TREATMENT OF RESPIRATORY VIRAL INFECTIONS

Abstract

The present invention relates to the treatment of respiratory viral infections, including those caused by coronaviruses.

Claims

1. A medicament comprising at least one amino acid degrading enzyme for use in a method for the treatment of a virus infection of the respiratory tract.

2. The medicament of claim 1 wherein the virus infection is a Coronavirus infection.

3. The medicament of claim 1 wherein the virus infection is an infection with SARS-CoV-1, SARS-CoV-2 or MERS-CoV or a Coronavirus associated with common cold, particularly an infection with SARS-CoV-2.

4. The medicament of claim 1 wherein the virus infection is an Influenzavirus infection.

5. The medicament of claim 1, which additionally comprises an insulin.

6. The medicament of claim 5, wherein the enzyme and insulin are administered as a single composition.

7. The medicament of claim 5, wherein the enzyme and insulin are administered as separate compositions.

8. The medicament of claim 1, which is administered locally, e.g. by inhalation, or systemically.

9. The medicament of claim 8, wherein a single dose volume for inhalation is between about 1 ml and about 4 ml, preferably between about 2 and about 2.5 ml.

10. The medicament of claim 1, wherein the enzyme is selected from the group consisting of (i) asparaginase, (ii) arginase, arginine deiminase or arginine decarboxylase, (iii) methioninase, and (iv) tryptophan side chain oxidase, or any combination thereof.

11. The medicament of claim 1, which comprises a dose of about 500 to about 2,000 units enzyme per application for local administration or a dose of about 250 to about 2,500 units enzyme per kg body weight per day for systemic administration.

12. The medicament of claim 5, which comprises a dose of about 50 to about 100 units insulin per application for local administration or a dose of about 250 to about 500 units insulin per day for systemic administration.

13. The medicament of claim 1, which comprises asparaginase and an insulin, particularly a mixture of asparaginase and insulin, for administration by inhalation.

14. The medicament of claim 1, which comprises asparaginase in dissociated form, particularly in a urea-containing preparation, and optionally an insulin.

15. A method for the treatment of a virus infection of the respiratory tract comprising administering to a subject in need thereof a therapeutically effective amount of a medicament comprising at least one amino acid degrading enzyme.

Description

[0016] According to the present invention, the amino acid degrading enzyme is an enzyme, which is capable of degrading one or more of the above-specified amino acids. There are enzymes specific to the degradation of these amino acids; for some of them, multiple degradative pathways are known. For the purpose of killing cells infected by a virus, e.g. SARS-CoV-2, any degradative enzyme or any combination comprising at least two degradative enzymes is suitable.

[0017] In certain embodiments, the amino acid degrading enzyme is an asparagine-degrading enzyme such as asparaginase (EC 3.5.1.1). The asparaginase may be any available asparaginase, e.g. asparaginase produced in a bacterial cell such as Escherichia coli or Dickeya dadantii, including a recombinant asparaginase. In certain embodiments, the medicament may comprise asparaginase in a dissociated form, particularly in form of a monomer, e.g. as an aqueous preparation comprising urea, particularly in a concentration between about 3 mol/l to about 8 mol/l, more particularly in a concentration of about 4 mol/l to about 6 mol/l, e.g. about 5 mol/l, as described in co-owned application EP 19 178 062.6, the content of which is herein incorporated by reference.

[0018] In certain embodiments, the amino acid degrading enzyme is an arginine-degrading enzyme such as arginine deiminase (EC 3.5.3.6), arginase (EC 3.5.3.1), e.g. arginase type I or arginase type II, and arginine decarboxylase (EC 4.1.1.19), e.g. arginine decarboxylase type I or arginine decarboxylase type II. Of the two types of arginine decarboxylase—biosynthetic and biodegradative—the later has more favorable kinetic parameters to be used towards arginine depletion in humans and animals.

[0019] In certain embodiments, the amino acid degrading enzyme is a methionine-degrading enzyme such as methioninase (EC 4.4.1.11).

[0020] In certain embodiments, the amino acid degrading enzyme is a tryptophan-degrading enzyme such as tryptophan side chain oxidase (EC 1.13.99.3), e.g. tryptophan side chain oxidase type I or tryptophan side chain oxidase type II.

[0021] In certain embodiments, the medicament comprises a combination of two or more, e.g. three or four amino acid-degrading enzymes, selected from (i) an asparagine-degrading enzyme such as asparaginase (EC 3.5.1.1), (ii) an arginine-degrading enzyme such as arginine deiminase (EC 3.5.3.6), arginase (EC 3.5.3.1), e.g. arginase type I or arginase type II, and arginine decarboxylase (EC 4.1.1.19), (iii) a methionine-degrading enzyme such as methioninase (EC 4.4.1.11) and/or (iv) a tryptophan-degrading enzyme such as tryptophan side chain oxidase (EC 1.13.99.3), e.g. tryptophan side chain oxidase type I or tryptophan side chain oxidase type II.

