US20160279209A1 - Compositions and methods for administration of an enzyme to a subject's airway - Google Patents

Compositions and methods for administration of an enzyme to a subject's airway Download PDF

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US20160279209A1
US20160279209A1 US15/034,019 US201415034019A US2016279209A1 US 20160279209 A1 US20160279209 A1 US 20160279209A1 US 201415034019 A US201415034019 A US 201415034019A US 2016279209 A1 US2016279209 A1 US 2016279209A1
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composition
plasminogen activator
solution
subject
nebulized
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Robert O. Williams, III
Steven Idell
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University of Texas System
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/49—Urokinase; Tissue plasminogen activator
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21068—Tissue plasminogen activator (3.4.21.68), i.e. tPA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21073—Serine endopeptidases (3.4.21) u-Plasminogen activator (3.4.21.73), i.e. urokinase

Definitions

  • the present invention relates generally to the field of molecular biology, drug delivery and medicine. More particularly, it concerns compositions and methods for the delivery of therapeutic enzymes compositions to a subjects respiratory system.
  • ISALI Inhalational smoke
  • ISALI burn injuries affect over 1 million patients in the United Sates annually and ISALI affects thousands of smoke-exposed patients in civilian and military practice annually (Enkhbaatar et al., 2004a). ISALI contributes to more than 3000 deaths and 17,000 fire-related injuries in the United States annually and a fire-related mortality rate of 2-3/100,000 population, which is one of the highest in the developed world [Committee on injury and poison prevention (2000) Pediatrics 105:1355-1357]. Supportive care is suboptimal, protracted and expensive. Outcomes entail significant mortality and morbidity. Despite current supportive care including mechanical ventilation, the mortality rate of ARDS, including that associated with ISALI, approaches 30-40 percent (Phua et al., 2009).
  • ISALI is associated with severe respiratory impairment, protracted hospitalization and, often, the requirement for mechanical ventilation.
  • Long-term complications of ISALI include bronchial reactivity, accelerated pulmonary fibrosis and bronchiectasis.
  • ISALI is especially prone to aberrant fibrin turnover including fibrin casts that form in the large airways and fibrin in the alveoli (Enkhbaatar et al., 2004a). Bronchial casts interfere with gas exchange, often require bronchoscopic clearance and promote atelectasis.
  • the enzyme can be a tissue plasminogen activator, which includes a single chain urokinase plasminogen activator (scuPA) and a tissue plasminogen activator (tPA).
  • scuPA single chain urokinase plasminogen activator
  • tPA tissue plasminogen activator
  • the vibrating mesh nebulizer is an AERONEB® Professional Nebulizer or an EZ Breathe Atomizer.
  • a method of preparing an enzyme solution for administration to a subject's airway comprising nebulizing the enzyme solution to provide a nebulized solution.
  • the enzyme may be a plasminogen activator, such as a single chain urokinase plasminogen activator (scuPA) or a tissue plasminogen activator (tPA).
  • scuPA single chain urokinase plasminogen activator
  • tPA tissue plasminogen activator
  • nebulizing the enzyme solution may be by using a vibrating mesh nebulizer.
  • nebulizing the enzyme solution does not comprise use of a jet nebulizer or an ultrasonic nebulizer.
  • nebulizing an enzyme solution of the embodiments may comprise providing sufficient nebulization energy and/or time to provide a nebulized solution having a median droplet size of between about 2.5 ⁇ m and 10 ⁇ m, 2.5 ⁇ m and 8 ⁇ m, or 3.0 ⁇ m and 6 ⁇ m.
  • nebulizing the enzyme solution comprises obtaining a lyophilized enzyme composition, reconstituting the lyophilized enzyme composition in a solution (e.g., an aqueous solution) to provide an enzyme solution, and nebulizing the enzyme solution.
  • a nebulized enzyme solution produced in accordance with the methods of the embodiments.
  • composition or enzyme solution of the embodiments may be an aqueous solution.
  • the enzyme solution comprises a physiologically acceptable salt concentration and/or a pH buffering agent.
  • enzyme solution may be a sterile saline solution or phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • the composition or enzyme solution comprises scuPA.
  • a method treating a subject comprising administering a nebulized enzyme solution (e.g., a tPA and/or scuPA enzyme solution) to the airway of a subject in need thereof.
