Granted Patent B2

US 12,285,471 · App. 17/821,713 · Granted Apr 29, 2025

Inventors: Yow-Pin Lim (Providence, RI); Denice Spero (Providence, RI); Richard Andrews (Providence, RI)

Assignee: Prothera Biologics, Inc.

A61K38/57A61K9/0019A61K38/55A61P11/00A61P31/04C07K14/811A61K45/06

Abstract

Claims (109)

1. A method of treating acute respiratory distress syndrome (ARDS) or pneumonia in a subject in need thereof comprising administering to the subject inter-alpha inhibitor proteins (IαIps), wherein the subject is an adult human with a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO 2/ FiO 2 ) of about 300 mm Hg or less, wherein the method comprises administering the IαIps to the subject prior to development of sepsis, wherein the IαIps comprise IαI and PαI, and wherein the IαI and PαI are in physiological proportions.

2. The method of claim 1 , wherein:

a) the ARDS or the pneumonia is caused by a bacterial infection;

b) the subject has one or more symptoms of the ARDS comprising shortness of breath, cough, fever, rapid heart rate, low blood pressure, rapid breathing, chest pain, bluish coloring of nails, or bluish coloring of lips;

c) the subject has one or more symptoms of the pneumonia comprising cough, fever, shaking chills, shortness of breath, wheezing, chest pain, headache, excessive sweating, clammy skin, loss of appetite, low energy, fatigue, confusion, muscle pain, muscle weakness, or inflammation;

d) the ARDS comprises acute respiratory failure (ARF);

e) the ARDS results from pneumonia, ventilation induced pneumonia, trauma, damage to the brain, a blood transfusion, babesiosis, lung contusion, lung transplant, aspiration of stomach contents, drug abuse, drug overdose, a burn, pancreatitis, near drowning, inhalation of chemical fumes, or administration of resuscitation fluid;

f) g) the pneumonia comprises hospital-acquired pneumonia (HAP), health care-associated pneumonia (HCAP), nursing home-acquired pneumonia (NHAP), ventilator-associated pneumonia (VAP), or community-acquired pneumonia (CAP); or

g) the pneumonia results from an infection of lung tissue.

3. The method of claim 2 , wherein:

a) the bacterial infection is caused by an antibiotic resistant bacteria;

b) the ARDS results from inhalation of chemical fumes, and the chemical fumes are selected from the group consisting of smoke, phosgene, chlorine gas, acrolein, ammonia, ethylene oxide, formaldehyde, hydrogen chloride, hydrogen fluoride, hydrogen sulfide, methyl bromide, sodium azide, sulfur dioxide, cadmium fume, mercury fume, mustard gas, nickel carbonyl, oxides of nitrogen, and ozone;

c) the ARDS results from administration of resuscitation fluid, and the resuscitation fluid comprises colloid solutions;

d) the ARDS results from trauma, and the trauma is acidosis;

e) the pneumonia comprises CAP and the CAP is severe CAP (sCAP); or

f) the pneumonia results from an infection of lung tissue caused by a bacteria, a virus, a fungus, a parasite, or other microorganism.

4. The method of claim 1 , wherein the method comprises:

a) treating one or more symptoms of the ARDS comprising mild, moderate or severe hypoxemia as determined by Partial Pressure of arterial oxygen/Fraction of inspired oxygen (PaO 2/ FiO 2 ) or positive end-expiratory pressure (PEEP), bilateral opacities, respiratory failure, shortness of breath, labored breathing, cough, fever, increased heart rate, low blood pressure, confusion, extreme tiredness, rapid breathing, organ failure, chest pain, bluish coloring of nails or lips, a change in the level of one or more inflammatory markers, or need for mechanical ventilation;

b) treating one or more symptoms of the pneumonia comprising symptoms included in the CRB-65 test, the CURB-65 test, or the pneumonia severity index (PSI), cough, fever, shaking chills, shortness of breath, wheezing, chest pain, headache, excessive sweating, clammy skin, loss of appetite, low energy, fatigue, confusion, muscle pain, muscle weakness, or inflammation;

c) reducing inflammation and/or promoting repair in lung tissue;

d) reducing fluid in lung tissue;

e) administering IαIps to the subject prior to organ failure in the subject;

f) measuring the levels of IαIps in a biological sample derived from the subject prior to administration of the IαIps;

g) measuring the levels of histones or histone/IαI/PαI complexes in a biological sample derived from the subject;

h) restoring or exceeding the level of IαI and/or PαI in the lung tissue of the subject to that of a healthy subject;

i) administering a single dose or multiple doses of the IαIps sufficient to restore or exceed the level of the IαIps in the lung tissue of the subject;

i) neutralizing histones with the IαIps;

k) administering a composition comprising the IαIps;

l) administering the IαIps to the subject at least 10, 15, 20, 30, 60, or 120 minutes after a lung insult;

m) measuring the level of one or more biomarkers associated with the ARDS or the pneumonia in a biological sample derived from the subject;

n) administering a second treatment for the ARDS or the pneumonia; or

o) administering an inhibitor of complement activation.

