a pharmaceutically acceptable salt thereof.
  • the lung injury includes lung injury resulting from WHIM syndrome and the PTPIB inhibitor is DPM-1003 or a pharmaceutically acceptable salt thereof.
  • PTP1B inhibitors attenuate CXCR4 signaling and induce an aged neutrophil phenotype to protect against lethality in a mouse model of acute lung injury.
  • PTP1B inhibitors are used in accordance with methods of the present disclosure to attenuate lung injury and increase survival in a classical Transfusion-Related Acute Lung Injury (TRALI) model.
  • Treatment with PTP1B inhibitors in accordance with the present disclosure also attenuates neutrophil function, associated with release of myeloperoxidase, suppression of Neutrophil Extracellular Trap (NET) formation, and inhibition of neutrophil migration.
  • NET Neutrophil Extracellular Trap
  • PTP1B inhibition promotes an aged neutrophil phenotype.
  • FIG.s 1A-1P show PTP1B inhibitors improved survival and ameliorated lung damage in the TRALI mouse model.
  • A Schematic illustration of the TRALI induction and PTP1B inhibition protocol.
  • B The structural formulae of PTP1B inhibitor MSI- 1436.
  • E The structural formulae of PTP1B inhibitor DPM-1003.
  • FIG. 1 Top panel: representative images of H&E-stained lung tissue from no treatment mice (NT), and TRALI mice after administering saline, MSI-14362 mg/kg, or MSL 1436 10 mg/kg. Arrows indicate alveolar damage. Asterisks indicate edema or hyaline membranes. Scale bars: 25pm. Magnification: 40x.
  • BALF bronchoalveolar lavage fluid
  • Q Representative H&E staining images of lung tissues harvested from mice treated with saline only, saline 2 hours prior to LPS, and MSI-1436 2 hours prior to LPS administration.
  • FIGs. 2A-2M show Treatment with PTP1B inhibitors in vivo induced neutrophilia.
  • B The gating strategy used to identify the nine immune cell populations from the single cell suspension of lung tissue.
  • C The percentages of WBC subsets measured in the circulating blood collected from either NT or TRALI mice.
  • G, H Cytokine arrays generated from serum (G) or lung tissue (H) collected from NT or TRALI mice treated with saline or MSI-1436. Each group contained an equal amount of serum or lung tissue homogenate pooled from 5 mice.
  • FIGs. 3A-3F show Treatment with MSI-1436 in vivo induced an aged neutrophil phenotype.
  • A Reactome pathway analysis performed using g:Profiler for genes up-regulated upon MSI-1436 treatment.
  • D The flow cytometry analysis of MPO in the neutrophils following treatment with saline or DPM-1003 for 2.5 hours. MPO was quantified by MFI. Statistical analysis by two- tailed student’s t-test; *p ⁇ 0.05, **p ⁇ 0.01.
  • FIGs. 4A-4F show Treatment with MSI-1436 suppressed NET formation ex vivo and in vivo.
  • FIGs. 5A-5K show PTP1B inhibitors attenuated PI3Kg-mediated CXCR4 signaling.
  • C Immunoblot analyses showing the effect of MSI-1436 on CXCR4 signaling upon CXCL12 stimulation from primary neutrophils isolated from bone marrow. Representative immunoblot of four independent experiments.
  • D Immunoblot analyses of DPM-1003 treated neutrophils showing dose-dependent inhibitions of CXCR4-mediated AKT signaling.
  • E Immunoblot analyses showing the AKT signaling in response to PI3K isoform specific inhibitors in HeLa, HL-60, and mouse neutrophils.
  • Inhibitors used a-specific (HS-173, IpM); b-specific (GSK2636771, lOpM); d-specific (Nemiralisib, 100 nM); g-specific (Eganelisib, 200nM); pretreated 1 hour before CXCL12 stimulation. Representative immunoblot of three independent experiments.
  • F Immunoblot analyses showing the impact of pretreatment with MSI-1436 on AKT signaling in HeLa, HL-60 and mouse primary neutrophils.
  • FIGs. 6A-6H show the effect of mTOR inhibitor on the survival of TRALI model and induction of aged neutrophil phenotype.
  • D Immunoblot analyses showing the effect of P529 on mTOR signaling upon CXCL12 stimulation from primary neutrophils isolated from bone marrow.
  • PTP1B the prototypic protein tyrosine phosphatase (PTP) plays a role in down-regulating insulin and leptin signaling and is a validated therapeutic target for diabetes and obesity.
  • PTP IB also plays a positive role in promoting signaling events associated with HER2-induced breast tumorigenesis and has been validated as a target in cancer.
  • MSL1436 prototypic allosteric inhibitors have been identified and validated with improved drug-like properties.
  • PTP1B also serves an important regulatory function in immunity and host defense. It has now been found that in accordance with the presently disclosed methods PTP1B inhibitors provide a mechanism to address COVID- 19 acute lung injury and ARDS.
  • PTP1B inhibitors With respect to an anti-inflammatory effect of PTP1B inhibitors, deletion of PTP1B protects against cardiovascular inflammation associated with septic shock, inhibition of PTP1B induces M2 macrophage polarization and a potential anti-inflammatory effect, PTP1B has been suggested to be a therapeutic target for neuroinflammatory diseases, and PTP1B deficiency protects against hepatic fibrosis.
  • PTPIB-deficient mice clear P. aeruginosa more efficiently from their lungs than wild type mice; however, this effect is associated with increased cytokine production.
  • PTPIB-deficient neutrophils display enhanced bacterial phagocytosis and killing, with increased TLR4 signaling.
  • These studies make use of PTP1B knockout animals in which expression of the phosphatase is abrogated throughout their development and do not necessarily correlate to a situation, such as in COVID-19, where a short dose of PTP1B inhibitor is administered.
  • advanced COVID 19 patients already have high levels of cytokines, such as IL6, and one target of PTP1B is the JAK family of protein tyrosine kinases that transduce the signaling response of cytokine receptors.
  • a function of PTP1B is to attenuate JAK activity, such as in the context of leptin receptor signaling. Consequently, the possibility that a PTP1B inhibitor would activate JAKs further under hyperinflammatory conditions must also be considered. Therefore, in accordance with aspects of the present disclosure a suitable model of ARDS has been developed to test the impact of PTP1B inhibitors.
  • WHIM syndrome warts, hypogamma-globulinemia, infections, and myelokathexis
  • a rare immunodeficiency disorder arises from gain-of-function mutations of CXCR4 (Hernandez et al., 2003; Gulino et al., 2004).
  • Patients display greater than normal susceptibility to life-threatening infections.
  • WHIM syndrome involves panleukopenia, which underlies the increased susceptibility to bacterial and viral infection.
  • myelokathexis resulting from neutrophil retention in bone marrow, leads to neutropenia.
  • PTP1B inhibitors As disclosed herein, administrating a PTP1B inhibitors effectively increases the number of neutrophils in the peripheral blood by approximately threefold and inhibits CXCR4 signaling (Song et al, 2022).
  • PTP1B inhibitor administration attenuates aberrant neutrophil function that drives Acute Lung Injury and was associated with release of myeloperoxidase, suppression of Neutrophil Extracellular Trap (NET) formation, and inhibition of neutrophil migration.
  • NET Neutrophil Extracellular Trap
  • reduced signaling through the CXCR4 chemokine receptor for example to the activation of PI3Ky/AKT/mTOR, may be involved in PTP1B inhibition to promoting an aged-neutrophil phenotype, without being limited to any particular mechanism of action.
  • ALT acute lung injury
  • ALT remains a significant source of morbidity and mortality in critically ill patient populations. Defined by a constellation of clinical criteria (acute onset of bilateral pulmonary infiltrates with hypoxemia without evidence of hydrostatic pulmonary edema), ALT has a high incidence (200,000 per year in the US) and overall mortality remains high.
  • ALT is a disorder of acute inflammation that causes disruption of the lung endothelial and epithelial barriers.
  • the alveolar-capillary membrane includes the microvascular endothelium, interstitium, and alveolar epithelium.
  • Cellular characteristics of ALT include loss of alveolar-capillary membrane integrity, excessive transepithelial neutrophil migration, and release of pro-inflammatory, cytotoxic mediators.
  • Biomarkers found on the epithelium and endothelium and that are involved in the inflammatory and coagulation cascades predict morbidity and mortality in ALT include those presented in Table 1.
  • acute lung injury means acute hypoxemic respiratory failure with bilateral pulmonary infdtrates that is associated with both pulmonary and nonpulmonary risk factors and that is not primarily due to left atrial hypertension.
  • ARDS is a subtype of acute lung injury characterized by more severe hypoxemia.
  • the acute lung injury may be evidenced by the development of microvascular thrombi; in embodiments, the acute lung injury may be evidenced by hyaline membrane formation; in embodiments, the acute lung injury may be evidenced by injury of the alveolar epithelium and endothelium; in embodiments, the acute lung injury is evidenced by neutrophilic alveolitis; in embodiments, the acute lung injury is associated with inflammation; in embodiments, the acute lung injury is associated with sepsis; in embodiments, the acute lung injury is associated with ARDS; in embodiments the acute lung injury is associated with SARS- CoV-2 infection; in embodiments, the acute lung injury is associated with COVID-19.
  • acute lung injury is characterized by one or more symptoms including pulmonary edema, sepsis, mi crovascul ar thrombi, hyaline membrane formation, or neutrophilic alveolitis.
  • Any PTP1B inhibitor that provides a therapeutic benefit with respect to lung injury may be employed in accordance with the present disclosure. Suitable PTP1B inhibitors include, but are not limited to, MSI-1436 and DPM-1003.
  • MSI-1436 is:
  • DPM-1003 The structure of DPM-1003 is:
  • PTP1B inhibitors are known to skilled persons and could be used in place of one or both of MSI-1436 and DPM-1003 for all methods, uses, purposes, treatments, and clinical and other indications disclosed throughout this application, without restriction or limitation, and all such PTP1B inhibitors are hereby explicitly included in this disclosure for all such purposes.
  • References disclosing other such PTP1B inhibitors include, without limitation, U.S. Patent Number 9,365,608, U.S. Patent Number 9,546, 194, U.S. Patent Number 10,556,923, U.S Patent Application Publication Number 2020/0376006 Al , the entire contents of all of which are hereby incorporated by reference in their entireties.
  • a non-limiting, non-exhaustive, listing of illustrative examples of such PTP1B inhibitors includes MSI 1241, MSI 1255, MSI 1256, MSI 1271, MSI 1272, MSI 1303, MSI 1304, MSI 1317, MSI 1320, MSI 1321, MSI 1322, MSI 1336, MSI 1352, MSI 1370, MSI 1371, MSI 1409, MSI 1413, MSI 1431, MSI 1432, MSI 1433, MSI 1436, MSI 1437, MSI 1448, MSI 1459, MSI 1466, MSI 1469, MSI 1470, MSI 1486, MSI 1487, MSI 1520, MSI 1521, MSI 1561,
  • MSI 2550 MSI 2551, MSI 2552, MSI 2553, MSI 2554, MSI 2555, MSI 2556, MSI 2557,
  • a non-limiting, non-exhaustive, listing of illustrative examples of such PTP1B inhibitors includes salts thereof.