  • a nebulized enzyme solution e.g., a tPA and/or scuPA enzyme solution
  • the subject may have an acute lung injury or infection.
  • subject for treatment has inhalational smoke induced acute lung injury (ISALI), chemical-induced lung injury, plastic bronchitis, severe asthma, or acute respiratory distress syndrome (ARDS).
  • ISALI inhalational smoke induced acute lung injury
  • the plasminogen activator is nebulized using nebulizer, such as a vibrating mesh nebulizer (e.g., the AERONEB® Professional Nebulizer or the EZ Breathe Atomizer).
  • nebulizer such as a vibrating mesh nebulizer (e.g., the AERONEB® Professional Nebulizer or the
  • a composition comprising a plasminogen activator and a perfluorocarbon (e.g., a “breathing liquid”).
  • a perfluorocarbon e.g., a “breathing liquid”.
  • the plasminogen activator is scuPA and/or tPA.
  • the perfluorocarbon may comprise a cycloalkyl group.
  • the perfluorocarbon may be perfluorodecalin and/or perfluoro-octylbromide.
  • Another further embodiment of the invention provides a method for treating a subject having a lung infection or lung injury comprising administering to the subject a therapeutically effective amount of a composition comprising a plasminogen activator and a perfluorocarbon.
  • the plasminogen activator is a scuPA or a tPA.
  • the perfluorocarbon may be perfluorodecalin and/or perfluoro-octylbromide.
  • FIG. 1 is a graph showing that intratracheal delivery of recombinant scuPA in mice with bleomycin-induced ALI increases BAL uPA activity.
  • FIG. 2 shows that treatment of a sheep with nebulized scuPA provided detectable uPA activity associated with human uPA antigen after scuPA treatment (Lane 3). uPA antigen and activity were likewise found in lung homogenates (Lane 4) from the scuPA-treated animal Lane 1: uPA standard and Lane 2: baseline uPA activity.
  • FIG. 3 is a schematic showing the methods of preparing several different nebulized single chain urokinase plasminogen activator (scuPA) formulations.
  • scuPA single chain urokinase plasminogen activator
  • FIG. 4 is a schematic showing the activity of the nebulized scuPA formulations prepared according to FIG. 3 .
  • FIG. 5 is a schematic showing the activity of tissue plasminogen activator (tPA) once mixed with perfluorodecalin (PFD) or perfluoro-octylbromide (PFB).
  • tPA tissue plasminogen activator
  • a method of preparing an enzyme solution for administration to a subject's airway comprising nebulizing the enzyme solution using a nebulizer, such as a vibrating mesh nebulizer. It is a surprising finding of the present studies detailed herein that nebulization of enzymes, such by using a vibrating mesh nebulizer, results in nebulized compositions that maintain significant enzymatic activity levels. Also provided herein is a method of treating lung injuries and infections, such as inhalational smoke induced acute lung injury (ISALI) in a subject by administering to the subject a therapeutically effective amount of a nebulized plasminogen activator via an airway.
  • ISALI inhalational smoke induced acute lung injury
  • the plasminogen activator is nebulized using a vibrating mesh nebulizer.
  • a composition comprising a plasminogen activator and a perfluorocarbon, and a method for using the plasminogen activator /perfluorocarbon composition to treat lung injury and infection (e.g., ISALI).
  • an enzyme for use according to the embodiments is a proenzyme.
  • the enzyme a plasminogen activator.
  • an enzyme for use herein is a plasminogen activator selected from tPA and scuPA.
  • tissue plasminogen activator and “tPA” are used interchangeably and refer herein to a serine protease (in some embodiments, EC 3.4.21.68) that can be involved in the conversion of plasminogen to plasmin. It should be understood that the terms “tissue plasminogen activator” and “tPA” include recombinant forms including, but not limited to,retepase, reteplase, tenecteplase, and desmoteplase.
  • tissue plasminogen activator and “tPA” further include the single chain form (sc-tPA), the two chain form (ds-tPA), and mixtures thereof
  • the tPA is a human tPA or a human-derived tPA.
  • single chain urokinase plasminogen activator and “scuPA” are used interchangeably and refer herein to a proenzyme of a urokinase serine protease (in some embodiments, EC 3.4.21.73), which serine protease can be involved in the conversion of plasminogen to plasmin.