5. The method of claim 4 , wherein:

a) the one or more inflammatory markers is selected from the group consisting of TNF-alpha, interleukin 6 (IL-6), complement component 5a (C5a),damage-associated molecular patterns (DAMPs), extracellular-signal-regulated kinase (ERK), nuclear factor-kappa B (NF-κB), interleukin 10 (IL-10), and a serine protease;

b) the change in the level of one or more inflammatory markers is an increase;

c) the change in the level of one or more inflammatory markers is a decrease;

d) the symptoms of the ARDS begin within 2 to 72 hours after a lung insult;

e) the lung tissue in which inflammation is reduced and/or repair is promoted or in which fluid is reduced is alveolar lung tissue;

f) the method comprises measuring the levels of IαI, PαI, an IαIp heavy chain, an IαIp light chain, or a combination thereof;

g) the single dose comprises about 1 mg/kg to about 50 mg/kg of the IαIps;

h) the composition comprises about 1 mg/kg to about 50 mg/kg of the IαI and PαI;

i) the biological sample derived from the subject is a blood sample, a urine sample, a sputum sample, or a bronchiolar lavage fluid sample;

j) the composition is administered to the subject one or more times every 1, 2, 3, 4, 5, 6, 8, 12, or 24 hours, every 1, 2, 3, 4, 5, or 6 days, or every 1, 2, 3, or 4 weeks;

k) the lung insult occurs as a result of radiation treatment, chemotherapy, exposure to high altitude, swimming, diving, or surgery;

l) the one or more biomarkers comprise histone, histone/PαI complexes, histone/IαI complexes, histone/IαI/PαI complexes, tumor necrosis factor alpha (TNF-α), IL-6, IL-10, interleukin 1 (IL-1), interleukin 1 receptor antagonist (IL-1ra), interleukin 1 beta (IL 1B), interleukin 8 (IL-8), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 2 (MIP-2), c-reactive protein (CRP), procalcitonin (PCT), cytokine-induced neutrophil chemoattractant/keratinocyte chemoattractant (KC), a complement component, or fragments thereof;

m) the second treatment comprises one or more of an antibiotic, an antiviral agent, an antifungal agent, an antiparasitic agent, an anti-inflammatory agent, a bronchodilator, a vasopressor, a sedative, or mechanical ventilation; or

n) administration of the IαIps

i) inhibits activation of one or more complement components;

ii) reduces the likelihood of death or hospitalization time for the subject; and/or

iii) reduces the physiological response to inflammatory mediators selected from the group consisting of cytokines, chemokines, complement, and histones.

6. The method of claim 3 , wherein:

a) the ARDS results from administration of resuscitation fluid, and the resuscitation fluid comprises colloid solutions, and the colloid solution comprises hydroxyethyl starch solution and/or albumin;

b) the pneumonia results from an infection of lung tissue caused by a bacteria, and the bacteria is an Enterobacteriaceae species (spp.), Streptococcus pneumoniae, Staphylococcus aureus, Bacillus anthracis, Haemophilus influenzae, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Bordetella pertussis, Moraxella catarrhalis, Coxiella burnetii, Chlamydophila pneumoniae , a Legionella spp., or Mycoplasma pneumoniae;

c) the pneumonia results from an infection of lung tissue and the infection is caused by a virus, and the virus is an influenza virus, parainfluenza, swine origin influenza, Respiratory syncytial virus, Human parainfluenza virus, an Adenovirus, a Metapneumovirus, Severe acute respiratory syndrome virus, herpes simplex virus (HSV), Varicella-zoster virus (VZV), measles virus, Rubella virus, Cytomegalovirus (CMV), smallpox virus, dengue virus, rhinovirus, bocavirus, or Middle East respiratory syndrome virus; or

d) the pneumonia results from an infection of lung tissue and the infection is caused by a fungus, and the fungus is Histoplasma capsulatum, Coccidioides immitis, Coccidioides posadasii, Pneumocystis jirovecii, Blastomyces dermatitidis, Sporothrix schenckii, Cryptococcus neoformans, Cryptococcus gattii, Paracoccidioides brasiliensis , a Candida spp., an Aspergillus spp., or a Mucor spp.