  • MSI-1436 or DPM-1003 may be provided as an acid addition salt, a zwitter ion hydrate, zwitter ion anhydrate, hydrochloride or hydrobromide salt, or in the form of the zwitter ion monohydrate.
  • Acid addition salts include but are not limited to, maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, pantothenic, p-amino-benzoic, glutamic, benzene sulfonic or theophylline acetic acid addition salts, as well as the 8-halotheophyllines, for example 8-bromo-theophylline.
  • inorganic acid addition salts including but not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric or nitric acid addition salts
  • An effective amount of MSI-1436 or DPM-1003, or a respective pharmaceutically acceptable salt thereof for treatment of acute lung injury herein may advantageously be devoid of or exhibits less unwanted side-effects.
  • an effective amount of MSI-1436 or DPM-1003, or a respective pharmaceutically acceptable salt thereof for treatment of lung injury is surprisingly effective despite the increase in the number of neutrophils induced by administration of the PTP1B inhibitor.
  • the terms “effective amount” or “therapeutically effective amount” may be used interchangeably and refer to an amount of a compound, material, composition, medicament, or other material that is effective to achieve reduction, elimination or prophylaxis of acute lung injury.
  • a pharmaceutical composition including an effective amount of a PTP1B inhibitor such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof may contain from about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 100 mg to about 105 mg, about 105 mg to about 110 mg, about 110 mg to about 115 mg, about 115 mg to about 120 mg, about 120 mg to about 125 mg, about 125 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 300
  • a pharmaceutical composition containing an effective amount of a PTP1B inhibitor such as, for example MSI- 1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof includes 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg
  • Amounts below about 20 mg of a PTP1B inhibitor, such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof are less effective at relieving or eliminating acute lung injury than amounts in the effective range.
  • Amounts above about 125 mg of a PTP1B inhibitor, such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof may exhibit increased side effects than amounts in the effective range.
  • a PTP1B inhibitor such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof is administered to a subject at about 25 mg/per day, 30 mg/per day, 35 mg/per day, 40 mg/per day, 45 mg/per day, 50 mg/per day, 60 mg/per day, 65 mg/per day, 70 mg/per day, 75 mg/per day, 80 mg/per day, 85 mg/per day, 90 mg/per day, 95 mg/per day, 100 mg/per day, 105 mg/per day, 110 mg/per day, 115 mg/per day, 120 mg/per day, 125 mg/per day, 130 mg/per day, 135 mg/per day, 140 mg/per day, 145 mg/per day, 150 mg/per day, 155 mg/per day, 160 mg/per day, 165 mg/per day, 170 mg/per day, 175 mg/per day, 180 mg/per day, 185 mg/per day, 190 mg/per day,
  • a PTP1B inhibitor such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof is administered to a subject experiencing symptoms of acute lung injury via a pharmaceutical composition.
  • Pharmaceutical compositions herein encompass dosage forms. Dosage forms herein encompass unit doses. In embodiments, as discussed below, various dosage forms including conventional formulations and modified release formulations can be administered one or more times daily.
  • a PTP1B inhibitor such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof is administered to a subject once or twice a day, (e.g., morning and/or evening).
  • a PTP1B inhibitor such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof is administered to a subject at the start of an acute lung injury episode, whenever that may occur.
  • Any suitable route of administration may be utilized, e.g., oral, rectal, nasal, pulmonary, vaginal, sublingual, transdermal, intravenous, intraarterial, intramuscular, intraperitoneal and subcutaneous routes.
  • Suitable dosage forms include tablets, capsules, oral liquids, powders, aerosols, transdermal modalities such as topical liquids, patches, creams and ointments, parenteral formulations and suppositories.
  • a PTPlB inhibitor such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof is used to manufacture a medicament for treatment of acute lung injury.
  • methods of treating acute lung injury include administering to a subject in need thereof a pharmaceutical composition including a PTP1B inhibitor, such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof wherein the composition provides improvement in symptoms of acute lung injury for more than 1 hour after administration to the subject.
  • methods of treating acute lung injury include administering to a subject in need thereof a pharmaceutical composition including a PTP1B inhibitor, such as, for example MSI-1436, DPM- 1003, or a respective pharmaceutically acceptable salt thereof wherein the composition provides improvement in symptoms of acute lung injury for more than 2 hours after administration to the subject.
  • methods of treating acute lung injury are provided which include administering to a subject in need thereof a pharmaceutical composition including a PTP1B inhibitor, such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof wherein the composition provides improvement in symptoms of acute lung injury for more than 3 hours after administration to the subject.
  • methods of treating acute lung injury include administering to a subject in need thereof a pharmaceutical composition including a PTP1B inhibitor, such as, for example MSI-1436, DPM- 1003, or a respective pharmaceutically acceptable salt thereof wherein the composition provides improvement in symptoms of acute lung injury for more than 4 hours after administration to the subject.
  • methods of treating acute lung injury are provided which include administering to a subject in need thereof a pharmaceutical composition including a PTP1B inhibitor, such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof wherein the composition provides improvement in symptoms of acute lung injury for more than 6 hours after administration to the subject.
  • methods of treating acute lung injury include administering to a subject in need thereof a pharmaceutical composition including a PTP1B inhibitor, such as, for example MSI-1436, DPM- 1003, or a respective pharmaceutically acceptable salt thereof wherein the composition provides improvement in symptoms of acute lung injury for more than 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration to the subject.
  • the pharmaceutical compositions provide improvement of next day functioning of the subject having acute lung injury.
  • the pharmaceutical compositions may provide improvement in symptoms of acute lung injury for more than about, e.g., 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours after administration and waking from a night of sleep.
  • methods of treating antibody induced acute lung injury include administering to a subject in need thereof a pharmaceutical composition including a PTPlB inhibitor, such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of antibody induced acute lung injury for more than 1 hour after administration to the subject.
  • methods of treating antibody induced acute lung injury are provided which include administering to a subject in need thereof a pharmaceutical composition including (a PTP1B inhibitor, such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of antibody induced acute lung injury for more than 2 hours after administration to the subject.
  • methods of treating antibody induced acute lung injury include administering to a subject in need thereof a pharmaceutical composition including a PTP1B inhibitor, such as, for example MSI-1436, DPM- 1003, or a respective pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of antibody induced acute lung injury for more than 3 hours after administration to the subject.
  • methods of treating antibody induced acute lung injury are provided which include administering to a subject in need thereof a pharmaceutical composition including a PTP1B inhibitor, such as, for example MSI-1436, DPM- 1003, or a respective pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of antibody induced acute lung injury for more than 4 hours after administration to the subject.
  • methods of treating antibody induced acute lung injury include administering to a subject in need thereof a pharmaceutical composition including a PTP1B inhibitor, such as, for example MSI-1436, DPM- 1003, or a respective pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of antibody induced acute lung injury for more than 6 hours after administration to the subject.
  • a PTP1B inhibitor such as, for example MSI-1436, DPM- 1003, or a respective pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of antibody induced acute lung injury for more than 6 hours after administration to the subject.
  • methods of treating antibody induced acute lung injury include administering to a subject in need thereof a pharmaceutical composition including a PTP1B inhibitor, such as, for example MSI-1436, DPM- 1003, or a respective pharmaceutically acceptable salt thereof wherein the composition provides improvement in one or more symptoms of antibody induced acute lung injury for more than 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration to the subject.
  • the pharmaceutical compositions provide improvement of next day functioning of the subject experiencing antibody induced acute lung injury.
  • the pharmaceutical compositions may provide improvement in one or more symptoms of antibody induced acute lung injury for more than about, e.g., 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours after administration and waking from a night of sleep.
  • methods of treating acute lung injury associated with inflammation include administering to a subject in need thereof a pharmaceutical composition including a PTP1B inhibitor, such as, for example MSI-1436, DPM- 1003, or a respective pharmaceutically acceptable salt thereof wherein the composition provides improvement in symptoms of acute lung injury associated with inflammation for more than 1 hour after administration to the subject.
  • methods of treating acute lung injury associated with inflammation include administering to a subject in need thereof a pharmaceutical composition including a PTPTB inhibitor, such as, for example MSI- 1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof wherein the composition provides improvement in symptoms of acute lung injury associated with inflammation for more than 2 hours after administration to the subject.
  • methods of treating acute lung injury associated with inflammation are provided which include administering to a subject in need thereof a pharmaceutical composition including a PTP1B inhibitor, such as, for example MSI- 1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof wherein the composition provides improvement in symptoms of acute lung injury associated with inflammation for more than 3 hours after administration to the subject.
  • methods of treating acute lung injury associated with inflammation include administering to a subject in need thereof a pharmaceutical composition including a PTPlB inhibitor, such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof wherein the composition provides improvement in symptoms of acute lung injury associated with inflammation for more than 4 hours after administration to the subject.
  • methods of treating acute lung injury associated with inflammation are provided which include administering to a subject in need thereof a pharmaceutical composition including a PTP1B inhibitor, such as, for example MSI-1436, DPM- 1003, or a respective pharmaceutically acceptable salt thereof wherein the composition provides improvement in symptoms of acute lung injury associated with inflammation for more than 6 hours after administration to the subject.
  • methods of treating acute lung injury associated with inflammation include administering to a subject in need thereof a pharmaceutical composition including a PTPlB inhibitor, such as, for example MSI- 1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof wherein the composition provides improvement in symptoms of acute lung injury associated with inflammation for more than 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration to the subject.
  • the pharmaceutical compositions provide improvement of next day functioning of the subject having acute lung injury associated with inflammation.
  • the pharmaceutical compositions may provide improvement in symptoms of acute lung injury associated with inflammation for more than about, e g., 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours after administration and waking from a night of sleep.
  • compositions herein may be provided with conventional release or modified release profiles.
  • Pharmaceutical compositions may be prepared using a pharmaceutically acceptable “carrier” composed of materials that are considered safe and effective.
  • the “carrier” includes all components present in the pharmaceutical formulation other than the active ingredient or ingredients.
  • the term “carrier” includes, but is not limited to, diluents, binders, lubricants, disintegrants, fillers, and coating compositions. Those with skill in the art are familiar with such pharmaceutical carriers and methods of compounding pharmaceutical compositions using such carriers.
  • compositions herein are modified release dosage forms which provide modified release profiles.
  • Modified release profiles may exhibit immediate release, delayed release, or extended release profiles.
  • Conventional (or unmodified) release oral dosage forms such as tablets, capsules, suppositories, syrups, solutions and suspensions typically release medications into the mouth, stomach or intestines as the tablet, capsule shell or suppository dissolves, or, in the case of syrups, solutions and suspensions, when they are swallowed.
  • the pattern of drug release from modified release (MR) dosage forms is deliberately changed from that of a conventional dosage form to achieve a desired therapeutic objective and/or better patient compliance.
  • Types of MR drug products include orally disintegrating dosage forms (ODDFs) which provide immediate release, extended release dosage forms, delayed release dosage forms (e.g., enteric coated), and pulsatile release dosage forms.
  • ODDFs are orally disintegrating dosage forms which provide immediate release, extended release dosage forms, delayed release dosage forms (e.g., enteric coated), and pulsatile release dosage forms.
  • An ODDF is a solid dosage form containing a medicinal substance or active ingredient which disintegrates rapidly, usually within a matter of seconds when placed upon the tongue. The disintegration time for ODDFs generally range from one or two seconds to about a minute. ODDFs are designed to disintegrate or dissolve rapidly on contact with saliva. This mode of administration can be beneficial to people who may have problems swallowing tablets whether it be from physical infirmity or psychiatric in nature. Subjects in pain may exhibit such behavior.