  • the “single chain urokinase plasminogen activator” or “scuPA” can be activated by proteolytic cleavage between Lys158 and Ile159, resulting in two chains linked by a disulfide bond that form the serine protease enzyme.
  • Example 3 and FIG. 4 below describe the nebulization of scuPA using a vibrating mesh nebulizer and the surprisingly high enzymatic activity achieved following nebulization as compared to prior art methods of nebulization.
  • the vibrating mesh nebulizer is an AERONEB® Professional Nebulizer or an EZ Breathe Atomizer.
  • the term “enzyme solution” refers herein to any liquid formulation containing an enzyme that is suitable for nebulization.
  • the enzyme solution contains a pharmaceutically acceptable carrier or excipient as defined herein.
  • the enzyme solution is administered to a subject's airway via inhalation or any other method known to those of skill in the art.
  • airway refers herein to any portion of the respiratory tract including the upper respiratory tract, the respiratory airway, and the lungs.
  • the upper respiratory tract includes the nose and nasal passages, mouth, and throat.
  • the respiratory airway includes the larynx, trachea, bronchi and bronchioles.
  • the lungs include the respiratory bronchioles, alveolar ducts, alveolar sacs and alveoli.
  • Also provided herein is a method of treating inhalational smoke induced acute lung injury (ISALI) in a subject comprising administering to the subject a therapeutically effective amount of a nebulized plasminogen activator via an airway, wherein the plasminogen activator is nebulized using a vibrating mesh nebulizer.
  • the plasminogen activator is selected from a tPA and a scuPA.
  • the vibrating mesh nebulizer is an AERONEB® Professional Nebulizer or an EZ Breathe Atomizer.
  • treating ISALI indicates partially or completely delaying, alleviating, mitigating or reducing the intensity of one or more attendant symptoms of a disorder or condition such as an ISALI condition and/or alleviating, mitigating or impeding one or more causes of a disorder or condition such as an ISALI condition.
  • Treatments according to the invention may be applied preventively, prophylactically, pallatively or remedially.
  • the terms “treat,” “treating,” “treatment” and grammatical variations thereof include partially or completely reducing a condition or symptom associated with an ISALI condition as compared with prior to treatment of the subject or as compared with the incidence of such condition or symptom in a general or study population.
  • an ISALI condition includes one or more of: reduced oxygenation, airway obstruction (including a severe airway obstruction), fibrinous airway casts or debris, and alveolar fibrin deposition. Accordingly, treating an ISALI condition includes one or more of improvement of oxygenation, reduced airway obstruction, reduced fibrinous airway casts or debris, and reduced alveolar fibrin deposition. In some embodiments, an ISALI condition is treated with a reduced incidence of bleeding.
  • a composition comprising a plasminogen activator and a perfluorocarbon (PFC).
  • the plasminogen activator in the composition is selected from a tPA and a scuPA.
  • the PFC in the composition is selected from perfluorodecalin, perfluoro-1,3-dimethylcyclohexane, FC-75, perfluorooctane and perfluoro-octylbromide.
  • PFC is or comprises a PFC having a cycloalkyl group, such as perfluorodecalin, perfluoro-1,3-dimethylcyclohexane or FC-75. It should be understood that the plasminogen activator and PFC can be in any ratio or concentration.
  • the composition comprises a plasminogen activator at a concentration of approximately 0.005-0.040 mg/mL of PFC.
  • Example 4 and FIG. 5 demonstrate that a plasminogen activator, tPA, retained activity in a perfluorocarbon mixture.
  • the PFC and plasminogen activator additively foster airway debris removal as well as clearance of alveolar fibrin and improved outcome.
  • the PFC effectively delivers the plasminogen activator which promotes 1) dissolution and dislodgement of the airway casts; and 2) removal of airway and alveolar debris while supporting respiratory gas exchange.
  • the PFC effectively recruits lung volume.
  • the PFC distributes the plasminogen activator throughout the lung, potentially between casts and airway wall, thus breaking down the casts as they are being formed while slowing formation of new casts.
  • the plasminogen activator remains to further act to dissolve airway casts and alveolar fibrin.
  • the PFC volumes Upon redosing with PFC suspensions, the PFC volumes not only deposit additional drug but dislodge the casts and alveolar debris. Because the PFC is incompressible, it stents open damaged small airways and thereby aids recruitment.