7. The method of claim 6 , wherein:

a) the pneumonia results from an infection of lung tissue and the infection is caused by methicillin-resistant Staphylococcus aureus (MRSA);

b) the pneumonia results from an infection of lung tissue and the infection is caused by Legionella pneumophila; or

c) the pneumonia results from an infection of lung tissue and the infection is caused by an influenza virus A or an influenza virus B.

8. The method of claim 5 , wherein:

a) the lung insult is or is caused by pneumonia, ventilation-induced pneumonia, trauma, damage to the brain, a blood transfusion, babesiosis, lung contusion, lung transplant, aspiration of stomach contents, drug abuse, drug overdose, a burn, pancreatitis, near drowning, inhalation of chemical fumes, lung transplant, a large volume of fluid used during post-trauma resuscitation, or infection of lung tissue;

b) the method comprises measuring the levels of IαI and/or PαI in the biological sample from the subject;

c) the composition of subpart h) comprises about 5 mg/kg to about 15 mg/kg of the IαI and and/or PαI;

d) the blood sample is whole blood, serum, plasma, or a combination thereof; or

e) the complement component biomarker is selected from the group consisting of complement component 1 (C1), complement component 2 (C2), complement component 3 (C3), complement component 3a (C3a), complement component 3b (C3b), complement component 4 (C4), complement component 4b (C4b), complement component 5 (C5), C5a, complement component 5b (C5b), complement component 6 (C6), complement component 7 (C7), complement component 8 (C8), complement component 9 (C9), membrane attack complex, Factor B, Factor D, mannan-binding lectin serine protease 1 (MASP-1), and mannan-binding lectin serine protease 2 (MASP-2).

9. The method of claim 8 , wherein

the chemical fumes are selected from the group consisting of smoke, phosgene, acrolein, ammonia, ethylene oxide, formaldehyde, hydrogen chloride, hydrogen fluoride, hydrogen sulfide, methyl bromide, sodium azide, sulfur dioxide, cadmium fume, mercury fume, mustard gas, nickel carbonyl, oxides of nitrogen, ozone and chlorine gas.

10. The method of claim 1 , wherein the subject exhibits:

a) decreased levels of IαI and/or PαI relative to a healthy subject;

b) increased levels of histones relative to a healthy subject; or

c) increased levels of histone/IαI/PαI complexes relative to an untreated subject.

11. The method of claim 10 , wherein the level of IαI and/or PαI of a healthy subject is about 300 mg/L to about 1000 mg/L of circulating IαI and/or PαI.

12. The method of claim 4 , wherein the composition:

a) further comprises a pharmaceutically acceptable excipient, diluent, or carrier, or an antibiotic agent, an antiviral agent, an antifungal agent, an anti-parasitic agent, an anti-inflammatory agent, a vasopressor, a sedative, a bronchodilator, or an inhibitor of complement activation;

b) is formulated as a solid, or liquid, or is formulated for inhalation, insufflation, nebulization, or injection, or is formulated for oral, rectal, topical, or intraperitoneal administration; or

c) has a half-life of greater than 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 7.5, or 10 hours.

13. The method of claim 12 , wherein:

a) the injection is intravenous injection;

b) the composition further comprises an antibiotic agent, and the antibiotic agent comprises amoxicillin, penicillin, doxycycline, clarithromycin, benzylpenicillin, azithromycin, daptomycin, linezolid, levofloxacin, moxifloxacin, gatifloxcin, gentamicin, macrolides, cephalosporins, azithromycin, ciprofloxacin, cefuroxime, amoxillin-potassium clavulanate, erythromycin, sulfamethoxazole-trimethoprim, doxycycline monohydrate, cefepime, ampicillin, cefpodoxime, ceftriaxone, cefazolin, erythromycin ethylsuccinate, meropenem, piperacillin-tazobactam, amikacin, erythromycin stearate, cefepime in dextrose, doxycycline hyclate, ampicillin-sulbactam, ceftazidime, gemifloxacin, gentamicin sulfate, erythromycin lactobionate, imipenem-cilastatin, cefoxitin, cefditoren pivoxil, ertapenem, doxycycline-benzoyl peroxide, ampicillin-sulbactam, meropenem, cefuroxime, cefotetan, or piperacillin-tazobactam;