[0022] In particular embodiments, the medicament further comprises an insulin. The insulin may be any type of insulin, e.g. human insulin, an animal insulin, an insulin analogue, including insulin analogues with short half-life and with long half-life, or an insulinotropic peptide. The preferred insulin is of short half-life, e.g. a half-life of about 12 h or less, about 8 h or less or about 4 h or less, such as Actrapid® from Novo Nordisk. The medicament may be a single composition comprising a mixture of enzyme and insulin or a combination of several compositions wherein one composition comprises an enzyme and a further composition comprises insulin.

[0023] In certain embodiments, the medicament is administered locally, e.g. orally or nasally, particularly by inhalation, whereby dilution in the bodily fluids may be avoided. For example, a single dose total volume for inhalation may be between about 1 ml and about 4 ml, preferably between about 2 ml and about 2.5 ml. Several minutes of inhalation of aerosolized enzyme(s) solution can deliver an effective dose. For example, the medicament may be administered to the upper airways such as the oral cavity, the nasal cavity, the paranasal sinus, the pharynx and/or the throat, and/or to the lower airways such as the bronchi and/or the lung.

[0024] In certain embodiments, the medicament is administered systemically, particularly in advanced stage viral infections that have spread throughout the subject's body. In such a case, the medicament can also be delivered systemically, e.g. by i.v. infusion or i.m. injection as is practiced in oncology.

[0025] The medicament may be administered to the patient in any suitable dosage form, e.g. as a rinsing solution, a spray or an aerosol, or as an injectable or infundable preparation. Typically, the medicament is administered as a pharmaceutical composition comprising the active agent and a pharmaceutically acceptable carrier or excipient. Examples of suitable carriers and excipients are well known to the skilled practitioner.

[0026] In certain embodiments, the medicament is administered in an early infection stage, e.g. in an infection stage where the upper airways such as the oral cavity, the nasal cavity, the paranasal sinus, the pharynx and/or the throat are infected, but the lower airways such as the bronchi and/or the lung are not infected. In further embodiments, the compound is administered in a late infection stage wherein the lower airways such as the bronchi and/or the lung are infected. Further, the compound may be administered in an infection stage where the subject suffers from a respiratory dysfunction and optionally is ventilated.

[0027] The medicament is administered in a therapeutically effective amount. SARS-CoV-2, like most other respiratory viruses, infects primarily, possibly exclusively, the lining cells of the respiratory tract. The total surface area of lung alveoli is about 70 m.sup.2. A single cell layer covered by fluid containing lung surfactants separates the air from the capillaries on the backside of the alveoli. If the fluid layer is 1 micrometer thick, the volume in which the enzyme is to be delivered is about 10 to 100 ml. In vitro experiments have shown that amino acid degrading enzymes at 10 units/ml in the growth media have been effective in killing cancer cells but not healthy cells. Thus, in certain embodiments, particularly for local delivery, the medicament is administered in an amount comprising about 100 to about 10,000 units enzyme, particularly about 500 to about 2000 units enzyme per application.

[0028] For systemic delivery, the enzyme may be administered in a substantially higher dose. The dose to be administered to a human subject in need thereof will typically be in the range of about 250 to about 2,500 units enzyme per kg body weight per day, depending on the subject and the type and severity of the disorder to be treated. Typically, the dose to be administered to a human patient will be about 1,200 units/kg/day.

[0029] Insulin may be co-administered separately or mixed with the enzyme in a therapeutically effective amount. For local delivery, insulin may be administered in an amount of e.g. about 10 to about 500 units insulin, particularly about 50 to about 100 units insulin per application. For systemic delivery, insulin may be administered in higher amounts of e.g. about 50 to about 750 units insulin, particularly about 250 to about 500 units insulin per day. Inhalation, e.g. as dry powder, is a preferred route of delivery, but administration by i.v. infusion or i.m. injection, is also possible. When insulin is co-administered, glucose levels should be monitored, e.g. for a couple of hours after the administration and corrected if needed.

[0030] Depending on the stage and the severity of the infection, the medicament may be administered once or several times during the course of the infection. For example, the compound may be administered once a week, each second day, daily, or several times, e.g. 2 or 3-times daily.

[0031] The medicament may be administered alone or together with a further active agent. The further active agent may be selected from anti-viral agents such as remdesivir, ritonavir, and/or lopinavir, and/or interferon-beta, or antibodies against Coronavirus antigens.

[0032] According to a particularly preferred embodiment, a combination of asparaginase and an insulin, e.g. an insulin with a short half-life, is administered, e.g. as an aerosolized mixture. Since the main target in this application is only the lining cell layer in the lungs, a small volume, e.g. 0.5 to 1.0 ml of insulin, e.g. containing about 100 units/ml, mixed with about the same volume of asparaginase, e.g. containing about 2,000 units/ml, provides a base dose that can be delivered as an aerosol via inhalation during several minutes and then repeated as necessary after several hours.