  • ODDF can provide rapid delivery of medication to the blood stream through mucosa resulting in a rapid onset of action.
  • examples of ODDFs include orally disintegrating tablets, capsules and rapidly dissolving films and wafers.
  • Extended release dosage forms have extended release profdes and are those that allow a reduction in dosing frequency as compared to that presented by a conventional dosage form, e.g., a solution or unmodified release dosage form. ERDFs provide a sustained duration of action of a drug. Suitable formulations which provide extended release profiles are well-known in the art.
  • coated slow release beads or granules (“beads” and “granules” are used interchangeably herein) in which a PEP IB inhibitor, such as, for example MSI- 1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof is applied to beads, e.g., confectioners nonpareil beads, and then coated with conventional release retarding materials such as waxes, enteric coatings and the like.
  • beads can be formed in which a PTP1B inhibitor, such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof is mixed with a material to provide a mass from which the drug leaches out.
  • the beads may be engineered to provide different rates of release by varying characteristics of the coating or mass, e.g., thickness, porosity, using different materials, etc. Beads having different rates of release may be combined into a single dosage form to provide variable or continuous release.
  • the beads can be contained in capsules or compressed into tablets.
  • modified dosage forms herein incorporate delayed release dosage forms having delayed release profiles.
  • Delayed release dosage forms can include delayed release tablets or delayed release capsules.
  • a delayed release tablet is a solid dosage form which releases a drug (or drugs) such as a PTP1B inhibitor, such as, for example MSI-1436, DPM- 1003, or a respective pharmaceutically acceptable salt thereof at a time other than promptly after administration.
  • a delayed release capsule is a solid dosage form in which the drug is enclosed within either a hard or soft soluble container made from a suitable form of gelatin, and which releases a drug (or drugs) at a time other than promptly after administration.
  • enteric-coated tablets, capsules, particles and beads are well-known examples of delayed release dosage forms.
  • a delayed release tablet is a solid dosage form containing a conglomerate of medicinal particles that releases a drug (or drugs) at a time other than promptly after administration.
  • the conglomerate of medicinal particles are covered with a coating which delays release of the drug.
  • a delayed release capsule is a solid dosage form containing a conglomerate of medicinal particles that releases a drug (or drugs) at a time other than promptly after administration. Tn embodiments, the conglomerate of medicinal particles are covered with a coating which delays release of the drug. [0047] Delayed release dosage forms are known to those skilled in the art.
  • coated delayed release beads or granules in which a PTP1B inhibitor, such as, for example MSI- 1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof is applied to beads, e.g., confectioners nonpareil beads, and then coated with conventional release delaying materials such as waxes, enteric coatings and the like.
  • beads can be formed in which a PTP1B inhibitor, such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof is mixed with a material to provide a mass from which the drug leaches out.
  • the beads may be engineered to provide different rates of release by varying characteristics of the coating or mass, e g., thickness, porosity, using different materials, etc.
  • enteric coated granules of a PTPlB inhibitor such as, for example MSI- 1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof can be contained in an enterically coated capsule or tablet which releases the granules in the small intestine.
  • the granules have a coating which remains intact until the coated granules reach at least the ileum and thereafter provide a delayed release of the drug in the colon.
  • Suitable enteric coating materials are well known in the art, e.g., Eudragit® coatings such methacrylic acid and methyl methacrylate polymers and others.
  • the granules can be contained in capsules or compressed into tablets.
  • a PTP1B inhibitor such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof is incorporated into porous inert carriers that provide delayed release profiles.
  • the porous inert carriers incorporate channels or passages from which the drug diffuses into surrounding fluids.
  • a PTP1B inhibitor such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof is incorporated into an ion-exchange resin to provide a delayed release profile. Delayed action may result from a predetermined rate of release of the drug from the resin when the drug-resin complex contacts gastrointestinal fluids and the ionic constituents dissolved therein.
  • membranes are utilized to control rate of release from drug containing reservoirs.
  • liquid preparations may also be utilized to provide a delayed release profile.
  • a liquid preparation consisting of solid particles dispersed throughout a liquid phase in which the particles are not soluble.
  • the suspension is formulated to allow at least a reduction in dosing frequency as compared to that drug presented as a conventional dosage form (e.g., as a solution or a prompt drug-releasing, conventional solid dosage form).
  • a suspension of ion-exchange resin constituents or microbeads for example, a suspension of ion-exchange resin constituents or microbeads.
  • compositions described herein are suitable for parenteral administration, including, e.g., intramuscular (i.m ), intravenous (i.v.), subcutaneous (s.c.), intraperitoneal (i.p.), or intrathecal (i.t.).
  • Parenteral compositions must be sterile for administration by injection, infusion or implantation into the body and may be packaged in either single-dose or multi -dose containers.
  • liquid pharmaceutical compositions for parenteral administration to a subject include an active substance, e.g., a PTP1B inhibitor, such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof in any of the respective amounts described above.
  • the pharmaceutical compositions for parenteral administration are formulated as a total volume of about, e.g., 10 ml, 20 ml, 25 ml, 50 ml, 100 ml, 200 ml, 250 ml, or 500 ml.
  • the compositions are contained in a bag, a glass vial, a plastic vial, or a bottle.
  • compositions for parenteral administration may include one or more excipients, e.g. , solvents, solubility enhancers, suspending agents, buffering agents, isotonicity agents, stabilizers or antimicrobial preservatives.
  • excipients e.g. , solvents, solubility enhancers, suspending agents, buffering agents, isotonicity agents, stabilizers or antimicrobial preservatives.
  • the excipients of the parenteral compositions will not adversely affect the stability, bioavailability, safety, and/or efficacy of a PTP1B inhibitor, such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof used in the composition
  • parenteral compositions are provided wherei n there is no incompatibility between any of the components of the dosage form.
  • parenteral compositions a PTP1B inhibitor such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof include a stabilizing amount of at least one excipient.
  • excipients may be selected from the group consisting of buffering agents, solubilizing agents, tonicity agents, antioxidants, chelating agents, antimicrobial agents, and preservative.
  • buffering agents solubilizing agents, tonicity agents, antioxidants, chelating agents, antimicrobial agents, and preservative.
  • an excipient may have more than one function and be classified in one or more defined group.
  • parenteral compositions include a PTP1B inhibitor, such as, for example MSI-1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof and an excipient wherein the excipient is present at a weight percent (w/v) of less than about, e.g., 10%, 5%, 2.5%, 1 %, or 0.5%.
  • the excipient is present at a weight percent between about, e.g, 1.0% to 10%, 10% to 25%, 15% to 35%, 0.5% to 5%, 0.001% to 1%, 0.01% to 1%, 0.1% to 1%, or 0.5% to 1%.
  • the excipient is present at a weight percent between about, e.g., 0.001% to 1%, 0.01% to 1%, 1.0% to 5%, 10% to 15%, or 1% to 15%.
  • parenteral compositions of an active substance e.g., a PTP1B inhibitor, such as, for example MSI- 1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof are provided, wherein the pH of the composition is between about 4.0 to about 8.0. In embodiments, the pH of the compositions is between, e.g., about 5.0 to about 8.0, about 6.0 to about 8.0, about 6.5 to about 8.0.
  • the pH of the compositions is between, e.g., about 6.5 to about 7.5, about 7.0 to about 7.8, about 7.2 to about 7.8, or about 7.3 to about 7.6.
  • the pH of the aqueous solution is, e.g., about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.7, about 7.8, about 8.0, about 8.2, about 8.4, or about 8.6.
  • a PTP1B inhibitor such as, for example MSI- 1436, DPM-1003, or a respective pharmaceutically acceptable salt thereof that are provided herein are applicable to all the dosage forms described herein including conventional dosage forms, modified dosage forms, as well as the parenteral formulations described herein. Those skilled in the art will determine appropriate amounts depending on criteria such as dosage form, route of administration, subject tolerance, efficacy, therapeutic goal and therapeutic benefit, among other pharmaceutically acceptable criteria.
  • Clinical efficacy of treatment can be monitored using any method known in the art. Measurable parameters to monitor efficacy will depend on the condition being treated. For monitoring the status or improvement of acute lung injury, both subjective parameters (e.g., patient reporting) and objective parameters (e.g., arterial blood gas measurements, measurements of markers of oxidative injury in the lung, chest-radiography, etc.) can be used.
  • subjective parameters e.g., patient reporting
  • objective parameters e.g., arterial blood gas measurements, measurements of markers of oxidative injury in the lung, chest-radiography, etc.
  • “Improvement” refers to the treatment of symptoms of lung injury, including but not limited to pulmonary edema, sepsis, microvascular thrombi, hyaline membrane formation, or neutrophilic alveolitis.
  • “Improvement in next day functioning” or “wherein there is improvement in next day functioning” refers to improvement after waking from an overnight sleep period wherein the beneficial effect of administration of a PTPlB inhibitor, such as, for example MSI-1436, DPM- 1003, or respective a pharmaceutically acceptable salt thereof applies to symptoms of lung injury and is discernable, either subjectively by a subject or objectively by an observer, for a period of time, e.g., 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, etc. after waking.
  • PK refers to the pharmacokinetic profile. Cmax is defined as the highest plasma drug concentration estimated during an experiment (ng/ml).
  • Tmax is defined as the time when Cmax is estimated (min).
  • AUCo-® is the total area under the plasma drug concentration-time curve, from drug administration until the drug is eliminated (ng*hr/ml or pg*hr/ml). The area under the curve is governed by clearance. Clearance is defined as the volume of blood or plasma that is totally cleared of its content of drug per unit time (ml/min).
  • Treating can refer to the following: reducing, improving, relieving, ameliorating, mitigating, inhibiting, reversing and/or alleviating symptoms of lung injury in a subject, or delaying the appearance of symptoms of lung injury (prophylaxis) in a subject.
  • “treating”, “treat” or “treatment” may refer to preventing the appearance of clinical symptoms of a disease or condition in a subject that may be afflicted with or predisposed to the disease or condition, but does not yet experience or display clinical or subclinical symptoms of the disease or condition.
  • Treating also refers to inhibiting or relieving symptoms of lung injury, e.g., causing regression of symptoms of lung injury or at least one of its clinical or subclinical symptoms.
  • the benefit to a subject to be treated may be statistically significant, mathematically significant, or at least perceptible to the subject and/or the physician. Nonetheless, prophylactic (preventive) and therapeutic (curative) treatment are two separate embodiments of the disclosure herein.
  • “Pharmaceutically acceptable” refers to molecular entities and compositions that are "generally regarded as safe”, e.g., that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset and the like, when administered to a human.
  • this term refers to molecular entities and compositions approved by a regulatory agency of the federal or a state government, as the GRAS list under section 204(s) and 409 of the Federal Food, Drug and Cosmetic Act, that is subject to premarket review and approval by the FDA or similar lists, the U.S. Pharmacopeia or another generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • “Co-administered with”, “administered in combination with”, “a combination of’ or “administered along with” may be used interchangeably and mean that two or more agents are administered in the course of therapy.
  • the agents may be administered together at the same time or separately in spaced apart intervals.
  • the agents may be administered in a single dosage form or in separate dosage forms.