c) the composition further comprises an antiviral agent, and the antiviral agent comprises zanamivir, oseltamivir, peramivir, ribavirin, acyclovir, ganciclovir, foscarnet, or cidofovir;

d) the composition further comprises an antifungal agent, and the antifungal agent comprises amphotericin, caspofungin, voriconazole, itraconazole, posaconazole, fluconazole, or flucytosine;

e) the composition further comprises an antiparasitic agent, and the antiparasitic agent comprises nitazoxanide, melarsoprol, eflornithine, metronidazole, tinidazole, miltefosine, mebendazole, pyrantel pamoate, thiabendazole, diethylcarbamazine, ivermectin, albendazole, praziquantel, or rifampin;

f) the composition further comprises an anti-inflammatory agent, and the anti-inflammatory agent comprises a corticosteroid, a statin, a steroid, a nonsteroidal anti-inflammatory drug, or a glucocorticoid;

g) the composition further comprises a bronchodilator, and the bronchodilator comprises a beta 2 agonist, a xanthine, ipratropium, oxitropium, a muscarinic receptor antagonist, ipratropium, oxitropium, theophylline, theobromine, caffeine, salbutamol, isoproterenol, albuterol, levalbuterol, pirbuterol, metaproterenol, terbutaline, salmeterol, or formoterol;

h) the composition further comprises a vasopressor, and the vasopressor comprises epinephrine, isoproterenol, phenylephrine, norepinephrine, dobutamine, ephedrine, or droxidopa; or

i) the composition further comprises a sedative, and the sedative comprises propofol, diprivan, morphine, fentanyl, midazolam, lorazepam, infumorph, dexmedetomidine, or alfentanil.

14. The method of claim 12 , wherein the composition further comprises an inhibitor of complement activation and the composition inhibits activation of one or more complement components, and the complement components comprise C1, C2, C3, C4, or C5.

15. The method of claim 1 , wherein the subject:

a) has the ARDS or the pneumonia;

b) is hospitalized;

c) requires ventilator-assisted breathing;

d) has one or more organ failures;

e) is identified as being in need of treatment using one or more of the following: chest imaging, arterial blood gas level, partial pressure of oxygen (PaO 2 ) levels, partial pressure of carbon dioxide (PaCO 2 ) levels, blood pH, pathogen specific test, or sputum evaluation;

f) is identified as having mild, moderate or severe hypoxemia as determined by PaO 2/ FiO 2 or positive end-expiratory pressure (PEEP);

g) is identified as having bilateral opacities consistent with edema;

h) is identified as having confusion, blood urea nitrogen being equal to one more than 20 mg/dl, respiratory rate being equal to or greater than 30 breaths per minute, systolic blood pressure being less than 90 mm Hg, diastolic blood pressure being equal to or less than 60 mm Hg, or is 65 or older;

i) is identified as being a nursing home resident, having neoplastic disease, having a history of liver, heart, cerebrovascular, or renal disease, being in a state of altered mental state, having a respiratory rate greater than or equal to 30 breaths per minute, having a systolic blood pressure above 90 mmHg, having a temperature above 35° C. or greater than or equal to 40° C., having a pulse greater than or equal to 125/min, having an arterial pH less than 7.35, having a blood urea nitrogen greater than or equal to 30 ng/dl, having sodium levels being greater than 130 mmol/L, having glucose levels greater than or equal to 250 mg/dl or greater than 13.8 mmol/liter), having hematocrit values being less than 30%, having a partial pressure of oxygen less than 60 mm Hg, or by the presence of pleural effusion on X-ray; or

j) has undergone or is scheduled to undergo a lung transplant.

16. The method of claim 15 , wherein:

a) the subject is hospitalized, and the hospitalized subject is in an intensive care unit;

b) the subject requires ventilator-assisted breathing, and the ventilator-assisted breathing is mechanical ventilator-assisted breathing;

c) the subject is identified as being in need of treatment using chest imaging, and the chest imaging is chest X-ray;

d) the subject has two or more organ failures; and/or

e) the subject has respiratory failure.

17. The method of claim 16 , wherein:

a) the mechanical ventilator-assisted breathing is invasive or non-invasive mechanical ventilator-assisted breathing or is pressure-limited or volume-limited; and/or

b) the subject has failures of the liver failure, kidney, intestine, heart, or brain.

18. The method of claim 3 , wherein

the IαIps are at about 80% to about 100% purity.

Assignments (1)

Continuity (3)

References Cited (235)