  • contact with PFCs may also protect the underlying epithelium through attenuation of coagulation, which is initiated by tissue factor in the small airways and alveoli in virtually all forms of ALI.
  • tissue factor in the small airways and alveoli in virtually all forms of ALI.
  • the lower density debris float in the relatively more dense PFC, facilitating removal of airway fibrin cast fragments and debris.
  • the plasminogen activator is selected from a tPA and a scuPA.
  • the PFC in the composition is selected from perfluorodecalin and perfluoro-octylbromide.
  • a cell includes a plurality of cells, including mixtures thereof.
  • administering refers to an administration that is oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra joint, parenteral, intra-arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, by inhalation or via an implanted reservoir.
  • parenteral includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques.
  • the administration is via inhalation of a nebulized composition.
  • airway refers herein to any portion of the respiratory tract including the upper respiratory tract, the respiratory airway, and the lungs.
  • the upper respiratory tract includes the nose and nasal passages, mouth, and throat.
  • the respiratory airway includes the larynx, trachea, bronchi and bronchioles.
  • the lungs include the respiratory bronchioles, alveolar ducts, alveolar sacs and alveoli.
  • composition is intended to mean a combination of active agent and another compound or composition, inert (for example, a detectable agent or label) or active, such as an adjuvant.
  • compositions and methods include the recited elements, but not excluding others.
  • Consisting essentially of when used to define compositions and methods shall mean excluding other elements of any essential significance to the combination.
  • a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like.
  • Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this invention. Embodiments defined by each of these transition terms are within the scope of this invention.
  • a “control” is an alternative subject or sample used in an experiment for comparison purpose.
  • a control can be “positive” or “negative.”
  • “Mammal” for purposes of treatment refers to any animal classified as a mammal, including a human, domestic and farm animals, nonhuman primates, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, etc.
  • enzyme refers herein to one or more polypeptides that catalyze a specific biochemical reaction or to a proenzyme.
  • proenzyme refers to a biologically active substance that is metabolized into an enzyme.
  • the enzyme is a tissue plasminogen activator (tPA).
  • tPA tissue plasminogen activator
  • scuPA single chain urokinase plasminogen activator
  • fibrinolysin refers herein to any of several proteolytic enzymes that promote the dissolution of blood clots.
  • a fibrinolysin includes, but is not limited to, plasmin, tissue plasminogen activator (tPA, sc-tPA and dc-tPA), urokinase (uPA), and urokinase proenzymes (scuPA).
  • identity or “homology” shall be construed to mean the percentage of amino acid residues in the candidate sequence that are identical with the residue of a corresponding sequence to which it is compared, after aligning the sequences and introducing gaps, if necessary to achieve the maximum percent identity for the entire sequence, and not considering any conservative substitutions as part of the sequence identity. Neither N- or C-terminal extensions nor insertions shall be construed as reducing identity or homology. Methods and computer programs for the alignment are well known in the art. Sequence identity may be measured using sequence analysis software.
  • ISALI inhalational smoke induced acute lung injury
  • ALI is also referred to as “mild ARDS.”
  • ALI can be defined by finding one or more of the following conditions in a subject: 1) bilateral pulmonary infiltrates on chest x-ray, 2) when measured by right heart catheterization as clinically indicated, pulmonary capillary wedge pressure ⁇ 18 mmHg (2.4 kPa), and 3) PaO2/FiO2 ⁇ 300 mmHg (40 kPa).
  • treatment of ISALI includes treatment of one or more of the following conditions: reduced oxygenation, airway obstruction (including a severe airway obstruction), fibrinous airway casts or debris, and alveolar fibrin deposition.
  • the terms “nebulizing,” “nebulized” and other grammatical variations, refer herein to the process of converting a liquid into small aerosol droplets.
  • the aerosol droplets have a median diameter of approximately 2-10 ⁇ m. In some embodiments, the aerosol droplets have a median diameter of approximately 2-4 ⁇ m.
  • perfluorocarbon and “PFC” are used interchangeably and refer herein to an organofluorine compound that contains predominantly carbon and fluorine. It should be understood that the term “perfluorocarbon” is meant to include highly fluorinated molecules that contain molecules in addition to carbon and fluorine, and are commonly referred to as fluorocarbons. Examples of perfluorocarbons include, but are not limited to, perfluorodecalin, perfluoro-octylbromide, FC 77, PF 5060 and Rimar 101.