  • Subject in need thereof includes individuals that are experiencing symptoms of lung injury or are about to experience symptoms of lung injury with reasonable certainty.
  • the methods and compositions including a PTP1B inhibitor, such as, for example MSI- 1436, DPM- 1003, or a respective pharmaceutically acceptable salt thereof may be provided to any individual including, e.g., wherein the subject is a neonate, infant, a pediatric subject (6 months to 12 years), an adolescent subject (age 12-18 years) or an adult (over 18 years).
  • Subjects include mammals. “Patient” and “subject” may be used interchangeably herein.
  • pharmaceutically acceptable salt refers to derivatives of the compounds defined herein, wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include but are not limited to mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • Such conventional non-toxic salts include but are not limited to those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, tolunesulfonic, naphthalenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic salts.
  • the pharmaceutically acceptable salts can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods.
  • mice Male Balb/c mice (7-14-week-old) were obtained from Charles River and male C57BL/6J mice (7-10-week-old) were purchased from The Jackson Laboratory. All the mice were housed in the animal facilities of Cold Spring Harbor Laboratory. All experimental protocols were reviewed and approved by the Cold Spring Harbor Laboratory Institutional Animal Care and Use Committee and were conducted in accordance with the NIH’s Guide for the Care and Use of Laboratory Animals. Mice were housed five per cage and maintained on a 12h light/dark cycle and an ambient temperature of 25°C, with sterile food and water, in conventional space. All mice were acclimatized to the animal facility for a minimum of 7 days prior to enrollment in experiments.
  • TRALI induction Male Balb/c mice (7-9-week-old) were given an intraperitoneal injection with 0.15 mg/kg lipopolysaccharide (LPS) in 100 pl physiological saline (0.9%). Twenty-six hours later, mice received an intravenous injection through retro-orbital venous sinus of 100 pl 1.5 mg/kg anti-mouse MHC Class I (BioXcell, clone 34-l-2s). Two hours before TRALI induction, the mice were treated either with saline or different doses of MSL1436 or DPM-1003, intraperitoneally.
  • LPS lipopolysaccharide
  • anti-MHC-I was administered at ZT13 (7 p.m.) Mice were observed for up to 2hrs during the acute phase of TRALI. Mice were euthanized when they appeared moribund by physical inspection as evidenced by change in mobility (endpoint of the experiment). Time to endpoint was used for statistical analysis of overall survival.
  • mice Male C57BL/6J mice (8-10-week-old) were administered a subcutaneous injection in the flank of analgesic (72-hour sustained release Buprenorphine (1 mg/kg)) 15 min before surgery. Then, mice were anesthetized with isoflurane, and surgery were performed under aseptic survival conditions. A small midline incision was made and the cecum was exteriorized and ligated (2 cm) using non-ab sorbable 3-0 suture. A 23-gauge needle was then used to puncture one hole in the middle of the ligated segment, and a small amount of feces was extruded to ensure constant drainage of puncture.
  • analgesic 72-hour sustained release Buprenorphine (1 mg/kg)
  • the ligated and punctured cecum was repositioned inside of abdominal cavity without the feces touching the incision to avoid infection of the surgical wound.
  • the peritoneum was closed with surgical absorbable Vicryl sutures, and the skin was closed using sterile 7 mm wound clips. Survival was monitored for 10 days, and mice were euthanized once they became moribund and a humane endpoint was reached.
  • LPS-induced sepsis Male C57BL/6J mice (7-9-week-old) were given LPS (E. coli Ol l i :B4) at the indicated concentrations through intraperitoneal injection. Two hours before LPS challenge, 10 mg/kg MSI-1436 or saline were administered intraperitoneally. Mice were observed for up to 5 days for survival, and mice were euthanized once they became moribund. [0072] Histology. Two lung fixation methods were used in this study. For both techniques, animals were euthanized with CO2 immediately prior to procedure.
  • the first technique required exposing the trachea and lung, followed by making an incision in the trachea to allow insertion of a 20-gauge catheter (Exel Safelet catheter).
  • the catheter and trachea were secured with sutures and the lungs were slowly inflated with approximately 1ml of 4% paraformaldehyde (PF A).
  • PF A paraformaldehyde
  • the trachea was then tied to prevent deflation and the lungs were dissected and immersed in 4% PFA at room temperature for 24 hours to ensure thorough fixation.
  • animals were first transcardially perfused with 30ml of physiological saline solution (0.9%), to flush out blood, using a 25-27GA needle.
  • the lungs were then inflated by repositioning the needle from the left ventricle of the heart into the right ventricle and perfusing with an additional 3-5ml of saline.
  • the lungs were dissected and drop fixed in 4% PFA at room temperature for 24 hours. After dehydration, the fixed lungs were embedded in paraffin and 5 pm sections were cut coronally, to represent all the lobes, and mounted on slides. Tissue sections were stained with hematoxyline and eosin (H&E), and scanned using Aperio ScanScope CS (Leica Biosystems).
  • H&E staining slides were read blindly and scored for lung damage.
  • H&E- stained sections were scored according to severity, distribution, amount and content of edema, alveolar damage, hyaline membranes and vessel damage. Severity was scored 0-4 based on the least to most affected lung in the study. Distribution was scored 1-4 based on the percentage of the lung involved (focal, multifocal, locally extensive, and diffuse). Edema scores were 0-4 based on the distribution, severity, and intensity of the edematous proteinaceous exudate in the alveolar space.
  • Alveolar damage was scored 0-4 according to the degree of loss of alveolar wall integrity and alveolar pneumonocyte reaction (type II hyperplasia and sloughed cells in alveoli). Hyaline membranes were scored according to number and extent of membrane formation. Vessel damage was scored 0-4 according to the degree of endothelial damage. The scores of each lesion were added to give a final overall score.
  • BALF bronchoalveolar lavage fluid
  • a 20G catheter (Exel Safelet catheter 20G 1”, Exelint) was inserted into the trachea, and tied firmly with silk thread.
  • PBS (1ml) was injected into the lungs, and slowly recovered after ⁇ 1 minute.
  • a total of 600 -700 pl BALF was recovered from each mouse, and kept on ice.
  • BALF was centrifuged (300xg, 10 min, 4°C), and the protein concentrations in the supernatants were determined using Pierce BCA Protein Assay Kit (Thermo Fisher Scientific) according to the manufacturer’s instructions.
  • mice were anesthetized with 120 mg/kg ketamine and 8 mg/kg xylazine. After immobilization, mice were positioned prone on the imaging cradle of either a Mediso nanoScan PET/CT or SPECT/CT system (Mediso), and secured with tape and gauze to prevent movement.
  • the scanner’s field of view was set using a 2D scout scan to cover the lungs and airways, and images were acquired using the following x- ray settings: beam energy of 50 kVp, exposure of 186 pAs, in an axial scan with 720 projections.
  • TRALI was induced for one saline- and one MSI-1436-treated mouse at similar times (6 p.m. - 10 p.m.), and placed alternately on either CT scanner.
  • the viable lung volume was defined as the volume within the total lung ROT below a threshold of 0 HU, and percent viable lung volume was calculated by dividing this value by the total lung volume at each timepoint.
  • Blood count Blood was collected by cardiac puncture into a syringe freshly coated with 0.5 M EDTA, then transferred into EDTA-coated tubes (Microvette 500, Sarstedt). We ensured that blood used for functional analysis in this study was clot free, in order to avoid neutrophil activation. Blood (50 pl) was analyzed for differential counts using a ProCyte Dx Hematology Analyzer (Idexx Laboratories).
  • Lung immune cell infiltration analysis Lung tissues were harvested from control and TRALI mice 30 minutes post MHC-I antibody challenge. Lungs were rinsed in cold PBS and mechanically dissociated into small pieces, and further enzymatically digested for 30 min at 37 °C in 5 ml of RPMI with 2% FCS and containing Dispase (2.5 U/nil, #07913, Stem Cell), Collagenase D (0.1 mg/ml, #11088866001, Sigma), DNase I (25 U/ml, #04536282001, Sigma), and Liberase DL (0.2 mg/ml, #05466202001, Sigma).
  • Dispase 2.5 U/nil, #07913, Stem Cell
  • Collagenase D 0.1 mg/ml, #11088866001, Sigma
  • DNase I 25 U/ml, #04536282001, Sigma
  • Liberase DL 0.2 mg/ml, #05466202001, Sigma.
  • the suspensions were then passed through a 70 pm cell strainer (#352340, BD Falcon), and centrifuged at 1,500 rpm for 5 minutes at 4 °C. After removing the red blood cells by incubating with 5 ml of ammonium-chlori depotassium (ACK) buffer for 3 min on ice, the suspensions were then centrifuged (1,500 rpm, 5 min) and resuspended in FACS buffer (1% FCS and 0.02% sodium azide in PBS). The singlecell suspensions were finally collected by passing through a 40 pm cell strainer. For flow cytometry analysis, lung single-cell suspensions (1,000,000 cells) from each sample were fixed in 2% of PFA for 10 min on ice.
  • ACK ammonium-chlori depotassium
  • CD8+ T cells CD45+CD3+CD8+
  • CD4+ T cells CD45+CD3+CD4+
  • yo T cells CD45+CD3+gdTCR
  • NKT cells CD45+CD3+CD335+
  • B cells CD45+CD3-CD19+
  • NK cells CD45+CD3-CD335+
  • Neutrophils CD45+CDl lb+Ly6G+Ly6C+
  • Macrophages CD45+CD1 lb+Ly6G-F4/80+
  • DC cells CD45+CD1 lb+Ly6G-F4/80-CDl lc+).
  • cytokine array Multiplex cytokine array.
  • the cytokine arrays were performed with serum and lung tissue homogenates from NT (no treatment) and TRALI mice 30 min after MHC-I antibody injection.
  • blood was collected by cardiac puncture, then allowed to clot for 30min at room temperature.
  • the serum was isolated by centrifuging at 1,500 x g for 15 minutes in a refrigerated centrifuge.
  • lung tissue homogenates lungs were harvested and weighed, homogenized using a Precellys Evolution tissue homogenizer (Bertin Instruments) at 6,800 rpm, 0°C. The samples were homogenized for three cycles, 20 s per cycle, and 30 s pause after each cycle. Samples were analyzed with the Proteome Profiler mouse cytokine array kit, panel A (R&D systems, ARY006) according to the manufacturer’s instructions.
  • Enzyme-linked immunosorbent assay (ELISA). ELISA was performed with serum, plasma or lung homogenates to measure the levels of CXCL1 (R&D systems, DY453-05) and CXCL2 (R&D systems, DY452-05) following manufacturer’s instructions.
  • BM neutrophils were isolated by density gradient centrifugation, as previously described (1). Briefly, BM was flushed from tibias and femurs using HBSS. The cell pellet was resuspended in ACK buffer and passed through 100 pm cell strainer (Falcon). Different concentrations of Percoll (Cytiva, 17089102) were prepared according to previous publication (2). Neutrophils were enriched using gradient centrifugation at 1,300 x g for 20 min, and collected from the band at the interface between the 81 and 62% Percoll layers. Cells were washed with HBSS, and resuspended in RPMI at the desired concentration.
  • RNA isolation and RNA-seq library preparation were isolated from bone marrow (BM), and treated with either saline or 10 pM MSI-1436 for 2 hours. Total RNA was extracted from cells using TRIzol reagent (Thermo Scientific, Cat# 15596018). Chloroform (200 pl) was added to 1 mL TRIzol and incubated at room temperature for 10 minutes. After centrifugation at 10,000 x g for 15 minutes in the cold, the aqueous phase was taken, mixed with an equal volume of isopropanol and supplemented with 0.5 pl glycogen, to increase RNA recovery.
  • RNA-seq libraries were prepared with NEBNext UltraTM II RNA Library Prep Kit (NET, E7770) for Illumina sequencing, following the manufacturer’s instructions. Samples were pooled together and sequenced on NextSeq with Single Read 75 bases.
  • RNA-seq analysis The sequencing reads were aligned to customized mm 10 gtf- containing protein coding genes by using salmon 1.0.0 with default setting. Expressed genes (TPM > 0.5 in either control or treatment) were subjected to differential gene expression analysis with DESeq2. Genes were then ranked by their log2 fold change and upregulated genes were subjected to g:Profiler for Reactome analysis. (GEO accession: GSE184197)
  • MPO myeloperoxidase
  • cells were fixed with 4% PFA for 10 min at room temperature, permeabilized with 0.1% Triton-XlOO, and blocked with PBS containing 5% donkey serum and 0.1% Triton X-100 for 1 hour. Samples were next incubated at 4°C overnight, washed with PBS, and incubated with Donkey anti-Goat IgG, Alexa 488 (1 :400, Invitrogen, A-l 1055) for 1 hour at room temperature. To determine the levels of surface markers or MPO in the neutrophils, the scatter plots were gated on Ly6G lu8h population, and the MFI of surface markers or MPO were calculated.
  • the cells were first fixed with 4% PFA for lOmin, washed with PBS, blocked and permeabilized with 5% donkey serum, 0.1% Triton X-100 in PBS for 1 hour at room temperature, and incubated with anti-MPO (1:300, R&D systems, AF3667) overnight at 4°C. Next day, cells were washed with PBS, incubated with Donkey anti-Goat IgG, Alexa 488 (1:400) and DAPI (Abeam, ab228549) for 1 hour at room temperature, washed with PBS and then Ibidi mounting medium was added (Ibidi, 50001).
  • mice were injected intraperitoneally with either saline, 2mg/kg MSI- 1436 or 10 mg/kg MSI-1436. Peripheral blood was collected through cheek bleeding 2.5 hours after compound administration, and 50 pl blood was required for each well.
  • blood was obtained from untreated mice. Red Blood Cells (RBCs) were removed with ACK buffer, and the leukocytes were plated onto poly-L-lysine-coated 8-well p-slide.
  • RBCs Red Blood Cells
  • DMSO or PMA 100 nM was added for ex vivo test; DMSO, PMA, or PMA together with MSI-1436 was added for in vitro test.
  • cells were fixed, permeabilized and stained for MPO, citH3 (Abeam, ab5103), DAPI, and were visualized using a Zeiss LSM 780 confocal laser scanning microscope. Quantitation was performed based on triple colocalization of DNA, MPO and citH3, using ImageJ and a custom- made macro, available in FigShare (DOI: 10.6084/m9. figshare.14401958).
  • mice were subject to TRALI and euthanized with CO2 30 min after MHC-I antibody injection. Mice were then perfused with 20 ml of saline through the left ventricle of the heart, and the lungs were collected in cold PBS. Afterwards, lungs were fixed at 4 °C overnight in PBS with 4% PFA and 30% sucrose. After three washes of I h with PBS at room temperature, tissues were permeabilized in methanol gradients in PBS for 30 min (PBS > 50% MeOH > 80% MeOH > 100% MeOH).
  • tissues were bleached with Dent’s bleach (15% H2O2, 16.7% DMSO in MeOH) for 1 h at room temperature, and rehydrated through descending methanol gradients in PBS (80% MeOH> 50% MeOH > PBS). Then tissues were incubated with blocking buffer containing PBS with 0.3% Triton X-100, 0.2% BSA, 5% DMSO, 0.1% azide and 25% FBS overnight at 4 °C with shaking. Afterwards, lungs were stained with antibodies against cit-H3 (Abeam, ab5103), MPO (R&D, AF3667) and CD31 (BioLegend, 102502) for 2 days at 4 °C with shaking.
  • Dent Dent’s bleach (15% H2O2, 16.7% DMSO in MeOH) for 1 h at room temperature, and rehydrated through descending methanol gradients in PBS (80% MeOH> 50% MeOH > PBS). Then tissues were incubated with blocking buffer containing PBS with 0.3% Triton X
  • Quantitation was performed with Imans (Bitplane), using spots on a triple-colocalization channel of DNA, MPO and citH3. Neutrophils were quantified using spots based on MPO signal. Frequency was calculated as the number of NETs / number of neutrophils in the 3D volume.
  • AZD-5069 The CXCR2 antagonist AZD-5069 (MedChemExpress, HY-19855) was given to mice orally (100 mg/kg). Before feeding AZD- 5069, mice were trained to consume 100 pl 10% sucrose through pipette tips for 3 days. On the day of oral administration of AZD-569, compound was freshly prepared in 10% DMSO, 40% PEG-300, 5% Tween-80, 45% physiological saline (0.9%) AZD-5069 was completely dissolved before adding next solvent. AZD-5069 solution (20 mg/ml) was kept in the 50°C water bath until ready to feed mice.
  • AZD-5069 solution (20 mg/ml) was kept in the 50°C water bath until ready to feed mice.
  • Palomid 529 (Selleck Chemicals, S2238) was freshly prepared in a micronized formulation in 8% DMSO, 40% PEG300, 5% Tween80, 47% ddFLO, in which the solvents were added individually and in the order in which they are listed. Before each injection, the tube was vortexed to retain suspension. The compound was administered IP in doses up to 25 mg/kg.
  • Chemotaxis assay were performed using Corning HTS Transwell-24 well permeable supports (6.5 mm diameter, 3 pm pore size, Sigma, CLS3398- 2EA) and Coming Ultra-Low attachment plates (Sigma, CLS3473-24EA). Either 600 pl of RPMI-1640 as a negative control, or RPMI-1640 containing 100 ng/ml CXCL12 (R&D systems, 460-SD-010), was added to the lower chambers. The upper chambers were seeded with neutrophils, 200 pl at 5 X 10 6 cells/ml.
  • the neutrophils were pre-treated with the indicated concentration of PTP1B inhibitors for 30 min, and then loaded into the upper chambers. After 1-2 hours incubation at 37°C, 5% CO2, EDTA was added to the lower chambers to a final concentration of 10 mM, for 10 min, to detach the cells. The number of neutrophils in the lower chamber were counted using Guava easyCyte.
  • Example 1 PTP1B inhibitors improved survival and prevented lung damage in the TRALI and LPS-induced sepsis mouse models.
  • the 2mg/kg MSI-1436-treated group also displayed reduced edema and hyaline membranes in the alveolar space.
  • a lung injury score that reflected a combination of gross examination of damage distribution (multifocal, locally extensive, diffuse), accumulation of edema and hyaline membrane, and alveolar and vessel damage (Figure IF). Consistent with the survival data, treatment with MSI-1436 at 2 mg/kg improved the lung injury score reflecting moderate injury, whereas 10 mg/kg-treated mice did not present signs of lung injury.
  • pulmonary permeability we measured the protein leakage in the bronchoalveolar lavage fluid (BALF) and edema formation.
  • BALF bronchoalveolar lavage fluid
  • mice We administered either saline or 5 mg/kg MSL1436 2 hours before surgery.
  • the saline-treated mice all died within 96 hours after CLP surgery, whereas -20% of mice were alive at day 10 in MSI-1436-pretreated group ( Figure IK).
  • Example 3 Treatment with PTP1B inhibitors induced neutrophilia.
  • [0101 ] We profiled the accumulation of immune cells in lungs and the circulation 30 min after anti-MHC I antibody injection. In agreement with reports that neutrophils are critical for the initiation of TRALI (21, 30-32), the most dramatic increase we observed was in neutrophil numbers ( Figures 2A-2C). Unexpectedly, we observed that following pretreatment with MSL 1436, CD1 lb+Ly6C+Ly6G+ neutrophil infiltration into lung tissues after TRALI induction was elevated compared to saline-treated mice ( Figure 2D). This increase of pulmonary neutrophil accumulation prompted us to examine directly the effect of PTP1B inhibitors on neutrophils. We examined hematological parameters after treatment with PTP1B inhibitors and observed that the number of neutrophils in the peripheral blood increased ⁇ 3-fold following administration of either MSI-1436 or DPM-1003 ( Figures 2E and 2F, and Table 4).
  • Example 4 Treatment with PTP1B inhibitors induced an aged neutrophil phenotype in vivo.
  • neutrophils The ability of neutrophils to clear pathogens is conferred primarily by three processes, degranulation, formation of NETs and phagocytosis (35), which are modulated during neutrophil aging (8, 9).
  • Neutrophil granules contain antimicrobial and proteolytic proteins, which facilitate digestion of microorganisms in response to infection, but have potential to cause harm to highly vascularized tissues, especially lungs, if not controlled appropriately. In the systemic circulation, neutrophils release granules in a controlled fashion, becoming less toxic and less able to cause tissue damage before they infiltrate the lungs (9).
  • neutrophil aging There is a temporal heterogeneity, referred to neutrophil aging, in which fresh neutrophils are released from bone marrow, then undergo phenotypic changes to become aged neutrophils that are eventually eliminated from circulation (7).
  • intrinsically aged neutrophils display decreased granule contents, reduced ability to form NETs, and their predominance in the circulation coincides with diminished risk for damage to the vascular system (8-10, 36).
  • neutrophil aging is a physiological strategy to dampen the toxic nature of neutrophils before they infiltrate the lung and to prevent tissue damage.
  • Example 5 Treatment with MSI-1436 suppressed formation of NETs ex vivo and in vivo.
  • NETs are formed in a neutrophil cell death pathway, referred to as NETosis.
  • NADPH oxidase-induced reactive oxygen species (ROS) stimulate MPO to promote the translocation of neutrophil elastase (NE), a serine protease, to the nucleus and the decondensation of chromatin.
  • ROS reactive oxygen species
  • NETs which consist of DNA decorated with citrullinated-histone H3 (citH3) and granule proteins, were designated by colocalization of DNA, citH3 and MPO, using confocal microscopy.
  • PMA phorbol 12-myristate 13-acetate
  • PLC protein kinase C
  • Example 6 The effect of PTP1B inhibitors on neutrophil aging was mediated via the CXCR4-CXCR2 signaling axis.
  • CXCR4-CXCR2 signaling axis The trafficking of neutrophils between bone marrow and the circulation is controlled by the CXCR4-CXCR2 signaling axis (38).
  • Stromal cells express a high level of CXCLI2 (SDF-1), which interacts with CXCR4 and sequesters neutrophils in the bone marrow (38).
  • CXCL1 and CXCL2 which activate CXCR2 signaling, promote the egress of neutrophils into the blood stream (39).
  • the level of surface CXCR4 is upregulated, leading to homing back to the bone marrow (40).
  • Example 7 Treatment with PTP1B inhibitors impaired CXCR4 signaling.