  • PFCs used according to the present invention share similar physicochemical properties with respect to gas solubility, density and surface tension but may differ with respect to radio-opacity and kinematic viscosity which could have an impact on visualization and mobility of airway casts during debridement.
  • Each listed perfluorocarbon includes all relevant isomers such as stereoisomers, enantiomers, and diastereomers.
  • plasminogen activator refers to a serine protease polypeptide that conversts plasminogen to plasmin, and includes, but is not limited to, tPA, uPA (two chain or active forms) and a proenzyme scuPA as defined herein.
  • a “pharmaceutical composition” is intended to include the combination of an active agent with a carrier, inert or active, making the composition suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo.
  • the term “pharmaceutically acceptable carrier” or “excipient” encompasses any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, saline (including sterile saline), water, and emulsions, such as an oil/water or water/oil emulsion, where “oil” represents the water immiscible phase of the emulsion that is pharmaceutically acceptable, and various types of wetting agents.
  • the compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see Martin, REMINGTON'S PHARM. SCI., 15th Ed. (Mack Publ. Co., Easton (1975)).
  • pharmaceutically acceptable salts refers to any acid or base addition salt whose counter-ions are non-toxic to the subject to which they are administered in pharmaceutical doses of the salts. Specific examples of pharmaceutically acceptable salts are known to those of ordinary skill in the art.
  • pharmaceutically effective amount refers to the amount of a compound such as an ACPD composition that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • polypeptide is used in its broadest sense to refer to a compound of two or more subunit amino acids, amino acid analogs, or peptidomimetics.
  • the subunits may be linked by peptide bonds. In another embodiment, the subunit may be linked by other bonds, e.g. ester, ether, etc.
  • amino acid refers to either natural and/or unnatural or synthetic amino acids, including glycine and both the D or L optical isomers, and amino acid analogs and peptidomimetics.
  • a peptide of three or more amino acids is commonly called an oligopeptide if the peptide chain is short. If the peptide chain is long, the peptide is commonly called a polypeptide or a protein.
  • a polynucleotide or polynucleotide region has a certain percentage (for example, 80%, 85%, 90%, or 95%) of “sequence identity” or “homology” to another sequence means that, when aligned, that percentage of bases (or amino acids) are the same in comparing the two sequences.
  • This alignment and the percent homology or sequence identity can be determined using software programs known in the art, for example those described in CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (F. M. Ausubel et al., eds., 1987) Supplement 30, section 7.7.18, Table 7.7.1.
  • default parameters are used for alignment.
  • a preferred alignment program is BLAST, using default parameters.
  • prevent refers to a method of partially or completely delaying or precluding the onset or recurrence of a disorder or conditions and/or one or more of its attendant symptoms or barring a subject from acquiring or reacquiring a disorder or condition or reducing a subject's risk of acquiring or reacquiring a disorder or condition or one or more of its attendant symptoms.
  • subject is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
  • pharmaceutically effective amount refers to the amount of a compound such as a tPA and/or scuPA composition that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • single chain urokinase plasminogen activator and “scuPA” are used interchangeably and refer herein to a proenzyme of a urokinase serine protease polypeptide (in some embodiments, EC 3.4.21.73), which serine protease can be involved in the conversion of plasminogen to plasmin, or to a proenzyme as described in U.S. Pat. No. 7,332,469, incorporated herein by reference.
  • scuPA single chain urokinase plasminogen activator
  • scuPA homolog refers herein to homologs, orthologs, and paralogs of the proenzyme of the urokinase serine protease polypeptide identified as EC 3.4.21.73 and other sequences having greater than 70% homology to the proenzyme of the urokinase serine protease polypeptide identified as EC 3.4.21.73, or to a proenzyme as described in U.S. Pat. No. 7,332,469.
  • a “subject,” “individual” or “patient” is used interchangeably herein, which refers to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets.
  • therapeutically effective amount includes that amount of a compound such as a tPA and/or scuPA composition that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of an ISALI abnormality being treated.
  • the therapeutically effective amount will vary depending on the compound such as a tPA and/or scuPA composition, the disorder or conditions and their severity, the route of administration, the time of administration, the rate of excretion, the drug combination, the judgment of the treating physician, the dosage form, and the age, weight, general health, sex and/or diet of the subject to be treated.