  • CXCR4 inhibits the signaling output of CXCR2
  • PTP1B inhibitors phenocopied ablation of CXCR4 from myeloid cells in mice
  • GPCRs G protein-coupled receptors
  • CXCRs C-X-C chemokine receptors
  • pl 10 PI3Ks are recruited to plasma membrane to activate AKT signaling.
  • the catalytic subunit of PI3K, pl 10 consists of four isoforms, among which pl 10a, -
  • PI3K isoform selective inhibitors to study the contribution of different pl 10 isoforms in regulating AKT downstream of CXCR4.
  • Example 8 mTOR inhibitor improved survival in the TRALI model and induced an aged neutrophil phenotype.
  • Neutrophils which are the most abundant white blood cell type, play an important role in the innate immune response, providing protection from invading pathogens (5). These beneficial anti-microbial functions, which include phagocytosis, degranulation, and NET formation, have to be balanced with potentially deleterious inflammatory effects. This balance is achieved in part through a neutrophil aging process that follows a circadian rhythm and contributes to the homeostasis of neutrophil number and phenotypic status (7). Neutrophils, which are produced from hematopoietic stem cells in the bone marrow, differentiate into a mature form that is enriched in the granules and secretory vesicles that underlie the microbicidal function (55).
  • neutrophils Upon their controlled release into the bloodstream, the neutrophils circulate throughout the body and distribute to the sites of infection or inflammation in various tissues. Finally, upon homing back to bone marrow, they are eliminated by macrophages and dendritic cells (56). It has now been established that neutrophils undergo morphological changes, from when they leave the bone marrow as fresh neutrophils until they age and are cleared from circulation (7). Tn this current study, we have demonstrated that a single dose of either of two, distinct, allosteric inhibitors of PTP1B induced a phenotype that exhibited features of neutrophil aging.
  • Both MSI-1436 and DPM-1003 are allosteric inhibitors that target primarily the non-catalytic, disordered segment in the C-terminus of PTP1B. This segment is a unique portion of the PTP1B protein that is unrelated to TC-PTP, its closest relative, or to any other member of the PTP family (19). Consequently, we expect that such inhibitors have the potential to be highly specific for PTP IB over other members of the PTP family.
  • MSI-1436 In our initial study of the impact of MSI-1436 on PTP1B in models of breast cancer, we reported a double mutant, PTP1B- L192A/S372P, in which catalytic function was preserved but inhibition by MSI-1436 was abrogated (19).
  • the process of neutrophil aging features a cell-intrinsic signaling module, in which chemokine receptors CXCR2 and CXCR4 functionally oppose one another.
  • CXCR2 promotes mobilization of neutrophils into the blood stream
  • CXCR4 retains neutrophils in the bone marrow, with CXCR4 playing a dominant role over CXCR2 (38).
  • As neutrophils circulate in the blood they upregulate the expression of CXCR4 to promote migration back to bone marrow, where the level of the chemokine ligand CXCL12 is constitutively high (57).
  • the signaling module is driven by BMAL1, a transcription factor that regulates the circadian clock (58).
  • BMAL1 controls the expression of CXCL2, a chemokine ligand of CXCR2, to promote neutrophil aging; in contrast, CXCR4 impairs the aging process (8).
  • CXCR4 impairs the aging process (8).
  • deletion of Cxcr4 from the myeloid lineage promotes the acquisition of an aged phenotype.
  • treatment of mice with inhibitors of PTP1B phenocopies the loss of CXCR4, including neutrophilia, progressive loss of granule content, downregulation of fresh neutrophil markers CD62L and CXCR2, and decreased formation of NETs in the lung. This suggests that one mechanism by which our inhibitors of PTP1B exert their effects is through suppression of the inhibitor of aging, CXCR4.
  • CXCR4 is a G protein-coupled receptor (GPCR) that can activate diverse downstream signaling pathways (59).
  • GPCR G protein-coupled receptor
  • PI3K plays an important role in regulating neutrophil migration, ROS generation, and the respiratory burst (42).
  • PI3Ky is the preferentially expressed isoform, and its activity is regulated by G protein 0y heterodimers (46).
  • Mice deficient in the p l lOy PI3K catalytic subunit showed a higher number of neutrophils in the circulation, impaired neutrophil migration and ROS generation, phenotypes similar to the mouse model of Akt2 deletion (42, 60, 61).
  • PTP1B In response to fMLP, activation of p38 MAPK promotes neutrophil migration. PTP1B dephosphorylates p38 MAPK directly (13), which likely explains why PTP1B inhibition enhanced fMLP-mediated signaling. In contrast, intermediary chemokines primarily function through PI3K (68), consistent with a different point of action of PTP1B.
  • PTP1B can serve to dephosphorylate and inactivate the insulin receptor and the leptin receptor-associated kinase JAK2; this is what laid the foundation for excitement about PTP1B as a therapeutic target for diabetes and obesity (71, 72).
  • PTP1B serves as a positive regulator of signaling, for example, downstream of the HER2 oncoprotein tyrosine kinase (73, 74). In such cases, inhibition of PTP1B would be expected to suppress signaling.
  • GPCR G protein coupled receptors
  • PTP1B has been implicated in various immune responses, including attenuation of CD40 and B cell activating factor receptor pathways in B cells (13), negative regulation of JAK/STAT5 pathway in T cells (79), and modulation of macrophage activities (14-16).
  • Neutrophils are important pathological drivers in ARDS and many other inflammatory diseases, such as multiple sclerosis, psoriasis, chronic obstructive pulmonary disease (80-82).
  • manipulation of neutrophil aging to dampen the neutrophil activity may be an attractive anti-inflammatory therapeutic approach.
  • Tonks NK. PTP1B from the sidelines to the front lines! FEBS letters. 2003;546(l): 140- 8.
  • Protein tyrosine phosphatase IB is a regulator of the interleukin- 10-Induced transcriptional program in macrophages. Science signaling. 2014;7(324):ra43-ra.
  • Wiede F, Lu K-H, Du X, Zeissig MN, Xu R, Goh PK, et al. PTP1B is an intracellular checkpoint that limits T cell and CAR T cell anti -tumor immunity. Cancer Discovery. 2021.

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Abstract

L'invention concerne des méthodes et des compositions pour traiter une lésion pulmonaire comprenant l'administration d'une quantité efficace d'un inhibiteur de PTP1B à un patient en ayant besoin. La lésion pulmonaire peut, par exemple, être une lésion pulmonaire aiguë, une lésion pulmonaire aiguë induite par un anticorps, une lésion pulmonaire aiguë associée à une inflammation, une SDRA, une lésion pulmonaire résultant d'une infection par le SARS-CoV-2, une lésion pulmonaire résultant de la COVID-19 ou une lésion pulmonaire résultant du syndrome WHIM.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9365608B2 (en) 2007-09-06 2016-06-14 Ohr Pharmaceutical, Inc. Method for treating diabetes
US9546194B2 (en) 2012-04-20 2017-01-17 Ohr Pharmaceutical, Inc. Aminosteroids for the treatment of a PTP1B associated disease
US20200376006A1 (en) 2017-11-06 2020-12-03 Cold Spring Harbor Laboratory Method and compositions for forming a copper-containing complex and uses thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9365608B2 (en) 2007-09-06 2016-06-14 Ohr Pharmaceutical, Inc. Method for treating diabetes
US9546194B2 (en) 2012-04-20 2017-01-17 Ohr Pharmaceutical, Inc. Aminosteroids for the treatment of a PTP1B associated disease
US10556923B2 (en) 2012-04-20 2020-02-11 Ohr Pharmaceutical Inc. Aminosteroids for the treatment of a PTP1B associated disease
US20200376006A1 (en) 2017-11-06 2020-12-03 Cold Spring Harbor Laboratory Method and compositions for forming a copper-containing complex and uses thereof

Non-Patent Citations (94)

* Cited by examiner, † Cited by third party
Title
ADROVER ET AL.: "A Neutrophil Timer Coordinates Immune Defense and Vascular Protection", IMMUNITY, vol. 50, 2019, pages 390 - 402
ADROVER JMAROCA-CREVILLEN ACRAINICIUC GOSTOS FROJAS-VEGA YRUBIO-PONCE A ET AL.: "Programmed `disarming'of the neutrophil proteome reduces the magnitude of inflammation", NATURE IMMUNOLOGY, vol. 21, no. 2, 2020, pages 135 - 44
ADROVER JMDEL FRESNO CCRAINICIUC GCUARTERO MICASANOVA-ACEBES MWEISS LA ET AL.: "A neutrophil timer coordinates immune defense and vascular protection", IMMUNITY, vol. 50, no. 2, 2019, pages 390 - 402,e10
ADROVER JMNICOLÁS-ÁVILA JAHIDALGO A: "Aging: a temporal dimension for neutrophils", TRENDS IN IMMUNOLOGY, vol. 37, no. 5, 2016, pages 334 - 45
BAFFI TRLORDEN GWOZNIAK JMFEICHTNER AYEUNG WKOMEV AP ET AL.: "mTORC2 controls the activity of PKC and Akt by phosphorylating a conserved TOR interaction motif", SCIENCE SIGNALING, vol. 14, 2021, pages 678
BENTIRES-ALJ MNEEL BG: "Protein-tyrosine phosphatase 1B is required for HER2/Neu-induced breast cancer", CANCER RESEARCH, vol. 67, no. 6, 2007, pages 2420 - 4
BURAS JAHOLZMANN BSITKOVSKY M: "Animal models of sepsis: setting the stage", NATURE REVIEWS DRUG DISCOVERY, vol. 4, no. 10, 2005, pages 854 - 65
BUTT YKURDOWSKA AALLEN TC: "Acute lung injury: a clinical and molecular review", ARCHIVES OF PATHOLOGY AND LABORATORY MEDICINE, vol. 140, no. 4, 2016, pages 345 - 50
CASSATELLA MAOSTBERG NKTAMASSIA NSOEHNLEIN O: "Biological roles of neutrophil-derived granule proteins and cytokines", TRENDS IN IMMUNOLOGY, vol. 40, no. 7, 2019, pages 648 - 64, XP085721526, DOI: 10.1016/j.it.2019.05.003
CAUDRILLIER AKESSENBROCK KGILLISS BMNGUYEN JXMARQUES MBMONESTIER M ET AL.: "Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury", THE JOURNAL OF CLINICAL INVESTIGATION, vol. 122, no. 7, 2012, pages 2661 - 71, XP055288311, DOI: 10.1172/JCI61303
CHEN JTANG HHAY NXU JYE RD: "Akt isoforms differentially regulate neutrophil functions", BLOOD, THE JOURNAL OF THE AMERICAN SOCIETY OF HEMATOLOGY, vol. 115, no. 21, 2010, pages 4237 - 46, XP086510684, DOI: 10.1182/blood-2009-11-255323
CHONG ET AL.: "CXCR4 identifies transitional bone marrow premonocytes that replenish the mature monocyte pool for peripheral responses", J. EXP. MED., vol. 213, 2016, pages 2293 - 2314
DEKKER LVSEGAL AW: "Signals to move cells", SCIENCE, vol. 287, no. 5455, 2000, pages 982 - 5
DELADERIERE AGAMBARDELLA LPAN DANDERSON KEHAWKINS PTSTEPHENS LR: "The regulatory subunits of PI3Ky control distinct neutrophil responses", SCIENCE SIGNALING, vol. 8, no. 360, 2015
DOUDA DNYIP LKHAN MAGRASEMANN HPALANIYAR N: "Akt is essential to induce NADPH-dependent NETosis and to switch the neutrophil death to apoptosis", BLOOD, THE JOURNAL OF THE AMERICAN SOCIETY OF HEMATOLOGY, vol. 123, no. 4, 2014, pages 597 - 600
DOWN KAMOUR ABALDWIN IRCOOPER AWDEAKIN AMFELTON LM ET AL.: "Optimization of novel indazoles as highly potent and selective inhibitors of phosphoinositide 3-kinase δ for the treatment of respiratory disease", JOURNAL OF MEDICINAL CHEMISTRY, vol. 58, no. 18, 2015, pages 7381 - 99, XP055282212, DOI: 10.1021/acs.jmedchem.5b00767
EASH KJGREENBAUM AMGOPALAN PKLINK DC: "CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow", THE JOURNAL OF CLINICAL INVESTIGATION, vol. 120, no. 7, 2010, pages 2423 - 31, XP008171402, DOI: 10.1172/JCI41649
EVANS CALIU TLESCARBEAU ANAIR SJGRENIER LPRADEILLES JA ET AL.: "Discovery of a selective phosphoinositide-3-kinase (PI3K)-γ inhibitor (IPI-549) as an immuno-oncology clinical candidate", ACS MEDICINAL CHEMISTRY LETTERS, vol. 7, no. 9, 2016, pages 862 - 7, XP055311463, DOI: 10.1021/acsmedchemlett.6b00238
FORONJY ET AL., MUCOSAL IMMUNOLOGY, vol. 9, 2016, pages 1317 - 1329
FOX EDHEFFERNAN DSCIOFFI WGREICHNER JS: "Neutrophils from critically ill septic patients mediate profound loss of endothelial barrier integrity", CRITICAL CARE, vol. 17, no. 5, 2013, pages 1 - 11, XP021167404, DOI: 10.1186/cc13049
GALIC SHAUSER CKAHN BBHAJ FGNEEL BGTONKS NK ET AL.: "Coordinated regulation of insulin signaling by the protein tyrosine phosphatases PTP1B and TCPTP", MOLECULAR AND CELLULAR BIOLOGY, vol. 25, no. 2, 2005, pages 819 - 29, XP055027866, DOI: 10.1128/MCB.25.2.819-829.2005
GIRBL TLENN TPEREZ LROLAS LBARKAWAY ATHIRIOT A ET AL.: "Distinct compartmentalization of the chemokines CXCL1 and CXCL2 and the atypical receptor ACKR1 determine discrete stages of neutrophil diapedesis", IMMUNITY, vol. 49, no. 6, 2018, pages 1062 - 76
GRANT LSHEARER KDCZOPEK ALEES EKOWEN CAGOUNI A ET AL.: "Myeloid-cell protein tyrosine phosphatase-1B deficiency in mice protects against high-fat diet and lipopolysaccharide-induced inflammation, hyperinsulinemia, and endotoxemia through an IL-10 STAT3-dependent mechanism", DIABETES, vol. 63, no. 2, 2014, pages 456 - 70
GULINO ET AL.: "Altered leukocyte response to CXCL12 in patients with warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome", BLOOD, vol. 104, 2004, pages 444 - 452
HE RONG-JUN ET AL: "Protein tyrosine phosphatases as potential therapeutic targets", ACTA PHARMACOLOGICA SINICA, vol. 35, no. 10, 15 September 2014 (2014-09-15), GB, pages 1227 - 1246, XP055839701, ISSN: 1671-4083, Retrieved from the Internet <URL:http://www.nature.com/articles/aps201480> DOI: 10.1038/aps.2014.80 *
HE WHOLTKAMP SHERGENHAN SMKRAUS KE JUAN AWEBER J ET AL.: "Circadian expression of migratory factors establishes lineage-specific signatures that guide the homing of leukocyte subsets to tissues", IMMUNITY, vol. 49, no. 6, 2018, pages 1175 - 90,e7
HEINONEN KMDUBE NBOURDEAU AAPP WSTREMBLAY ML: "Protein tyrosine phosphatase 1B negatively regulates macrophage development through CSF-1 signaling", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 103, no. 8, 2006, pages 2776 - 81
HEIT BTAVENER SRAHARJO EKUBES P: "An intracellular signaling hierarchy determines direction of migration in opposing chemotactic gradients", THE JOURNAL OF CELL BIOLOGY, vol. 159, no. 1, 2002, pages 91 - 102
HERNANDEZ ET AL.: "Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease", NATURE GENETICS, vol. 34, 2003, pages 70 - 74, XP055397310, DOI: 10.1038/ng1149
HIRSCH EKATANAEV VLGARLANDA CAZZOLINO OPIROLA LSILENGO L ET AL.: "Central role for G protein-coupled phosphoinositide 3-kinase in inflammation", SCIENCE, vol. 287, no. 5455, 2000, pages 1049 - 53
JANSSENS RSTRUYF S: "Proost P. The unique structural and functional features of CXCL12", CELLULAR & MOLECULAR IMMUNOLOGY, vol. 15, no. 4, 2018, pages 299 - 311
JULIEN SGDUBE NREAD MPENNEY JPAQUET MHAN Y ET AL.: "Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis", NATURE GENETICS, vol. 39, no. 3, 2007, pages 338 - 46
KAPUR RKIM MASLAM RMCVEY MJTABUCHI ALUO A ET AL.: "T regulatory cells and dendritic cells protect against transfusion-related acute lung injury via IL-10", BLOOD, vol. 129, no. 18, 2017, pages 2557 - 69
KATAYAMA II: "Development of psoriasis by continuous neutrophil infiltration into the epidermis", EXPERIMENTAL DERMATOLOGY, vol. 27, no. 10, 2018, pages 1084 - 91, XP071778688, DOI: 10.1111/exd.13746
KOLACZKOWSKA EKUBES P: "Neutrophil recruitment and function in health and inflammation", NATURE REVIEWS IMMUNOLOGY, vol. 13, no. 3, 2013, pages 159 - 75, XP037923271, DOI: 10.1038/nri3399
KRISHNAN NKOVEAL DMILLER DHXUE BAKSHINTHALA SDKRAGELJ J ET AL.: "Targeting the disordered C terminus of PTP1B with an allosteric inhibitor", NATURE CHEMICAL BIOLOGY, vol. 10, no. 7, 2014, pages 558 - 66
LAHOZ-BENEYTEZ JELEMANS MZHANG YAHMED RSALAM ABLOCK M ET AL.: "Human neutrophil kinetics: modeling of stable isotope labeling data supports short blood neutrophil half-lives", BLOOD, THE JOURNAL OF THE AMERICAN SOCIETY OF HEMATOLOGY, vol. 127, no. 26, 2016, pages 3431 - 8
LE SOMMER SMARTINA PMARTIN-GRANADOS CDELIBEGOVIC M: "Protein Tyrosine Phosphatase 1B (PTP1B) in the immune system", INFLAMMATION & CELL SIGNALING, 2015
LE SOMMER SMORRICE NPESARESI MTHOMPSON DVICKERS MAMURRAY GI ET AL.: "Deficiency in protein tyrosine phosphatase PTP1B shortens lifespan and leads to development of acute leukemia", CANCER RESEARCH, vol. 78, no. 1, 2018, pages 75 - 87
LEE HJUNG KHJEONG YHONG SHONG S-S: "HS-173, a novel phosphatidylinositol 3-kinase (PI3K) inhibitor, has anti-tumor activity through promoting apoptosis and inhibiting angiogenesis", CANCER LETTERS, vol. 328, no. 1, 2013, pages 152 - 9, XP002797054, DOI: 10.1016/j.canlet.2012.08.020
LELIEFELD PHWESSELS CMLEENEN LPKOENDERMAN LPILLAY J.: "The role of neutrophils in immune dysfunction during severe inflammation", CRITICAL CARE, vol. 20, no. 1, 2016, pages 1 - 9
LI XLEE YJJIN FPARK YNDENG YKANG Y ET AL.: "Sirtl negatively regulates FcεRI-mediated mast cell activation through AMPK-and PTPIB-dependent processes", SCIENTIFIC REPORTS, vol. 7, no. 1, 2017, pages 1 - 12
LIU LDAS SLOSERT WPARENT CA: "mTORC2 regulates neutrophil chemotaxis in a cAMP-and RhoA-dependent fashion", DEVELOPMENTAL CELL, vol. 19, no. 6, 2010, pages 845 - 57
LOONEY MRGILLISS BMMATTHAY MA: "Pathophysiology of transfusion-related acute lung injury", CURRENT OPINION IN HEMATOLOGY, vol. 17, no. 5, 2010, pages 418 - 23
LOONEY MRNGUYEN JXHU YVAN ZIFFLE JALOWELL CAMATTHAY MA: "Platelet depletion and aspirin treatment protect mice in a two-event model of transfusion-related acute lung injury", THE JOURNAL OF CLINICAL INVESTIGATION, vol. 119, no. 11, 2009, pages 3450 - 61
LOONEY MRSU XVAN ZIFFLE JALOWELL CAMATTHAY MA: "Neutrophils and their Fcy receptors are essential in a mouse model of transfusion-related acute lung injury", THE JOURNAL OF CLINICAL INVESTIGATION, vol. 116, no. 6, 2006, pages 1615 - 23
LUND IHANSEN JANDERSEN HMAILER N: "Billestrup N. Mechanism of protein tyrosine phosphatase 1B-mediated inhibition of leptin signalling", JOURNAL OF MOLECULAR ENDOCRINOLOGY, vol. 34, no. 2, 2005, pages 339 - 51
MARTIN CBURDON PCBRIDGER GGUTIERREZ-RAMOS J-CWILLIAMS TJRANKIN SM: "Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence", IMMUNITY, vol. 19, no. 4, 2003, pages 583 - 93
MARTIN-GRANADOS CPRESCOTT ARLE SOMMER SKLASKA IPYU TMUCKERSIE E ET AL.: "A key role for PTP1B in dendritic cell maturation, migration, and T cell activation", JOURNAL OF MOLECULAR CELL BIOLOGY, vol. 7, no. 6, 2015, pages 517 - 28
MATTHAY MAZEMANS RL: "The acute respiratory distress syndrome: pathogenesis and treatment", ANNUAL REVIEW OF PATHOLOGY: MECHANISMS OF DISEASE, vol. 6, 2011, pages 147 - 63, XP055399826, DOI: 10.1146/annurev-pathol-011110-130158