  • tissue plasminogen activator and “tPA” are used interchangeably and refer herein to a serine protease (in some embodiments, EC 3.4.21.68) that can be involved in the conversion of plasminogen to plasmin. It should be understood that the terms “tissue plasminogen activator” and “tPA” include recombinant forms including, but not limited to,retepase, reteplase, tenecteplase, and desmoteplase.
  • tissue plasminogen activator and “tPA” further include the single chain form (sc-tPA), the two chain form (ds-tPA), and mixtures thereof
  • the tPA is a human tPA or a human-derived tPA. It should also be understood that tPA homologs are also included in the present invention.
  • tPA homolog refers to homologs, orthologs, and paralogs of the tissue plasminogen activator polypeptide identified as EC 3.4.21.68 and other sequences having greater than 70% homology to the tissue plasminogen activator polypeptide identified as EC 3.4.21.68.
  • the tPA is a single chain form such as the ALTEPASETM form.
  • treat include partially or completely delaying, alleviating, mitigating or reducing the intensity of one or more attendant symptoms of a disorder or condition such as an ISALI condition and/or alleviating, mitigating or impeding one or more causes of a disorder or condition such as an ISALI condition. Treatments according to the invention may be applied preventively, prophylactically, pallatively or remedially. In some instances, the terms “treat,” “treating,” “treatment” and grammatical variations thereof include partially or completely reducing a condition or symptom associated with an ISALI condition as compared with prior to treatment of the subject or as compared with the incidence of such condition or symptom in a general or study population.
  • an ISALI condition includes one or more of: reduced oxygenation, airway obstruction (including a severe airway obstruction), fibrinous airway casts or debris, and alveolar fibrin deposition.
  • an ISALI condition is treated with a reduced incidence of bleeding.
  • vibrating mesh nebulizer refers herein to any nebulizer that operates on the general principle of using a vibrating mesh or plate with multiple aperatures (an aperture plate) to generate a fine-particle, low-velocity aerosol.
  • Some nebulizers may contain a mesh/membrane with between 1000 and 7000 holes, which mesh/membrane vibrates at the top of a liquid reservoir (see, e.g., U.S. Patent Publn. 20090134235 and Waldrep and Dhand 2008, each incorporated herein by reference).
  • the vibrating mesh nebulizer is an AERONEB® Professional Nebulizer, Omron MICROAIR®, Pari EFLOW® or an EZ Breathe Atomizer
  • a vibrating mesh nebulizer has a vibrating frequency of between about 50-250 kHz, 75-200 kHz 100-150 kHz or about 120 kHz.
  • a sheep was treated with nebulized scuPA (2 mg/treatment begun 4 hours after induction of ISALI and continued every 4 hours ⁇ 48 hours.
  • Airway cast burden (obstruction score 12) fell into the range of sheep treated with nebulized tPA at 4 mg q 4 hours (vs. 20.7 in vehicle treated sheep with ISALI) (Enkhbaatar et al., 2004b). As shown in FIG.
  • BAL bronchoalveolar lavage
  • scuPA solutions containing 1 mg/mL of scuPA dissolved in either physiological buffered saline or normal saline were also conducted on scuPA solutions containing 1 mg/mL of scuPA dissolved in either physiological buffered saline or normal saline, and then nebulized using two types of vibrating mesh nebulizers, the EZ Breathe Atomizer and the AeroNeb Pro nebulizer.
  • scuPA readily dissolved in both liquid carriers. It was confirmed that the activity of scuPA before and after nebulization was not affected by the nebulizing conditions (e.g., solution formation, shear and temperature from the nebulizing process in the nebulizer). Also, it was confirmed that the median geometric particle size for the scuPA solutions was 3-4 microns with a narrow and acceptable size distribution. The materials, methods and results are provided below and a schematic of the procedure is provided in FIG. 3 .
  • the phosphate buffered saline (DPBS, Lot 14190-250, Gibco) was purchased from Biostore at UT-Austin.
  • the compositions of the PBS were as shown in Table 1.
  • the pH of the PBS was 7.3 ⁇ 0.1.
  • the sterile saline was purchased from B. Braun Medical Inc (Lot JIH573). Both preparations were stored at ambient room temperature, and excessive heat was avoided.