MEDGYESI DHOBEIKA EBIESEN RKOLLERT FTADDEO AVOLL RE ET AL.: "The protein tyrosine phosphatase PTP1B is a negative regulator of CD40 and BAFF-R signaling and controls B cell autoimmunity", JOURNAL OF EXPERIMENTAL MEDICINE, vol. 211, no. 3, 2014, pages 427 - 440
MEIJER MRIJKERS GTVAN OVERVELD FJ: "Neutrophils and emerging targets for treatment in chronic obstructive pulmonary disease", EXPERT REVIEW OF CLINICAL IMMUNOLOGY, vol. 9, no. 11, 2013, pages 1055 - 68
NEMZEK JAHUGUNIN KOPP MR: "Modeling sepsis in the laboratory: merging sound science with animal well-being", COMPARATIVE MEDICINE, vol. 58, no. 2, 2008, pages 120 - 8
NICHOLLS DJWILEY KDAINTY IMACINTOSH FPHILLIPS CGAW A ET AL.: "Pharmacological characterization of AZD5069, a slowly reversible CXC chemokine receptor 2 antagonist", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTIC, vol. 353, no. 2, 2015, pages 340 - 50
PENG ZLIU CVICTOR ARCAO D-YVEIRAS LCBERNSTEIN EA ET AL.: "Tumors exploit CXCR4hiCD62Llo aged neutrophils to facilitate metastatic spread", ONCOIMMUNOLOGY, vol. 10, no. 1, 2021, pages 1870811
PETRI BSANZ M-J: "Neutrophil chemotaxis", CELL AND TISSUE RESEARCH, vol. 371, no. 3, 2018, pages 425 - 36, XP036434846, DOI: 10.1007/s00441-017-2776-8
PIKE KAHUTCHINS APVINETTE VTHEBERGE J-FSABBAGH LTREMBLAY MI ET AL.: "Protein tyrosine phosphatase 1B is a regulator of the interleukin-10-Induced transcriptional program in macrophages", SCIENCE SIGNALING, vol. 7, no. 324, 2014
RANKIN SM: "The bone marrow: a site of neutrophil clearance", JOURNAL OF LEUKOCYTE BIOLOGY, vol. 88, no. 2, 2010, pages 241 - 51
RAVICHANDRAN LVCHEN HLI YQUON MJ: "Phosphorylation of PTP1B at Ser50 by Akt impairs its ability to dephosphorylate the insulin receptor", MOLECULAR ENDOCRINOLOGY, vol. 15, no. 10, 2001, pages 1768 - 80
RIDLEY AJSCHWARTZ MABURRIDGE KFIRTEL RAGINSBERG MHBORISY G ET AL.: "Cell migration: integrating signals from front to back", SCIENCE, vol. 302, no. 5651, 2003, pages 1704 - 9
ROSALES C: "Neutrophil: a cell with many roles in inflammation or several cell types?", FRONTIERS IN PHYSIOLOGY, vol. 9, 2018, pages 113
SALMEEN AANDERSEN JNMYERS MPTONKS NK: "Barford D. Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B", MOLECULAR CELL, vol. 6, no. 6, 2000, pages 1401 - 12
SANTOS SSKCRIGATO OMACHADO FRSILVA ESALOMAO R: "Generation of nitric oxide and reactive oxygen species by neutrophils and monocytes from septic patients and association with outcomes", SHOCK, vol. 38, no. 1, 2012, pages 18 - 23
SARBASSOV DDGUERTIN DAALI SMSABATINI DM: "Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex", SCIENCE, vol. 307, no. 5712, 2005, pages 1098 - 101, XP002379044, DOI: 10.1126/science.1106148
SASAKI TIRIE-SASAKI JJONES RGOLIVEIRA-DOS-SANTOS AJSTANFORD WL, BOLON B ET AL.: "Function of PI3Ky in thymocyte development, T cell activation, and neutrophil migration", SCIENCE, vol. 287, no. 5455, 2000, pages 1040 - 6, XP002214938, DOI: 10.1126/science.287.5455.1040
SCHEIERMANN CKUNISAKI YLUCAS DCHOW AJANG J-EZHANG D ET AL.: "Adrenergic nerves govern circadian leukocyte recruitment to tissues", IMMUNITY, vol. 37, no. 2, 2012, pages 290 - 301
SCHLOSS MJHORCKMANS MNITZ KDUCHENE JDRECHSLER MBIDZHEKOV K ET AL.: "The time-of-day of myocardial infarction onset affects healing through oscillations in cardiac neutrophil recruitment", EMBO MOLECULAR MEDICINE, vol. 8, no. 8, 2016, pages 937 - 48
SHEN XCAO KZHAO YDU J: "Targeting Neutrophils in Sepsis: From Mechanism to Translation", FRONTIERS IN PHARMACOLOGY, vol. 12, 2021
SMITH AMMAGUIRE-NGUYEN KKRANDO TAZASLOFF MASTRANGE KBYIN VP: "The protein tyrosine phosphatase 1B inhibitor MSI-1436 stimulates regeneration of heart and multiple other tissues", NPJ REGENERATIVE MEDICINE, vol. 2, no. 1, 2017, pages 1 - 10
SMITH ASHLEY M. ET AL: "The protein tyrosine phosphatase 1B inhibitor MSI-1436 stimulates regeneration of heart and multiple other tissues", NPJ REGENERATIVE MEDICINE, vol. 2, no. 1, 3 March 2017 (2017-03-03), XP093074640, Retrieved from the Internet <URL:https://www.nature.com/articles/s41536-017-0008-1.pdf> DOI: 10.1038/s41536-017-0008-1 *
SONG ET AL.: "PTP1B inhibitors protect against acute lung injury and regulate CXCR4 signaling in neutrophils", JCI INSIGHT, vol. 7, 2022, pages e158199
SREERAMKUMAR VADROVER JMBALLESTEROS ICUARTERO MIROSSAINT JBILBAO I ET AL.: "Neutrophils scan for activated platelets to initiate inflammation", SCIENCE, vol. 346, no. 6214, 2014, pages 1234 - 8, XP055184191, DOI: 10.1126/science.1256478
STARK MAHUO YBURCIN TLMORRIS MAOLSON TSLEY K: "Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17", IMMUNITY, vol. 22, no. 3, 2005, pages 285 - 94, XP055050379, DOI: 10.1016/j.immuni.2005.01.011
SUMMERS CRANKIN SMCONDLIFFE AMSINGH NPETERS AMCHILVERS ER: "Neutrophil kinetics in health and disease", TRENDS IN IMMUNOLOGY, vol. 31, no. 8, 2010, pages 318 - 24
TONKS NK: "PTP1B: from the sidelines to the front lines", FEBS LETTERS, vol. 546, no. 1, 2003, pages 140 - 8, XP071244434, DOI: 10.1016/S0014-5793(03)00603-3
TONKS NKMUTHUSWAMY SK: "A brake becomes an accelerator: PTP1B—a new therapeutic target for breast cancer", CANCER CELL, vol. 11, no. 3, 2007, pages 214 - 6
TRAVES ET AL., CELL DEATH & DISEASE, 2014, pages e1125 - e1125
WEIGELT BWARNE PHLAMBROS MBREIS-FILHO JS: "Downward J. PI3K pathway dependencies in endometrioid endometrial cancer cell lines", CLINICAL CANCER RESEARCH, vol. 19, no. 13, 2013, pages 3533 - 44, XP093059093, DOI: 10.1158/1078-0432.CCR-12-3815
WENGNER AMPITCHFORD SCFURZE RCRANKIN SM: "The coordinated action of G-CSF and ELR+ CXC chemokines in neutrophil mobilization during acute inflammation", BLOOD, THE JOURNAL OF THE AMERICAN SOCIETY OF HEMATOLOGY, vol. 111, no. 1, 2008, pages 42 - 9, XP007911687, DOI: 10.1182/blood-2007-07-099648
WIEDE FLU K-HDU XZEISSIG MNXU RGOH PK ET AL.: "PTP1B is an intracellular checkpoint that limits T cell and CAR T cell anti-tumor immunity", CANCER DISCOVERY, 2021
WINTERS BDEBERLEIN MLEUNG JNEEDHAM DMPRONOVOST PJSEVRANSKY JE: "Long-term mortality and quality of life in sepsis: a systematic review", CRITICAL CARE MEDICINE, vol. 38, no. 5, 2010, pages 1276 - 83
WOODBERRY TBOUFFLER SEWILSON ASBUCKLAND RLBRUSTLE A: "The emerging role of neutrophil granulocytes in multiple sclerosis", JOURNAL OF CLINICAL MEDICINE, vol. 7, no. 12, 2018, pages 511
WU JIANZHI ET AL: "Ferulic Acid Ameliorates Hepatic Inflammation and Fibrotic Liver Injury by Inhibiting PTP1B Activity and Subsequent Promoting AMPK Phosphorylation", FRONTIERS IN PHARMACOLOGY, vol. 12, 8 September 2021 (2021-09-08), XP093074629, DOI: 10.3389/fphar.2021.754976 *
WU JXUE XFAN GGU YZHOU FZHENG Q ET AL.: "Ferulic acid ameliorates hepatic inflammation and fibrotic liver injury by inhibiting PTP1B activity and subsequent promoting AMPK phosphorylation", FRONTIERS IN PHARMACOLOGY, vol. 12, 2021
WU XIALEI ET AL: "Ferulic acid alleviates lipopolysaccharide-induced acute lung injury through inhibiting TLR4/NF-[kappa]B signaling pathway", JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, vol. 35, no. 3, 2 November 2020 (2020-11-02), US, XP093074634, ISSN: 1095-6670, Retrieved from the Internet <URL:https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jbt.22664> DOI: 10.1002/jbt.22664 *
WULLSCHLEGER SLOEWITH RHALL MN: "TOR signaling in growth and metabolism", CELL, vol. 124, no. 3, 2006, pages 471 - 84, XP055122745, DOI: 10.1016/j.cell.2006.01.016
XU QWU NLI XGUO CLI CJIANG B ET AL.: "Inhibition of PTP1B blocks pancreatic cancer progression by targeting the PKM2/AMPK/mTOC1 pathway", CELL DEATH & DISEASE, vol. 10, no. 12, 2019, pages 1 - 15, XP055880594, DOI: 10.1038/s41419-019-2073-4
XU XWANG XGUO YBAI YHE SWANG N ET AL.: "Inhibition of PTP1B promotes M2 polarization via microRNA-26a/MKP1 signaling pathway in murine macrophages", FRONTIERS IN IMMUNOLOGY, vol. 10, 2019, pages 1930
XUE QHOPKINS BPERRUZZI CUDAYAKUMAR DSHERRIS DBENJAMIN LE: "Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability", CANCER RESEARCH, vol. 68, no. 22, 2008, pages 9551 - 7, XP008154527, DOI: 10.1158/0008-5472.CAN-08-2058
YAO ZDAROWSKI KST-DENIS NWONG VOFFENSPERGER FVILLEDIEU A ET AL.: "A global analysis of the receptor tyrosine kinase-protein phosphatase interactome", MOLECULAR CELL, vol. 65, no. 2, 2017, pages 347 - 60, XP029890335, DOI: 10.1016/j.molcel.2016.12.004
ZHANG DCHEN GMANWANI DMORTHA AXU CFAITH JJ ET AL.: "Neutrophil ageing is regulated by the microbiome", NATURE, vol. 525, no. 7570, 2015, pages 528 - 32
ZHAO SCHEN FYIN QWANG DHAN WZHANG Y: "Reactive oxygen species interact with NLRP3 inflammasomes and are involved in the inflammation of sepsis: from mechanism to treatment of progression", FRONTIERS IN PHYSIOLOGY, vol. 11, 2020
ZHENG XMWANG YFALLEN CJ: "Cell transformation and activation of pp60c-src by overexpression of a protein tyrosine phosphatase", NATURE, vol. 359, no. 6393, 1992, pages 336 - 9
ZHOU PYANG X-LWANG X-GHU BZHANG LZHANG W ET AL.: "A pneumonia outbreak associated with a new coronavirus of probable bat origin", NATURE, vol. 579, no. 7798, 2020, pages 270 - 3

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