  • the EZ Breathe Atomizer nebulizer and AeroNeb pro nebulizer were used for testing.
  • the Aeroneb® Professional Nebulizer System (vibrating mesh, Aerogen, Galway) was a portable medical device for multiple patient use.
  • the Aeroneb® is intended to aerosolize physician-prescribed medications for inhalation that are approved for use with a general purpose nebulizer.
  • the EZ Breathe Atomizer (vibrating mesh, Nephron Pharmaceuticals Corporation, USA) is a device that is intended to spray liquid medication in aerosol form into the air that a person will breathe. These devices can be used by patients with and without mechanical ventilation, or other positive pressure breathing assistance.
  • A. scu-PA vials were held at room temperature (20° C.-25° C.) until they melted into solution. Two mL of the solution was transferred from the vial to a new 10 mL vial using a 6 mL syringe.
  • Both nebulizers were loaded with the two kinds of 5 mL scu-PA at a concentration of 1 mg/mL as samples and pure saline and pure PBS as blank controls, separately (8 samples in total).
  • the geometric particle-size distribution (PSD) was determined using a Malvern Spraytec. A standard nebulization procedure was performed 5 times; each test lasted for 5 seconds. All determinations were carried out at ambient room temperature, barometric pressure, and humidity.
  • PSD geometric particle-size distribution
  • scuPA solutions are optimized for nebulization focusing on identifying the best nebulizer.
  • Other parameters that are studied for nebulizer administration include confirming the effect of processing parameters (e.g., optimum solution composition for scuPA activity, aerodynamic properties including fine particle fraction, mass median aerodynamic diameter, and total emitted dose, temperature effects on scuPA activity during nebulization (e.g., using different nebulizer mechanism types), and the effects of shear (e.g., atomization pressure, ultrasonic vibrations, mesh size) of the liquid on scuPA activity.
  • processing parameters e.g., optimum solution composition for scuPA activity, aerodynamic properties including fine particle fraction, mass median aerodynamic diameter, and total emitted dose
  • temperature effects on scuPA activity during nebulization e.g., using different nebulizer mechanism types
  • shear e.g., atomization pressure, ultrasonic vibrations, mesh size
  • FIG. 5 shows that suspension of tPA in PFCs is stable and that tPA activity is preserved.
  • the tPA/PFC suspensions (18 mL of the tPA-PFC suspension made at 0.22 mg/mL) were injected through the endotracheal tube (7 mm adult endotracheal tube) during the 50 minute hold time at 37° C. using a 10 mL syringe and 21 gauge needle. It was noted that the tPA was adequately wetted and deagglomerated in the PFCs.
  • Other parameters that are studied for tPA administration include confirming the effect of processing parameters (e.g., particle size reduction of the tPA, viscosity of the PFC and resulting tPA-PFC suspension, solids content of the tPA-PFC suspension and its effect on administration during bronchoscopy on the tPA activity). The same approach is then used to analyze the formulations of the scuPA-PFC interventions.
  • processing parameters e.g., particle size reduction of the tPA, viscosity of the PFC and resulting tPA-PFC suspension, solids content of the tPA-PFC suspension and its effect on administration during bronchoscopy on the tPA activity.
  • the PFC and fibrinolysins additively foster airway debris removal as well as clearance of alveolar fibrin and improved outcome.
  • the PFC effectively delivers the fibrinolysins which promote 1) dissolution and dislodgement of the airway casts; and 2) removal of airway and alveolar debris while supporting respiratory gas exchange.
  • the PFC effectively recruits lung volume.
  • the PFC distributes the fibrinolysin throughout the lung, potentially between casts and airway wall, thus breaking down the casts as they are being formed while slowing formation of new casts.
  • the fibrinolysin remains to further act to dissolve airway casts and alveolar fibrin.
  • the PFC volumes Upon redosing with PFC suspensions, the PFC volumes not only deposit additional drug but dislodge the casts and alveolar debris. Because the PFC is incompressible, it stents open damaged small airways and thereby aids recruitment. Contact with PFCs may also protect the underlying epithelium through attenuation of coagulation, which is initiated by tissue factor in the small airways and alveoli in virtually all forms of ALI. With in-line suctioning, the lower density debris float in the relatively more dense PFC, facilitating removal of airway fibrin cast fragments and debris.

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